DR. PELLEGRINO: Floyd, may we turn the meeting
over to you? Would you like to comment from there or up at
DR. BLOOM: I can do it from here just fine.
DR. PELLEGRINO: Okay. Thank you.
DR. BLOOM: I want to start by thanking
Dan and Ed for giving me the chance to relive the last three years
of the President's Council and go through the enormous literature
that you've produced on the controversies in embryonic stem
And I was reminded in so doing that in 1997 the Thompson paper
appeared in Science while I was editor, and we wrote an editorial
on publishing controversial research, not realizing at the time
how really controversial the entire topic area would be.
I want to congratulate you, Dr. Schöler , on such an intellectual
inspiring and graphically advanced presentation. I had thought
from the papers that were sent to us on your work that you were
going to emphasize cell fusion. So in a minute I'll ask
you about that, but in fact, what you've done is give us a great
introduction to the next hour's worth of work of reexamining
the progress that's been made across the field.
My questions for you really start with your own opening slide
where you said that you were trying to develop the oocytes to the
point where you could do somatic cell nuclear transfer into them.
But then you explored all of the range of options from cell fusion
to embryonic cancer cell extracts, to small molecules that can cause
de-differentiation. I find the whole concept that you can
de-differentiate a somatic cell into a pluripotent cell such
an astonishing biological result that it is really hard to imagine
how that can take place scientifically and under control.
What you've shown us though is that the research is advancing
very, very broadly across a wide range of mouse embryonic stem cell
opportunities. And my first question for you is regardless
of whether you take fusion or somatic cell nuclear transfer, how
much of what you've talked about in the mouse can we imagine
in the near future taking place with any of the human embryonic
cell lines that exist for which there is the opportunity to do research?
And if so, which are the ones that are most likely to be successful?
DR. SCHÖLER: I think that the papers
that have been published so far show that things that have been
developed in the mouse system to a large extent can be transferred,
can be also repeated in the human system.
I think Kevin Eggan's paper is a wonderful example for that.
By using human embryonic stem cells, you can reprogram adult somatic
The nuclear transfer that is working now very efficiently in mouse
might be a much bigger hurdle in human, and I think there may be
at the end intelligent ways of reprogramming by fusion or by using
a cocktail of factors, which will be faster, we will see.
We have to see because there's not a lot of things I learned
from Woo-Suk Hwang's paper, but one thing I learned: that
he used 2,221 or so oocytes, and still it did not work. So
it's kind of an negative result, but it tells us a lot.
We have to improve the procedure, and I think he had some points
that he made that will help future researchers how to in an intelligent
way go on with that type of research.
Personally I'm always saying that if he would have worked
together with James Thompson to derive embryonic stem cells from
clones, a person that knows what he's doing, not repeating something
that others have, I think he had the wrong collaborators to derive
it. That's my personal understanding. He might have
had embryonic stem cells at the end. I might be wrong, but
that's what I think.
But nuclear transfer at the end might turn out to be much more
difficult. Maybe Gerald Schatten with his Brevia published
in Science at the time was more right than he afterwards
But I don't see why the procedure published by Shinya Yamanaka
should not work. Maybe you need to exchange one or the other player,
but in principle, that procedure I think will work.
From what we and colleagues are doing, we're actually thinking
in a different direction that maybe even factors that you get from
Drosophila, from Planaria, and so on can do a lot of the job with
respect to reprogramming.
This is still something of which I think there are still some
parts missing in the picture. I think that's what Orkin's
laboratory with their beautiful paper in Nature is showing,
is how complex interactions, protein-protein interactions and so
So if you just take the middle player and put it into a somatic
cell, you might have problems with efficiency. You might have
problems with really reprogramming the cell, but this was such an
important step into the right direction, I think, that others will
— if he's not doing it, others will fill the gaps to get
to a more pluripotent state.
And as I don't see why this should not be possible with embryonic
stem cells, I don't see why this should not be possible with
the existing human embryonic stem cells.
From my perspective, with respect to basic science, understanding
the general principles, I think you can get very far with the existing
embryonic stem cell lines. There are certainly problems if
you would like to think about therapies, if you want to go into
DR. BLOOM: Maybe we just focus on that
because we're going to spend this next hour talking about all
of the areas of advances, and the science is clearly advancing.
There's no question about that, but for this Council's purposes,
the really important questions have to do with if you have to start
with a human embryonic stem cell, we're back where we were.
If you have to start with a human oocyte, we're back in the
supply business where we were.
So we're not going to debate the science with you because
the science is going to do what it is, but if you had to put your
resources into the most likely place of advancing to achieve regenerative
medicine potential without the destruction of a human embryo, where
today would you put your resources?
DR. SCHÖLER: Basically, I would try
to go along with the three major areas that I've described.
I think at this stage we just don't know which is going to be
the most successful.
I think that if you are reprogramming a somatic cell and you have
to go back to an intermediate stage, a pluripotential cell is an
intermediate stage, it's not going to be as perfect as if you
go all the way back and then go again to that intermediate stage
because here you would have a full erasure, and then you would come
to a stage and the different layers of gene regulation are then
If you go back to reprogram a somatic cell to become a pluripotential
cell, I think we will find out more and more problems.
So in respect to therapies, if I would bet, I think you have at
this stage to use oocytes, and we can discuss the sources for the
oocytes, but going back and then to that stage is something that
is the only way so far based on the mouse work that is giving pluripotential
cells, which have the same quality as embryonic stem cells derived
from IVF embryos.
And so all of the other things, is exciting basic science, but
in terms of if you ask me where I would fit, I would use oocytes,
and that would mean you would need to derive new cell lines.
DR. PELLEGRINO: Thank you very much.
We are now open to questions from the Council. Dr. Gazzaniga.
DR. GAZZANIGA: In your Cdx2 example, was
it not the case that you were fusing an oocyte with a male sperm,
that first slide you showed?
DR. SCHÖLER: Yes.
DR. GAZZANIGA: And then you introduced
the micro RNA to stop the processes and develop the two classes.
The reason to be addressing these problems is to try to get around
certain moral questions that people have. Why wouldn't
the people that have those concerns not be happy with that approach
either? Because you're basically taking an entity that
could be developed into a human, an animal, a mouse in your case,
and therefore, it has all of the problems of somatic cell nuclear
transfer and all of the rests.
DR. SCHÖLER: So first of all, I would
like to stress that we have been using this specific stage and there's
no reason for us to believe that we won't be able to use this
approach also as an earlier stage, like the metaphase II stage for
a nuclear transfer.
It's a different approach than what we have done in comparison
to the one that has been proposed in the ANT procedure, where the
nucleus has been changed. We are introducing this to the oocyte.
So the genetic material has not changed.
We have not done this experiment for the sake of developing an
ethically sound way, but we have to do this for the science and
we found that there are some parts there that might be interesting
with respect to the ethical problems that we have or many people
have with that type of research with embryos.
So, first of all, that's something which I don't think
is fixed to that specific stage. The reason why I think this
isn't part of the solution is because I don't see it as
an embryo. This is like cell division. It's like
a cell that is dividing. It's not giving rise to an embryo,
and I've tried to make the point that even if you look at the
whole genome profile, and you have to do this if you really want
to compare one to the other, you see tremendous differences, and
they get bigger and bigger because just not having this second lineage.
And if you agree with the fact that an embryo at that stage requires
a trophoblast and inner cell mass, from the viewpoint of a development
biologist, this is not an embryo.
So if you say that you're manipulating something that ought
to be like a fertilized oocyte, ought to be an embryo and you're
changing that from what you're doing, you won't convince
somebody who has a problem with doing that.
But if you extend this really to the other direction, combine
this, for example, with ANT, I mention this type of research because
I think it's giving you some ideas about what's happening
with the embryo, regardless if you're doing nuclear transfer
according to the ANT or if you inject this in the oocyte or in later
Just to give you a complete picture because so far people are
just saying these embryos fail, and you have no idea what we're
talking about. Now I think if we ask for this, you get a clearer
picture that they're failing because the inner cell mass needs
support. We think ATP is of real importance for this embryo
And what we have been doing, we have been replacing the trophoblast,
which is not present because this is not an embryo, by the feeder
layer, and if it only works that you get embryonic stem cells, if
you put them on a feeder layer. The feeder layer is nurturing the
pluripotential cells, this then gives this nice ball of green cells,
and then you can derive very efficiently embryonic stem cells.
That is my understanding what is going on here. We're
trying to or we might have succeeded in supporting what we think
maybe is supporting also this ANT procedure.
Did this answer your question?
DR. GAZZANIGA: It's kind of fascinating
because if I recall correctly, basically human embryonic stem cell
research cannot go forward in Germany presently, and so you are
taking opportunity to advance stem cell biology in various animal
models, and one of the unintended consequences is that maybe German
biology is actually advancing the understanding of what's actually
going on in these incredible phenomena like de-differentiation,
where we have sort of slowed down in that within our own country.
DR. SCHÖLER: May I disagree on this
point? I think that —
DR. GAZZANIGA: Am I wrong?
DR. SCHÖLER: I think that the last
papers that I've shown, Stuart Orkin, Rudolf Jaenisch, Ihor
Lemishka, they are going to the key points of what a pluripotential
cell is, and what I think is very interesting, that Stuart Orkin,
Ihor Lemishka, and also Irving Weissman, these are people who have
been working all their life with hematopoietic stem cells and now
putting a lot of their resources into trying to understand embryonic
stem cells and trying to understand what pluripotential cells mean.
And with all of their experience that they have developed with
human embryonic stem cells, they now kind of dive into that topic
in a way that is very, very astonishing, and this is from this country.
It's not from Europe. You have such a great amount of
science here in this country.
So even if they are more than Germany into working with human
embryonic stem cells, we still can do work with human embryonic
stem cells in Germany. I also want to make that point clear.
It's just that it's like four, five months later, the cell
lines that we can use, and the presidential cell lines were from
the first of January 2002, the ones that we can use in Germany.
And we have a discussion now, a big discussion if that date is
going to be shifted or going to be dropped. I have here this
what has been presented last Friday from the DFG, the major German
funding agency. Ernst-Ludwig Winnacker has had a press conference
where this has been presented, (speaking German) "Stem Cell
Research in Germany, Possibilities and Perspectives."
But he has been asking in Germany to drop this date..., not even
to push it, and there's a lot of discussion. I just received
an E-mail this morning that our chancellor, Angela Merkel, has been
looking very positive into that something has to be changed.
So we have a discussion, a big discussion in Germany. It
still won't be possible that we as scientists would be allowed
to derive our own stem cell lines. We only also in the future
would be able to import them. That's for German scientists.
It's a problem when interacting with scientists from other countries,
who say, "Why don't you do it yourself?" This
is a problem, but we have to live with that.
DR. PELLEGRINO: Professor Schöler
has kindly agreed to send us a translation of that paper which we'll
distribute to the members of the Council.
Thank you very much.
We have three commentators waiting, Dr. George, Dr. Foster, and
Dr. Kass, in that order.
PROF.GEORGE: Dr. Schöler , I just
would like to ask a brief follow-up to Dr. Gazzaniga's question.
From your description, it sounds to me — and I'm asking
you to correct me if I'm wrong about this — from the description
you give, it sounds as though not only would you not have an embryo,
something that would qualify as an embryo, but the lack of integration
and self-direction or capacity for self-direction along a developmental
trajectory in the direction of maturity such that you wouldn't
really be able to say you have an organism of any sort here.
It just isn't an organism.
So my question is is it right to say not only is this not an embryo.
It's not an organism. Do you see so far as to distinguish
between an embryo and say a non-embryonic organism?
DR. SCHÖLER: So first of all, I would
like to apologize that I've been using the term "embryo"
in a very loose way. I'm in a way caught in a situation
that whenever I give this structure a name, I'm being accused
of trying to hide something. So if I call this "structure"
or if I call this "pluripotency ball," somebody stands
up and says, "Why don't you call it embryo?"
Actually I always try to say this is a stage which corresponds
to the eight-cell embryo, and during a talk I might lose this and
not [always stress that] this is a stage that corresponds to the
blastocyst stage or this corresponds to that.
But I hope that you forgive me if I have not in every case done
it that very way during my talk, but that's what I meant.
So whenever I had this comparison, I wanted to point to the embryonic
So I don't consider this an embryo. I don't consider
this an organism anyway. No, I think this is, for me, this
is cleavage. This is cell division of a structure that starts
off as an oocyte, but it would not cleave and divide to give rise
to an organism.
PROF.GEORGE: Am I correct that in thinking
about what is and is not an embryo, what is and is not an organism
the focus should be on whether we have a self-integrating entity
that is developing along a trajectory in a direction? Is that
the correct way to think about it?
So that if we see a lack of integration and a lack of self-directed
development along a certain trajectory that we associate with the
normal developmental trajectory of the species, if we see a lack
in these respects, that would be the ground for judging that we
have here something that is not an embryo, that is not an organism.
If, on the other hand, we find that there is a degree of integration,
that there is self-development along a trajectory, we would
conclude that we have an embryo although in a particular case the
embryo may be damaged, the embryo may have defects that will prevent
its full manifestation of its potential. There may be an impossibility
of implantation. There may be an impossibility of survival
so that we might not have viability, but we would still have an
embryo as something as distinct from something that's not an
Am I looking at it in the way that you would advise?
DR. SCHÖLER: I think one would have
to look at it exactly the way you have been describing it because
otherwise, if you would not be looking at that that way, you could
conclude that an embryo that will fail at some stage, like in mouse
there's this one mutation, Lim-1, which gives rise to fetuses
without a head, and you could say this doesn't have any potential.
The answer would be: why don't we produce these and at the end
we can use their organs, which I think would be not in agreement
with the view that you have been presenting.
I think the view that you have presented is the view I would see
it as well.
PROF.GEORGE: Thank you.
DR. GAZZANIGA: But were you here for the
PROF.GEORGE: I got here late.
DR. GAZZANIGA: So he missed the key slide,
which is the fusion of the oocyte with the fertilization, and that
occurred first and then the intervention of the micro RNA that caused
for the two classes of embryo.
So you're starting out with something that is on that trajectory,
and you are interfering with it to produce this artifact that can
be used in the way that has been demonstrated.
So the question is that I thought would offer you a problem in
the final analysis.
PROF.GEORGE: So then the question would
be does Dr. Schöler agree that what he's beginning with
is an embryo that is transformed into a non-embryonic condition.
DR. SCHÖLER: A [pronuclear] zygote
to my understanding is not yet an embryo.
DR. ROWLEY: But it is an oocyte.
DR. HURLBUT: When you gave your presentation,
you were talking about the use of pronuclear stage, but in answer
to Mike Gazzaniga's previous question, I understood you to say
that the same thing would almost certainly work if you did the silencing
in the oocyte —
DR. SCHÖLER: Yes.
DR. HURLBUT: — before nuclear transfer
or before whatever procedure, the point being that that would satisfy
the full concern about ever creating an embryo.
DR. SCHÖLER: Yes.
DR. HURLBUT: And some people might argue
that a pronuclear stage entity is a embryo. I know German
law says differently, but the point is in America that criterion
probably wouldn't be the same.
So to satisfy the American concern, one would have to do the silencing
in the oocyte, and you say that you think that's feasible.
DR. SCHÖLER: That's why we're
trying to see if nuclear transfer into oocytes can be [combined
with this procedure to imporove embryonic stem cell derivation].
As I tried to explain, we have at this time not done the experiments
for getting out of ethical problems, but for scientific reason,
and if we would have planned them differently, we would have started
at an earlier stage.
DR. PELLEGRINO: On this point? I
have a list, Bill, of people who are waiting. You're on
DR. HURLBUT: Yes, on this point.
I just want to clarify that the way we've been using the term
"altered nuclear transfer" from the very beginning is
that the alteration can be either in the cytoplasm or the nucleus
or both. So the procedure of knocking down the siRNA and the
cytoplasm of the metaphase II oocyte would be a form of altered
nuclear transfer. What you've described would be altered
nuclear transfer, not just what we would be interested in the nucleus.
DR. PELLEGRINO: Thank you.
DR. FOSTER: I didn't have any comment.
I was just glad to get here.
DR. FOSTER: I was just waving, having waited
seven hours to get a flight and then get canceled twice.
DR. PELLEGRINO: Dr. Kass.
DR. KASS: Well, I want to say hi to Dan
Foster and wave, too, and thank Dr. Schöler for really a remarkably
exciting and illuminating presentation.
I have really basically two factual questions and then a more
theoretical question. First, these stem cells that you got
from the Cdx2 altered cells, have they been tested for pluripotency
by the gold standard tests and shown to be pluripotent? The
And second, neither you nor our colleague Dick Roblin in preparing
the materials for this discussion referred to the publicized but
not published work of Dr. Verlinsky. These were fusion experiments
done in humans with human embryonic stem cells, and I haven't
seen any publications, but I wondered if one knows anything more
Among the things that were striking about that report was that
according to his experiments, it was the cytoplasts rather than
the nucleoplasts that seem to contain the materials that could successfully
produce the reprogramming of the somatic cell with which the cytoplasts
And then the more searching question has to do with your comment
about the superiority of going all the way back to pluripotency,
to totipotency, to —
DR. SCHÖLER: To the oocyte.
DR. KASS: — to the very beginning
oocyte and then coming forward. Since it's clear that
for therapeutic reasons one wants to have partial differentiation,
as you pointed out at the beginning, to more specialized stem cells
so that you don't have the tumorigenic concerns, why if you
had a rather controlled process of de-differentiation to some place
that was reproducible? Wouldn't you be — and by
these sort of cytoplasmic factors you knew what you were doing.
You knew to what stage you got it .- why does the fact that
you haven't gone all the way back to the oocyte present a real
That's a more searching question. The other two were
just questions of fact.
DR. SCHÖLER: So first of all, I've
just briefly scanned over that one slide because I was realizing
that I'm talking very long. So there was one slide that
was showing that we have done our homework, that the ES cells derived
from the Cdx2 treated pronucleate zygotes, fulfill all of the criteria
of pluripotent cells.
The one I've put my head a little bit out of the window was
saying that the most important thing is that you show tetraploid
aggregation. That's what we're currently doing.
But all the others, chimerism and so on, that has already been
done. The nice thing about Cdx2 is that it also plays a role
for intestine stem cells. If that would have not been a transient
effect, what we have done, the injection into the enucleated zygote
and deriving ES cells, if that would have been a more stable effect,
there should have been a problem with these intestine cells, and
I've only shown you a picture with an intestine where you saw
some blue cells. This was from a ten months old mouse where
we waited that long to make sections, to show that this cell compartment
is produced by derivatives of these injected cells. So this
is transient, which is the best indication that it's not a long
And if you think about what's going on is you're reducing
Cdx2 in a compartment that might not even give rise to the embryonic
stem cells. It's an open question. If the outer
cells are confused cells because they still carry on material from
the oocyte or if they, indeed, can be used to derive embryonic stem
cells, we don't know that.
But by all means, we can get germ cells from these after injection
and so on. We think that they don't have a problem.
The second question, Verlinsky's and Strelchenko's work
that they have published in the meantime in Reproductive Biomedicine
Online — in the meantime means, I think, half a year
or so ago — I think if you read the publication, first of
all, we initially only knew about that work from, I think, The
Scientist, that was citing a patent. I have then the patent.
We didn't get an idea of what was specific about how they did
it, and I didn't get it from the paper very well. So I
asked them how they exactly did it [and neither did I get it later
from the paper very well].
And the way I understand it is that they are doing this fusion
on glass plates where the nuclei have been removed by centrifugation.
DR. KASS: Yes. They plate, I think,
the embryonic stem cells —
DR. SCHÖLER: Yes.
DR. KASS: — on little glass cover
slips. They centrifuge them upside down. The nuclei
come out. They're left with the cytoplasts and they fuse
the somatic cells if I'm not mistaken.
DR. SCHÖLER: Yes, but what
I couldn't get from the paper is that when they do this and
do the fusion, if they can exclude that this on the cover slip is
forming something like a syncytium where you have cells fusing,
and since the removal of nuclei is not complete, that you could
have nuclear factors coming from the leftover nuclei and doing the
And since the efficiency is extremely low, that's something,
which is clear from the paper, you don't know what actually
did the job.
I think that what we had [originally] published, and I just briefly
mentioned our publication, where we have been using nuclei, we were
hoping that the cytoplast [would suffice]. That would have
been easier. [Imagine] you send vesicles to the clinics and
they put in the nucleus and you get your embryonic stem cells.
That would have been a dream. Maybe with other processes we
can still get there. We don't know.
But that's what we tried. We took embryonic stem cells
apart and adult stem cells apart and recombined everything, and
we could make a big sac out of the cytoplasts in a clean way.
Never did we get any reprogramming. We needed the nucleus
to do this.
And the work from Shinya Yamanaka is kind of confirming this because
he needs four nuclear factors. So I don't think that this
will turn out to be a key paper, this cytoplast piece of work.
The other question concerning going back and forth again... This
[idea] might turn out to be wrong at the end because somebody is
doing a clever experiment to prove me wrong, but my understanding
is that if you [need to] make tabula rasa, you [need to] clean up
everything and then start building things up again. It's
easier than taking things out, things that at this stage we have
no idea what you have to take out, the levels of repression that
you need to get expression along one or the other lineage.
If you basically clean the table and then allow the things to
develop by itself into the right direction, I think the different
layers of gene regulation are then set by the oocyte. They
[the oocytes] are doing the job.
If you push it to that point, since you might have more leftovers
of things that are not perfectly reprogrammed, I think at the end
that would be more difficult, and so far all the evidence is kind
of suggesting that I'm right, because whatever people have obtained
by the procedures is not as good as nuclear transfer where an oocyte
Is that okay?
DR. PELLEGRINO: Dr. Rowley.
DR. ROWLEY: I, too, want to thank you for
a comprehensive overview of the area and the directions you and
others are trying to pursue.
I have a couple of questions, one of which is a follow-on of Mike
Gazzaniga's with the comments of Dr. Hurlbut and Robby George,
and it does seem to me if you have to start with an oocyte and then
you knock down a Cdx2, that the moral problems of using oocyte remains
regardless of what you've done, and whether you've added
siRNA or new nucleus to that oocyte to my mind isn't different.
And so to form that in the way of a question, is it different?
But I'm not sure.
I have two other questions. One, is it really correct to
call the primitive germ cell unipotent? Because, in fact,
if that cell is fertilized, it goes on to give rise to an embryo
which gives rise to all three layers, ectoderm, mesoderm and endoderm.
So in my own view, I don't think of it as unipotent.
So that's a question. Why do you call it or is it correct
to call it unipotent?
And then more not philosophical but scientific question.
In your view why is it so difficult to begin to develop somatic
cell nuclear transfer in humans or primates as compared with mice
or other mammals?
We have the example of the South Koreans where at least at the
present time it said that they use more than 2,000 oocytes and then
get a single cell line, and there has to be some difference.
Do you have any insights as to what those differences are?
DR. SCHÖLER: So first to the statement
about that not changing the moral, ethical problems by still using
oocytes, is this because of the problems of egg donation or is this
from your point of view because of that we still have something
which was supposed to give rise to an embryo?
DR. ROWLEY: Well, I should really let somebody
like Robby George answer that because I don't personally have
a problem, but it would seem to me that for individuals who do have
a problem with using oocytes that, in fact, it should still cause
PROF.GEORGE: Perhaps I could respond on
that then. I think that people on my side of this debate,
and I've been a critic of the destruction of embryos for purposes
of this research, are concerned not to destroy living human embryos.
So they're not concerned on that issue with oocytes as such,
but rather with embryonic human life.
But then on the question of the use of oocytes, the concern is
with how they're obtained and whether they would be obtained
in a way that's potentially harmful for women and especially
if it might result in the exploitation of women to obtain the larger
number of eggs that would be required if therapeutic uses were found
for these technologies.
So they're really two distinct questions that I think perhaps
have been run together. So that if there would be a way of
obtaining oocytes without exploiting women or subjecting them to
danger or harm, and if those oocytes could be used to produce embryonic
or embryonic type stem cells without the destruction of embryos,
then we would be out of the ethical problem as far as I'm concerned.
DR. ROWLEY: Well, but then what Robby is
sort of suggesting is if you go the way of John Gearhart, which
is to use oocytes from fetuses and they are therapeutically aborted
fetuses, but which raises another issue, but getting oocytes from
them, then he has no problem
I think it's not an easy issue. Certainly the question
of egg donation by healthy women who do have to undergo hormonal
treatment in order to release a lot of oocytes, that for me is a
separate issue. I agree from the ethical issue of using oocytes.
DR. SCHÖLER: So with respect to egg
donation, then let's say a combination between the ANT procedure
and using what is now currently discussed a lot in Germany because
of what the group in Newcastle has asked to do, nuclear transfer
into bovine oocytes, with respect to egg donation at least, that
should be fine; is that right?
PROF.GEORGE: That's correct from my
point of view, yes. If I understand what you're saying
correctly, where you would not use oocytes taken from female humans
DR. SCHÖLER: Yes.
PROF.GEORGE: — you would rather be
using non-human, animal oocytes for the procedure, do I have that
DR. SCHÖLER: Yes.
PROF.GEORGE: Yeah, that does not strike
me as — as long as we're not then creating an embryo,
it doesn't strike me as having an ethical problem.
DR. SCHÖLER: Okay. So the first
question concerning the primordial germ cells, they are considered
to be unipotent because on their own they just give rise to germ
cells. At the end you have an oocyte or an egg, which are
terminally differentiated cells. These are the most exciting
cells for me, but they are terminally differentiated.
The exciting thing is that if you bring them together, the clock
is set back and now you're getting from two unipotent cells...
a totipotent one, but as long as they're on their own, they
are considered by scientists to be unipotent.
They're still on what I call the totipotent cycle, because
they give rise to an organism, and I call it now germline cycle
because people have been confused by having cells, which are unipotent,
on the totipotent germline cycle.
So that's what I would like to answer with respect to the
potency of these cells.
And why is cloning so inefficient? I think this has a lot
to do with what you're depleting when you remove the chromosomes,
and the spindle and so on might be something, which is different
between the different species.
So that might be a reason for problems. This has been
nicely described by Gerald Schatten, why he thinks cloning is so
inefficient, and I think from what he has been saying at that time,
I think he has been correct.
It was just that Hwang, when he came out with this astonishing
result, he [Schatten] thought, oh, maybe I was wrong. But I think
he was right.
DR. PELLEGRINO: Dr. Dresser.
PROF. DRESSER: Thank you.
I had another question about , SCNT in humans, and I understand
that one of the main basic science reasons people want to do it
is to create stem cells from cells from patients with genetic disease
so that they can learn more about the development of the disease
and test drugs and so forth.
So, number one, it looks as though that will be difficult to do
in humans. So I wonder about alternatives to that. I
wonder if any of the procedures you describe offer a way to study
that sort of problem.
And the other question I had was whether the difficulties with
SCNT would lead researchers to want to try to create embryos with
genetic problems through IVF and whether that will be an emerging
issue to address.
I suppose you have to have it confirmed on people who have genetic
disease to try to make an embryo. That would be a disease
model that would be more efficient than SCNT or perhaps some of
these other models.
DR. SCHÖLER: Yes. So actually
to maybe start with the second question. I think if we come back
to the [work] of Verlinsky, he has derived an extensive [set of
embryonic stem cell lines] from patients with genetic disease.
These, from what I understand, have been obtained by fertilization.
I think he has done preimplantation diagnosis and then correlated
this with the disease.
I think this is, of course, far more efficient than doing nuclear
transfer. The big, big advantage if nuclear transfer would
work is that you have the history of a patient documented.
You know the outcome of what you're expecting to understand.
If you're doing it with one of these cell lines, you don't
know how much genetics is playing a role in the outcome of what
Of course, there are other problems that we might not see at this
stage, but if you know the disease, how the disease develops and
you're trying to understand this process in the dish, I think
that's the best way of going ahead. It's like the
reverse way of what you do in mice. You destroy the mutated
gene and then you're trying to see what happens.
In this you know what's happening. This is a disease
that this patient is suffering [from], and if you're taking
nuclei of, let's say, a handful of patients and trying to derive
stem cell lines [from these], you get to some degree a variation
of what you can investigate in the dish.
And I think this will be a focused way of looking at disease.
Of course, you can't get to an understanding of what happens
in the whole organism, but by correlating this understanding with
the understanding that you have obtained from the patient, I think
we will learn a lot. That's what I think will be very
important for the future.
Then the —
PROF. DRESSER: But I guess my question
is: what if that proves to be too difficult? Say it
takes thousands of eggs or .-
DR. SCHÖLER: Yes.
PROF. DRESSER: — it's just not
DR. SCHÖLER: That was basically your
first question. So for understanding disease, I couldn't
do this approach in Germany anyway, from a practical point of view,
but also in terms of the way you can screen for the successful results,
the embryonic stem cells are — that's my understanding,
again, I might be wrong, but that's my understanding —...
the most potent system because you can plate cells. You can
[use] selectable markers...
And since embryonic stem cells have the power of proliferating
in a way that you can get from one to millions and millions of cells,
you can screen for rare events, and you can't do yjsy with oocytes.
That's one problem that will remain in the future, that you
can't really screen for something where you have a limited number
of cells to start off with.
So I, indeed, will be trying to see if we can use the different
reprogramming procedures that have been described with embryonic
stem cells, if we can get disease this way into the dish, which
might not be good enough to use these cells for patients, but may
be good enough to understand at least certain aspects of disease.
And then a final point to this is that in science it's very
important that different people test different approaches.
This is our approach. It might not work; it might work.
Others might be more successful with nuclear transfer, and we have
to see at the end who is successful. The patient will win
if one of the processes is successful.
DR. PELLEGRINO: I have Dr. Hurlbut and
DR. HURLBUT: Just a comment on what you
were saying. That fertilization would work for certain dominant
alleles, but it wouldn't necessary work as well for a lot of
genetic diseases because it's the whole context of the existing
genome that counts.
So obviously, the ideal would be to create an identical gene aligned
from an identical genome, and this is sort of a question and a comment,
just because there's something else I want to ask you.
Even with IVF embryos we don't know if we take the cells at
the four-to-five cell stage, we don't know if those genomes
can actually produce a full organism yet. So is it something
to consider, that even IVF might not produce perfect cell lines?
Why don't you answer that first?
DR. SCHÖLER: So if we look how efficient
preimplantation development is, well, at the end we are disappointed
how inefficient it [actually] is. I'm not sure exactly
about the numbers, but it's in the range of, I think, 50 percent
or so that are failing prior to implantation.
So if you take two germ cells and combine them and force these
to do something that in vivo they might not have a chance
to do, you're not really sure about the outcome of what you
have in hand at the end. So that is an important point.
But if you bring that up, you also have that problem with nuclear
transfer because the problem with nuclear transfer is that you're
skipping all of the selection that you have along gametogenesis
because from my understanding, that if you have a problem with germ
cells, germ cells basically don't try to repair what's going
wrong. The [organism] gets rid of such germ cells. There's
a lot of apoptosis. [That has been described.]
If you have a gene that is expressed in germ cells, [that is]
during germ cell development, it's often that you see they are
driven into apoptosis, active cell death. Because my understanding
is that [the organism tries] ... to get rid of something [compromised,
instead of]... maintain[ing] it to start the next generation. [However],
if you're doing nuclear transfer, you're jumping over this.
So you might at the end have something which, as a germ cell,
would have had no chance to get to that point. That's
also — we have to talk about both sides. And in vitro
fertilization, actually the problem would be only a short problem,
whereas nuclear transfer would be all the way through.
DR. HURLBUT: Yes, but the fact that you
can get successful production of full organisms, in this case mice,
using tetraploid complementation does confirm that at least some
of the time you're getting a fully functional genome.
DR. SCHÖLER: Yes, some.
DR. HURLBUT: And, by the way, I'm correct,
aren't I, that when he did his experiments with altered nuclear
transfer, Rudy Jaenisch did do tetraploid complementation studies?
DR. SCHÖLER: Yes.
DR. HURLBUT: So those cells really were
confirmed, and if I understood you earlier, none of the other methods,
reprogramming or any other methods have established that you can
get tetraploid complementation to work.
DR. SCHÖLER: Yes.
DR. HURLBUT: Is that right?
DR. SCHÖLER: That's correct, but
also, if you get to embryonic stem cells, you also have a selection
for those embryos that give rise to embryonic stem cells.
It's also something you're — if you would try to force
embryonic stem cells at earlier stages which the structures don't
have a chance to get to the blastocyst stage, you maybe have more
problems with these tetraploid complementation experiments.
I'm just saying that you always have to think about the selection
you're doing or not doing in that process, and maybe cloning
is inefficient because the genetic material, to some extent, is
not as good as it is from germ cells.
So there's so many things we still don't know.
DR. HURLBUT: And finally, could you just
say a little more about your statistics of increased efficiency
of harvesting ES cell lines using the Cdx2 knock-down, was very
interesting. You got practically a doubling of the efficiency
and at the eight cell stage, which is earlier than we had previously
thought you could get ES cells.
Could you just expand on that a little bit?
DR. SCHÖLER: Yes. I realize
at the end I have been too fast on that point. The one astonishing
experiment from Robert Lanza, was that actually he can derive ES
cells from single blastomeres from an eight-cell embryo...
So it is to me.
DR. HURLBUT: But his paper indicated he co-cultured
DR. SCHÖLER: Yes.
DR. HURLBUT: That's important because
they were signaling.
DR. SCHÖLER: I agree, but that [showed]
that it works. So I wouldn't take it as too much of a
surprise that if you take an eight-cell embryo and try to derive
stem cells from there using also a feeder here in our case, that
experiment, which we did also with the control treated one, but
we wouldn't have had to do that because they grow on the outgrowing
trophoblast cells, and so that would have been the feeders, but
we don't have that in the knockdown experiment. So to
compare both, we had to use feeders in both cases.
If you take these cells, these structures from the Cdx2 knock-down
experiment, you had green cells throughout the structure, and we
think that the increase of potential candidates to give rise to
embryonic stem cells at the end started an increase of about 50
percent in efficiency.
So it means if you take the control treated embryos, compare these
with the structures, the Cdx2 treatment didn't worsen the derivation,
but improved it. So our hope is that if you do the Cdx2 siRNA
treatment at the metaphase II stage for nuclear transfer, that this
would also even result in an increase.
Maybe this way we make nuclear transfer more efficient with respect
to embryonic stem cell derivation. That we have to see.
We don't know.
DR. PELLEGRINO: Dr. McHugh.
DR. McHUGH: I, too, want to thank you very
much for your presentation, and I'm still thinking about it,
and so I'm the slow member of the class trying to ask some simpler
questions really simply, in part because of the important issues
that you evoke for me, anyway, and for many other people about our
existing science, our science base, and the directions we're
And so I just wanted to ask simply three or four questions that
came out from what you said. The first thing you said was
that, you know, using existing embryonic stem cells we're really
quite able to do wonderful things, and you said we have kilograms
of these cells now available.
Now, does that mean that, in fact, the cells that were made available
really at the birth of this Council by President Bush when he said
that he would give federal funding, anyway, to research that based
itself on those cells, that in point of fact those cells are adequate
for the work that is being done?
Are they adequate in number and in character? That's
the first question.
The second question is, of course, like everyone else I'm
very amazed and think it is a wonder, this Cdx2 business.
I want to be really sure that we've answered the question that
we're not dealing as we might have been in other situations
with essentially a wounded embryo.
I think that's really what we come down to, and from your
slide that you began with, you showed that, in fact, in the mouse
like in every other creature, the cycle of life begins with a fertilized
ovum. I want to be sure if I understand correctly that in
this situation we are not beginning with a fertilized ovum.
We've done the treatment beforehand.
The third thing is that you mentioned the possibility that neurotrophic
factors and the like would be helpful in reprogramming things, and
of course, that's a very exciting prospect for all of us because
if trophic factors are there, they ultimately can be synthesized
because they're chemicals, and how close are we to getting to
synthesize them? And then we don't even have to have anything
to do with cells. After all, we won't use the penicillin
And then the last little one, it's a tiny point, but you mentioned
that the laws in Germany were going to change in some respects in
relationship to this research. Are they changing in such a
fashion that IVF embryos now can accumulate in Germany the way they
have accumulated in other countries and be a source of problems
DR. SCHÖLER: So the adequacy of the
cell lines. So as long as people like Rudolf Jaenisch, Doug
Melton, and so on are able to publish in Cell, Nature,
Science with these cell lines for basic research, I think
you can do quite a lot, and that's why I was trying to distinguish
between what you can do to quite some extent in basic research in
comparison to applied science.
And if you would, just one scenario, if you would try to use the
existing cell lines, which have been cultured for a very long time,
have been cultured in the presence of animal cells, sera, and so
on, and you would use a primate model; let's say you want to
try to cure or at least alter the phenotype of a monkey model for
Parkinson's, and you transplant these cells and you have a tumor
or the cells are rejected. At the end you will not be able
to know is this because your procedure has not been developed in
an appropriate way or is it because the cells were not good enough
for the procedure to start off with.
If you have a tumor, is it possible that cells that you differentiated
from the embryonic stem cells, let's say you have progenitors
for neurons; let's say you have neuronal stem cells. In
embryonic stem cells you might not see that the genes have been
mutated over the many passages, but once you get to an intermediate
stage or even to the differentiated stage, maybe it's then when
they exert their problems.
So if you think about testing this in an animal model, you rather
want to start this with genetic material, which is perfect.
DR. McHUGH: But at the level of the basic
science, which is often the complaint about the Bush proposal, that
it would block basic science, as far as you say at the basic science
study of stem cell they're adequate you're saying.
DR. SCHÖLER: So for the type of research
I am doing —
DR. McHUGH: Yes.
DR. SCHÖLER: — basic research
I'm doing, I don't have a problem. The problem I have
with the cells now is that in Germany — I'm talking about
the problems I have as a scientist — I have a problem with
interacting with scientists in other European countries because
if we're getting cells, let's say, fromWiCell, we have to
sign contracts. [Other European scientists say:] "We
have our own cell lines. [Why can't we use our cells?]"
DR. McHUGH: Right.
DR. SCHÖLER: So then it happened with
the Sixth Framework that because they wanted to include certain
German scientists, they had to use the old cell lines and not the
newer ones and said, "But we have our own."
So in the end they say, "Why don't we leave Germans out
of... the scheme because we can happily work together?" and
so on. So that's another issue, but that's a German
DR. PELLEGRINO: Thank you very much, Dr.
Schöler . We've been working you very, very hard.
I'd like to just for a moment ask the Council if they have
any comments they want to make on the summarization of alternate
procedures that was prepared for us by the staff, Adam Schulman
and Dick Roblin, and also if you have any comments on the relationship
of these alternatives and also the comments by Professor Schöler
to our publication on alternate sources.
That's a little complicated question, but I think any aspect
of that we'd appreciate your guidance on.
DR. GAZZANIGA: Dr. Pellegrino, just before
maybe going there, I think this wounded embryo question is central
to a lot of the conversation this morning, and maybe he could answer
that before we move on to the general.
DR. PELLEGRINO: All right.
DR. SCHÖLER: So if you would consider
the pronuclear state zygote, the pronuclear zygote as an embryo,
then you would say we would be doing something to an embryo, and
then it would be in your view a wounded embryo.
So that's why I was saying to address that question one would
have to do the treatment earlier, before fertilization, but that's
DR. GAZZANIGA: Which is possible to do.
DR. SCHÖLER: And there is no reason
to believe why it's not possible to do, but before you have
seen the results, you don't know.
But as I said, we want to go as early as the metaphase II.
That's the point where you would put in the nucleus. That
would be the earliest that we have seen that there's obviously
Cdx2 RNA. So I don't see why it should not work.
DR. ROWLEY: Well, but I think it's
very critical to emphasize that he hasn't done it.
DR. SCHÖLER: Yes.
DR. ROWLEY: An it may be that Cdx2 at that
point activity or gene expression is critical for the process of
fertilization. Because you have to ask why is it so high.
DR. McHUGH: That's right. That's
DR. ROWLEY: And it's not high for no
reason, I would suspect, and it's just that we're jumping
to the conclusion that you can do it at this stage, and until it's
actually done and shown to be successful and as efficient as a later
stage, this is an unanswered question.
DR. McHUGH: Yes, Janet. I agree with
that. The whole reason for putting forth the concept of wounded
embryo is to get us into this discussion of where the science is
and what we can depend on and what we can't depend upon.
And that's most helpful; your comment is most helpful in that
DR. SCHÖLER: If I may add something
to this, this experiment I've shown you to give you an idea
about the outcome. So this has not been described, I think,
to that extent in the Development paper by Janet Rossant
and also not in the Nature paper by Rudolf Jaenisch.
That's the outcome.
But Rudolf Jaenisch has shown a way to address that question not
having a wounded embryo, like doing this at a stage, at the metastage
II phase to transfer a nucleus...
I assume that we have a very similar outcome, and I think from
what is published that we might even have a more severe problem.
So if you can accept what they have done, I think ours is going
to be the effect of Cdx2 knock-down is going to be worse even at
the pronucleus stage.
So if you do it earlier, we have to wait for the outcome, but
I don't see why that should be better. And if it's
not working there, then you say that's unacceptable. That's
the outcome, but we have to see.
DR. HURLBUT: Not worse; better though for
our purposes is what you mean, right?
DR. SCHÖLER: Yes.
DR. HURLBUT: Better in preventing an embryo
from coming into being.
DR. SCHÖLER: Yes. Thanks for
DR. HURLBUT: Yes.
DR. SCHÖLER: The procedure works better.
DR. PELLEGRINO: Other questions or comments?
DR. SCHÖLER: So I have not yet answered
all of those four questions. Should I?
DR. KASS: Mr. Chairman, I think our guest
has one more thing he wanted to add in response to Paul.
DR. PELLEGRINO: Did I?
DR. KASS: No, I think Dr. Schöler .
DR. SCHÖLER: [I do not think that
such a] change in Germany [will result in]more IVF embryos.
I don't think that this will — first of all, we're
not allowed to derive our own embryonic stem cells. So there's
no reason to believe that by any of these procedures that we will
increase the numbers of in vitro fertilized embryos.
...I think[that] the numbers that are officially in German fridges
are extremely low, but Prof. Autiero might also add something.
I think in Germany they're extremely low.
DR. McHUGH: That's what we had heard
previously, and we just wanted to know or I just wanted to know
whether this was going to change and that the number of IVF embryos
would now accumulate in Germany like they have here.
DR. SCHÖLER: No.
DR. McHUGH: With the implications that
they bring to our discourse.
DR. PELLEGRINO: Leon.
DR. KASS: Well, I think I would like to
sort of put on the record my own delight and to some extent astonishment
that we are November '06. The Council's white paper
was published in May of '05. A quick subtraction, 18 months,
right? In 18 months we've had peer reviewed publications
showing proof of principle, depending on what you think about the
reprogramming studies, how much of proof of principle that we've
But there's been active research in all of these areas, and
I don't think from the conversations we've had around here
that the doubts and the skepticisms have been completely set aside.
There are large scientific questions that remain, and there are,
of course, questions that the people who are keen on working with
embryonic stem cells have been too polite to press in the discussion,
but from their point of view it's not clear why the research
need wait for the development of these alternative sources.
That research goes on.
And I think I appreciate very much your suggestion that the full
understanding of what's going to work in this area will depend
upon the work that's done with adult stem cells and with pluripotent
stem cells derived whether from embryos or from some of these alternative
So I think this research would have gone on I'm sure without
the Council's prodding. I think we owe Bill Hurlbut, I
think, a considerable debt of gratitude for having insisted that
we somehow lift this possibility that science might find a technical
way around an ethical dilemma so that the research, if this is successful,
could go forward at a very high level in ways that no one will feel
morally compromised. I think this is very exciting.
Whether there's enough here to warrant our saying anything
more other than having this very fine update from you on this occasion,
I have my doubts. I mean, I think it would be very nice if
the larger community could have been here to hear this really very
elegant presentation and also the summaries that Dick Roblin has
prepared on the literature I think are helpful reminders to all
of us as to what's going on really in the last two to three
years in this area, and maybe there is a way to use our Website
to call attention to this presentation and to these publications,
but since I guess there was partly a discussion last time as to
whether we, the Council, need another publication at this
particular juncture on this subject, I myself don't see it.
DR. PELLEGRINO: Thank you.
Any further comment on Leon's comment or any other related
to the alternative sources? Yes.
DR. GAZZANIGA: Ever since the alternative
sources have been proposed, there has been no, I don't think,
doubt that various kinds of biologic experiments could be applied
to those questions. I don't think that's an issue.
I do think that the concern of some of us is that we're dealing
with what the economists think is called lost opportunity cost,
that there is a way laid out in the scientific community to go forward,
and we are allocating resources, limited as they are, to approaches
that for some of us don't seem to really answer the moral question,
which were why these ideas came up.
So we just have learned that the Cdx2 experiments, in fact, do
have the moral problems that were raised by many on the Council.
Robby George is the most articulate with that view, I think.
And I think the de-differentiation suggestion, if you really think
about it has similar problems for those who are concerned about
a viable entity that could be a human being.
And one could go through on the other two cases and make other
moral arguments. So I guess I, for one, would be more relaxed
about these efforts if I actually thought the people who have these
concerns truly are at rest with the moral dimensions of it as they
Nonetheless, it was a great review, and we thank you.
DR. SCHÖLER: Thank you.
DR. PELLEGRINO: Dr. George.
PROF.GEORGE: Yes. I think —
DR. PELLEGRINO: And then Dr. Meilaender
and then Dr. Gómez-Lobo.
PROF.GEORGE: When you call on them I thought
they were going to be —
DR. PELLEGRINO: No, no. In the order
in which I call them out.
PROF.GEORGE: Thank you, Dr. Pellegrino.
I think I should just say something in response to Mike Gazzaniga's
last comment, and perhaps I misunderstood Mike, but just to be clear
about my own position, I found myself reassured by what Dr. Schöler
was saying, that in the relevant alternative methods that he was
discussing, we are not talking about the creation and destruction
So far from being persuaded that the methods he's discussing
have the same moral problems, it seems to me that he was arguing
that they don't; that, in fact, we not only don't have an
embryo in the research he was discussing, but we don't even
have an organism.
So we have, you know, some sort of a tissue culture perhaps, a
collection of cells that lack the organization and self-direction
of an embryo, but if that's right, then we don't have that
Now, we still might have the moral problem with the use of oocyte,
but Dr. Schöler has also proposed without going into nearly
as much detail that there may be alternative sources of oocytes
that will not involve exposing women to super ovulation and the
possibility of exploitation.
So have I misunderstood you, Mike?
DR. GAZZANIGA: Well, no. There's
a little bit of a unclarity with this. Paul McHugh asked the
question driving home the point of whether these were wounded embryos.
I happened to notice you were out of the room, and Dr. Schöler
answered, well, if you consider a union of an egg and a sperm the
beginnings of life and an entity that's on the trajectory towards
whatever organism you're talking about, then, in fact, by introducing
the RNAs, we do have a wounded embryo.
So this was the answer to the question which finds me stating
the thing that I stated.
PROF.GEORGE: Well, let me see then if I
understand Dr. Schöler 's position, and he can simply clarify
this. Take, for example, the kind of work done by Jaenisch.
In your opinion has Jaenisch created wounded embryos or has Jaenisch
created non-embryonic sources of pluripotent cells?
DR. GAZZANIGA: Just to be clear, we're
talking about his experiments, and we're talking about his Cdx2
PROF.GEORGE: Well, maybe you could tell
us your opinion in both cases.
DR. SCHÖLER: So what I tried to show
here is the outcome of the Cdx2 experiment under these conditions,
and to avoid that one has a wounded embryo according to what you
said. One would have to do that at an earlier stage.
I don't see any reason why the outcome should be any different.
If at all, it would be more severe, even more severe.
PROF.GEORGE: But would that mean you don't
have an embryo at all?
DR. SCHÖLER: No.
DR. SCHÖLER: If you do it at an earlier
stage, you definitely don't have a —
PROF.GEORGE: Definitely don't have
DR. SCHÖLER: — an embryo, and
it's a matter of what — now we caught in different cultures
or systems. And according to the German law, law, not church,
law, the pro-nuclear zygote is not considered to be an embryo, whereas
Hans Schöler, a developmental biologist, would say as soon
as you fertilize the oocyte you're starting the process.
Ergo, I would consider this to be an embryo.
Ergo, you would be right by saying that's a wounded embryo,
but if I, Hans Schöler , would say is that something that should
be protected or not, I would say no.
But from what you've been saying, this reprogramming, bringing
back, you're not even getting close to something that is an
DR. GAZZANIGA: Well, just to make my point
clear, if we go back to somatic nuclear cell transfer and you have
a moving a film forward, you go through stages where you do have
cells that could become, if implanted, an animal or a human being,
depending on the organism in question.
So that was a moral concern to many people on this Council, that
possibility. So you have to understand the context of
the arguments that have been here.
DR. SCHÖLER: Absolutely.
DR. GAZZANIGA: So by dedifferentiating
a human cell back to some point, some totipotent place, there you
will go again. You'll have those cells that if implanted
could be a human being.
So the de-differentiation technology doesn't answer this deep
problem that some people have, and that's my simple point.
DR. SCHÖLER: These are two different
areas. If you talk about de-differentiation, we are talking
DR. GAZZANIGA: Yes, correct.
DR. SCHÖLER: If you look at transfers,
that's not de-differentiation. That's reprogramming
because what you're doing is you're putting a nucleus into
an oocyte. The very second if you say de-differentiation,
I'm thinking about a cocktail of factors and pushing it toward
the pluripotent state, and I've been answering —
DR. GAZZANIGA: But you have got those same
DR. SCHÖLER: No, you get to a stage
which is pluripotent, and what I was saying to the kind of scientific
question, that where would I bet my money on is that with respect
to therapy, I was saying if you go all the way back and then forward,
that would be in my opinion the better way of doing this for of
the reasons that I've been mentioning.
And if you can do this the way Dr. Hurlbut has proposed it, then
you wouldn't get to something which is an organism embryo.
That's the difference.
DR. McHUGH: Since I coined the term, can
I come back at it then? I'm concerned ethically with using
wounded embryos, but I am not concerned with changing gametes.
Okay? So that from those gametes we could produce cells.
As I understand it, you're saying, and Janet was talking back
and forth with me about how this has to be proven that the Cdx2
could work on the gametes, but it has not been demonstrated yet.
If it was with the gametes, then Robby, me and everyone doesn't
think we've got a wounded embryo that we're working with
So I gathered from what you said that at least it looks like you
can use the Cdx on gametes, and gametes and oocytes are unfertilized,
and then go from there. If that's the case, you don't
have an organism and I don't have a problem.
DR. SCHÖLER: Yes. So you can
be assured that actually when I'm back at my computer I will
push that we're going to test even earlier, but that was not
the scientific question.
DR. McHUGH: No, I understand that.
I just want my terms to be clear, why I used the terms I did.
DR. ROWLEY: Well, wait. So you're
saying it's okay to use a wounded zygote, a wounded oocyte that
will then be fertilized by a normal sperm to get a zygote that has
the genetic defect. So you're using a wounded oocyte.
I mean, you know, I don't think this is going anywhere, but
I just want to point out that —
DR. McHUGH: I think it's going somewhere.
DR. ROWLEY: — the manic morass we've
gotten ourselves into.
DR. McHUGH: Yes, I think we're going
somewhere. I think that at the level of cell reproduction
and cell things, if they cannot — if you have a wounded gamete,
it cannot be fertilized and turned into an organism it seems to
DR. ROWLEY: Yeah, but if it can't be
fertilized, then he can't get an eight cell stage structure
to use, and he's betting that, in fact, a wounded oocyte plus
a normal sperm will give you this Cdx2 deficient eight cell stage
organism or structure that will be useful for cell lines.
DR. SCHÖLER: I personally have a real,
real problem to the terminology "wounded" with respect
to a cell.
DR. SCHÖLER: I've seen wounded
people, but I think this is creating pictures in our heads, which
I don't consider to be absolutely valid.
DR. PELLEGRINO: The Chair just wants a
word for a moment. We want to give everybody a chance to talk.
There are a lot of hands waving desperately. I must say I've
lost the order a little bit. The order we had was Meilaender,
Gómez-Lobo and Bloom and others who want to get into it put
your hand up. Leon, you had your hand up. I think, Dr.
Foster, you had your hand up, did you?
DR. FOSTER: I was just going to make one
comment without making — the only thing is, you know, I was
very encouraged to hear this morning from Robby, for example, for
the first time. Nobody is more concerned about wounded embryos
and so forth, if you want to use that, than he is, and he's
very encouraged by this.
There are going to be some people who think that if you mutate
DNA, you've stopped an embryo. I thought it was tremendously
encouraging for the first time we've been in this Council to
say we may be able to go forward along these things.
I think we ought to drop this thing about seeing what cells are
wounded. I mean, it's sort of silly, but there are going
to be people in this world that no matter what you do, you'll
never do a stem cell research, and you just have to accept that
they are going to do it.
So I thought the comments were tremendous from this side of the
room and very different from the comments early on because of different
Thank you for letting me interrupt.
DR. PELLEGRINO: Yes, you did. Thank
you. Thank you for speaking while you were interrupting.
We have Meilaender, Gómez-Lobo, Bloom and anybody else
that wants to get on the last time, ask Professor Schöler ,
who has been very, very kind to agree to wait and not respond until
you've all made your comments and then he'll put his response
together because I suspect there may be some overlap.
PROF. MEILAENDER: Three comments, each
very short. The first, I suspect that actually not a one of
us lacks clarity on what we've been talking about here.
I mean, I don't know anything about cell biology, but we all
understand that what Dr. Schöler reported on with respect to
his own research is something that might perhaps be called an embryo
that had then been disabled, but that he thinks — he's
actually fairly confident — that it would be possible to do
similar research in a way that didn't do it.
I think we're all clear on that, and I don't see any need
to run around that pole indefinitely.
The second point, I want to say a word, Mike Gazzaniga, about
your lost opportunity cost point. I thought the mantra all
along had been good science proceeds on as many fronts simultaneously
as possible. Therefore, you don't know; you can't
quantify opportunity cost lost or gained until you're at the
end of the process.
So it seems to me or at least I've always been told that good
science proceeds on different fronts at the same time, and therefore,
this is not a case of lost opportunity cost but good science going
in various directions.
And then third, just sort of to second what Leon said earlier,
I don't know that I see that there's something new to say
particularly. I mean, undoubtedly one could do little riffs
on different parts of the white paper, but it seems to me that we
did a pretty good job actually on that, and it has stood the test
of time quite well.
DR. PELLEGRINO: I have Gómez-Lobo,
Bloom, and, Leon, I have you down here. I wasn't trying
to cut you off.
Anybody else who wants to get on the list, and Bill Hurlbut, but
let's go again according to procedure, and we'll ask Professor
Schöler to hold off until we've heard from all of you.
DR. GÓMEZ-LOBO: Thank you.
First of all, a question of terminology. I would drop the
word "wounded" altogether. I think it is more or
less standard to talk about mutilated or disabled embryo.
Now, if that's the case, I think we're talking here about
the question is whether we have a mutilated embryo or non-embryonic
structure at all. Now, if this is obtained by modifying the
gametes, from a moral point of view I don't see any problem.
In fact, I'm a bit disheartened by Mike Gazzaniga's remark
because precisely here there has been a convergence. I mean,
there's many of us who are concerned about the intentional destruction
of human embryos that are seeing a light here, are seeing a possibility
of doing this research in a morally acceptable way.
If there's no embryo and if the de-differentiation does not
lead to an embryo, there are no more problems whatsoever.
In fact, I was encouraged even by Bob Lanza's experiments because
in principle he was accepting the idea that it made sense to try
to derive embryonic stem cells without killing embryos.
Now, he didn't do it, but that was the point.
DR. PELLEGRINO: Thank you.
DR. BLOOM: This is not necessarily for
Dr. Schöler 's presentation nor comments, but I wanted
to expand the possibility of the list that Dick has been tracking
for us to mention the work of Diana Bianchi, which deals with pregnancy
associated progenitor cells, fetal cells of origin that persist
in the maternal circulation for years and seem to be stem-like cells
that can repair injured organs in the mother.
Since they are fetal cells, they will have both maternal and paternal
genomes represented, and it seems to me that this is a very underexplored
area. It has been largely in the clinical literature, and
it seems to me there is some very exciting cell biology that could
be done with this because these are stem cells that don't require
the destruction of any kind of embryo at all.
DR. PELLEGRINO: Thank you very much.
DR. HURLBUT: Hans, I understood you to be
saying — I think you used this very term that what is created
is not an embryo but a single lineage cell culture if you start
with the oocyte; is that correct? That's the kind of terminology
you would accept?
DR. SCHÖLER: Yes.
DR. HURLBUT: Also, do I understand you correctly
saying that even though there are barriers in the procurement of
oocytes making SCNT or any kind of ANT work in non-human primates
and then later with humans, and — well, suffice it those two,
the oocytes and the SCNT. Those are all barriers right now,
but I understood you to say that you thought those were technical
problems that by reasonable scientific estimation they could be
overcome. Without knowing for sure, it's reasonable to
say that these will —
DR. SCHÖLER: Could you repeat the
DR. HURLBUT: Well, we will find ways eventually
to derive oocytes without having to superovulate women. You've
made that point several times, and also that you thought it was
reasonable that we could, not certain, but reasonable that we could
make nuclear transfer work in primates.
DR. SCHÖLER: Yes.
DR. HURLBUT: So given those positions, I
just want to underscore what Gil was saying. There's lost
opportunity cost if we don't pursue these methods because whether
one agrees or not, there's a political impasse, and pursuing
these methods could open up what isn't open now. We could
get stem cell lines that could qualify for federal funding and that
would be wonderful because they could be used with good ethical
oversight. They could be used on a national and international
level for collaboration, and if the techniques work, we could get
unlimited source of genotypes to work with.
So that strikes me as an opportunity that's worth pursuing,
but not to mention the fact that how much better would it be for
our civilization if we could go forward with this research with
social consensus? Besides the fact that this is a bitter controversy,
the fact is that if this ever does come to cell therapies, it would
be so much better if every patient who entered the hospital and
would partake of these cell therapies felt comfortable morally with
the way the therapies were developed.
So on both the social and a personal level, it seems like a very
positive thing to see an alternative source of these cells, and
from what you've said, it sounds like scientifically there's
strong reason to believe that's possible. Is that all
a fair statement?
DR. PELLEGRINO: Can you hold?
Dr. Kass and then we'll have Dr. Schöler .
DR. KASS: Pass.
DR. PELLEGRINO: Dr. Kass passes.
Dr. Schöler .
DR. SCHÖLER: So first of all, for
me it is something very important to have social consensus.
That's something that when I came back to Germany from the States
about two years ago I had a lot of discussions along these lines...
[O]ne person for whom I really, really [have a lot of] respect has
been a major player in the Bundestag, Mrs. von Renesse, with
whom I discussed this point, that society should not be torn apart
by what we scientists are doing, and I think this is very important.
I also think it's for the sake of scientists themselves very
important. I've been in Germany as a student when the
"Zornigen Viren," that is, the angry viruses — that's
[what] the people were called who burned down labs in Germany.
I remember what Oliver Brüstle had had to suffer, because his
name was put in the newspaper in a way that he had to be under police
And so I think there will be certain groups in society who try
to take this as an excuse to do harm to others, and for all these
reasons, for more reasons, for these reasons and so on, I think
as scientists we have a responsibility to take care that society
is not torn apart. I think that's very important. [At
least] that is a very important issue for me.
Regardless if I have certain points that differ with respect to
other points, I think as a scientist I have to agree to the view
that is providing the most consensus on these very critical issues.
And that's why I think going along these lines where people
have less, I'm sure that you're never going to satisfy everyone,
but by getting the problems solved in a way that more and more people
have less of a problem with that type of research I think is extremely
important, and that's why if I'm being faced by other scientists
who say you're wasting your time because you're not going
to please anyone, I think that's wrong.
Some people will try to hold up the stick higher and higher and
say, "Now jump over this one," if you see how high it
has to be until you stumble.
But I think having said this to the other part of your question,
I think a lot of these things are really technical problems.
If you find a drug that disassembles the things that you right now
remove together with the chromosomes, that's something that
you have to do research on...
I think what science has shown, that normally there are solutions
to problems. It's just like it takes smart scientists
together with people who know more about certain issues. That's
a teamwork effort, and we're going to get to solutions.
I'm very optimistic that we're going to find solutions.
If we are patient enough right now to wait until we are through
this bottleneck, if we say — that's something that has
been discussed a couple of times — that it's important
that we move on as many fronts as possible to see which one
is the most successful, and what we, as a society, are willing to
accept or not. Maybe this is more promising, but we don't
want to have it. At the end we have to say if we will see
if we were right or wrong what we're doing.
But where I see myself in the dilemma, I think a lot of things
are possible here that are not possible even in Germany, and in
Germany at the end things will be imported; therapies will be imported
from countries where things were developed and Germans did not participate,
and we're using the fruits of what has been done. That's
where I personally, Hans Schöler, see a problem.
Did that answer yours?
DR. PELLEGRINO: Thank you very much, Dr.
Schöler , for a very, very comprehensive and stimulating and
obviously provocative presentation, which I think has been very
useful to all of us. We're much indebted to you.
DR. SCHÖLER: Thank you.
DR. PELLEGRINO: We recess until two.
(Whereupon, at 12:21 p.m., the meeting was
recessed for lunch, to reconvene at 2:00 p.m., the same day.)
SESSION 3: OVERVIEW: GENETIC RESEARCH
AND CLINICAL APPLICATIONS
DR. PELLEGRINO: As you all know, we've been
having discussions over the last six or eight, nine months on various
aspects of screening of newborns. We're going to continue that
discussion this afternoon, looking at some of the broader aspects
than we've engaged before and the clinical aspects and some
of the social aspects.
Our first speaker is Dr. Robert Nussbaum of the University of
California at San Francisco, and again, Dr. Nussbaum, our custom
has been not to provide a long curriculum vitae, so you won't
have the schizophrenic experience of saying, "Who is it they're
DR. PELLEGRINO: But we do have your curriculum
vitae in the book. It's in the book and you can all refer to it.
Dr. Nussbaum is going to address us on the clinical aspects
of gene medicine, genomics.
DR. NUSSBAUM: Thank you all for inviting me. It's
really a great pleasure.
So what I'll be talking about briefly and trying to leave
plenty of time for discussion of, is a broad overview of just one
aspect, one particular application of the Human Genome Project,
and that is a public health application in an area that is often
referred to as personalized medicine.
Before I begin, I did a search on this, and it's interesting. The
first time that I could find anyone use the term "personalized
medicine" — I'm sorry it's cut off at the bottom
as we have Macintosh PC problems. It's a different kind of
PC — in that it was back in 1990, and it was a paper called
"Rewarding Medicine, Good Doctors and Good Behavior."
And what they said was we need to choose persons for medical careers
who will find patient-centered care rewarding, and we need to provide
those persons the training and socialization and underscore the
value of personalized medicine. That was 1990, but that was also
the time that the Human Genome Project was just getting off the
Fifteen years later, when the Genome Project was pretty much complete,
personalized medicine took on a very different tone. This is a
quote from my former boss, Francis Collins, NHGRI. "At its
most basic, personalized medicine refers to using information about
a person's genetic makeup to tailor strategies for the detection,
treatment or prevention of disease," and it is in this context,
in this definition of personalized medicine that I'll be referring
to for the rest of this talk.
So I also want to say what my sort of bedrock supposition is here
and one that I think we should all agree upon, and that is that
gene variants are not completely determinative of disease or phenotypes
of various kinds; that we're dealing with an interaction between
genes and environment.
In some diseases, environment is a minor contributor. For example,
in cystic fibrosis your genotype is the predominant determinant
of whether you're going to get this disease or not, although,
of course, there's variation in your genotype, which particular
mutant alleles can have an effect on the severity of disease, and
there are also clearly environmental factors.
On the other end of the spectrum, we have a disorder like
AIDS where the environmental impact of the virus infection is the
overwhelming factor, but there's still a strong genetic
contribution, for example, whether or not one has a mutant allele for a
cell surface receptor that blocks the ability of the AIDS virus to get
into the cell.
And in most disorders, for example, Type 2 diabetes or
Type 1 diabetes, we have an interaction between environment and genes
in some very complex way that we are just now starting to try to
dissect out, but it is a very difficult and challenging job to dissect
out the environmental and genetic contributions.
But I'd like to point out that these are not mutually
exclusive; that if we can understand, for example, the genetic
contributions to disease, that will make us much smarter in being able
to ferret out what are the environmental factors because we will then
have some context.
As hard as it is to find these genetic contributions, we do
have only about 25,000 genes, but the environmental impact, the
environmental factors are broader. They occur over time, and it's
actually in some ways a much more challenging problem.
Okay. So variation between two chromosomes. We have these
variants. The most common are polymorphisms that are called SNPs or
single nucleotype polymorphisms, and so here's an example of three
polymorphic SNPs on a stretch of DNA.
On average, we have about one SNP for every 1,250
nucleotides. We're talking about close to three million between
any two chromosomes that one inherits from a father and a mother.
But if you look through all of humankind, we're talking about
a lot more SNPs, already identified, ten million SNPs that have
been found. These are single-based changes in different populations
across the world.
So there's a significant amount of variation, and of course,
one of the challenges is how many of these SNPs actually have functional
significance. Some are going to be in neutral areas, and some are
going to affect gene expression in extremely subtle ways. Some
of them may be actually in the coding regions of genes and change
the amino acid that is encoded by that gene. Others will change
the way the gene is spliced. Others will change the way the promoter
works, and others affect the function of the gene in ways that we
do not understand at this point.
And of course, the non-coding parts of the genome are the
vast majority of all the DNA. Only a very small percentage of all of
your DNA actually has the triplet code that codes for amino acids.
So the other important point I'd like to make about these
SNPs is that as a result of the genome project and the catalogue
of SNPs, we are starting to be able to trace the history of DNA
variants: where they come from, and in particular, that there are
groups of variants that stay together and have stayed together for
tens of thousands of years.
And so that if you carry one variant in that location, you are
very likely to carry other neighboring variants, and what location
are we talking about? Well, that's all over the genome, and
it includes regions that are perhaps anywhere from 2,000 to 3,000
base pairs up to 10,000 or even 50,000 base pairs, depending on
what part of the genome you're talking about and what population
you're talking about. The population history plays an enormous
role in this degree of what we call linkage disequilibrium, that
is, having multiple variants that are nearly always found together
on a single chromosome.
So the idea here is that a variant may arise on a certain
founder chromosome, and this would be in a small group of people. Then
as the population expands, and of course, we as human beings are
actually quite recently developed as a huge population. We started
from a much, much smaller group of people in Africa.
So you have population expansion, and what happens of
course is that every time you make eggs or sperm, chromosomes cross
over with each other. So you end up with this shuffling of parental
chromosomes in the offspring.
But what happens is that when these regions are close together,
the chance of shuffling gets lower and lower and lower to a point
where these yellow bars represent regions of genome that have stayed
together over hundreds of generations, and so all of the variants
present here will be found together on a given chromosome in what's
called linkage disequilibrium, the importance of which I'll
bring up in a minute.
So let's talk about, first of all, the basic science.
You start with DNA sequencing, and you identify variation. The next
question you want to ask is to what extent do those variants contribute
to susceptibility to disease. That's really the basic science
The basic tool for trying to understand that is association analysis.
It's an epidemiological tool, and it's very simple in some
ways, and in other ways it is very challenging.
You take a group of people and you ask simply how many of
them have the disease and how many of them don't or how many will
develop the disease and how many don't develop disease. If you
follow people over time and you ask among those what fraction have the
genetic variant that you're interested in and how many of them
don't have it, and this variant can be two copies of a variant
allele on both chromosomes or one copy on one chromosome.
This is essentially what epidemiologists call the
exposure. You're either exposed to the variant or you're not,
and you divide up the population in this way, and the fundamental
question when asked is: what is the relative risk? What is the
fraction of people with a variant who get the disease versus the
fraction of people without the variant who get the disease?
And what is that? Well, here's our two-by-two table again
for association study, and this is the basic issue, the relative
risk. This would be A over A plus B. It's the fraction of
people with the disease who have the variant. That's the people
who have the variant, divided by the fraction of people with the
disease who don't have the variant. Okay? That's the relative
When it's greater than one, and it's statistically
significantly greater than one, there's an association between the
variant and the disease.
Now, you can have a variant that's highly associated
with a disease in a population for a number of different reasons, some
of them biological and some of them artifactual.
What are the biological reasons? Well, the first is the
variant you're testing for association is actually responsible for
the susceptibility. It's because of that variant affecting the way
the gene is being regulated or expressed or the way the protein looks
that you're actually affecting the function and, therefore, the
It could also be as I described, that the variant
you're asking about is in linkage disequilibrium with the variant
that's actually responsible for the susceptibility. The
association will still be there, but not the functional connection.
And it's also possible that this association that you
see is actually an artifact, an artifact of the way you put the study
together. You can have what's called stratification artifacts, and
I don't want to go into any of the details, but this is one of the
reasons why with association studies people have repeatedly said with
good reason that an association needs to be replicated. You need to
see it happen in more than one population and make sure that it's
not either a statistical quirk or actual artifact of the way you put
your study together.
So here is, I think, an example of a recent association
study that has been quite interesting and replicated and, I think,
important, and that is this gene called TCF7L2. It's a
transcription factor. It's expressed in the beta cells of the
pancreas, the cells that make insulin.
About the common variants in introns associated with increased
risk: now this is not in the coding part of the gene. This is in
the spacers between the coding part. Common variants in introns
are associated with an increased risk of Type 2 diabetes, and this
was found through a study by DeCode Genetics, which is the company
that's working in Iceland comparing genetic information and
clinical information obtained through medical records in the country
What's interesting is the effect appears to be
pan-ethnic. So once this was found in Iceland, obviously a number of
other people jumped to look.
Oh, excuse me. This is the extent of the relative risk.
So if you have no copy, that's defined as being one. If you have
one copy of the variant, your relative risk is one and a half times,
and if you have two copies of the variant, it's about 2.3 or 2.4
So that's the degree of relative risk, and I want to
stress that this is a very significant finding, and yet its effect on
relative risk is moderate. We're not talking about if you have
this variant you're 100 times more likely to develop Type 2
diabetes than if you didn't have the variant. We're talking
about one and a half to two and a half times.
Okay. So this has been repeated now in Indian-Asians and
Afro-Caribbeans, and these numbers are not relative risks. They're
actually odds ratios, which are very similar to relative risks, and
I'm happy to explain what the difference is, but it has to do with
the way the study is designed.
But the important point is that all of these numbers are
greater than one. They're all significantly greater than one.
They all increase when you go from one copy to two copies. So I think
that this is a real finding, that variants in this gene in the entrons
are associated with Type 2 diabetes in more than one ethnic group.
So what are the basic science questions? Are the entronic
variants the actual functional variants responsible for susceptibility
or are they an LD, linkage disequilibrium, with the responsible
variants? Those questions are being answered.
Whatever the variant is that's responsible for the
positive association, what effect do the responsible variants have on
gene function? Why do these variants increase your risk for Type 2
And finally, how does this effect on gene function increase
Okay. So future progress. You certainly want to know what
are the susceptibility variants for a variety of common disorders.
Type 2 diabetes is one. There are many others. We'd like to know
what those variants are.
In addition, there's a whole other area which I'm
very happy to talk about, and that is identifying the variants that
don't increase your susceptibility for diseases, but increase your
risk of an adverse drug reaction or increase your risk for not having
effective drug therapy.
And so this whole area of pharmacogenetics now is becoming
extremely interesting and important, and the search for such variants
Okay. So we talked a little bit about the basic science.
We want to find the susceptibility variants, but how do you use them?
And that's really where I'd like to spend the rest of the time.
Clearly, if you can identify susceptibility variants,
what's the translational science? Well, you certainly would like
to be able to do individual risk assessment, in other words, test
patients that come to your office for these susceptibility variants who
may not have any disease at all, but would allow you to identify people
who are at increased risk for developing disorders so that you could
prevent it, intervene in some way either medically, behavioral changes,
life style changes, whatever.
Also, if you can identify susceptibility variants, it may
help you understand how to treat people better who actually have the
disease. If we understood why that transcription factor alteration
affects Type 2 diabetes, we might be able to then treat people with
Type 2 diabetes more effectively and more rationally.
And this, of course, is something that people talk about a
lot, have talked a lot about, and I'm not going to in this context.
Okay. So what are the translational science questions for the
TCF7L2 variant Type 2 diabetes? How can we use knowledge of susceptibility
variance and devise new drugs or behavioral therapies? And what
does having a positive test for a variant mean to an individual
person whether they have the disease or not?
Let's talk first of all about the ones who don't,
and this leads us to this basic area, which I call the three
"-itys": analytical validity, clinical validity, and
clinical utility of any genetic test. You want to try to analyze
these. What are they?
Analytical validity I'm not going to spend any time talking
about. It's essentially the technical aspects of "Do you
get the test right?" Do you know how to do the test? Can
you find the variant that you think is there through the laboratory
Clinical validity is, all right, suppose you've got the
right genotype. You know what variant the person is carrying. How
well does that predict the phenotype, the disease?
And then finally, if you successfully predicted phenotype,
what's the usefulness of it? What's the clinical utility?
Does it result in an improved outcome to that person?
Clinical validity. How predictive of disease is a positive
test for any one patient?
Well, for that you really need these basic pieces of
information, what's called the positive predictive value.
That's the fraction of people with a test who have or will develop
the disease, and the negative predictive value, the fraction of people
who are negative on the test who will not have the disease.
In other words, you can rule out or reduce their risk by
doing the test and find they have a negative test.
Well, this is a busy slide, but it is, I think, the best
way for me to demonstrate this. You've got three factors you need
to take into account. One is how frequent is the variant in the
population. Is it a rare or common variant?
Number two, how common is the disease in the population?
So that's disease prevalence. So here I've got one in 1,000
people have the disease, one in 100 people have the disease, one in ten
people have the disease. That would be obviously very common.
Here's the genotype frequency, one in 1,000, one in
100, one in ten.
And then finally, what is the relative risk conferred by
having that variant? And I've generated these relative risks,
everything from 1.5 or two, which is where we were for the Type 2
diabetes variant, up to 100, which would be a very substantial relative
And what I've plotted here on the vertical axis is the
positive predictive value, and I think that what you can see here is
until you are at very high relative risks and common disorders, having
a positive test has very little positive predictive value.
I mean, down here, for example, if you have a relative risk
of, let's say, one and a half or two with a disease that affects
one in 100 people and with a variant that is present in one in ten or
one in 100 people in the population, we're talking about positive
predictive values well below ten percent.
In other words, out of every 20 people or so walking into
your office and you test them and they test positive, 19 out of 20 will
not develop this disease. Only one in 20 will.
So for most multigenic disorders that we're dealing with,
these are common disorders where the disease prevalence is high,
relative risk ratios are modest, one and a half, twofold. Positive
predictive values are very low, and the non-genetic factors are
going to be very important.
So these are clinical validity issues. So how about for the Type
2 diabetes? These are the calculations that I did for preparing
for this. Disease prevalence, about six percent I think is a reasonable
assessment for Type 2 diabetes. The allele frequency for this variance
has been found. It's about .28. So 28 percent of the population
will carry either one or two copies.
The positive predictive value of carrying one copy is 7.5
percent. So 92 and a half percent of people who carry one of those
variants won't develop the disease. And for two copies, 11 percent,
or 89 percent won't develop the disease. Eleven percent will.
So you can see from a clinical usefulness point or I should
say from a clinical validity point of view, this test is not very good
at predicting your chance of developing disease.
Okay. But now that leads us to the other issue, which is
suppose even so, you do the test and you find people have this
genotype. How useful is it? So this is an interesting quote from Kari
Stefansson. He is a CDO of DeCode. "It's terribly important
to know if you have this gene variant. It gives you an added incentive
to exercise and eat right."
And so the question really is: given that people might carry this
variant, how is that going to change what you actually tell the
patient sitting in your office about what that person should do?
Now, there are a number of common variants and common diseases
that have been identified, and I put these down because they really
in some ways cover the gamut. One is ApoE4 for Alzheimer's disease,
the disorder for which we can do susceptibility testing, but we
can't intervene in any way. We don't have any way of trying
to suppose you identify someone with increased susceptibility.
On the other hand, we have Factor V Leiden, which is an alteration
in one of the coagulation factors; it increases your susceptibility
for deep vein thrombosis and possible pulmonary embolists, clots
in the lung. That's something you can intervene on. You can
intervene with anticoagulation.
And down the list, these all vary to a greater or lesser
extent. Hemochromatosis, you can intervene by removing blood and
taking iron off of people, et cetera.
Okay. So this leads us of the clinical utility. Assuming
the result is interpreted properly, is having an individual's test
results useful or harmful? That's really the essence of clinical
utility. What good is knowing the information?
And is that utility evidence-based? Do you actually have retrospective
data at a minimum, prospective data preferably, i.e., data that
affects health outcome and economic and also has a beneficial effect
on economic factors?
Of all the areas where this sort of genetic testing seems
to be closest to really coming to use is in pharmacogenetics, and
probably the number one area that people are looking at this very
carefully now is in the use of the cumadin or warfarin, the blood
This is a drug that has a very high rate of adverse events. We're
talking about significant bleeding occurring per year in a few percent
of people on this drug: three to five percent of people on this
drug, some estimates as high as ten percent will have a significant
bleed per year that they're on it.
A lot of people are on it: people with atrial fibrillation, people
with deep vein thrombosis, a variety of other people that are at
risk for clots going to their lungs are on this drug.
The drug is metabolized through a variety of enzymes that
have variants in the population, that are common, common variants, and
depending on what your variants are, the proper dose for this drug can
vary by as much as fivefold.
So that it is possible for someone to sit in your office,
two people. You see them back to back in your office. You give them
the same dose of warfarin, and one is going to bleed and the other is
going to clot because one dose isn't enough.
Now, what do you do? Well, what physicians who use
warfarin do is they start the drug and then they monitor people
closely. They look at their anti-coagulation by doing what's
called an INR. It's the degree of blood thinning.
And people have gotten very, very good at following the
INRs and adjusting the dose. Despite that, we still have a significant
level of harmful outcomes from coumadin use or warfarin use, and so the
question is: do we have any actual evidence that if we genotype the
people for the variants that affect warfarin metabolism, would it
And it's sort of amazing that the FDA is right now in
the process of thinking about changing the labeling for warfarin, and
yet we actually don't have any clear prospective evidence that it
actually affects outcome and very little retrospective evidence.
There is excellent evidence that if you genotype people you
can get their INRs within range more quickly and more stably. So if
your outcome is the blood test, the degree of blood thinning,
pharmacogenetic analysis is helpful. If your outcome is serious
bleeding, we don't know.
The same is true for other drugs. For example, there's
a chemotherapeutic agent, arinatikan (phonetic), which is metabolized
by an enzyme that has some significant variation in the population.
You can give people this same drug and one person will drop their white
counts and get bone marrow suppression. Another person won't.
That is now on the FDA label.
Another drug, mercaptopurine used in leukemia chemotherapy,
also a tenfold difference in the proper dose of that drug depending on
what your genetic makeup is.
So I think from the science, clinical utility point of
view, pharmacogenetics is right at the top, and it's what we are
going to see coming into clinic now.
Once you step back from that and you start asking, all right,
well, what difference does it make to an overweight patient who
is at risk for Type 2 diabetes whether they have the variant or
not in that transcription factor if the positive predictive value
is ten percent or eight percent? First of all, what harm would
you do that person by genotyping them at that locus? One question.
What harm would you do by labeling people as being a "susceptibility
carrier" if they actually are never going to end up getting
diabetes? Would you then draw back and say, "Well, it's
not so important for you to lose weight and change your diet and
your life style because you don't carry the variant."
What other sorts of problems might you be then allowing this person
How good are we at using genetic information to motivate
patients? Would it actually motivate patients? There's very
little information about this.
There's one interesting study that was done by my
former colleague, Colleen McBride who looked at variants in an enzyme
that metabolizes some of the constituents of cigarette smoke, and she
did this study among an African American population in North Carolina
where they genotyped them for these variants and then tried to use that
information to try to intervene and convince people that they should
stop smoking because they're at greater risk for bad outcomes.
At six months after instituting this prospective study, the
people who had gotten genotypic information had a better rate of
quitting smoking. By 12 months it was gone.
And so our ability to intervene with behavior modification is
questionable as to whether this genotype information is going to
help or not. I am not one of these people who says it's useless
because I just don't think we know. It has never really been
put to the test.
So in summary: We're in the era of personalized medicine.
Common genetic variants increase susceptibility rather than cause
disease. Genetics empowers the basic science investigations and
drug discovery in a very important way, and I do not want to downplay
the significance of this for basic science.
The direct application to patient care requires evidence of
validity and utility, and this has to be done on a case-by-case basis,
disease by disease and locus by locus.
And with that I'll stop and be happy to answer
questions and discussion.
DR. PELLEGRINO: I'll ask Dr. Janet Rowley to
open the discussion. Will you do this for us, Janet?
DR. ROWLEY: Thank you, Doctor Pellegrino.
Well, I'm sure I speak for all of my colleagues, Bob,
when I thank you for a thoughtful, logical, but very sobering primer
related to genetics. I wasn't here for the last meeting. So
I've likely missed some of the pertinent discussion then which has,
I believe, led to some of this afternoon's presentations, but it
seems to me that much of what Bob Nussbaum discusses is tangential to
some of our earlier discussions on prenatal genetic testing.
Therefore, at present as far as I know, although Kathy may disagree,
PGD is done for single gene disorders with a clear association for
a particular disease, usually one with a sufficiently serious or
fatal outcome so the parents with to avoid having a child with that
disorder, realizing, of course, as Bob pointed out that the accuracy
of the test and the degree of penetrance certainly makes clear-cut
When we come to the era of personalized medicine, the
decision to have any kind of genetic testing is complex, and it depends
on the individual, on social factors, particularly the family, and the
information regarding the disorder and the genetic complexity of the
But I think that it's important to separate out single gene
disorders, such as Tay-Sachs, with high penetrance from some of
the others that we've been talking about, and I'm sure that
there are good data available, though I don't know.
What's the proportion of individuals at risk of
Tay-Sachs, say, amongst the Ashkenazi Jewish population? How many of
those patients were screened, and what kind of impact did it have?
You've indicated that related to smoking the long term
impact was little. My impression is in Tay-Sachs with a very educated
and committed and concerned population, maybe the answers are somewhat
You also raised the question of the interaction of
environmental factors and also the interaction of other genes with a
particular gene in question, and these are critical factors that we
So I think that — and this is something that we've
discussed in the past — that genetic testing is going to be very
unlikely for determining a person's height, athletic prowess or
pulchritude, but the screening is going to be limited, in general, to
serious genetic diseases.
And I think that one of the other issues is whether therapy
is available, and we can test for Huntington's disease, but many
very intelligent individuals who are at risk for Huntington's
disease don't want to know whether they've got the disease or
not or are at risk of having the disease because there isn't any
treatment for it in any case.
So this goes back to your question as to what is the utility of
this, and we had some readings under Tab 60 that you provided, Bob,
that have different points of view. Holtzman and Marteau are relatively
negative about the impact of genomics on medicine, whereas Guttmacher
and Collins are quite understandably more positive.
I think it's worth noting that the former was written
in 2000 and the latter in 2005, and given the rapidity with which the
field is moving, I think the difference is critical.
And you raised linkage equilibrium. Certainly the
development of the HapMap, which really defines how these blocks of DNA
— not defines, but gives us information about these blocks of DNA and
their inheritance in different populations — is going to be extremely
important because rather than asking about a single genetic variant,
one can say for a particular disease or group of patients who have,
say, heart disease, are certain blocks inherited more frequently in the
affected population than in those that don't have the disease?
And whereas it doesn't give you the gene because as Bob
indicated, some of these blocks can be rather large, they certainly
narrow down regions that we should be paying attention to.
And I think we also have to remember that some genes are
associated with decreased susceptibility rather than increased
susceptibility so that we're really a mixture and a balance, if you
will, of those that decrease or susceptibility with other genes that
increase susceptibility, and this just goes to confirming the
complexity of complex diseases.
If every factor accounts for one or two percent in an
individual, you know, you have to have 50 or 60 factors, probably not
that many, but a large number of factors that are going to be involved.
So I think that Bob's points about genetic variance may
increase the susceptibility rather than cause the disease is a very
critical one, and then going to the question of whether the variants
are functionally involved in the disease and if so, how their altered
function is associated with the disease is very critical.
Now, my own view is that personalized medicine already has
an impact on cancer treatment, and it isn't one you mentioned,
Bob, but in part I think it's because we're further along in
our understanding of the genes or genetic changes that are associated
So you know, we know not all of the individual genes that
increase the risk, but also regions that are gained or lost that are
associated with malignancy. So I disagree with Francis' statement
in his paper at Tab 8 that in the future we're going to sequence
tumors. I think instead what we're going to do is for large
classes of tumors, breast cancer, prostate, et cetera, we'll have a
series of known genes or chromosomal segments of interest, and
we're going to monitor them in the tumor from the individual
patient and then tailor treatment depending on what the answer is.
I do think in the future that we're going to do the same for
common diseases, and then partly the question isat what age should
monitoring begin. The simplest thing is as you're drawing blood
for Guthrie test and others, you draw blood for at least a HapMap.
Francis' dream is that we're going to have the
$1,000 genome sequence, but then whether it's worthwhile spending
$1,000 on every newborn to get the sequence, I'm not sure that
we're there, but I can see reasons for doing a HapMap on children,
and it certainly is going to depend on the disease. And only time is
going to tell whether personalized medicine really can fulfill some of
but I think in some areas it has already shown that it's important.
DR. PELLEGRINO: Thank you very much.
DR. NUSSBAUM: Well, I thank Janet very much for
underscoring what I think is really a very important distinction, and I
chose not to talk about single gene disorders of extremely high
penetrants, such as Tay-Sachs disease.
There the relevant risks are infinite. I mean, you
essentially get the disease if you have two copies of defective gene.
The effect on a population screening, heterozygote carrier in Tay-Sachs
has been among, for example, a targeted population, a self-targeted
population, Ashkenazi Jews, has been very high. The rate of Tay-Sachs
in the last ten or 15 years has dropped to, I believe, somewhere
around five percent of what it was before based on carrier detection
and people either choosing prenatal diagnosis or in some cases the
arranged marriage is disarranged.
So this has had a very serious effect, a very significant
effect. I was really trying to focus much more on the multi-factorial
complex disorders and the issue of really the validity and utility of
that sort of testing for common disorders, and it's really a
DR. PELLEGRINO: Thank you.
DR. NUSSBAUM: I was going to say the other thing is that I
think the effect of genetic analysis in cancer has been profound, but
once again, I'd like to make a distinction. I think most of
what's been done has been on the cancer cells, and so it has
allowed us a lot of information and is going to provide even much more
information about how to treat a cancer.
And in some ways that's a lot like what we have already been
doing since the discovery of sulfa and penicillin, and that is studying
the microbe to see what they're sensitive to and susceptible
to so that we pick the right treatment. That is where the cancer
treatment is going, and I think it already is having a significant
What hasn't happened in cancer yet, I think, is a
screening where we are finding people who are constitutionally
susceptible to cancer and then intervening in some way.
You know, there are people that are carriers for atxitillangetasia
mutations, Bloom's Syndrome mutations that have a significant
increased risk for various cancers, but in the modest range, similar
to what I showed you before, quite different, for example, through
BRCA-1 and 2 where we have a highly penetrant gene depending on
what study between 50 and 80 percent of people who carry this gene
will develop breast cancer and/or varying cancer, and there personalizing
the medicine for that family, identifying the mutations and counseling
people on an individual basis I think is already having a very substantial
So there's a difference between the single gene and the
complex is one that's worth keeping in mind.
DR. PELLEGRINO: Thank you very much.
Janet, do you want to respond? Your light is on.
DR. ROWLEY: I agree with him.
DR. PELLEGRINO: Open for general discussion now.
PROF. DRESSER: Thank you very much. That was
elegant and very clear to a non-scientist.
You mentioned that finding out more about genetic
susceptibility would help discover environmental factors, but isn't
it always going to be very difficult?
I mean, cellular Type 2 diabetes susceptibility, so that
you've narrowed it down some, but you still have a huge percentage
DR. NUSSBAUM: I mean, for example, something
near and dear to my heart and that's Parkinson's disease
and trying to understand Parkinson's disease. We have already
identified single gene defects which cause a small percentage of
Parkinson's disease. By understanding the pathway that's
affected, we can now look and see, all right, well, what does this
pathway interact with, and is it involved with how pesticides are
handled? Is it involved with the way reactive oxygen species are
So I think that the genes will shed light on pathways that
they will help be smarter about asking about environment because as a
non-epidemiologist, as a geneticist, I find environment very, very
daunting. It is not like the Genome Project where 25,000 genes and ten
million variants. I mean, that's a lot, but you can get your hands
DR. PELLEGRINO: Other questions? Gil.
PROF. MEILAENDER: Well, this is sort of a quirky
question. So make of it what you will, but as I was thinking about
what you said, you know, the example about the smoking case that
after I think it was 12 months the information seemed to have ceased
to affect behavior.
But it also strikes me that even if for many of us
information like that would cease to affect our behavior, if without it
costing us too much because, say, our insurance paid for it or
something, the information were available, lots of people would want to
know, and those are strange things to try to put together, kind of.
You know, a lot of us would want to know this information, and that it
wouldn't make a lot of difference in the long run in our behavior.
Now, I don't have any evidence really, but does that
strike you as true? And what, if anything, should one conclude from
I realize this goes beyond the kinds of sort of technical
questions you were raising, but I'd just be interested in hearing
you talk about that.
DR. NUSSBAUM: Yeah, I'd be happy to. I think it's
really a very interesting point.
Some people, and I think there are differences between different
people in terms of their personality, are very big into control.
They like to feel like they're in control and to be told, for
example, that they can't be tested for a susceptibility to cancer
from smoking. Whether it affects their behavior or not, what they
will say is, "I want the information, and then it is up to
me to decide whether I want to act on it or not and how I want to
act on it," and it's a matter of personal control.
I remember very clearly when the BRCA-1 gene was first
cloned, first identified, and some of the first mutations were found.
We really didn't have a good handle on what the penetrance was. So
if you carried one of these variants, how likely was it you were going
to develop breast cancer?
And so that the push came from NIH and from other areas
that we need a study to find that out before people got tested, and I
remember very clearly there was a letter to the editor from a breast
cancer survivor saying, "Don't patronize me. I don't want
that sort of paternalism. I want to know and I should be able to go
get the testing now."
And I think that there is some validity to that approach
that people have.
On the other hand, you do have to be careful because
information can be dangerous. It can hurt people. It can hurt
people's self-image. It can hurt them in terms of employment,
insurance, and a whole variety of other ways. So if they're being
tested for genetic variance and increased susceptibility, they have
very little positive predictive value. What are you doing to — what
good are you doing for them?
So you have to balance their feeling of "I
want." You know, it's about me. It's my body, my DNA. I
want this information.
On the other hand, what is having that information going to
do from a negative and positive point of view? My view of it is that
it's not clear cut at all and that it's going to vary from
person to person, just in the same way as Janet brought up. Even with
a disorder like Huntington's disease, there are people that say,
"I want to know."
I mean, I counseled a man two months ago who had through a
research study gotten the information. He wasn't supposed to get
the information back, but he insisted, and in fact, the researchers
couldn't deny it to him, that he was a homozygote ApoE4 carrier for
apoepiprotein E, and therefore had an increased risk for development
Alzheimer's somewhere between 15 to 25 years earlier than the
general population, and he demanded to know that information. He
wanted the information because he was making life decisions. He knew
that there was nothing he could do to intervene, but you know, should I
sell my house and buy a condo? You know, there are certain things he
wanted to know and had to do if — having control over his life by
knowing this information.
So that's my view of it.
DR. PELLEGRINO: On this point, Gil?
PROF. MEILAENDER: Just to follow it up, I mean, that was
a nice and helpful response.
If we had some kind of national health insurance program
and we put you on the committee to decide how we should rank, what sort
of a lexical ranking we should come up with even though we can't
fund everything in the world, how high would — sort of how important
would be paying to test for some of these multi-factorial diseases that
you talked about. I mean, obviously they're of interest to you.
You've studied them, but now we've put you on this committee
that's got to make this other kind of decision. Where would it
DR. NUSSBAUM: I hope I don't get put on that
committee, but if I were and since you've just put me on it, I
would try to test for those variants that reasonable clinical validity,
and that they have utility. Can you intervene so that you can improve
the outcome of this person? Can you benefit economics? Is it going to
in the long run save us, save society money by knowing?
And so, for example, very high on the list, I think my
personal feeling would be everybody who comes in for the routine
physical at some point is going to have a complete pharmacogenetic
survey done. That information only has to be done once. It goes into
that person's record, and then it will inform all drug therapy
So that in the long run adverse drug reactions are an
enormous source of morbidity and mortality and cost in this country.
Billions of dollars a year are spent because of adverse drug
reactions. If we could understand what the genetic basis for those are
and prevent them prospectively by knowing the genetic information, I
think we could have a major impact on well-being and economics. So
that would be high on my list.
So I think things with decent validity and demonstrated
DR. PELLEGRINO: I have Drs. Lawler, Kass, and
Carson, in that order.
DR. LAWLER: So, for example, diabetes, it would
seem to pass the two tests but in a relatively trivial way, right?
For example, as a physician, as someone comes into your office,
how would you judge, for instance, the diabetes? Would it be the
genetic test or the fat gut?
I think the fat gut test would be much more telling,
especially if it's fat in a certain way, as you know. So this
diabetes information, I think, by itself just wouldn't be striking
enough to me, the genetic information, to cause me to exercise more,
and my doctor could tell me to lose weight without that genetic
So the genetics goes two for two on the test. Nonetheless,
if you were on this committee, would you bother?
DR. McHUGH: I'd like to actually make two comments.
One is that one should not forget what is probably the single biggest
personalized medicine intervention that we've had for years, and
that is the family history, and so a family history of diabetes, I
think, would play a role, and there is information that people's
behavior can be motivated to some extent by a family experience.
See, family history has two effects. One is it
demonstrates that there is a low susceptibility variance in that family
that your patient is at risk for inheriting, but the other is the
social aspect of it, which is that this person will have known somebody
who has had this disorder and may have seen Uncle Joe end up with an
And so family history is a major effect. I'm not sure
at this point that the variant for Type 2 diabetes make it at the
clinical utility level. I mean, we really don't know that.
On the other hand, I'd love to see some well funded,
decent prospective studies that really go at it. I mean, that study
with the genetic variants on the glutationous transferase that was done
by Colleen McBride is one of the fe studies I can find in the
literature where people have actually tried to do it and actually put
it to a test, in essence, a randomized trial of genetic information to
affect behavior. We need more of those sorts of trials because for one
thing, it may teach us how to do it better.
DR. ROWLEY: Can I just intervene here? So if you had ten
or 15 factors for diabetes, and actually there are a few additional
genes that I guess are more of Type 1 than Type 2, what would your
answer be to Peter?
DR. NUSSBAUM: Yeah, so the answer would be twofold. One
is if you had a constellation of variance that raised the relative risk
very substantially, then I think the positive predictive value and the
clinical validity would go up.
However, what has to be factored in is that the more
variance you have, the rarer you are in the population, and so that the
impact from a public health point of view is probably reduced. so
that's the tradeoff.
DR. PELLEGRINO: Leon. Dr. Kass.
DR. KASS: Thank you.
And thank you for that wonderful presentation.
I want to, I guess, continue on this theme of clinical utility,
which I think you presented quite admirably, and it is sort of of
two parts. The study that you cited, and I don't know how many
such studies there have been, it seems to me it would be interesting
to replicate these things to see what the comparison is between
the fear that might be generated by a genetic risks factor from
other sorts of things that could be held up as a way of providing
changes to the incentives to change behavior.
It's not enough, I think, to sort of simply look at does this
genetic knowledge somehow lead to a greater incentive to quit smoking
and displaying, you know, photographs of cancers and taking someone
to visit, you know, the hospital.?
Since in so many of these things which are not single gene disorders
with high penetrants, where the environment plays a large role,
it seems to me that it would be very desirable to have some kind
of well thought out, prospective disorders to see what is the efficacy
of genomic knowledge compared to other sorts of things.
And I wondered if you could comment on that, and then I
guess second — well, a footnote to that. The change of behaviors that
would be required will differ a lot. I mean, it's one thing for
someone who for a variety of reasons likes to eat and likes to eat to
excess. The loss, the calculations of present pleasures versus future
risks, very different. Much harder to motivate certain kinds of people
to exercise than others.
And so it would seem to me that to really do this study
right, you would a great deal of multi-variables in terms of the
environmental things, and not all diseases are going to look the same.
The other thing is I wondered if genomic knowledge and
genetic knowledge — maybe this will change — still has a kind of
mystique about it, not necessarily to the scientists who work on it,
but to lots of people in the public, and you can tell them till
you're blue in the face this is not a determinant. This is part of
They hear this as there's a certain element of
fatedness about this, and I wondered to what extent that is beneficial
or misleading in the source of doing your own sort of clinical
counseling, especially when you're dealing with things with the
penetrants as low and the meaning of this genomic knowledge to you will
differ from its meaning to the people to whom you give it.
There wasn't a clear question in there. I'm sorry,
but it sort of circles around the questions of how do the people
receive this kind of knowledge in contrast to other sorts of knowledge,
and if you're interested in clinical utility, how will a profession
that might come, notwithstanding all of your caveats, to regard the
genomic element as very high? How are we going to know that that
really is the best way to try to begin to influence the behaviors that
would make for really clinical usefulness?
It wasn't as clear as I would have liked, but you nod.
So maybe you can do something with that.
DR. NUSSBAUM: No, I think those are all very useful and
important points that you're making. In terms of the first part,
I'm not a behavioral scientist, and I just think we need to do a
lot more work. I can put a small plug in here for my former
colleagues, Colleen McBride and Larry Brody at the National Human
Genome Research Institute in the intramural program, that are
undertaking now, I think, a very interesting prospective trial where
they are typing people for variants that are thought to affect things
like bone density and so for a risk of osteoporosis and a variety of
other such complex disorders.
From the point of view of trying to really study how do you
communicate that information and what do people remember about it and
how do they use it and do they used it, I just think we need a lot more
The other point you're making is actually one of the
areas where I was told in my charge that I was supposed to particularly
identify areas that are of ethical issues, ethical dilemmas, and I
think you put your finger on a major one, this issue of genetic
determinism and what negative effects that will have or could have on
So in terms of thinking about genetic variants that
increase susceptibility to disease, there have been a lot of studies
done looking at do people take a fatalistic point of view or do they
take a sort of empowerment point of view.
And the answer is yes. Different people, different
perspectives, different responses, and it's really quite
fascinating. The genetic counseling literature has a lot of such
Unfortunately the vast majority of them are sort of hypothetical.
You would go to someone and say, "Suppose we had genetic variants
that increase susceptibility for alcoholism. What do you think
about that? Would you want to be tested?" et cetera, et cetera,
Once we start actually finding variants, then I think those
studies are going to take a very different kind of tone.
The other area, I think, is in genetic variants that change
our susceptibility not so much for type 2 diabetes, but things like
alcoholism, drug addiction and other sorts of traits that have a
disease component, but also have more social effects.
And there I'm very concerned about over stressing of
genetic determinism for traits that have, you know, major social
impacts. And so I think it's really incumbent upon everyone who
does genetics and people that are interested in genetics to continue to
repeat the message that a complex trait is a complex trait with
environmental effects that can be intervened in through environmental
ways, and that if we were at the end of the day to have a situation
where people thought they could be tested and then this would make a
prediction as to whether they would have violent behavior or whether
they would or would not become alcoholics with high positive predictive
value, that I think would be a serious disservice.
DR. PELLEGRINO: Dr. Carson.
DR.CARSON: I'd like to add my thanks for that clear
and interesting presentation. My initial question was really along the
same lines as Leon's and you sort of answered it to a degree.
But one question or I assume that you're quite pro, you know, genetic
testing. It certainly seems like a worthwhile thing to do, and
yet it's really in my opinion not that different from many things
we've been doing for decades, you know, some of the enzymatic
testing, for instance, that we do on newborns. You know, every
man when he has his annual physical gets a PSA, which is not necessarily
100 percent predictive, but certainly can provide some guidance
in terms of clinical utility.
Doesn't it seem to you like we could use very much the
same type of argument for genetic testing? It's just maybe perhaps
a little more sophisticated than what we've been doing in the long
run, but in principle it's no different.
DR. NUSSBAUM: So I think you're making an excellent
point, and to use that old, hackneyed phrase, the devil is in the
details. So in newborn screening, for example, if we successfully
identify a child at risk for PKU, that child will develop PKU, and
it's not a matter of having a low positive predictive value.
It's a screening test that obviously needs to be followed up, but
I'm talking about the whole system, not just the one Guthrie test,
but the whole system or the one tandem aspect, the whole system results
in a test which is very predictive and which we can intervene on, an
enormous clinical utility, enormous clinical validity.
And so that, I think, is in a different pot. I shudder to
talk about PSAs with someone with the kind of experiences that
you've had as a surgeon, although I guess prostate surgery is
probably not your area — well, yeah, the other end.
DR.CARSON: But my understanding is PSA testing also is an
issue, and to what extent should it be done and at what age, and what
really is the clinical utility and validity of testing people over age
60 or 65 with PSA?
And so in that sense I think they're very similar and
the same kinds of questions should be applied.
The argument, and I think Dr. Kass brought this up, too, which
is this genetic exclusivity or the specialness of genetic testing.
I think what it comes down to, to some extent, is that a lot of
the testing that we do is to test for the early signs of a developing
phenotype like abnormal glucose tolerance or an elevated blood pressure,
well before there is any disease from it, but at least there's
a measurable change in the phenotype of that patient.
With genetic testing, there is no phenotype yet, and there
may never be, and so I think that's the area where we really have
to apply real critical thinking and decide.
In some situations I'm absolutely convinced that
genetic testing is going to be life saving. It's going to reduce
economic cost. It's going to reduce hospitalization. As I said, I
think the top of the list is pharmacogenetic testing from my point of
view, although even that requires more demonstration.
In other areas, until the science changes, and of course,
what would I be saying sitting here five years from now if within the
next five years we develop an effective treatment that prevents the
onset of Alzheimer's? then I think whether one would test for
ApoE4 or not becomes a very different question.
DR. PELLEGRINO: Dr. Hurlbut.
DR. HURLBUT: I appreciate your emphasis on the utility of
the single cause model and the causal web and the polygenic nature of
many traits. What I want to ask you is sort of a slightly different
angle on the clinical utility question.
Am I right in thinking that when it comes to recombination
events that there are hot spots, that it isn't just simple random
DR. NUSSBAUM: It depends on the scale. So if you're
looking at the whole chromosome level or even down to a few megabase
level, it's quasi random. There are some differences. The tips of
chromosomes have a higher recombination area than the area around
centromeres, but in general it looks pretty uniform.
But just like with a digital picture, once you get up
really close and start seeing the pixels, then you start seeing very
different recombination frequencies, and there is some evidence that
the linkage disequilibrium blocks that have been detected as
statistical associations have biological reality in that the boundaries
between those blocks have been at least in some cases demonstrated to
be areas of high recombination.
DR. HURLBUT: The reason I ask that is because it strikes
me that it would be very clever of nature to have several genes
contributing to a single trait, segregating together consistently.
That way you could select for the trait, and that's the reason I
wanted to ask you the question.
Because in an earlier report we worked on preimplantation
genetic diagnosis, and we pointed out rightly in that report that
selecting for traits for most things we care about wasn't very
likely; that it's much easier to select for a gene that's a
broken link in a chain and, therefore, cause of a disease, but for
positive traits or desired variations, that's a lot harder.
But now what you're saying implies that there might be
haplotypes that could be selected for, in which case the idea of doing
genetic testing for reasons other than disease analysis might have
some attraction here.
PARTICIPANT: It becomes more realistic.
DR. HURLBUT: Yeah. Do you think there's anything to
DR. NUSSBAUM: I guess I think that the element that's
missing from that picture is that it's very likely that it's
going to be multiple haplotypes distributed throughout the genome
rather than one single one.
DR. HURLBUT: But 50,000 base pairs could still subsume
quite a few genes.
DR. NUSSBAUM: Yes, in the area where we already know that
there's linkage disequilibrium and significant effects over long
ranges in the MAC, the HLA region where there are alleles that move
together, and for reasons that are unclear that may not have to do with
whether recombination is random or not, but have to do with selection
for certain alleles being kept together.
And so I don't think we really know. I think
you're raising an important scientific question, is that certain
alleles in regions in multiple genes may have been kept together for
reasons other than failure of recombination to occur.
DR. PELLEGRINO: Dr. George.
PROF.GEORGE: Dr. Nussbaum, I wanted to follow up — oh, was
somebody ahead of me? — on some of the comments and questions of
Professor Meilaender and Kass, and really the question I have is one
that people in your business probably ask very frequently. It's
the forbidden knowledge question.
And here what I have in mind is not whether an individual
is better off not knowing something about himself or a family is better
off not knowing something about a family member, but rather the more
general question: are there some questions about genetics that we, in
general, are better off not asking? Is there genetic knowledge that we
are better off as a society not knowing about?
And we divide those two questions along another axis. If
there's anything to the idea of forbidden knowledge, are there some
things that, for example, it's better off not knowing absolutely,
that there are no circumstances in which a decent society would really
want to know because of the bad things likely to happen if we do know.
And the other would be a category of things that we're
better off not knowing now because knowing it is dangerous, potentially
harmful before we know other things. Now, maybe after we learn other
things, the possession of the first body of knowledge would not be
Now, I ask this not as a rhetorical question. I myself
have a strong aversion to the very idea of forbidden knowledge, but
you're working right smack in the area, and I bet you've asked
yourself the question, and I'll bet it is kicked around. So what
are your own thoughts and what do people say about this?
DR. KASS: Are you going to give an example?
PROF.GEORGE: Yeah. Do you have one, Leon? Maybe if you
DR. NUSSBAUM: I'd love one.
PROF.GEORGE: Things having to do with links of genetics
with crime. There's a term, but is it called criminogenic, a
criminogenic basis for behavior, that kind of knowledge?
DR. NUSSBAUM: So I can approach this two ways.
PROF.GEORGE: Or even just your own — sorry to interrupt
DR. NUSSBAUM: Sure.
PROF.GEORGE: — your own example that you were talking
about with alcoholism. I think you were getting near raising a
question about whether we really are better off as a society knowing
about it, knowing about a genetic link with alcoholism or a
predisposition to alcoholism because of the nature of alcoholism is not
simply a disease, although there is a disease component to it, I guess,
by the prevailing account.
DR. NUSSBAUM: Major account.
PROF.GEORGE: But there's so many other things connected
with it, social factors connected with it.
DR. NUSSBAUM: Right.
PROF.GEORGE: I wish I could think of a better example. If
somebody has a better one, toss it in, but this is the general thrust
of my question.
DR. NUSSBAUM: Right. It's a very difficult question.
It's actually one that bothers me at two o'clock in the
morning when I wake up and I'm having trouble sleeping.
So is there such a thing as forbidden knowledge in
genetics? I approach it sort of in two ways. One is I can kind of
assuage my concern by just reminding myself that we're not talking
about genetic determinism. We're talking about susceptibility
variants, which are going to be, as Dr. Rowley pointed out, probably
balancing acts of various kinds. Certain variants that might increase
one's relative risk for certain things and others that would
decrease it, and so that knowing those at an individual locus-by-locus
or gene-by-gene way might not necessarily have a major impact on the
individual. There's going to be a mixture of these things.
So there's that. However, I still personally have
concern about what I think is the major challenge facing complex
genetics now, and that is what are we learning about human origins and,
in particular, human geographic origins, and what is the overlap
between the science of human genetic origins and the social construct
that we call race.
That, I think, is a major, significant, serious societal issue,
and one could imagine — and this has already happened to some
extent. Janet brought up the question about Tay-Sachs disease among
Ashkenazi Jews. Ashkenazi Jews were very fast to promote heterozygote
screening. Ten, 15, 20 years later, a very different attitude among
quite a few Ashkenazi Jews about the breast cancer gene. It was
actually quite different, even though they have a significant allele
frequency for certain variants that predispose to breast cancer.
The feeling that this was a variant that was stigmatizing them as
a social group.
DR. PELLEGRINO: Dr. Foster.
DR. NUSSBAUM: Is that even close to addressing?
PROF.GEORGE: Yes. Indeed, it is, and the only follow-up I
would have is what about the potential uses. Do you ever worry about
potential uses of genetic knowledge, for example, in a military context
that could make matters worth — what weaponizations that are made
possible by virtue of advances in genetic knowledge? Is there anything
there to worry about?
DR. NUSSBAUM: That has not occurred to me, and I can't
imagine it, but I mean, maybe someone could convince me, but I
don't know of it.
PROF.GEORGE: It sounds like Janet knows something about it.
DR. ROWLEY: I don't, but you didn't
really ask the question of forbidden knowledge or answer the question,
and I'm curious as to what your thoughts are on that matter.
Are there some things — say, take the example of alcoholism
— are we better off not knowing about susceptibility to alcoholism
or drug abuse as a society rather than understanding that?
That's just one example that was tossed out.
DR. NUSSBAUM: So my answer to that is that I think that
those are not examples where we should — those are not examples of
where we should not go. I'm sorry to do the double negative, but I
think those are examples of where we should go, but the individual
autonomy of being able to choose whether one wants to be personally
tested or not, needs to be absolutely protected.
But I think that that knowledge of susceptibility to
alcoholism, drug abuse, other sorts of traits that have societal impact
is valuable. I'm actually not that worried about that.
I guess the example I come back to often is, I mean,
I'm an Ashkenazi Jew, and there are, quote, Jewish diseases. There
are rare carriers of rare disorders for a whole host of disorders,
Gauche disease, Canovan disease, Tay-Sachs disease. You can go down
My own personal feeling is I'm grateful to have that
knowledge so that we can do something about it. I don't feel
stigmatized because I know that every group around the world has their
own sect, and it's just to some extent we've discovered them.
In many situations we haven't discovered them. So we're all in
the same boat together. It's just that we're sitting in
different places in the boat, but we're all in the boat.
DR. PELLEGRINO: Dr. McHugh.
DR. McHUGH: On the forbidden knowledge thing, you have to
remember that sometimes the very study of the possibility of a
connection to behavior and genes has provoked many people to be beset
by anger about this.
The XYY study, you remember, we were looking to see whether
young children with XYY were criminal, and I think quite rightly we
said that was perhaps stigmatizing them right at the start and putting
before them the possibility that might not be there if we weren't,
in fact, studying it.
So it became a forbidden form of study. Fortunately, it
turned out that they weren't.
DR. NUSSBAUM: Well, I should say that my very close friend
and actually my mother-in-law —
DR. McHUGH: That's pretty close.
DR. NUSSBAUM: Yeah. — was involved in the study in
Denver run by Arthur Robinson, which was a prospective study of
newborns looking for SEC (phonetic) chromosome abnormalities, and as
opposed to what happened with the Walter study, that study was allowed
to continue, and they ended up following 40 or 50,000 newborns, and it
was done as a therapeutic interaction between social workers,
geneticists and the families.
And what it demonstrated was that knowledge could be used
for intervention, particularly in the area of education for the
children who actually have learning disabilities which are not the 47
XYYs, but the 47 XXYs nd the 47 XXX females.
DR. PELLEGRINO: Dan, you've been waiting very
patiently. Thank you.
DR. FOSTER: Well, that's right. I want to just make a
brief comment that's not meant to be amusing or anything about it,
but there is another form of genetic terminism that is rampant in
clinical medicine, and you know, it really is in the old phrase that,
you know, my genes made me do it, and probably the most important
generalized disease in the world right now has to do with obesity and
Type 2 diabetes. When you get the metabolic syndrome you might — I
can't remember whether I said this last meeting or not — but the
leading cause of liver disease in the world is non-alcoholic fatty
livers. It gives you more cirrhosis than you get with alcohol and so
If you take care of patients with diabetes, as I do, and
Type 2 is the common thing, and all are overweight, and it's an
absolutely curable disease right now. You don't need a kidney
transplant. You don't need anything. You prevent the eye
disease. It's an environmentally cured disease, but they always
say they see this new gene for Type 2 diabetes and said, "I always
knew that the reason that I couldn't lose weight was because of
And as a consequence, a defense against the cure of major
diseases, like lung cancer and smoking, coronary artery disease, almost
all of these things have a huge environmental component.
Now, we learn other things about doing the genes. I've been
involved in the discovery of an effect on the insulin fairly recently
in Asian Indians, which gives you the metabolic syndrome without
obesity. It's a very interesting thing. There's a little
review coming out fairly soon about that.
So you learn these things, but a very great amount of the
disease that we deal with right now can be controlled without the
genes, and this is not to say that, you know, endocanibinioid receptors
and hedonic pleasure networks are not important, you know. I mean, we
now think that the eating signals are hooking up with the same place
marijuana goes and so forth so that there are things that drive you.
But these are curable diseases, and so we have to — I
think we have to be careful to not give an excuse to do the things that
we can do is the minor point that I want to make.
Mike Brown, who works at our place, always tells the
medical students that disease is a consequence of both genes and
environment, and he said, for example, a person that was just hit by
the car out in front of the medical school and broke his hip had a
And the students all say, "Well, wait a minute, Dr.
Brown. How can you say that? I mean, that's a pure environmental
disease. The car hit you and he broke the thing."
And he says, "Well, if you had better hearing or
better seeing, you know, you would have gotten out of the way and you
wouldn't have had it."
But I do want to say we have to be a little bit careful
about a defense against things that we can do right now on a genetic
basis because of the assumption that these polymorphisms and whatever
they are are going on are true, and we need to do all of those things,
I think. I mean, you're going to learn how to maybe do specific
treatments in that.
DR. NUSSBAUM: I think it's a fascinating question in
behavior science to ask the question does knowing that information make
one more motivated to act on it or retreat into a fatalism and say,
"Because of my genes there's nothing I can do about it."
I think it's an open question. It's probably
different for different people, but what I think is really a
fascinating question is can we now build on that to do behavioral
science research and figure out how better to get people to intervene
in the environmental factors and cure these diseases that they're
DR. PELLEGRINO: Other questions?
PROF. SCHAUB: Do you have views on direct to consumer
genetic testing, given your concerns about misapplications or
misunderstandings of the information?
DR. NUSSBAUM: Yeah, I do have strong issues about it, and
actually I was at a meeting that Dr. Hudson organized quite recently
precisely on that topic.
So I think there are some potential benefits of certain
kinds of testing in terms of empowering people, is what I was speaking
to Dr. Meilaender about, which is people want to know information and
perhaps use it.
On the other hand, there's a lot of direct to consumer
testing that, first of all, is false in terms of clinical validity. It
is without any clinical utility, and on top of it all, in some
situations is bound together with completely unproven neutroceutical
interventions that I think are essentially something that the Federal
Trade Commission should look hard at in terms of false advertising.
So, yeah, I do have strong feelings about it.
DR. PELLEGRINO: Leon.
DR. KASS: This is an indulgence, but I don't see other
hands. So if you'll indulge me, this is back to the subject of
dangerous knowledge. Just an anecdote.
I was a young staff person on an NRC committee just like
this one in 1970 to 1972, and I was stunned when the report review
committee of the academy decided to censor the report that our little
committee had produced on the grounds that if people read that document
they would cut off all funds for biomedical research. That was
dangerous knowledge, number one.
DR. KASS: But the more interesting one was it was
coincident with another example of self-censorship, one which I
applauded, when William Shockley proposed that the academy come out in
favor of a study of race and IQ, then I don't think was anything
like the genomics studies, which now could in principle at least be
undertaken, but Dubjanski was appointed the head of a serious
committee, and it was a model, just a model of prudence saying that
there was absolutely no good that could come from this kind of a study,
and we ought not to give it our blessings.
And it seems to me — and you've touched on this
already — we may yet face certain kinds of difficulties. The African
American community did not take to the proposals for routine screening
for sickle cell disease the way the Jewish community did over Tay-Sachs
partly because of all kinds of other concerns about what this meant in
terms of stigmatization, absence of care, and I think not without
DR. PELLEGRINO: Dan.
DR. FOSTER: All racial things are not problems at all. I
hope you didn't mean to do that because it would be just like the
sickle cell thing. Helen Hobbs has discovered a new gene that means
that if you're carrying it if you're an African American, you
don't get coronary artery disease for the same level of cholesterol
and so forth.
I mean, this is a terrific thing that came out of the
Dallas heart study. I mean, you know, and the Dallas heart study was
deliberately aimed at why African Americans have more heart disease
than other things.
You know, we measure blood pressures in barber shops. I
mean in other words, what they — I don't have anything to do with
this, except it's at my school — and the whole community, not only
the religious community, but it turns out if you want to get your blood
pressures checked regularly, go to the barbers for men. It's the
men that are a problem, you know, to do that.
And so we have these little things all over town, and the
enthusiasm of the community because things are coming out that may save
their lives and so forth. So it's one thing to talk about — I
mean I agree with you wholeheartedly about minor changes in intellect
that might say that somebody who lived in Texas was going to be more
stupid than somebody who lived in Massachusetts or something, you know,
but these other things, I don't want to leave the impression that
racial studies in and of themselves are dangerous or should not be
DR. KASS: I agree with you completely. I didn't mean
to imply otherwise.
DR. FOSTER: Well, I was sure you didn't mean to imply
DR. KASS: I'm glad to have it on the record.
DR. PELLEGRINO: I think it's time for a break
until 3:45. See you all then.
(Whereupon, the foregoing matter went off the record
at 3:30 p.m. and went back on the record at 3:51 p.m.)
SESSION 4: OVERVIEW: GENETIC ETHICS AND
DR. PELLEGRINO: Next, this is an overview
of genetic ethics and public policy. We have the privilege
of hearing Dr. Kathy Hudson, the Director of Genetics and Public
Health Policy at Johns Hopkins University. She knows we don't
give long introductions and she's pleased with that.
So I'll ask you to jump right into the matter at present.
DR. HUDSON: Thank you very much for the
invitation to be with you today.
I have a narrow subject about genetics ethics and public policy,
and what I thought I'd do is divide my remarks into three sections
and talk about ethics and policy issues in genetics research, in
clinical practice, and in non-medical contexts.
So first, in talking about genetics research issues, there are
a number of policy issues and ethics issues which are really garden
variety issues and are common to all biomedical research and really
don't pose immediate problems in genetic research, and some
examples are given there.
Then there are issues that are special but manageable issues in
genetics research, including impacts on family members, including
non-paternity ownership of specimens and data, and intellectual
property issues which, while present in all biomedical research,
are particularly acute, I think, in genetics research.
And then there's the really tough issues, and I think some
of these really tough issues are emerging as a consequence of the
rapid proliferation of very large cohort studies with large biobanks
So Bob has talked a little bit about the intersection between
genetic factors and environmental exposures and lifestyle and behavior.
And in order to dissect out the weak genetic contributors —
probably numerous genetic contributors to any specific health outcome
— and the numerous environmental exposures, lifestyle and
behavior inputs, it has been proposed that in order to unknot that
problem, that we do a large scale, population-based study where
we collect information about all of these inputs.
So the proposal has been made, but not funded and probably won't
be funded for some time, to study a very large cohort of people
in America. And I should mention that this has already been under
way in a number of countries around the world, including Iceland,
which is where the diabetes allele that Bob mentioned was found.
So in the U.S. it has been proposed that half a million people
be followed, that DNA and biological specimens be collected, that
clinical data be collected, lifestyle and behavioral information
be collected, and environmental exposures, and that folks be followed
over a decade. And this is all to provide a very large research
resource in which people can use that resource in order to be able
to identify weak genetic, environmental, and behavioral contributors
to health outcomes.
I should mention that in terms of the technologies for being able
to do this, the genetic technologies are really ripe to be able
to do the genetic component of this. The technologies for
accurately assessing lifestyle behavior and environmental exposures,
I think, are really sort of akin to where we were in the '80s
with genetics, where we really don't have very precise measures
of some of these things. They are coming along. So sensors
that can be worn that measure air quality, for example.
So what issues are raised by such a study? There are issues
in terms of whether or not the primary data is returned to the individual
research participants, and if information is revealed that places
that participant at high risk, imminent risk, what is the obligation
of the researchers to provide immediate care?
What kind of research or what kind of consent is provided for
this secondary research, with this very large database?
As Bob in the discussion mentioned, the personal and social reactions
to potential group findings, findings that are relevant to different
social groups. And then, of course, how do we protect the participants
in terms of privacy and discrimination?
And certainly within the study, information will be collected
about people's participation in illegal or stigmatizing behaviors.
So in many large DNA studies oftentimes the samples and the information
is de-identified and thereby it becomes no longer subject to some
of the rules and regulations that guide human subjects research.
And just to remind you that human subjects research guidelines define
a human subject as somebody who's alive, somebody from whom
data is collected through an intervention or interaction, and it
contains private identifiable information.
The office at HHS responsible for implementing and enforcing these
rules has said that it doesn't consider coded private information
to involve human subjects if the information was not initially collected
expressly for the purpose of the second study or third study or
105th study, and if the investigator cannot readily assess the identity.
So it's not that anybody can't ascertain the identity.
The investigators can't readily identify the individuals.
And I think that raises some issues for us collectively, whether
severing the link between researcher and participant is a good thing
or a bad thing. Is DNA ever really not identifiable?
Amy Maguire and Richard Gibbs have published a paper recently
in Science in which they argue that we might need to reconsider
the rules governing the use of de-identified samples in the absence
Specifically, in a proposed large cohort study severing the link
between the participant and the researcher may, in the end, sever
the ability of individuals who participate to receive information
about that study that may be relevant to their own health.
So I'm going to move now to clinical genetics issues, and
I'm going to just give three little tidbits of information,
I think, that are relevant to the clinical genetic situation in
terms of policy and ethics.
And the first — and just to remind everyone — the
number of genetic tests is increasing steeply. Most of the
genetic tests prior to the present day were for rare Mendelian genes
More recently, they are for more common variants that contribute
to complex diseases and for pharmacogenetic tests, and you can see
that the slope is getting steeper on this line, and I think that's
likely to continue.
And there have been projections that we will have handy-dandy
devices that can read out our entire genomes within the next few
years. This is an article by George Church that was in a recent
So this committee has considered the issue of preimplantation
genetic diagnosis in the past. To remind you embryos produced
through in vitro fertilization have a single blastomere removed.
Genetic analysis is performed, and based on that analysis embryos
are selected for transfer back into a woman's uterus.
This committee, when it issued its report, "Reproduction
and Responsibility," said, and I quote — or maybe I'll
paraphrase — that there really wasn't enough information
about PGD to help the committee or other policy makers formulate
policies to govern this area of clinical practice and research,
and the committee recommended that studies be undertaken to really
get a good handle on what was going on in terms of preimplantation
In the wake of that recommendation and our own work, we conducted
a survey that I would like to share just a couple of top line results
from. We surveyed 415 assisted reproductive technology clinics in
the United States, had a 45 percent response rate, and what we learned
was that three-quarters of the IVF clinics are performing preimplantation
We ask them to estimate the number of cycles of PGD — this
is not babies, this is cycles of PGD — in 2005 and had among
our group 3,000 cycles reported, and we estimate that that's
about four to six percent of all the IVF cycles in the United States.
This committee has talked a lot about for what purposes preimplantation
genetic diagnosis is performed, and so we asked clinics whether
or not they offered PGD for these different purposes: aneuploidy
testing to look at abnormalities in chromosome number, autosomal
disorders, chromosomal rearrangements, X-linked diseases, non-medical
sex selection, adult onset disease, HLA typing in combination with
a single gene test, and HLA typing in the absence, and finally to
select a disability.
And you can see here that overwhelmingly, aneuploidy testing is
the most common. Most clinics that are performing PGD are
offering PGD for aneuploidy.
Of interest, of note is that 42 percent of the clinics indicated
that they are offering preimplantation genetic diagnosis for non-medical
We also asked them about how many cycles they perform for each
of these purposes, and you can see that there's a big drop,
notably in everything except for aneuploidy. You can see that
while 42 percent of the clinics are offering non-medical sex selection,
this constituted only nine percent of the cycles (performed) in
...There have been a number of really heartbreaking stories about
misdiagnosis in preimplantation genetic diagnosis. We asked
clinic directors about their awareness of inconsistencies between
PGD results and subsequent genetic testing. And nearly a quarter
of the clinic directors said they were aware of such a circumstance.
That doesn't mean that 21 percent of the cases are misdiagnoses.
It means 21 percent of the directors had been aware of such a case
at some point. It may have been their own. It may have
been another laboratory's.
So data I think areimportant, and this sort of reiterates your
own recommendations, are needed for informed patient decisions,
for quality improvement in PGD, and for evidence-based policy.
And as a result, we are in the process of putting together a voluntary
registry for preimplantation genetic diagnosis, and we are working
collaboratively with the American Society of Reproductive Medicine,
the Society for Assisted Reproductive Technology, and the PGD International
We have the data fields all collected. We know what we want
to collect. We have the collaboration and cooperation of the
leadership of these organizations, and are now seeking funding for
So moving to my second issue, one that's near and dear to
my heart, which is the quality of genetic testing. We talked
about the clinical utility of tests and focused on that in Bob's
remarks on the clinical validity of tests. I'm going to
focus somewhat on the analytic validity, that "-ity" of
So as background, genetic testing laboratories are governed by
the Clinical Laboratory Improvement Amendments, which were put in
place in the wake of bad Pap smear test results going back to women
in the '80s.
The responsibility for implementing CLIA is given to the Centers
for Medicaid and Medicare Services, and CLIA was really intended
to assure analytic validity. When a laboratory does a test
and says there's a mutation there, you want to be quite confident
that they're right — analytic validity. Whether or not
that mutation has an association with a health outcome and if there's
something useful that you can do with it are the two other "-ities."
I'm talking about the first "-ity."
So the law directs the government to issue standards to assure
consistent quality performance, including a whole bunch of measures
that you would expect would be in laboratory quality, including
Of note, there is a special category for high complexity tests
and all genetic tests are high complexity tests, and specific requirements
can be developed for specific types of tests through the creation
of a specialty area. For example, there are specialty areas
for microbiology, toxicology, immunology, chemistry, et cetera.
There has been no specialty created for genetic testing despite
the fact that I believe it is the fastest growing area of the diagnostics
market, and creating a specialty area really is a prerequisite for
mandating proficiency testing programs, which Congress believed
was the best way to directly measure whether or not a laboratory
can get the right answer consistently.
So we're not the first people to notice that this is a problem.
Advisory committees over time have pointed out that there needed
to be enhancements in laboratory quality for genetic testing.
The NIH-DOE task force nearly a decade ago, and the Secretary's
Advisory Committee on Genetic Testing in 2000, specifically recommended
the creation of a genetic testing specialty. And in 2000 HHS said,
"Yes, we're going to create such a thing," and create
tailored standards for this complex set of tests.
After six years went by and no regulation came out, we looked
at the comments that were submitted in response to that notice of
intent and found, in fact, that most people were supportive, and
we were pleased when we communicated with the Department that they
said that they were planning to publish a proposed rule for genetic
testing as soon as possible, and that was in January.
A couple of months later they put it on their regulatory agenda,
which is their signaling "we're going to do this"
in a formal way, but then there was an abrupt change within CMS.
They have first privately, and more recently publicly, indicated
that they have no intention to create special standards for genetic
And according to a CMS official earlier this week at another advisory
committee meeting, they said that genetics is moving very fast,
and that's true.
They said that CLIA does not address clinical validity, and that's
They said that CLIA does not address all of the complicated ethical,
legal, and social issues, and that, too, is true.
They said that there are not many samples available or formal
programs for proficiency testing, and that is also true.
They said that there is not an evidence of a problem, which I
do not believe is true, and that genetic testing laboratories participate
in other specialty areas, the relevance of which is unclear to me.
If you can do a blood chemistry test, it doesn't tell me that
you can do a genetic test.
So we did a survey of genetic testing laboratories and found that
there are deficiencies in genetic testing laboratories and that
the more a laboratory participates in proficiency testing,
the fewer analytic errors they observe.
So proficiency testing is doing exactly what it was intended to
do. It's reducing analytic errors. CLIA was intended
to reduce analytic errors so that when you get a test result and
you make a profound decision based on that test, you know the answer
We document this sort of sad history in a report that I think
was included in your briefing book, and we also have formally requested
that the agency move ahead with rulemaking, along with Public Citizen
and the Genetic Alliance, and we're awaiting a response to our
So that's the laboratory end of things. What's FDA's
responsibility here? Genetic tests can be done as home brews.
That's a laboratory developed test where the lab makes all of
the ingredients itself. They don't really buy anything
except for general purpose reagents.
Then there's home brews using analyte specific reagents
which are purchased, and then there are genetic tests using kits
that are premanufactured. FDA regulates analyte specific reagents
and they regulate kits.
So of the 1,000 or so genetic tests that are are available out
there, only five have been reviewed and approved by the Food and
Drug Administration. Actually a couple of these Bob
talked about. CYP450 is a pharmacogenetic test. UGT1A1
is the test that will tell you whether or not you are at risk for
an adverse reaction to irinotecan for colon cancer.
So laboratories are not required to use test kits if they're
available, which creates an unequal system in the marketplace, and
there are two paths to the market. People for good reason
take the path of least resistance.
FDA has recently jumped into this fray and has said that they
will regulate one specific type of laboratory developed test, which
they call in vitro diagnostic multivariate index assays,
if you can say that five times real fast... And so they've caused
quite a lot of consternation, I would say, in the laboratories and
in genetic testing companies and in the biotech industry and in
the patient community because it's unclear where FDA is going
Why did they jump into IVDMIAs? The guidance is really based
on the technology used and not the risk necessarily posed by these
kinds of tests, and it's very unclear what the big picture plan
is and how can we ensure quality and also ensure access as we move
forward. What's the big strategy here for how we move
So CMS has thrown in the towel and gone home. FDA has put
its toe in the pool. It's not clear what the overall strategy
here is, and so we all are getting conflicting signals or at last
So we need transparency. We need quality. We need
a level playing field. We need to reward innovation, we need
to ensure access, and we need a good plan for how to do that, which
we don't yet have.
We talked — you talked — a little bit about direct
to consumer testing, and I'm going to end the clinical chunk
by talking a little bit about this, not the specifics of the oversight
system that's in place for these, but rather to give you a couple
of examples of what's on the market.
There is a test available for women that can tell you whether
your child will be male or female at five weeks of pregnancy by
looking supposedly at fetal DNA circulating in maternal blood.
There have been a lot of complaints about this. Some report
that they get the right answer about 50 percent of the time.
DR. HUDSON: More disturbingly, the company
has contacted women who have had the test and told them, "Your
fetus has severe chromosomal abnormalities. You need to see
a doctor immediately." People have gone through intensive
testing and screening and then given birth to healthy babies with
normal karyotypes. So there's some troubling characteristics
DNA Direct offers a number of genetic tests — including
for people who are desperately trying to have a child — infertility
testing, where they look at chromosomes and do Factor V testing.
Of course, the first thing you really should do is go to your doctor
and make sure that you're producing the two key reagents, oocytes
DR. HUDSON: Factor V testing they say is
a common genetic variant. I think "common" in genetic
parlance and "common" to the lay public has very different
meaning, and they talk about women having recurrent miscarriages
may carry this particular mutation. In fact, I think most of the
scientific literature points to this mutation only being associated
strongly with third trimester pregnancy losses, and the overwhelming
majority of pregnancy losses are first trimester.
There's a stress gene test, (and I know I've got it).
There's the Alzheimer gene test that's available, despite
the widespread agreement that this is not ready for prime time.
And then there's my favorite, CyGene Direct, which can give
you a genetic test for your athletic performance. Some of
us don't need a genetic test to tell us that.
And then this test is no longer available, although the offer
has popped up in a new company offering similar testing:
"Are you concerned about your child's future? Does
your child have a genetic trait that leads to disruptive addictive
personality? DNA testing can help you understand and manage
your child's behavior before it gets out of control. Imagene
will test a panel of dopaminergic related Reward Deficiency Syndrome
And the physicians in the crowd, I'm sure, learned a lot about
reward deficiency syndrome in medical school.
So we can talk about what we need to do or not need to do about
direct to consumer testing in the conversation. I'm going
to move quickly to the non-medical uses of genetics, and probably
the most common use of genetics outside of a medical context is
in law enforcement, identification of suspects with DNA presented
as evidence, the Innocence Project having successfully exonerated
a number of people who were wrongly accused and convicted.
More troubling, I think, or somewhat troubling, I think, are the
increasing use of DNA dragnets where DNA is asked to be voluntarily
supplied by people in a particular area or meeting a particular
And then DNA profiling, where people — in fact, a company
— will take the genotype and give you the probable phenotype
of the suspect.
Although this hasn't happened much lately, there's some
reasonable chance, I think, that genetic information will be used
in the courtroom, especially in the sentencing phase in determining
So to talk about the other non-medical issues, I want to tell
a little story of this family, and we're going to call this
woman down here Beth. Beth's father has pre-senile dementia
and is now being principally taken care of by her mother. Her two
brothers, who are older than her, have early symptoms, very similar
to what her father had in earlier years.
Her mom learns about a test that's available for presenile
dementia. This is one of those cases where there's nothing
you can do about it, like ApoE4. In this case, the gene is
presenilin-1, which is a real gene, which also leads to presenile
So the family gets tested except for Beth, and in fact, the affected
family members are found to have a mutation in the presenilin-1
gene. So Beth is thinking, "Should I get tested, too?"
So if there were an intervention, the whole equation would change,
right? If there were something she could do to prevent the
onset of dementia, I think what she would be thinking about and
the magnitude would be very different.
One thing she might be thinking about is whether or not this information
might be used against her, specifically in the health insurance
context, but luckily Congress, with some foresight in passing the
Health Insurance Portability and Accountability Act, included genetic
information among the factors that group health plans cannot use
to deny coverage or increase rates. So if Beth is in a group
health plan, she's protected.
What else might she be thinking about? Well, she might be
thinking about whether or not her employer can get this information.
There has been a debate over the last decade about whether or
not the Americans with Disabilities Act provides sufficient protection
for predictive genetic information, and specifically, the Equal
Employment Opportunities Commission has said that predictive genetic
information would be covered under the so-called third prong of
the ADA and that people with predictive genetic information, if
they were discriminated against, would be regarded as having a disability.
There have been some cases that called that into question, and
most courts are now very narrowly construing what meets the definition
of having a disability under the ADA. And so in the wake of that
lack of clarity, in 2000, President Clinton signed an executive
order which remains in place today that the federal government as
an employer cannot deny jobs or employment benefits based on genetic
And when he signed that order, he said, "I'm trying to
set an example for the private sector," and he called on the
Congress to pass an equivalent law.
Unfortunately his example was not followed, and one year and one
day later there was a case at Burlington Northern-Sante Fe Railroad
where they were surreptitiously testing employees for whether or
not they had a genetic predisposition for Carpal Tunnel Syndrome.
There has been a bill pending for a long time in the House and
the Senate. Its most recent iteration would prevent genetic
discrimination in employment and in the individual health insurance
market. It passed in the Senate by 98 to zero, not much opposition
there. It has been stalled in the House despite the fact that
it has 244 sponsors. It's very likely that in the next
Congress this bill will be reintroduced in both the House and Senate
and pass pretty quickly.
So that means that when Beth goes to make her decision, her doctor
can tell her with absolute clarity that this information cannot
be used against her in health insurance and employment, something
that right now is having a very negative impact on genetic research
and clinical practice.
My last little example here is assuming that Beth is in the military,
she joined up to serve in Iraq and she has this mutation or she
may have this mutation. Would she be protected?
The Department of Defense provides benefits to our Armed Service
men and women, including providing medical and disability benefits
for retired service men and women, but they have this funny little
policy that any injury or disease discovered after a service member
enters active duty is presumed to have been incurred in the line
of duty, with the exception of congenital and hereditary conditions.
I met this young man, Jay Platt, a number of years ago.
He had served in the Marines on two tours of duty in the Gulf War,
had been diagnosed with a number of cancers, and was diagnosed with
von Hippel-Lindau disease, which is a cancer syndrome.
He requested a medical discharge. It was denied, which meant
he would not receive benefits, and only because of his perseverance
and only because the NIH intervened on his behalf and argued a technicality,
frankly — we argued that he lost function in the other allele,
maybe because of something he was exposed to in the war —
and he got his benefits reinstated.
Most people aren't as clever as Jay is. I think that
this policy is not viable over the long term, and it's certainly
not a just policy if you think that the people whose genetic contribution
is known today don't get benefits, and if your genetic contribution
is not yet known, you do get benefits. It doesn't make
sense to me.
So what do we need to do for Beth? There's a lot of
stuff we need to do for Beth, and the most important one is to develop
an effective intervention. That's thing one.
So we need to support a robust research pipeline. We need
to make sure that she and other members of the public are confident
in the research enterprise and confident in the medical enterprise.
We need to demand that genetic testing is of exceptionally high
quality by creating a genetic testing specialty, rationalizing the
FDA system, tracking outcomes over time which can then feed back
into the clinical utility question. It would be much easier
if we had electronic health records.
We need to provide health provider tools so that health care providers
know who to test with what test and what to do based on that test.
We need to protect against privacy and misuse of genetic information,
and perhaps reconsider the standards for research using de-identifying
I'm going to close with a word of caution. I'm not
sure exactly what the discussions have been about this Council taking
up issues in genetics more broadly outside of the reproductive context
where you have done such great work in the past. But I want
to remind you that there are a number of other committees who take
genetics issues quite seriously.
Most of these are within the Department of Health and Human Services,
and they are listed here, some with quite unpronounceable acronyms.
If anyone can pronounce that, I'd be interested in hearing it.
These are all committees that are focused — this one is newly
created actually this week — all four of these committees
are focused expressly on genetics issues, and then the Advisory
Committee on Human Research Protections focused more broadly on
biomedical research issues.
And so with that, I'd like to thank you and look forward to
DR. PELLEGRINO: Thank you very much, Dr.
Dr. Schaub, would you be kind enough to open the discussion?
PROF. SCHAUB: Thank you very much for that
My remarks and questions are based on the two advanced readings
that we received from you, and I think I'll leave it to my colleagues
to follow up on some of the new information and policy proposals
in your talk.
The first report that you supplied to us calls for the creation
of a genetic testing specialty under the CLIA, arguing that it's
critical to the public's health.
The second report suggests, in addition, that the FDA expand its
purview to insure that all genetic tests are analytically and clinically
It would certainly be odd to say that one is opposed to folks
being competent at their jobs. So if a designated specialty
with standard procedures and ways to test both the tests and the
tester would improve the accuracy of genetic information being supplied
to individuals, then that seems like a good thing.
However, accurate genetic information is only a good thing to
the extent that genetic information itself is a good thing, and
I guess I think that in addition to these policy options that you
put before us, there are some prior inquiries that our council may
want to take before joining in the quest for accuracy.
I would want to ask whether and in what cases and for whom the
information is desirable in light of the fact that our ability to
test for disease or increased risk for disease is so far in advance
of our ability to actually treat or cure these diseases. I'm
not certain that better information about ones future fate is better
for the human beings concerned.
Know thyself is a human desideratum, but I have some doubts as
to whether individualized genetic information contributes to self-knowledge
Indeed, I'm not even sure that it contributes always to health.
Both reports assert that reliable tests are critical to the public's
health, and you give five, in one of the reports, you give five
illustrative instances of the serious consequences that laboratory
errors can lead to.
Two of those involved prenatal genetic testing and a third one
involved parental testing with a view to procreation.
In each case parents were wrongly informed that their child would
not have a particular disorder.
The implication is that had they had the correct information,
they would have aborted the fetus. I'm not sure where
precisely the threat is here to the public's health, unless
we mean that allowing unhealthy individuals to be born is the threat.
In other words, genetic information pretty quickly lends itself
to eugenic uses, fueled in these instances not by government mandate,
but by the longing of parents for unblemished offspring.
You know, if your insurance company finds out what you're
going to develop certain genetic diseases, it won't insure you.
If your parents find out, they may not welcome you into their arms.
I was very struck by what we learned at the last Council meeting
about testing for Huntington's and the efforts that are made
to protect the privacy of the young, at least once born, even against
the parents by not permitting testing until age 18. So I think
there are some real questions to be raised about the ethics of testing
not oneself, but another, although another who is, in the case of
parents, admittedly also one's own.
Can you tell us what proportion of the genetic testing being done
today is prenatal?
In the examples that were given, the errors all led to individuals
being born who otherwise might not have been. I suppose that
the errors also occur in the other direction. A fetus is diagnosed
with a genetic disorder. The fetus is aborted, and then perhaps
found to be quite healthy.
Does that happen or do we not know since follow-up testing is
In the second reading, you suggest that a focus on the quality
of testing could actually help us to answer questions about who
should have access to which tests, along with these questions about
advertising and commercialization.
If we went that route right now, and required greatly increased
federal regulation and oversight, would the effect be a dramatic
scaling back in the availability of genetic testing, at least a
temporary dramatic scaling back, since at present only four of the
900-some genetic tests have FDA approved test kits, would laboratories
have to close off access, especially this direct to consumer access
until FDA approval is secured and appropriate guidelines are developed?
Finally, I want to just say something about the art work by Dennis
Ashbaugh which accompanies the article in Issues in Science and
Technology. I thought the paintings were very beautiful
and the colors were very beautiful, but they seemed to me to illustrate
one of the perils of genetic testing. To me at least the paintings
displayed a form of misreading that goes beyond the misreading committed
by insufficiently trained technician.
The misreading that I'm worried about lodges in the popular
imagination. Dennis Ashbaugh says that the point of his DNA
paintings is to "reveal the inner code beneath appearances."
And on page 64, there's a reproduction of a painting entitled
"Son of Sam." Presumably it shows a section of the
notorious mass murderer's DNA.
And while the scientists might assure us that Son of Sam was not
coded for mass murder and while a scientist might tell us that the
relation between the genotype and the phenotype is more complicated
than the inner code beneath the appearances, I suspect that non-scientists
will not really get the message.
Indeed, we've been told that even physicians often have a
very sketchy grasp of the meaning of genetic test results that are,
you know, returned to them.
Human beings have always sought knowledge of their individual
fate. The Greeks visited the Oracle at Delphi. Other
peoples looked to the stars and astrology for predictive power.
Yet others have turned to evidence supposedly offered by the body
itself as in palm reading or phrenology.
I certainly don't mean to suggest that genetic testing is
fraudulent in the way that these earlier fortune tellers were.
Not at all. Part of the danger today may be that genetic testing
will be embraced by the public not for its real, albeit limited,
value, the sort of thing that was sketched out for us by Professor
Nussbaum in talking about pharmacogenic results, but rather that
it will be embraced as a scientifically valid version of palm reading.
In seeking more detailed information about our bodily fate, in
doing that, will we become a nation of fatalists?
Even when genetic information is sought in order to stave off
or to avert one's fate, one is nonetheless obsessed with fate,
and in that sense a fatalist. Alexis de Tocqueville predicted
that democratic peoples would be strongly inclined toward both fatalism
and materialism. And he argued that it would be important
for democratic legislators not to contribute to this doctrine of
So in the Council's consideration of the ethical meaning of
genetic testing and the public policies to be adopted, I would hope
that we would remember Tocqueville's warning that it is a question
of elevating souls and not completing their prostration.
DR. PELLEGRINO: Thank you very much.
DR. HUDSON: Thank you very much for those
So this committee has previously dealt a lot with the reproductive
uses of genetic testing, and I think that while I'm not aware
of any concrete data on the proportion of all genetic tests that
are performed in the reproductive context, I'm fairly confident
that it represented the majority of testing certainly up until the
And part of the reason [that most of the genetic tests were done
in the reproductive arena was that most] genetic tests [provide]
information only about [conditions about] which you can do nothing,
[and only a few provide] genetic information [that allows you to
intervene and correct or treat the condition, which is what] we
hope for in Beth's case...
And so in the absence of being able to do anything for the individual,
reproductive uses of this technology, whether to prepare for the
birth of an affected child or to terminate a pregnancy, have been
very commonly used.
One would hope, and maybe it is but a hope, that as we move forward
and understand the molecular mechanisms underlying some of these
diseases that we can develop interventions whereby we're treating
the individual as a living person and there will be less focus on
the reproductive context.
So certainly today we are doing genetic testing for Coumadin dosing,
for example, outside of the reproductive context. The CYP450
that I listed as one of the FDA approved tests is testing for enzymes
that are involved in the metabolism of a huge proportion of prescription
drugs and presumably could decrease adverse drug effects, and the
cost of those, substantially.
So it's my hope that we move outside of the reproductive context
for most of our focus in genetics. They're hard choices
no matter how you feel on the pro-life/pro-choice question.
The issue of quality and whether or not our focus on quality would
reduce access, I think is something important to keep in mind.
We certainly would not want to suddenly have a reduction in the
access of patients to get tests that are so vital to their futures.
There are some proposals that are being developed. Senator
Kennedy has a draft bill that has been circulated now where —
and I haven't read the most recent draft carefully — but
where he proposes allowing genetic tests to remain on the market
and therefore accessible, while everybody lines up and goes through
a review. And so once your number is up and you go to the
deli counter, you can no longer be on the market if you don't
pass FDA's seal of approval.
But until that time, nothing is taken off of the market.
I think there may be an exception in the bill for direct to consumer
testing. There are, as I showed, some very questionable tests
that are being offered, as the intersection of the Internet and
genetic technology give rise to this new business model.
Dr. Nussbaum suggested that the Federal Trade Commission has a
role here. I think at a minimum if we could guarantee that
people had access to information about what those tests can do and
what they can't do, then at a minimum people have appropriate
A lot of these tests that are being offered on the Internet and
even by laboratories not over the Internet, it's very hard to
get information about what is the gene, what is the variant, what
is its prevalence, what's the positive predictive value, how
many people were in the study that demonstrated that there is this
correlation. It's very hard to get at this information.
And so at a minimum if we could get some transparency in the system,
I think we could facilitate good provider decision making and good
patient decision making.
And with regard to the art, we didn't pick it. We didn't
see it until it came out.
DR. PELLEGRINO: Thank you.
Any comments? Yes, Janet.
DR. ROWLEY: Well, I'm sort of surprised
that you think that most genetic testing is related to reproduction.
I guess I would have thought that most of it is Guthrie type testing
or maybe you don't.
DR. HUDSON: Newborn screens.
DR. PELLEGRINO: Dr. George.
PROF.GEORGE: Yes, just
to be clear and to follow up on what Diana was saying, when you
say in the reproductive context, does that mean predominantly for
DR. HUDSON: Without commenting on what
is and is not eugenic —
PROF.GEORGE: Well, I mean
with a view — well —
DR. HUDSON: — so the most —
so in 2001, for example, the American College of Obstetricians and
Gynecologists adopted a guideline, health professional guideline,
that indicated to obstetricians and gynecologists that they should
offer cystic fibrosis carrier testing to all couples of a reproductive
As it turns out, in practice that test is most frequently offered
after a couple already has a pregnancy under way, when, in fact,
it makes much more sense, and was the guideline's intent, to do
that testing prior to initiating a pregnancy.
So I don't think there's any concrete data on the absolute
number of CF carrier tests that are being performed today, but it
has got to be a vast, vast number now, not to the extent of newborn
screening, but it's a big number.
PROF.GEORGE: Do you happen
to know why things went awry in that one example that you used?
Why did it end up being the case that most testing was done after
conception rather than before?
DR. HUDSON: I'm not a medical doctor.
PROF.GEORGE: It wasn't
DR. HUDSON: Yeah. I think part of
it is that when a woman shows up for her first prenatal visit obstetricians
are accustomed to offering a series of tests, and that's the
time when they do that test. When in fact women, many, many women
go in for their annual Pap smear and that's the only doctor
visit they see. In theory it should be at those visits that the
gynecologist says, "Hey, are you thinking about — let's
talk about — let me give you some information about..."
Unfortunately, that's not yet happening, and maybe testing
will move earlier. Certainly ACOG is making every effort to
see that happen.
the normal way that that information is communicated so that changes
in practice actually take place?
DR. HUDSON: Well, professional guidelines,
and actually the CF testing guideline is a rarity; so with 1,000
genetic tests out there, increasingly for common diseases and conditions,
there's only a tiny handful of professional guidelines that
are available right now.
There are some efforts under way, funded by CDC, to develop the
evidence base that would facilitate health professional guideline
development, but it takes a lot of resources and intensity for those
guidelines to be developed. The CF guideline was supported
by federal funding from the NIH, and I think that there is data
about how long it takes from the time that a health professional
guideline comes out to when a majority of practitioners are actually
following it, and it's a fairly substantial lag time.
It's sort of just the normal diffusion time.
DR. PELLEGRINO: Rebecca.
PROF. DRESSER: Kathy, I was wondering about
CF and these home brew tests. would the Kennedy bill get any
jurisdiction over that?
And do they say they don't have jurisdiction because there
isn't interstate commerce or I don't understand.
DR. HUDSON: Yeah, yeah. So they —
actually years ago, they said in the preamble to some regulation
— they said we believe that laboratory developed genetic tests
are medical devices, and they are subject to the Food, Drug and
Cosmetic Act devices amendments.
But we are using enforcement discretion and saying we're not
going to pay attention to them. So for years and years and
years they said, "We're not paying attention to them, but
we have jurisdiction." There was sort of a silence for
a period of time when the General Counsel at FDA was rumored to
believe that they were not under FDA's jurisdiction.
At a hearing in July, on direct to consumer testing, an FDA official
shocked us all when he said, "Not only do I believe we should
have jurisdiction, but we do have jurisdiction," and shortly
thereafter they put out this draft guidance which would cover one
subset of laboratory developed tests. This sort of shook up
PROF. DRESSER: Did they explain anything
about why they chose that limited kind of a test?
DR. HUDSON: Yes. These are tests
that are looking at multiple analytes at one time. So think
of a microrray either looking at DNA variants or expression patterns
where it's not just a binary answer. They're using
some sort of computer algorithm to develop a risk profile, a recurrence
One of the companies that's out there that would presumably
be an IVDMIA is Genomic Health, which looks at gene expression from
a number of genes and calculates a recurrence risk for breast cancer.
So they view this algorithm as being sort of a black box where no
well trained health professional would be able to understand really
how they got the answer, and so that's sort of their hook.
Whether or not that's higher risk than getting the wrong result
on a Huntington test I'm not sure.
DR. PELLEGRINO: Dr. Rowley.
DR. ROWLEY: Well, I just wanted to make
a comment about this de-identified samples, and I don't think
that the general public really understands what a serious medical
problem this is.
Well, let me give you two examples. One is from a very well
respected investigator at Harvard who could get DNA samples from
women de-identified, and he found five of 100 women had BRCA-1 mutations.
Now, because the samples were de-identified, he didn't have
any idea which of the five women were actually at risk, and in order
to find that out, one would have to go back and do the tests all
So I think that de-identified samples are a bad idea, and particularly
in cancer as we're trying to associate genetic abnormalities
in tumors with survival. If you are given de-identified samples,
you have no idea once you find the genetic abnormality what its
So we've talked a lot about patient privacy, but I think there
are a number of very important examples where patients are actually
done badly by having de-identified samples.
DR. HUDSON: I don't know that I have
a formulated opinion yet about the costs and benefits of de-identification,
but I agree with you that severing that link does deny [researchers]
the ability to get back with important health information.
It seems to me that with information technology and the Internet,
that some process of sort of an ongoing, rolling consent model might
be preferable to just absolutely severing this link and the set
of responsibilities that researchers and participants have towards
DR. PELLEGRINO: Dr. Kass.
DR. KASS: Thank you very much, Kathy for
a very fine presentation.
I have a couple, maybe three questions. One, you cited the
Council's "Reproduction and Responsibility" report
and the call for, among other things, longitudinal studies, the
effects of PGD on the children born. In your own study that
you cited then, the word "outcomes" appears, and it's
a collaborative study involving ASRM.
How are you going to get the ASRM people to pay attention to more
than just "a live baby was produced here?" I mean,
the really interesting things I think one needs to have evidence
for are pediatric studies and things going further on. I'm
wondering if that has been taken into account. Okay?
The second question, I was very struck as you pointed it out,
the percentage of the IVF clinics that are offering PGD for non-medical
sex selection. I think the number was 42 percent, although
they haven't at all done it.
This ought to raise some further doubt in case one didn't
have it already about the efficacy of the practice guidelines because
the ASRM is on record on this subject. They are also on record
not enforcing these guidelines, and I wonder whether — I mean,
one would like where possible to rely on professional self-regulation,
but I wonder whether or not the experience there is a kind of warning
to us if we're sort of thinking about the degree to which we
can rely on practice guidelines unenforced, especially where the
commercial interests become very, very large to do the job of protecting
Finally, and this is just a factual question, you put up a slide
of the things that the CMS said when they sort of drew back from
where you thought they were going. Four of the items you said
were true, and the fifth most important one, they deny that there's
a problem. It seemed to be false.
Do you know — this is a political question — do you
know what happened and is there powerful, organized economic lobbying,
that if one wants to think about public policy in the area of testing
that one should address, we certainly met these lobbies with respect
to other things that we were engaged in?
And if you could help us think about that, I at least would be
DR. HUDSON: In terms of the registry and
how it might help track and assess children over time, we know and
you certainly know that IVF clinics currently really have no reach
into the family with the baby and so, for example, the data they
collect on malformation rates among children of IVF are lower than
in general population.
So the data is of very poor quality on the health of the babies
born after IVF. So what we are proposing to do here is that
when data is entered into the registry, there will also be entered
whether or not the family is providing their consent for recontact
for subsequent studies. The registry would provide a research resource
for subsequent investigators to actually construct, devise, and
carry out studies of the sort that would be needed to really assess
the children's outcomes.
Now, there's not that many PGD babies in the United States,
and there have been studies that have been designed in the past
where children have been assessed from various different technologies
and where people have gotten in their vans and driven around the
country and actually done direct health assessments of children.
So this would enable that. It would not in itself do it,
and the registry we would propose would have a set of research priorities
so that entry into — being able to access the information
and the patients would be based on the priorities that the registry
governance body had created, and this is the number one priority.
Oh, and then in terms of the non-medical sex selection and whether
or not professional guidelines are sufficient in the absence of
a big stick, I'm going to quote Joe Leigh Simpson here, who
I think has spoken to the Council in the past, former president
of ASRM and a prominent geneticist. And he has recently published
an article where he has talked about the PGD registry and proposed
that it may be a means of identifying and eliminating, quote, outliers.
Whether or not that can actually come to fruition and how that
would come to fruition, I'm not sure, but I just put before
you what Joe Leigh Simpson has proposed.
And then lastly, what happened with CMS? A mystery, somewhat
of a mystery. The personalized medicine coalition —
which is pharmaceutical companies, biotech, academic organizations,
large organizations — has supported the creation of a specialty.
The American Society of Human Genetics has supported the
specialty. The majority of our survey respondents, the regulated
community, has supported the creation of a specialty.
... [A]pparently it got yanked at CMS. So it never went...to
the Office of Information and Regulatory Affairs [at] OMB,
it was somewhere else. I have heard it was within CMS that
the decision was made, and that it was based on their competing
priorities. So it was viewed within the agency as not that
DR. PELLEGRINO: Dr. Hurlbut.
DR. HURLBUT: Kathy, can you say a little
more about the issue that's brought up in one of your reports
of surreptitious testing and also the need for required counseling?
This strikes me as a very worrisome — very, very worrisome,
and then I have a follow-up question.
DR. HUDSON: Thank you very much for raising
the question. There's an interesting issue which has not
been real enough until recently to really worry about, which is
that you leave DNA everywhere, right? And there are now companies
that will test various clothing to tell you whether or not you might
have had infidelity in your family. Parents — perhaps
disgruntled parents — can test their children without their
permission or consent to find out whether or not that child is actually
So there is this non-permitted, non-consented taking and examination
of DNA that is permitted right now, and it may be that we are approaching
a time where we need to think very seriously about whether or not
there should be some limits on whether or not it should be permitted
— lawful — to do genetic testing [without consent] except
under certain circumstances — for example, at a crime scene.
I can't read my handwriting. So I can't remember
DR. HURLBUT: Required counseling.
DR. HUDSON: Counseling.
DR. HURLBUT: I know of a case where an elderly
woman was told that she carried apolipoprotein E4 allele, and she
told me that she went through over a year of waking up in the night
every night crying and worrying about arranging her whole life around
the reality that she was going to get Alzheimer's disease, and
then finally just mentioned something from the doctor about when
is it going to come on.
I mean, it just strikes me as an amazingly tragic potential out
there, and especially combined with what Dr. Nussbaum mentioned
about the over interpretative determinism of these tests.
By the way, just to add a little element, you were talking about
tests not to do. I do think we ought to do tests in this,
but it struck me that just think of the impact of not just tests
like Huntington disease, which by the way sometimes people who have
gotten results that said they weren't going to get the disease
have had decompensations that were quite severe.
But it strike me that there are quite a few grayer zones with
polygenic traits like depression, for example, that — I mean,
if you're already susceptible to depression, hearing a depressing
result might not do you much good.
DR. HURLBUT: And counseling seems to me
to be really crucial here.
DR. HUDSON: Yeah, particularly for serious
diseases for which there is no intervention. I think the standard
paradigm of pre- and post-test counseling really needs to be adhered
to, but it's really about what's the content of that counseling,
and how much are counselors really able to get the individual to
think about "what will you do with the test result if it's
this way and that way."
And even with that, I think there is the reality that what you
think you're going to do when you have a piece of information
and what you actually do when you have that piece of information
don't always line up, and that's just the reality.
Because genetics — we've been in this state, this sort
of uneasy state for such a long time with being able to, you know,
tell parents what their recurrence risk is for having a child with
a specific genetic disease. Now we're entering a different
phase, albeit slowly, and so in some ways it's time to sort
of question the paradigm of genetic counseling. Do you really
need pre- and post-test counseling to tell you that you're a
fast metabolizer, for example? Do you need to think about
the implications for your family of you being a fast metabolizer?
So we need to sort of realize that genetics isn't all on that
one end of the spectrum any more of serious diseases where you can't
do anything about it, but across the spectrum, and sort of attenuate
our expectations for what health care providers do.
The one other thing I'd say is people who provide genetic
counseling, which are often not genetic counselors, don't get
paid for what they do really. The time — you know, you
can't evaluate with somebody what are you going to do if you
find you have the ApoE4 allele in 15 minutes. And so how we
are coding and reimbursing for genetic services and genetic tests
is, I think, a significant issue.
DR. HURLBUT: Can I have one follow-up on
DR. PELLEGRINO: Yes, yes.
DR. HURLBUT: Kathy, from what we heard earlier,
it seems realistic that there might be the $1,000 genome in the
future, and actually you could do much easier and quicker and cheaper
analysis of 100,000 or 200,000 sailient alleles or locations, coding
And it strikes me that all of this individualized testing may
be outmoded in a couple of years, not a couple, but maybe ten or
12 years, and our policies might just be coming into place then.
It strikes me we need to anticipate that possibility, and by the
way, what a nightmare scenario for counseling because now you're
looking at 20,000 genes with various percentage probabilities.
Do you see what I'm saying?
DR. HUDSON: Sort of to reinforce that,
I have heard that there is a company that's going to be launching
soon that will be looking at a large number of variants, in the
thousands, and be providing that information back to people and
then providing them sort of a Web portal to do their own investigation
about what each of those variants means.
So stay tuned and get ready.
DR. PELLEGRINO: Dr. Carson.
DR.CARSON: Thank you for that presentation.
You know, the thing that worries me a little bit is the whole
concept of mission creep. You know, as a pediatric neurosurgeon,
I remember many years ago I would get referrals of babies who in
utero were diagnosed by ultrasound with anencephaly. Well,
you know, that was pretty easy.
And then it was hydroanencephaly. You know, they had a little
bit of a cortical-matter, but not much function, and then it just
became, you know, hydrocephalus, and then it became questionable
And the question at each stage was, you know, what should be done
with this baby, and you know, what recommendation would you have
to keep the same kind of mission creep from happening as we develop
more of this genetic information and people not wanting to risk,
you know, abnormalities?
DR. HUDSON: I'm afraid I don't
have a concrete answer. I will reinforce the problem by sharing
stories that my genetic counseling friends have shared with me,
which is that during amniocentesis when you just look at the chromosomes,
you look at a karyotype. When you find a chromosomal rearrangement,
a little tip of a chromosome that's sitting on the tip of another
chromosome, for example, a chromosomal rearrangement that you haven't
seen before. And so the family, you know, you tell the family that
there's this chromosomal rearrangement, and they say, "What
does it mean?"
And you say, "We don't know," right? What
do parents do in that circumstance? And that's the nature
of the analysis, the information that you get and the information
that parents get and make decisions on.
Sort of related to this, there was a bill that, well, is still
a bill, a bill introduced by Senator Brownback that suggested that
parents when making the decision to have prenatal genetic testing
be given better, more comprehensive information about the conditions
that are being tested for, specifically Down Syndrome.
And it's no doubt true that in genetics because it's easier
to identify the extreme phenotype that that's how we define
things, right? We define things by the extreme phenotype and
not so much by the gradations in phenotype, and so the emphasis
there was how can we provide more complete information about what
this really means, hooking parents up to families that have children
with that condition as a means of trying to help people make informed
decisions and not sort of lump everything together.
And I didn't understand what any of those terms were that
DR. PELLEGRINO: Any other comments?
PROF. LAWLER: At the end of the day, given
all of the problems you talk about, given the need for more federal
leadership, does this Council provide any of this federal leadership
or should these problems we addressed somewhere else?
DR. HUDSON: I think that there are a number
of these issues that are being seriously undertaken by others, some
of the issues that I talked about that were seriously undertaken
by others, and yet there are some where. especially, I think, sort
of the more anticipatory issues, the ones that aren't here right
now but that might come to become more prominent. Like Bill mentioned,
the sort of unauthorized taking and testing, I think, are potentially
some issues here.
And it might be worth reviewing what's on the agenda for those
committees who are currently focused on genetics issues to see whether
or not there are issues that the Council is interested in that are
not being considered or not on the prospective agenda for those
DR. PELLEGRINO: Paul.
DR. McHUGH: I, too, thank you for what
you've done, and I'm raising just really two issues to get
your information on this.
The first one is what I tend to refer to as materialism in the
woman, and that is being pregnant today is a much tougher task and
a more frightening task for women than it ever was before, primarily
because of the information we've given about the material.
And at this Council's meetings and at other meetings, I've
protested about the psychological burden that women bear with the
triple test that gets them to change their odds about Down's
Syndrome, and the failure of genetic counselors and the like to
help these women even when they've had an amniocentesis and
they've got at least that test that shows that they don't
have a Down's Syndrome child.
But the encouragement that they get to press on in these ways,
and their sense of defect which seems to be a real frightening burden
that women carry, and I'm really surprised that our government
and our Public Health Services haven't been studying this matter
more carefully and seeing the burden that's come for women in
this matter. So that's the first thing I wanted to ask
you, if there's anything going on there.
The second thing that was interesting to me, you pointed out that
we have made great advances in genetics but we may not be making
any advances or we may be back in the 1980s on our studies of behavior
and life styles, and you put it, and I think quite correctly, that
part of the reasons for being in that is the difficulties in maintaining
privacy and the like.
But I wondered whether you had looked into the work, particularly
done in the NORC Center at the University of Chicago, where they
have worked out ways with interviewers to interview people about
the most intimate matters of their life in kind of dueling computers,
have been able to take that information in and then disperse it
into a body so that the people can be assured not only are they
private, but they're even private in the interview itself, which
is very hard, which is a very important thing to get the information.
I just wondered whether those things were coming to the fore.
So those are the two questions.
DR. HUDSON: I think you're quite right
that there is a real burden of information on women. There
was a beautiful article in the New York Times ten years ago
by Natalie Angier where she talks about the burden of information
on women as they're pregnant, and it was beautifully, beautifully
And at the time I was actually pregnant and I had chicken pox
during my first trimester of pregnancy, and that is ostensibly linked
to various forms of birth defects, and you know, when you know too
much you can know too much. So I knew way too much and had
the phone call from my doctor after a sonogram telling me to please
call the office. There were abnormal results.
That was 6:30 at night when I got the message. You can imagine
how much I slept. He later indicated to me that there was an abnormal
interocular distance in the fetus, and I said, "Well, what
does that mean?"
And he said, "We don't know, but we need to do more testing,"
which we politely declined, deciding that if our son looked like
Lyle Lovett that was okay with us.
DR. McHUGH: By the way, I'm surprised
that you got just this information at 6:30 and by not responding
til the next morning you didn't get ten more messages between
6:30 and 5:00 a.m. because the obstetrician is so fearful that if
he doesn't let you know this, he'd be sued.
DR. HUDSON: There's going to be a lawsuit,
And then in terms of the privacy technology, I think there are
wonderful ways of getting accurate information from individuals,
and particularly, you know, there is an effect when you actually
see a human being. You give them the response that you think
that they want to hear, and so you get very different responses
from people when you actually take the other person out of the room.
So Internet based or paper based surveys and information collection
devices are much more effective than actually having a person sitting
across from you because I want to give you the answer that I think
you think is okay.
In terms of the privacy though, when you link that with DNA it's
still kind of identifiable, and I'll give you an example of
how it can be identifiable.
There was a case of a man whose father was a sperm donor, and
he wanted to contact his father and find out who his biological
father was, and so he himself put his DNA into one of these genealogical
databases where you can trace your ancestry and who's related
to whom, and he found out that there were a group of people who
were genetically related to him in a certain part of the country.
He contacted those people, asked if there are any young gentleman
family members who happened to be in the Boston region or whatever
city it was in the year that he was born, and managed to locate
DR. McHUGH: Good for him.
DR. McHUGH: By the way, as I was saying,
the Nork thing, although it is face to face, the dueling computers
made it possible. There are advantages, of course, to having
somebody speaking to somebody and at the same time having that somebody
not have any clue as to what your answer is.
So this kind of development of technology and appreciating the
data I'll follow with great interest, and I'll look up that
article in the New York Times.
DR. PELLEGRINO: Any other questions or
comments on this subject?
DR. PELLEGRINO: If not, let me thank you,
Dr. Hudson, for again a very, very excellent presentation.
DR. PELLEGRINO: And let me ask the Council
for a moment tomorrow morning we'll be going over a paper by
Eric Cohen and Sam Crowe with suggested policies having to do with
some aspects of organ transplantation. I'd like to be
very specific about that tomorrow and have us concentrate on it,
and so I would suggest just for that if you could some time look
at page 1 and 2 for the guidelines that are now being used in organ
transplantation and then look at the recommendations that are being
made, and I'd like to find your opinions and get your opinions
specifically on those you think that are important, those that may
not be of significance.
Speaking now of the specific recommendations made by Sam Crowe
and Eric Cohen rather than the guidelines that are current,
except as to background against which you would want to think about
the proposed policy changes.
Thank you very much. Have a good evening.
(Whereupon, at 5:06 p.m., the meeting was adjourned,
to reconvene Friday, November 17, 2006.)