Thursday, September 4, 2003
Session 4: Stem Cells: Moving Research from the Bench Toward
the Bedside: The Role of Nongovernmental Activity
Thomas Okarma, President and CEO, Geron Corporation
Theo Palmer, Michael J. Fox Foundation for Parkinson’s
William Pursley, President and CEO, Osiris Therapeutics,
Robert Goldstein, Juvenile Diabetes Research Foundation
CHAIRMAN KASS: Could we get started, please?
Our fourth session of the day is on stem cells, moving research
from the bench to the bedside, the role of non-governmental activity.
Progress in stem cell research proceeds not only with government
support, important though such support surely is. Biotech companies
are vigorously active in the field both with embryonic and non-embryonic
cells, and disease related and other philanthropic foundations are
actively supporting such research.
Our monitoring of stem cell research would not be complete without
some review of what is going on under these auspices. This afternoon
we are fortunate to have with us representatives from two leading
biotech companies very active in stem cell research and from two
leading private philanthropic research foundations who will tell
us something about the strategies they are pursuing to develop stem
cell based experimental therapies, how close they are to developing
such therapies, and what obstacles currently stand in the way.
As they have all been asked to avoid commercial pitches, criticisms
of competitors, or advocacy for or against legislation currently
pending before Congress, I would ask Council members to refrain
from prodding them to do otherwise or to ask them for investment
tips or other privileged information.
CHAIRMAN KASS: Our guests in order of presentation are
Dr. Thomas Okarma, who is the President and CEO of Geron Corporation,
a company that emphasizes embryonic stem cell research and formerly
supported the work, among others, of John Gearhart and James Thomson,
and that has solid patent positions in this field.
Second, Dr. Theo Palmer, who is an assistant professor in the
Department of Neurosurgery at Stanford, a stem cell researcher working
on nervous system applications, and today representing the Michael
J. Fox Foundation for Parkinson Research on whose scientific advisory
board he serves.
Third, William Pursley, President and CEO of Osiris Therapeutics,
Inc., a company in the forefront especially of mesenchymal stem
cell research, with many strong patents in this area and exploring
clinical applications for cardiac therapy, immunomodulation, among
Finally Dr. Robert Goldstein, who is the Chief Scientific Officer
of the Juvenile Diabetes Research Foundation International, an organization
with extensive activities, including a recently announced program
of training grants to draw top young researchers into the stem cell
Gentlemen, thank you very much for taking time from your busy
lives to travel here and to give us the benefit of your knowledge.
We'll start with Dr. Okarma.
DR. OKARMA: Thank you, Dr. Kass, for the opportunity to
spend some time with you today. It's a visit that's probably
You asked me to address three topics: our progress in the development
of products based on embryonic stem cells; our thoughts about immune
tolerance and immune rejection of the transplanted cells; and, lastly,
impacts of various policies on our progress in the private sector
in 15 minutes. So I will be terse and not do justice to either
question, but try to give you an overall picture.
By way of background and the take-home point, clearly human embryonic
stem cells are a special case, and this Council has certainly debated
the issue of the moral status element of that specialness. But
I would argue that there are two other elements to its specialness.
First, the biology which is unique amongst all the cells in the
universe and its promise for medical therapeutics.
And thirdly and not well understood, this paradigm is in the industrial
sector, not in the academic sector, and that has some very important
implications to the development of this technology, and I'll
try to make those points as I go through.
Geron, as you may know, has been at the forefront of human embryonic
stem cell research since 1995 when we first entered the field.
We funded the work done in Jamie Thomson's lab, John Gearhart's
lab, and Dr. Pedersen's lab at UC-San Francisco, and as such,
we're the movers technically, technologically and proprietarily
in this entire field.
We have spent over $70 million on this technology, most of it
since 1999 after the cells were derived. That's a number against
which the NIH disbursements pale by both absolute and relative terms,
and there are some reasons for that that I will touch on.
So let me move first then into our development plans and our developmental
progress. First, let me talk a bit about some of the infrastructure
basic science components that we've established.
You've heard a lot of discussion about how these cells are
grown on mouse feeder cells. We've established a scalable way
to grow these cells not only off of feeder cells, but now with a
fully qualified set of reagents. These can be scaled virtually
We've established ways to scalably produce seven different
differentiated cell types from each of the lines that we have.
So one line now makes seven different kinds of cells that we'll
describe in a moment.
We have verified the stability of the embryonic stem cell line
in culture. Some of the lines have been grown continuously for
over three years, more than 600 population doublings, and there's
a manuscript in press now describing four lines studied over that
period of time that demonstrates that the karyotype, surface marker,
differentiation potential, and gene expression level, the stability
of these undifferentiated cell lines grown under our culture conditions.
We have had a preliminary meeting with FDA, and we have now qualified
two of our cell lines for human use. They have passed every assay
the FDA has asked us to submit them to, even though they are appropriately
classified as xenogeneic. I will return to that later.
In collaboration with Celera, we've established an annotated
genomic database of undifferentiated embryonic stem cells. One
hundred fifty thousand EST sequences have been sequenced, and the
physical clones are deposited in Menlo Park.
This is fully annotated. We can query this database. We understand
what the gene expression pattern of stemness really is and what
genes are up and down-regulated as these cells differentiate. That
has been a crucial foundation for our ability to learn how to produce
differentiated cell types.
And lastly, we, too, have developed methods to genetically modify
Now, the cells that we have learned how to make are characterized
by their normalcy. Virtually every cell that we have made, without
exception, expresses completely normal cell biology. So the islet
cells we have derived express insulin, and they express insulin
in a dose-dependent fashion as a function of glucose concentration
in the media.
The oligodendrocytes we have made myelinate spinal cord cells
The dopaminergic neurons we have made secrete dopamine.
The cardiomyocytes that we have made express all of the molecular
markers consistent with their being human cardiomyocytes. They
respond in appropriate dose response fashion to cardioactive drugs.
The bone cells that we have made in Roslin have absolutely normal
biology. The techniques to look at the bone formation these cells
make in vitro by X-ray diffraction are absolutely spot-on
We are close, but have not yet derived chondrocytes. That is
also a project funded at the Roslin Institute.
And lastly, bone marrow cells, hematopoietic progenitors, which
again are absolutely normal in their cell biology, producing all
three cell lines normally.
Now, some of these cells have progressed into animal studies,
and I'll detail those in a moment. The first take-home point
to make is that we have never ever seen in any single animal the
formation of a tumor. That is because we only put in differentiated
The issue about growing the cells in the undifferentiated state
is to keep them from differentiating. So when we remove them from
the undifferentiated culture conditions, these cells want to differentiate,
and we have molecular markers to prove that they are differentiated.
We also have cytotoxic technology capable of detecting one out
of ten million cells that are undifferentiated should we need to
apply that later on in scale-up.
So which cells are in animal models? Well, first the hematopoietic
cells are in Canada, and we've demonstrated now engraftment
of these human embryonic stem cell derived hematopoietic cells in
the appropriate nude mouse model, which repopulates the animal's
peripheral blood. That has important implications not only for
an alternative source of cells for bone marrow transplantation,
but for the second question regarding immune rejection.
We've made dopaminergic cells which are engrafting robustly
in animal models of Parkinson's disease. This is a huge tissue
engineering challenge where these cells must penetrate to the cortex
of the animal to completely correct the Parkinsonian defect.
We have not yet demonstrated significant behavioral improvement
in the animals. We are still working on that, but the cells engraft
robustly and, again, without tumors.
The cell type that is most advanced is the oligodendrocyte, and
there will be a very exciting manuscript later this year from our
collaborator at UC-Irvine, Hans Keirsted, in which we have transplanted
the human oligodendrocytes into a model of spinal cord injury and
not only show statistically significant functional improvement of
the animal, but we have shown at the histologic level that the animal
cells are remyelinated by the cells that we have injected.
Lastly, we are now in animal studies in three different labs with
cardiomyocytes injected into animal models of heart failure and
myocardial infarction. Again, no tumors; again, the cells engraft,
and we have histologic evidence that these cells begin now to communicate
with the animal cell in situ in the heart.
So the work is early. There is much more to do, but we are quite
pleased with the progress that we've made thus far and would
predict that the oligodendrocyte will be the first cell to enter
the clinical environment, and that an IND, if all goes well, could
be submitted in late '04 or early '05, which is quite a
bit ahead of most people's expectations.
At this point our second cell type into the clinic would probably
be cardiomyocytes, based on the data set we have today.
As part of that first question, you asked about obstacles. There
are clearly many, many technical and scale-up obstacles that we
yet have to traverse, but those we think are fungible. Our major
problem is funding. We have done two reductions in force in the
company since a year ago. We are one third of our former size.
The political uncertainty of this field not only turns off investors,
but also turns off the other source of funding for biotech, which
are pharmaceutical partners, who at this point in time are completely
uninterested in this field.
Turning to the issue of immune rejection, first, there are a number
of very exciting, new immunosuppressive drugs in clinical development.
So I think the field of immune suppression through pharmacology
will dramatically advance, and we hope to take advantage of that.
Secondly, it's now known that pure effector cell transplants,
in other words, not organs that are contaminated by the donor's
immune system, are much less immunogenic in animal models and in
a few cases in human than is an entire organ transplant, again,
auguring well for the size of the problem of immune tolerance.
Thirdly, there is some very exciting work that we are doing not
yet published, so I can only hint at it, that establishes the human
embryonic stem cell as being unusually unique in its immunologic
properties. It has inherited some of the immunosuppressive properties
that are existent in the blastocyst.
Why is it that the mothers never immunologically reject what is
an allograft, the blastocyst? Well, there are specific reasons
for that, and those reasons are, in fact, inherent in the undifferentiated
embryonic stem cell.
But in terms of our strategy, notwithstanding the prior points
of how to control immune rejection, we have one that makes a lot
of sense, and that is hematopoietic chimerism. We know from the
bone marrow transplantation work that if a patient who gets a bone
marrow donation from me will be completely tolerant to receiving
a kidney allograft or a heart allograft from me. The prior bone
marrow transplant has tolerized the patient to the antigens in my
We also know now from work done at Stanford that patients who
are status post whole organ transplant patients can be completely
weaned off of immunosuppressive drugs by giving them a mini bone
marrow transplant taken from a donor with the same tissue type as
the prior kidney donor.
This is the strategy we plan to use out of the box in our clinical
program, having now established that we can derive hematopoietic
progenitors from one of the lines. A dose of those cells should
tolerize the patient to any effector cell transplanted into that
individual derived from the same stem cell line. So that is my
answer to Question 2.
Lastly, you asked me to address issues of policy that affect our
ability to develop the programs. Certainly the fact that this is
primarily an industrial paradigm helps with regard to FDA. I've
worked with Kathryn Zoon and Phil Noguchi since the mid-'80s
in my prior company in cell therapies. Many of the points to consider
that are now published came from our mutual collaboration in the
early work in the '80s and '90s in cell transplantation.
The pathway to regulatory testing and commercialization with this
technology is clear. There are some idiosyncracies, it is true,
but we understand the pathway, and we have thus far been very pleased
with our early interactions with the agency.
The NIH has a different issue: to recognize the primary role
in this field that has been played by industry. That is not their
fault. They were prohibited by law from funding this arena. That
is how we got into it. That is how we got ahead of everyone.
But that has some special implications. For us, as I manage Geron,
we have two platforms: the stem cells that we're talking about
today and a cancer program based on telomerase. And the management
and depth of technology in both of those platforms is hugely different
with, I think, important consequences both for patients and for
On the cancer side, we have sent the telomerase gene to hundreds
of laboratories all around the world. We have many, many collaborators.
Many people have worked independently of us on telomerase. So as
we move into the clinic with our anti-cancer platform, our scientific
understanding of how to use telomerase as a vaccine, how to develop
drugs that inhibit telomerase, how to use the promoter of telomerase
to drive oncolytic viruses is very, very deep.
That reduces risks to patients and increases the likelihood that
our first entré into the clinics will be successful, as we
are, in fact, seeing with our telomerase vaccine program in the
clinic at Duke.
That is to be contrasted with our program in embryonic stem cells,
where we have a small number of collaborators, the bulk of which
are frankly either in California funded by us and the State of California,
or in other countries, the U.K. and in Canada.
So there's no question that when we think we are ready to
move into the clinic expeditiously and cautiously, having checked
all of the appropriate boxes the FDA wants us to check, we will
still be skating on relative thin ice in terms of the science behind
the product that we are testing in people.
So the narrower science base in embryonic stem cell research increases
risk of technical failure and exposes patients to greater risk from
The second point under policy I would make sort of illustrates
a problem that's about to happen. We've heard a lot about
the issue of are the old existing lines okay. What about new lines?
Will they be different? Will they be better?
Well, the existing lines, as you've heard today, can be used
in human clinical trials, but they will not last forever, we don't
think. There's no reason to assume that. And these current
lines, all of them, were derived on mouse embryonic layers and,
as such, are appropriately classified as xenogeneic transplants
with increased risk to patients and a much increased burden on the
sponsor to follow these patients for life after they receive these
cells. That's appropriate.
So the FDA is urging us appropriately to derive new lines that
not only have not seen mouse feeders, but whose entire pedigree
is from reagents that are qualified for human use and that the entire
process of derivation be under GMP, good manufacturing practices.
We will be successful in doing this. We will generate such a
line very quickly, very soon, and then the implication of the current
policy, however, is that arguably this would be the best line to
use and to qualify and to share, but because it was derived after
2001 in August, the NIH will be prohibited from studying it.
And what are the implications for when we take that cell line
into the clinic? Will we be unable to share that cell line either
from a funding or a technology perspective with the NIH?
So those are my brief comments on the three questions. We are
unquestionably the leader in the field because of circumstances
that enabled us the freedom to operate, and in some ways, particularly
with regard to FDA and scale-up and GMP, that's good for the
But in terms of getting this technology embedded rapidly in the
most sophisticated biomedical community in the world, we are amiss.
CHAIRMAN KASS: Thank you very much.
I think we should hear from all four people together and then
Dr. Palmer, please.
DR. PALMER: Thank you, Chairman Kass, members of the Council.
I'm here on behalf of the Michael J. Fox Foundation, and I
was asked by the foundation and by the Council to give a little
bit of an overview of the foundation's efforts in targeting
Parkinson's disease. So I'll talk to you a little bit about
Parkinson's disease, or PD, and then also the role of stem cells
in our portfolio; finally, a little bit about what we've learned
in three years of trying to use stem cells in this very targeted
The foundation is relatively new. As you know, it started in
late winter of 2000. The goal of the foundation is to match funding
to scientists who are pursuing every avenue of research to find
a cure for Parkinson's disease.
Our secondary goal and my primary goal as an advisory board member
is to make sure that this funding reaches the investigator with
speed, and one of the things that we've found that has really
speeded the research is to short circuit some of the delay in an
investigator coming up with a good idea and then getting the funding
to that research.
So we're targeting Parkinson's disease, and our efforts
in stem cells are quite narrow compared to many of the applications
that you'll hear today. But Parkinson's disease is the
accelerated loss of a dopamine neuron in the adult brain. These
neurons control movement, and the loss of the neuron does not allow
the brain to initiate movement.
So one of the strategies, of course, is to replace those neurons
with a stem cell derived dopamine neuron population. This is part
of our research effort.
The other part, and in fact, a larger part, is to understand the
disease itself and then prevent or augment the remaining system,
So the brain doesn't replace these neurons, and the stem cell
biology really comes into play when you've got a patient who's
missing a substantial portion and is now dysfunctional in terms
of their ability to move.
It's a slow disease. It progresses over years, often decades.
There's a declining quality of life, and the disease is lethal.
It affects more than a million people in the U.S. alone, and there's
In the context of PD, stem cell technology has promised two significant
advances that are not available in any other context or form. A
single culture can create enough dopamine neurons to cure the entire
population of PD patients if we can get the technology to work.
This may not necessarily be true in practice, and we heard one
reason why this might not be true, if there are limits to the ability
to expand the culture. But a second reason and perhaps one that's
not very well explored by the Council is the ability to use ES cell
lines as a tool for research and particularly as a way of making
authentic human dopamine neuron for drug screening or high throughput
assays of some sort or another.
Now, this is a very important point I'll come back to later.
I'd like to go over the portfolio of the Fox Foundation and
just give you a picture of the research that's being funded
in PD by a private sponsor of research. To date the foundation
has funded 28 million in Parkinson's related research overall.
This is since our inception in late 2000.
Twenty percent of that fund has gone to stem cell research of
one sort or another, and it's a carefully chosen array of stem
cell strategies in mouse, non-human primate, and human embryonic
stem cell systems.
At the time the grants were funded, so beginning in 2000, very
few investigators had either the ability or access to human lines,
and by default rather than by design, at this point except for one
study, all of the studies that we fund use approved lines.
Now, this will change in the near future, and we anticipate in
the next rounds that we may see a significant increase in the request
for funding on non-approved lines. And in part, we feel this is
driven by the FDA and the requirement for lack of adventitious agents
and just the ease at getting a cell line product through the approval
process if it has been isolated without the use of the animal cell
lines or animal products that were not characterized.
So we have seen in the past several years a significant increase
in requests for stem cell funding in the review of our funding portfolio
and our upcoming funding efforts so that we're attracting new
scientists, people who have not really used stem cell technology
in their research into the area of Parkinson's disease.
So as a tool, it's an attractive tool for a scientist who
knows Parkinson's as a model, but now wants to expand their
repertoire to use a tool that seems to have much higher promise
than the current strategies they're using. So we're seeing
an increase in new researchers in the field.
In our annual fast track funding, this is an independent, investigator-initiated
pilot study where investigators send in unsolicited proposals.
In 2001, we had roughly 200 applications in Parkinson's in general.
Ten of these were stem cell applications. The total request at
that point was just a little over a million dollars.
In 2002, we had a similar number of total applications, and our
requests went up. We had 12 requests. Two and a half million dollars
would have funded all of those stem cell requests.
And in our pending round in 2003, we have over 200 total applications
that we're anticipating, and more than 20 of these are stem
cell related. And over time, we're seeing a significant increase
in both the application of stem cells to cell replacement in Parkinson's,
but more interestingly, a recognition of their utility as an in
vitro source of authentic human neurons, where people can study
drug effects or the genetics of Parkinson's disease itself.
And these are studies that are not necessarily targeted at replacement,
but more at understanding the disease and then coming up with a
non-stem cell basis for treatment.
So the foundation's experience has given us some insights
into what a moratorium would mean in terms of research on stem cells
and also what the current policy on federal funding is. We have
a diverse portfolio. We have studies on embryonic stem cells as
well as fetal stem cells and adult stem cells. Many of these projects
were funded early in our round because the advisory board felt that
stem cell strategies had very high merit, and one of our first efforts
was in creating cell lines that could be used for transplantation.
So we have now and unusual point of view where we can actually
compare the preliminary results from a variety of efforts. After
two years of focused research, we can see that if this was a foot
race and we were comparing adult stem cells to fetal stem cells,
there's no competition. There really is no race involved at
We have data generated from our funded research that shows that
the adult tissues are not presently a robust source of cells, particularly
when it comes to creating dopamine neurons in our focused effort
to treat Parkinson's disease.
Optimists would say that there's still potential, and there
is still potential in leveraging the adult stem cell to our goals
as a Parkinson's research foundation.
But to contrast the progress made in the same time frame with
embryonic stem cells, it's a fragile hope at best to say that
in the immediate future the adult cells hold the promise that we
had hoped two or three years ago that we would see in the research.
So it is now clearly demonstrated in vitro, and when we
started this was still an unknown, but now quite well established
in several of our funded laboratories that the human embryonic stem
cells can make authentic dopamine neurons. What's left now
is the practical application of making this work in a transplant,
and these are ongoing studies.
So I mentioned a moment ago the proliferative potential provides
a means to treat many individuals from a single isolate. Unfortunately
our research experience is now encompassing a number of cell transplant
strategies. The farthest along of these is fetal tissue transplantation
where you harvest from the fetal tissue an authentic dopamine neuron
and transplant that into a Parkinson's patient.
One of the key observations now that we have had blinded clinical
trials tell us that there may be additional problems that were unforeseen,
a key point is the presence of a fairly robust immune response in
many of these patients, and this is something that cannot really
I have to take my hat off right now and put on my own personal
hat so that I'm no longer a foundation representative here.
I work in adult stem cell biology, and it's my hope that we
can make endogenous neural progenitors do the job of an embryonic
stem cell, but in studying the behavior of newborn neurons from
endogenous precursors, we have just run into a very serious impediment
that involves the immune system.
The immune system, if activated in the context of a developing
neuron, essentially shuts off this early progenitor's ability
to make a functioning neuron, and if we're looking at cell transplantation
as a way to cure Parkinson's disease and the cell transplants
are not well matched to the host or if there isn't a strategy
for making the host tolerant, then having just a few lines is going
to be a very serious impediment to applying the existing lines to
So getting back to the foundation portfolio, there is another
benefit to looking at additional lines of ES cells. Putting cell
replacement aside and now looking at the technology that stem cells
in the culture dish provides, there's a body of research that
has been going on for nearly 20 years or more, and that's the
technology of transgenic animals and, more recently, the use of
embryonic stem cells in creating mice that carry very discrete genetic
Now, one of the strategies that we as a foundation trying to cure
Parkinson's disease contemplate is the value of having embryonic
stem cells that actually carry the genetic profile of a Parkinson's
patient, and although we're not talking today necessarily about
nuclear transfer technologies, this clearly pops into mind as a
strategy for making an in vitro authentic dopamine neuron
population that is identical to a class of patients that are presenting
a certain disease phenotype.
So the disease is diverse. It presents early and progresses rapidly
or it can present very late in life when a tottering gait is really
commonplace in that age bracket and, therefore, it's not as
big of an effect.
But this variability is really as variable as human life itself,
and so having 11 or 12 lines from normal individuals does not allow
us to access to that technology, and the creation of drugs that
would more readily target a type of dopamine neuron depletion or
a disease context.
So the targeted manipulation of genes in an embryonic stem cell
is another aspect of this that is now just entering science, and
the ability to introduce genes into human ES cells or to target
mutations to an individual cell population obviously gives you a
potential way around this, but this is a technology that's novel.
Nuclear transfer technology would circumvent that. It gives us
the baseline from which to understand how to create ES cells through
a non-embryonic process, but there has to be a way to get from Point
A to Point B, and this is where the additional lines and the exploration
of new technologies comes into play.
I'd like to finalize or just summarize here with an overview
of current research concerns. In the near term, human ES cells
are already undergoing efficacy trials in preclinical models. So
human ES cells, as we heard earlier, are in animals, and there's
great hope that we'll see that they're at least as effective,
if not more so, if the immune complications can be overcome than
the fetal tissue transplants that are so commonplace now.
To move forward with these lines, there are several limitations
with current policy that seem to inhibit our progress as a foundation
that's trying to promote cure or intervention in stem cells.
The first is what I've targeted mostly in my presentation, and
that's the heterogeneity of these current cell lines and limited
So if you start with a few lines and the cell lines are heterogeneous,
some will make, in our experience, a lot of dopamine neurons, and
others really seem to be impeded in their ability to respond to
the same cues provided in the same dish.
So in this preliminary data that we see presented in summarizing
our funded work, we're observing that one line will work beautifully
well in a paradigm. Another line is basically eliminated from the
study because it has an inability to make enough dopamine neurons
to be useful.
So heterogeneity in the performance of an individual line may
limit what can be done with the existing lines, and of course, the
absence of genetic diversity within the existing lines, the absence
of a representation of disease genotype is limiting in what can
be done at the research bench in understanding the disease process,
and of course, heterogeneity in HLA matching may be a very serious
concern, and it will require additional complexity and treatment
if we don't have a matched donor and host or fairly stringent
strategies for tolerizing the host to the incoming cells.
Finally, I think there is this question that's been touched
upon quite broadly today, and that's the presence of adventitious
agents in the existing lines and whether or not the foundation's
research can transition quickly to clinic really depends on how
well an existing line can meet FDA requirements.
And I've heard that this is possible, but it also places an
extreme burden of follow-up on a funded project that makes it difficult
for a private foundation to fund.
So in the absence of federal funding, is private support really
up to the task? And I think really to summarize this, the private
foundation's focus is to pilot research, to find very good strategies
or promising strategies, and that's where our funding really
runs out. The NIH has typically stepped in at that point, after
the pilot study stage, and proceeded with the larger experiments,
the validation, the expansion.
If the foundation funds unapproved lines, that has nowhere to
go at this point. So there is a serious concern that though we
may be able to use private funding to our benefit, that there will
be a stall or serious delay in getting this to clinic.
So these burdens loom particularly large to us as a foundation
as the Baby Boomers age, and the number of Parkinson's patients
increases. The social and economic costs go well beyond just the
Parkinson's community, and I think the economic costs in terms
of the cost of clinical care is just one part of it. The economic
cost in delayed development of drugs because we cannot use in the
public sector privately funded ES lines for drug screening or nuclear
transfer lines for screening, lines that carry a disease phenotype.
I think this is an economic burden that our society has to face
and one that should be very carefully weighed in the Council's
I think the foundation very much appreciates the ability and the
invitation here to give our experiences, and we understand that
you have a very difficult task ahead of you as counsel to the President,
and we thank you for this opportunity.
CHAIRMAN KASS: Thank you very much, Dr. Palmer.
Mr. Pursley, please.
MR. PURSLEY: Yes. Thank you.
Thank you for having Osiris here. We've been involved in
mesenchymal stem cell, adult stem cell research for about 11 years
now. Our technology came out of Arnie Kaplan's lab and was
acquired from Case Western at that time, and we've been solely
focused in that area since on several applications.
Our development strategy is very straightforward. It's tissue
engraftment and regeneration without immune suppression.
Let me back up a moment, too, to set the record straight. In
some of the earlier media documents, it has me as a Ph.D. I'm
not a scientist or a physician. I'm a businessman, and if my
technical explanations aren't satisfactory, most of what I'm
going to report on is published or we believe will be published
in acceptable peer review journals, and in fact, correct me if I'm
wrong. This panel should have been provided privately an embargoed
manuscript that will be submitted.
Okay. Our technology is the universal application, and I'll
explain that term in a moment, of adult MSCs, or mesenchymal stem
cells, with no in vitro manipulation. In other words, if
you will, these very smart cells do what they do in vivo.
We simply put them in there and let them go, so to speak. And I'll
define that in some of our programs.
What I mean by universal application, we started out as an autologous
cell company and later found out that we can provide from any donor,
unrelated, HLA unmatched, any donor these cells to any recipient
without immune rejection.
And in fact, what you'll see in our first program, we found
them to be immune selective, T cell-suppressive in some instances.
So we are now working on what would be literally an off-the-shelf
product for whatever the indication may be.
The process we use under anappropriate IRB protocol, again, we
take an unrelated, unmatched, volunteer adult donor. We take a
bone marrow aspirate, a whole marrow aspirate from the iliac crest,
bring that back to our manufacturing, and then we will culture and
expand that currently to about 1,000 doses from one donor.
We are going through an expansion now that's not a change
in process. It's an expansion of process. We will ultimately
get that to about 10,000 doses per single donor.
A very nice advantage of this is that we don't have to expand
cells indefinitely. We can go back to new donors. Currently one
donor can provide bone marrow six times in their lifetime. These
are usually younger people because the younger you are, the more
MSCs you have.
We will then cryopreserve the finished product in liquid nitrogen,
and at that point it is ready to go to clinic for use. We also
now have done stability and potency testing to have that stored
at a lesser temperature over X period of time in certain containers
so that it's easier for the hospitals to use.
The safety of these cells in the universal application has been
proven now. Allogenic MSCs have been given to 56 human beings.
Thousands of various animals models have been used, rats, mice,
goats, dogs, pigs, and baboons.
This has been done in conjunction with the NIH, Hopkins, Cedar-Sinai,
Texas Heart, et cetera. And at this point, over several years now,
there has been no possibly or probably related serious adverse events
associated with MSCs. This includes no infusion or direct administrative
toxicity. There's no ectopic tissue formation. In other words,
they aren't differentiating in cartilage in the heart, on the
knee, et cetera, and there is no tumor formation at this time.
And, in fact, we have two lead programs in Phase 2, which by definition
from the agency standards, the FDA, means we have met their safety
standards for biologic in order to move into Phase 2. So we are
very happy to report we see and now the agency sees these cells
as safe, allowing us to move into Phase 2.
Now, the precise mechanism of action regarding this universal
application is not known. All we do know is apparently there are
certain cell surface characteristics of the MSC that do not elicit
an immune response, and in fact, as I said, as you'll see in
our first indication, are actually immune suppressive.
As far as how close are we to developing therapies, our first
two programs are in Phase 2. The first is peripheral blood stem
cell transplant support for patients with hematologic malignancies,
and again, forgive me if you're very familiar with this pathology,
but basically if you have a leukemia, a myeloma, a lymphoma, et
cetera, a blood cancer, you receive total body irradiation and/or
chemotherapy, with the goal of obliterating the bone marrow because
that's the source of the cancered blood.
These patients then need to receive a transplant. They receive
a peripheral blood transplant of hematopoietic stem cells so they
can produce enough platelets to clot and white cells to fight infection
and red blood cells for volume, and gain a natural state of hematopoiesis.
And those cells usually come from a sibling or a parent. The
problem is for these patients who have no choice but to go through
this, ten percent and up to 20 percent can actually die from this
procedure, with the vast majority of graft versus host disease,
and that means the hematopoietic stem cells are rejecting the recipient.
And so what we did in a Phase 1, in a multi-center Phase 1, is
provide MSCs, mesenchymal stem cells approximately four hours prior
to the transplantation with, first of all, in a Phase 1, the primary
goal for a biologic is always safety, and you look for secondary
efficacy trends, which are great if you reach them, and we did in
a very big way.
What we did is reduce significantly graft versus host disease.
So we believe there was a T cell suppressive effect in working with
the patient or with the hematopoietic stem cells not to reject the
patient, if you will.
Now, the reason we say selective T cells suppressive, these Phase
1 patients are now out three years. They have also had a significant
reduction in return of the cancer, which means we did not suppress
the T cells fighting GVL, graft versus leukemia.
This was a very big concern. If these are immune suppressive,
are we going to hurt the patient's own ability to fight the
cancer coming back? And what we've seen at three years out
is this is not only not the case. They have a less incidence of
return of the cancer.
So with those data we are in Phase 2. This is an IV preparation.
The status is we should have Phase 2 data reportable in time Q3
If that goes well, we will go into a Phase 3, and this should
be available to the hematologic malignancy population if things
go as planned, and Murphy has a way of raising his head in this
business and always will, but even with some of those considerations,
we would hope to be commercially available to humans by 2007 with
Just after that program, a very similar situation but a different
mechanism of action, which is the amazing thing about these cells.
That was a T cell suppression effect to reduced GVHD. In a similar
sense there are infants to adolescents primarily who don't have
matched donors who will receive cord blood transplants, and their
problem is not GVHD because there are so few hematopoietic stem
cells in the cord blood transplants. Their problem is establishing
a natural hematopoiesis.
So some of these kids will lay in the hospital an average of about
90 days. It's fairly replete in the literature, and they aren't
released from the hospital until they produce enough platelets to
get out, and so they can sit for 90 days in a subacute state with
bleeds and infections, et cetera.
This is a tiny population. It's an orphan indication, but
there's nothing that can be done for these, and in a Phase
1 study with an admittedly retrospective comparison to that database.
All of these kids are in a single database in the U.S.
Our primary goal was to decrease the time to platelet engraftment,
to get these kids out of the hospital and establish a natural hematopoiesis,
and the kids that received MSCs got out in an average of about 38
days compared to retrospective control, historical control of 90.
And so that program is in Phase 2, and we hope it would be available
also to humans in the '07 time frame.
The very large and much more talked about program, our cardiac
program for acute MI, will be in humans this December in conjunction
with Boston Scientific. Most of this preclinical work was done
in swine models at Cedar-Sinai and Hopkins, and the primary goal
here is for these cells to reshape the baseline morphology, the
heart, and regain the baseline function of the heart pre-MI.
It is fantastic preclinical data, and I say that with humility
after looking at preclinical data for 24 years in this business.
After you see so many pig hearts grow back and get back to normal
function, you start to believe it.
And the IND has been filed, and the FDA will allow us to go into
clinic at the NIH and Duke this December.
The idea here, too, in this indication, something we just found
out in '99 in rats, this will be an IV administration. It is
not a direct injection or catheter application to the heart. Apparently
these very smart cells—and I can call them that because I'm
not a scientist—find their way to an inflammatory site.
And an acute MI is a very strong inflammatory event, and an inflammatory
cascade that probably lasts in a strong manner for seven or eight
days. And basically these are given IV. They swim to the heart.
They regenerate the infarcted area of the heart, which the heart
doesn't then respond with a compensatory thickening like normal,
and that happens in about four to six weeks, and in about six months
the heart gets very close back to pre-MI function.
And if that gets in the clinic in December as planned, and it
should, these are going to be much larger trials because of acute
MI. We would like to think that this product could be available
to the public commercially in 2009 or 2010.
The next product which we have an IND filed for and will be in
humans before the end of '04 is meniscal repair in the knee.
This is the most common knee injury at least in this country. There's
about 850,000 meniscal tears, from the Weekend Warriors. This will
be a high regulatory bar. It should be. These are healthy young
people normally, and so the safety is going to be critical.
Preclinical work has been done in 72 goats, and basically what
we do is do a partial to full meniscectomy as is done with the patients.
There's nothing you can do for this today but take out part
or all of the meniscectomy to ease the pain. After whole or partial
meniscectomy, it is replete in the literature that one goes on to
And what we do is give about 150 million cells directly into the
knee, and it grows back the meniscus in about six weeks time, and
hopefully then it will obviate any progression to osteoarthritis,
and we hope to be in the clinic with that as well in, again, '04
and, again, should be commercially available to humans in a similar
time as the acute MI product in '09 or '10.
The last advanced program, also in concert with Boston Scientific,
is maybe the largest unmet definitive therapy in terms of societal
cost, and that's congestive heart failure or, maybe more appropriately,
chronic ischemia leading to congestive heart failure. At Texas
Heart, in the canine model, we put an amaroid occluder in place
in these dogs to mimic chronic ischemia. Basically you do that
for about 30 days until you create an ischemic model.
About 30 days later you give the MSCs. The ejection fraction
in the amaroid occluded non-treated dogs, once it drops below 17
percent, they die. The ejection fraction in the treated dogs with
the occluded, LAD still in place, the occlusion remaining in place,
goes back to normal function in about six months.
So basically we've restored the heart morphology and the baseline
heart function pre-ischemic model with the amaroid occluder in place,
and there is possibly some form of angiogenesis going on here.
So those are the advanced programs, and in all of these programs
and all of the animal models to this date, there have been no serious
adverse events associated with MSCs, again, neither infusional toxicity,
ectopic foci, or tumor formation.
Finally, we have many, many orthopedic models in a preclinical
area where we will or will not use a scaffolding or a matrix for
these cells in some of those applications.
And finally, we are involved in grants from DARPA and NIST looking
at wound healing and CNS repair, respectively.
As far as what obstacles stand in the way, the usual. One is
enough money, especially in today's very tight private equity
market, and it's probably going to stay that way until the IPO
lid comes off.
Cell biology talent. We will be forever understanding what goes
on with these, which leads to another point I'll get to in a
And then one, to put into an equal bag where we can all take an
equal share of guilt, and that's politics, corporate greed,
and academic ego, which is a bane always in the development of any
of these, and I don't say this lightly. Again, as a personal
comment after being involved in this 24 years and being fortunate
enough to be at Genentech when they grew up and then at Genzyme
when they grew up and at TKT with maybe the most elegant protein
technology I've ever seen. Have never seen anything like this.
The hardest thing about managing this company is keeping it focused.
There is no application that can't be brought up that we can
deny the possibility of the use of these cells or cells like this.
Bill Krivits up at Minnesota has given these to kids with lysosomal
storage diseases and they are not transduced. They just start secreting
the enzyme they're missing.
The immune modulation possibility now that we found out almost
serendipitously with our first program, that's a whole new area
of arthritis, et cetera. It literally is limited by our imagination,
and it's bigger than any of those entities I mentioned by far.
It is the closest thing—and I'm sorry for the drama—of a
human health care miracle that I've seen in a quarter century.
And I just hope somehow those entities can synergize to bring
this as quickly as possible and as safely as possible to the millions
and millions of people.
As far as approaches to overcome immune reaction, we don't
have any. We have found that there is no immune reaction against
these cells, and not only that. We have found them to be immune
suppressive selectively in appropriate situations.
As far as the federal policy impact, depending on what your patent
portfolio is, that drives your answer on this. Right now we think
from the Patent Office's perspective it's a very good thing.
We have had senior scientists that have stuck with this from the
beginning because they believe with this their inventions have been
protected, and it is allowed to go on in a protected manner to develop
As far as the NIH, again, anything that can be done by that institution
to further synergize itself with commercial endeavors without feeling
it is bastardizing its academic purity, and exactly what that means
and how that is getting done we don't have an answer, and I
don't know who does, but it certainly could help all efforts.
And the FDA, first of all, I want to say, again, in a long experience
over several technologies, they have been a very good partner with
us in this, and we appreciate that. We're a tiny company.
We need a lot of guidance, and it hasn't been an adversarial
situation. It has been a partnership situation, and anything to
continue to increase that.
We are in the good fortune of being by far the most advanced company
in the world in adult stem cell research, and so it has got to be
in partnership with the FDA that we understand how these are to
be regulated because I think that will set the bar for how it is
done from this point on.
I think one of the things that will be looked at, and we have
to understand where we draw the line to accept, is especially in
the technology where everything is happening in vivo, basically
from a cell that's the same ex vivo. Without all of
the black box answers for mechanism of action, why, how, where,
how long known is how that will be weighed against the actual clinical
outcomes of safety and efficacy and how that regulatory guide pole
is looked at is critical.
Thank you very much.
CHAIRMAN KASS: Thank you very much.
Dr. Goldstein, please.
DR. GOLDSTEIN: Chairman Kass and members of the President's
Council on Bioethics, thank you very much for inviting me to testify
I'm the Chief Scientific Officer for the Juvenile Diabetes
JDRF was founded in 1970 by parents of children with juvenile
diabetes to find a cure for diabetes and its complications through
the support of research, and this year we expect to fund approximately
$90 million worth of research.
Since its inception JDRF has funded diabetes research all over
the world, and it turns out it's the world's leading nonprofit,
non-governmental funder of diabetes research.
At your July 25th meeting, you heard from Charles Queenan, a JDRF
volunteer, who spoke about the advances in islet cell transplantation
that are showing dramatic results in people with Type I diabetes.
I'd like to briefly summarize.
As of April 2003, more than 250 patients worldwide had received
islets infusions using the so-called Edmondton protocol. About
half of these patients received islets alone. The other half received
islets in conjunction with or after a kidney transplant.
Most patients have enjoyed insulin independence, reduced hypoglycemic
episodes, and improved quality of life.
Despite this success, there are too few insulin producing cells
available from organ donors that at its max could help perhaps five,
six, 700 people a year. JDRF, therefore, believes that embryonic
stem cell research could lead to the discovery of new ways to develop
additional and unlimited supplies of insulin producing beta cells
with the hope that everyone with the disease can be treated and
With this background, I want to cover some of the activities that
JDRF is engaged in over the past several years in the United States
and abroad to help advance the embryonic stem cell research agenda.
In the spring of 2000, we announced our intention to support embryonic
stem cell research. We began to build a research portfolio that
promoted human and animal stem cell research.
To insure the ethical conduct of this research we formed a stem
cell oversight committee consisting of leading researchers, policy
makers, ethicists, and lay volunteers who were charged with providing
a second level of review in addition to the usual scientific peer
review for all human stem cell research applications that we received
We recognize that stem cell research may require innovative and
novel public/private partnerships, and we included in our request
or solicitation the notation that we would support the derivation
of human embryonic stem cell lines.
The scientific principles that form the basis for stem cell research
funding program is as follows. We recognize the need to support
research using human stem cells from all sources and that very
basic research is the necessary precursor for the development of
cell based therapies; that adult stem cell research is a complementary
approach. We have long supported efforts in both adult stem cell
research, as well as more recently human embryonic stem cell research.
JDRF believes in providing a collaborative environment that will
encourage or maximize the opportunity and promise of this research,
and we work to insure easy and public dissemination of embryonic
stem cell lines without major restrictions as to the usage, and
we're committed to sharing information and data as they become
We also participate in forums for public dialogue and dissemination
JDRF embryonic stem cell research activities today include everything
that I mentioned, cells from all sources. This year we have applied
approximately $6 million in support of stem cell research with out-year
commitments of about $16 million over the next four years. Of the
$6 million this year, about three million is for research to direct
the differentiation into glucose-responsive, insulin- producing
cells using human embryonic stem cells as starting material. About
two million is for research using human stem cells from other sources,
and one million for animal work.
About one third of JDRF's funding for human embryonic stem
cell research supports work done in the United States. The rest
supports research outside the United States where in many cases
investigators work in more favorable environments, often with special
government programs that provide extra resources for human embryonic
stem cell research efforts, for example, Sweden, the United Kingdom,
Australia, and Singapore.
We initially received very few applications from U.S. based investigators,
perhaps related to concerns over policies and restrictions. We
have received consistent feedback from U.S. investigators that they
are wary of entering this field even with private funding due to
the limitations imposed by the federal policy.
They, in addition, mentioned a limited number of federally approved
lines, the lack of genetic diversity among the lines, insufficient
characterization, variability in the developmental capacities of
the lines, difficulties in distribution, as well as the ubiquitous
presence of the mass feeder layers which we've been discussing
which make the development of clinically useful cell therapies not
impossible, but more difficult as has been mentioned.
These barriers we feel need to be removed to increase the value
of using the approved stem cell lines for research and then for
the development of therapies. We acknowledge and recognize the
efforts of the NIH, particularly the NIH stem cell task force, and
we are working closely with NIH on this.
But I think that it's our international partnerships that
are pertinent to the conversation this afternoon.
JDRF's international efforts have continued and been expanded
in the area of stem cell research both through independent funding
of investigators, as well as through partnerships directly with
other governments. We have established a series of co-funding partnerships
with government research agencies in the United Kingdom, Sweden,
Canada, Australia, France and Singapore, and we have ongoing discussions
In some of these partnerships, local foundations within those
countries also provide support.
In addition, in many of those countries, we have provided funding
for very basic embryonic stem cell research that was not necessarily
connected to diabetes in any particular way since the research was
at the earliest stage.
Because of our extensive international work and leadership, JDRF
was invited in January 2003 to be a founding member of the International
Stem Cell Forum established by the Medical Research Council of the
United Kingdom under the leadership of Professor Sir George Radda.
This group currently includes representatives from government
agencies in the United Kingdom, Australia, Canada, Finland, France,
Germany, Israel, Japan, Singapore, Sweden, and the Netherlands,
as well as the NIH.
The objectives of the forum are to encourage collaborative research
across nations, boundaries, and disciplines; to encourage sharing
of resources and data; to fully capitalize on the existing available
human stem cell lines; to identify key research gaps and address
these by capitalizing on national strength; and to identify funding
schemes that actually facilitate transnational collaborations.
In specific terms, this group has agreed to develop a set of criteria
that could be adopted globally for optimizing the derivation characterization
and maintenance of human stem cell lines from all sources; identify
a small number of international laboratories that would commit to
using the agreed criteria to characterize existing human embryonic
stem cell lines; and to identify opportunities for sharing resources,
cell lines, data protocols, and guidance documents on an international
basis; to coordinate or make an attempt to coordinate national stem
cell banking activities.
This group has already convened a working group to characterize
stem cell lines with a series of recommendations.
The United Kingdom has one of the more progressive environments
for stem cell research as a consequence of the British government
providing strong political, regulatory, and funding support in this
area. The recent establishment of the U.K. Stem Cell Bank is one
example. This will provide access to existing and new quality controlled
adult, fetal, and embryonic stem cell lines. It will have a good
manufacturing practice arm for research leading to clinical applications.
Academic researchers and companies from the U.K. and elsewhere
will be eligible to deposit and to access lines according to a code
of practice developed by interested parties.
This bank will serve as an outstanding example of how to foster
and enhance the research needed to develop therapies from stem cells
of all kinds.
Other countries are working toward the development of similar
resources, and it is envisioned that the International Stem Cell
Forum may serve to coordinate such activities in order to enhance
the exchange of information and to provide complementary efforts
in this burgeoning field of research.
Examples of activities under consideration include the establishment
of a registry posted on an international Web site that would provide
appropriate scientific information about lines not listed in the
current NIH registry; characterization of non-NIH registry lines,
and comparison with NIH lines; in addition, joint training programs
to assist new investigators.
Organizing and coordinating these international research activities
in order to better serve research efforts everywhere provides a
model that is highly likely to bring results to the clinic much
Well, this summarizes research activities to date. I do not want
to provide the impression that these international activities, for
example, can replace the resources which the federal government
and United States could provide for this research.
The limitations imposed by the current policy raise questions
and provoke uncertainties about the future of human embryonic stem
cell research in the United States. We think that one result is
fewer scientists working, fewer graduate students, postdocs, et
cetera, and universities who have less than an active willingness
to invest in facilities, a comment that was made earlier in the
These resources could make a significant difference to research
progress in the development of insulin producing beta cells for
the cure of diabetes, and in this area, they need to establish and
nurture collaborations between the world's experts in beta cell
biology and the world's experts in stem cell biology so they
can collectively conduct the necessary research. It remains a critical
Expanded federal embryonic stem cell policy would make an important
difference in helping promote this research.
Much of the current knowledge of beta cell development comes from
studies using mass embryonic stem cells that is not always easily
translatable into human work. Several protocols, however, have
been reported that direct mass embryonic stem cells to becoming
functioning islet cells. Early studies in human embryonic stem
cells suggest that they could be coached, though at the moment inefficiently
to insulin secreting cells, and this work has gone a little more
slowly than we would like.
We do continue to support research on the differentiation of adult
precursor cells into beta cells, but that's a severely limited
field in terms of how successful it has been.
Progress to date does underscore the need for continued investment
in research in this area, including the creation of an environment
in the United States that encourages and supports scientific discovery.
The potential for this research to have a positive impact on the
maybe 100 million Americans who suffer from a wide variety of diseases
and injuries who might benefit is just too great to be ignored.
Thank you for your invitation, your time, and your consideration.
CHAIRMAN KASS: Thank you, Dr. Goldstein.
Thank all of your for your fine presentations.
Let me just throw the floor open. Let me, so that everybody knows
where we are, we started late. We were originally scheduled to
go to 5:15. Let's go to at least 5:25 and get people's
questions out so that we take advantage of our guests who traveled
so far to be with us.
So, please, Jim Wilson.
PROF. WILSON: Several of you referred to the political
uncertainty of stem cell research in the United States, and in the
course of making these remarks, you listed many possibilities.
I would like to know from you as briefly as possible what you think
is the chief political uncertainty.
Is it money? Is it stem cell lines? Is it the number of researchers
or what? What is the political uncertainty that you're concerned
DR. OKARMA: Well, the quick answer is all of the above
that you just mentioned. If I were to prioritize them, it is the
pure political process of taking scientific inquiry out of the hands
and hearts of the scientists and into the halls of Congress.
Can the environment worsen with a different administration or
with the same administration? These are exactly the things that
our investors tell us that they are concerned about.
But the fact that there is a very thin infrastructure to complement
what we are doing at Geron, what other folks that you've heard
are doing here makes the risk higher to achieve a commercialable
and safe and effective product. They are intimately intertwined.
PROF. WILSON: That is true, but Congress has always, since
1938, placed under legislation by its action important therapeutic
regimes that might affect the safety or health of other people.
Is this supposed to be exempt from that?
DR. OKARMA: I'd like to hear an example of that that
compares to the—
PROF. WILSON: Well, the FDA constantly regulates.
DR. OKARMA: That's not political; that's not congressional.
This is different.
PROF. WILSON: Oh, there's a difference between the
FDA and Congress? You'll have to explain that to me.
DR. OKARMA: I think there certainly is.
PROF. WILSON: Anyone else have a response?
DR. GOLDSTEIN: The universities during the past two years-plus,
since the administration's policy, have had a variety of information
coming. As Dr. Zerhouni told you, it has only been since his arrival
that the stem cell task force was created. So some time was lost.
The most simplest example that I can give you is the confusion
over the application of federal policy to indirect cost of university
researchers, and it has only been in the past four to six months
where people have accepted the notion that they can do federally
funded research next door to privately funded research without getting
The clarification of that was painfully slow, and people just
didn't hop on the bandwagon immediately.
The second part, I think, has to do with what investigators tell
us, is it takes me six to eight months to work through my research
office to get a material transfer agreement to get one cell line
at $5,000. I'm hardly likely to be interested in studying two,
three, or more at that pace and would prefer some more economical
and more free distribution of more well characterized material.
So that inherent slowness is not exactly a terrific ingredient
for promoting and expediting research in a new area. It's one
reason why the international community, for example, has taken a
very strong position to complement the NIH activity and make materials,
information available on a more free exchange environment.
And you know, it's in a time when budgets for funding research
worldwide seem to be down. I would point out that the U.K., Japan
have put special extra money at this topic because they view it
as an opportunity. That coincident with decreases in their regular
So people see this as a major opportunity.
PROF. WILSON: Thank you.
CHAIRMAN KASS: Alfonso.
DR. FOSTER: Jim, were you through?
PROF. WILSON: Yes.
DR. FOSTER: Dr. Okarma, I wanted to ask one question
that I wasn't sure about. You emphasized the oligodendrocyte
as one of your chief cells that was moving on. You said you were
working on this in spinal cord injury, but I presume this would
be some myelinating agent in something like MS or multiple sclerosis
or something as well. I don't know that, but the question would
be if you put in a differentiated cell and let's say you have
a balance between, you know, some autoimmune disease that's
demyelinating and an oligodendrocyte that's myelinating, the
question I was going to ask is that apparently a lot of times there's
a block in the oligodendrocyte capacity to myelinate because there's
a block in the movement from the pre-oligodendrocyte to the oligodendrocyte
by, you know, a jagged notch interaction or something like that.
So I guess the question I'm asking: is this differentiated
cell going to be—we've talked about the problem of immune
rejection and things like that—but is there another problem in
certain diseases of differentiated cells that they might not work
because of the primary disease that's present?
DR. OKARMA: That's precisely correct, and we have
yet done no work on systemic autoimmune based demyelinating diseases,
although to your point, they could potentially be subject to—we
have only worked on oligodendrocyte precursors in acute spinal cord
DR. FOSTER: Thank you very much.
CHAIRMAN KASS: Alfonso Gomez-Lobo.
DR. GÓMEZ-LOBO: I don't know who this question
is going to go to. Probably Dr. Okarma.
I understand my charge here in this Council primarily as a duty
to worry about bioethics. I mean this is a Council on Bioethics,
and that's the way I see my social role in this context.
And one of the things that worries me is that in these presentations,
in these wonderful presentations you have made, I don't see
that dimension. For instance, it's one thing for there to be
political problems and perhaps concentrated on Congress, but I think
that there's the larger context of the whole nation and there's
the larger context of our lives and of the respect we owe to each
other, et cetera.
And then the question arises: shouldn't we see a problem
in the fact that a blastocyst that we know could be implanted and
continue its journey towards being like one of us, if that's
destroyed to extract the embryonic stem cells, whether we should
not worry at all about that? Is that a reason why some people may
have serious doubts not about the benefits, but about the means
to obtain these benefits?
DR. OKARMA: Well, first, sir, I was specifically asked
not to address those concerns, but let me assure you that they are
very prominent in the culture of our company. Approximately six
months after I arrived at Geron in December of '97, I formed
an ethics advisory board to discuss precisely those issues both
for my own uncertainties, to more vigorously and rigorously dissect
the issues as viewed by different Western religious traditions,
as well as secular perspectives, and to expose the workers in the
company to this body and have them ask their own questions of it,
which has helped us enormously and has informed us about the issues
of moral status and has comforted us in our position that this is
not an ends justifies the means argument, but that the special circumstances,
the scalability, the biological diversity, the normalness of the
cells that we're able to manufacture from a single stem cell
line made from a single embryo destined for destruction tilts the
moral seesaw in our direction.
And we are intellectually and emotionally convinced of that point.
DR. GÓMEZ-LOBO: May I?
CHAIRMAN KASS: Do you want to respond?
DR. GÓMEZ-LOBO: Fair enough. Now, that's a
straightforward utilitarian argument, and someone may say that,
you know, even one adult could be sacrificed for many. So there
are serious problems with that argument.
Let me leave it at that.
CHAIRMAN KASS: Does someone else want to respond to the
question as put before I call on someone else?
DR. GOLDSTEIN: I would like to make a general comment
that we took the issue so seriously that we added an additional
layer of oversight, and the charge to the committee was to provide
and consider and revisit issues as they come up.
We assumed this was going to be a dynamic field, and this committee
developed guidelines. It watches over and it considers many aspects
that we don't consider with typical research grants, with typical
research grants that the IRB approves and you have all of the signatures
So I think it has been taken in extremely serious ways. I don't
have a specific response about, yes, this is the correct or incorrect
or that kind of thing, but we made this effort because we saw this
as an issue, and we decided we needed a serious way to deal with
And this committee reports directly to our board.
CHAIRMAN KASS: Janet, Janet Rowley.
DR. ROWLEY: I'd like further discussion in two areas,
and I suspect that maybe it's both Dr. Okarma and Dr. Palmer
who might respond to this.
First, I was surprised at your discussion of your funding problems
at Geron and the fact that you're only a third of the size of
a year ago because implicit in much of what has been written and
discussed earlier this morning, the assumption was that the federal
funding wasn't going to be important because private funding
was so robust and we could sit back and let the private sector take
care of it.
And you've raised some question about that more rosy view.
I have another question though about the role of nonapproved cell
lines. So in a sense, both of you are counting on these nonapproved
cell lines because they will obviate the need for feeder cell layers
and things of that sort. But how do you view these being used in
the future or being of benefit or are they only going to be of use
outside of the United States and not be available for use for American
DR. OKARMA: Well, first, let me clarify the premise of
your question. There's no uncertainty that the current lines
in Menlo Park that we have qualified for human use can go forward
into early stage human trials. They are robust. They are clean.
They differentiate repeatedly in the directions that we want them
But they are xenogeneic, and they will eventually die off, we
think. We have no evidence for that yet, but we think it's
the conservative and appropriate assumption to make, that these
cells, despite their telomerase expression will not be immortal,
as is a tumor cell.
So for those two reasons, their natural life span and the desire
to improve by taking advantage of what we've learned from the
existing derivation protocols and improving them, putting those
derivation procedures under GMP with completely qualified and pedigreed
reagents so that even the antibody used to purify the growth factor
has never seen a murine antibody; that's what we're talking
about about GMP cell lines.
And that is a normal progression within the entire field of cell
therapy, and we think we are ahead of everyone in the restricted
arena of embryonic stem cells. So stay tuned for that announcement.
The issue, as you correctly point out, is that those cells by
definition of the current government policy will not be available
for study by U.S. government funded entities, and there's no
question, as you correctly imply, that the international community
will be very anxious to get their hands on those cell lines.
DR. PALMER: I'd like to add then to that the idea
of heterogeneity. If you're a publicly funded entity and would
like to explore the utility of these cells and you find that only
a few will perform the way that you are interested in and then only
a few of those will work in a portion of the patients that you are
interested in treating, then the new lines become absolutely critical;
that you could not cure Parkinson's. You could treat a few
people. If the cell lines run out, then you're done.
So it is a critical aspect of expanding the research to a level
where it's self-sustaining.
CHAIRMAN KASS: Bill Hurlbut. I'm sorry. Excuse me.
Michael and then Bill.
PROF. SANDEL: This is a question for Dr. Palmer, and it
goes back to something that Paul McHugh said in this morning's
discussion. He was giving an interpretation, a sympathetic interpretation,
of the President's current policy allowing the use of private
funds but not public funds for new embryonic stem cell lines and
limiting public funding to the preexisting.
And the way that Paul interpreted that was as a challenge to scientists
to say, "All right. Within this limited area, show us what
you can do. Show us that there's not just speculative promise,
but that there's genuine progress. Show us. Let the burden
be on you scientists to show us not only that, but also that redeeming
that progress depends on going beyond the 12 approved stem lines
that are currently available for distribution, and show us also
that redeeming that genuine progress requires federal funding for
more than the existing approved cell lines."
Now, much as I heard your comment, you were speaking in that spirit,
addressing that kind of challenge with respect very concretely to
Parkinson's, but I wonder if you could just, taking that challenge
directly of Paul, address to him in a summary way the answer.
As I understood your testimony just now, you in effect think you
already now have the answer for Paul, and then I'd be interested
to hear Paul's response.
DR. PALMER: Let me speak about data that I have seen,
but it's still proprietary and confidential in a general sense.
In funding stem cell research, about half of our stem cell effort
is in embryonic stem cells, and the remainder divided between adult
stem cells and fetal stem cells.
Within the embryonic stem cell projects, several of these proposals,
their specific aim was to contrast and compare cell lines that were
available to them, and what we have seen in the data that they present
is that there is beyond a shadow of a doubt huge potential to create
authentic dopamine neurons from human ES cells.
That's good. The problem is that within the limited number
of cell lines that they have tested that potential is hugely variable.
These are cell lines that are theoretically pluripotent, and they
should be equivalent embryonic lines. If you look at a picture
of them in the dish, they look strikingly different from line to
line, which has the stamp of their history, which cell lines they
have been exposed to, which sera they had applied to them, which
growth factors were used in their preparation in isolation.
And this history of experience from these ES cells then imprints
them to behave a certain way when their context is suddenly if they're
asked to produce a dopamine neuron.
So the heterogeneity tells me as a scientist that we have a problem,
that some of these lines may work some of the time for some of the
applications, but they will not all work for all applications.
And this is a very strong argument for expanding the variety and
the heterogeneity of the lines that we currently have access to.
Eleven or 12 is not enough.
DR. McHUGH: Yes, thank you very much, Michael, for asking
that question because it was rather what I wanted to ask. But I
have two responses to that.
First of all, the heterogeneity that you mentioned may or may
not be so compelling as to not allow you to find, after all, these
are immortal cells, and if you get one or two or three lines from
the 12 and the expansion of things that are going, you may well
be able to tell us that you're already achieving with what we
have in front of us adequate things for the future. That's
the first thing.
But more importantly to me, anyway, was what you said about the
issues of the autoimmune problem and how you thought that the autoimmune
problem was going to be the telling one as you have seen the cells
die in the process when they're exposed in this way in a foreign
turf and you looked forward to the opportunity perhaps of using
somatic cell nuclear transplantation to develop dopamine cells that
were, in fact, from the person themselves.
And I wanted to say that I, of course, have spoken in this conference
that I think that that is going to be the way in which embryonic
cells ultimately will—as one of the ways that will get to this
source of cells in ways that we will have to look more closely at
its ethical basis and I see as distinct from the ethical source
that comes from the zygote and the embryonic stem cells that the
President was talking about in his August 9 speech.
So, Michael, now to return to you, I just think that we've
seen today from these wonderful four presenters just the kinds of
things that I would like to see to enhance our conversation to get
us to a place where we will talk about the direction science will
go and the promise that it will take.
And let's just finish off by a very small question that I
wanted to ask you, Dr. Palmer, since I've got the floor, and
that was aspects of the biology of Parkinsonism itself and the concern
that I have that perhaps the disorder—are you sure that the disorder
will not in itself being directed against dopamine cells, might
not kill off the stem cells that are being produced and kill them
more quickly than even the endogenous cells?
So where is the understanding of the pathogenesis of Parkinsonism
in relationship to this transplantation treatment?
DR. PALMER: Let me turn this around maybe and expand your
horizon in thinking about ES cells, embryonic stem cells, and again
stepping one more step into the nuclear transfer arena or into the
area where you can engineer, genetically modify a traditional embryonic
So there is no guarantee that making a pure population of dopamine
neurons will cure Parkinson's disease. There is very good evidence
that under some circumstances dopamine neurons from fetal tissue
do help in Parkinson's disease, and what we would be striving
for is a population that is renewable that would not require the
use of fetuses for curing individuals.
So in that sense, there is a gold standard that is working relatively
well, but has problems to overcome to which ES cell strategies can
aspire to, and that does work. And so I am optimistic that the
stem cell strategy will also work, if not better, if we can eliminate
the aspects of the fetal tissue transplant that may be giving us
trouble in that particular clinical paradigm.
Now, flip-flopping this a little bit, you brought up the idea
that Parkinson's disease is a disease, and putting healthy cells
into the diseased brain may be a bad idea and may not make it work.
How would you understand the complexities of that disease?
The way one might approach this is to use ES cells that harbor
all of that genetic complexity of that disease and model it in a
tissue culture dish. Try your drug screening strategies. See if
you can't find mechanisms that are not possible to even understand
in a whole organism by recreating the system in the dish.
This is the real power of ES cell technology.
CHAIRMAN KASS: Bill—sorry. Paul, did you want to just
DR. McHUGH: No. Thank you very much for that.
CHAIRMAN KASS: Bill Hurlbut, the last question and then
DR. HURLBUT: Well, thank you for your presentations and
the very exciting prospects of going forward with the existing cell
lines and the others that you suggest. The future looks like it
has real possibilities.
What I want to explore for a second is beyond the therapeutic
potential. You've mentioned amazing possibilities for scientific
research and drug testing and so forth. So even if this technology
doesn't end up making its way into the clinics, it obviously
is going to be very, very important for the whole future of biomedical
So what I want to ask you is this. Given this amazing foundational,
early stage of this new medicine, kind of a whole new wing on the
mansion of medicine, and yet given the conflict that is going on
within our culture where, depending on who you believe, which survey
you believe, maybe half the population has problems about the moral
grounding of this future of medicine, here's my question.
I was speaking with a pediatrician recently, and she told me that
it's not uncommon to have parents whose children are going to
be vaccinated ask her was this vaccine grown on fetal tissues.
So the problem is that even if the individual patient doesn't
choose to employ the therapy that they have an ethical problem with,
the whole foundation of medicine is going to be built on this technology,
and so it's not just a vaccine that somebody can say, "Well,
I don't want it." It's just sort of like everything
will be built on this, right?
And beyond the question of whether or not the President could
change his policies, there is the Dickey amendment, and I think
we heard this morning that to a very large extent his decision was
an interpretation of the Dickey amendment itself.
So given half the population roughly has ethical problems, given
that this is going to be the future foundation of medicine, are
there ways in the kind of research you're doing; do you see
any hopeful ways that we can do this in a way that bypasses the
And as a part of that question, I'd like to ask you: how
important do you think cloning for biomedical research is, so-called
And recently the work of Gurdon at Cambridge suggested that maybe
you can find the cytoplasmic factors that can down-regulate or reprogram
the nucleus of a somatic cell. Do you see any hopeful ways out
And are there ways we could fund this current research such that
the moral impasse would be temporary if we could just get it launched
with a good deal of support?
DR. PALMER: I do agree with the sentiment entirely. So
the real issue is how. Let's take two hypotheticals.
One is that the U.S. is restricted in its ability to pursue these
technologies on ethical grounds, on moral grounds, yet other countries
are not. The moral question becomes can you then use the information
and technology that was developed offshore morally. And that's
something that would have to be discussed.
We would be far behind in our technologies, in our drug development,
in our ability to provide health care to our constituents. If we
had the ability to temporarily recognize the value of the lines
of research with the full intent that we need to understand what
these cytoplasmic factors are, nuclear transfer technology is the
prototype. It is the first working example of taking a genome,
which is totipotent. So a cell's genome has all of the information
that you need to make an individual.
My cheek cell, if it has all of its genes, is totipotent, given
the right cytoplasmic factors to program it. How will you circumvent
this moral problem unless there is a decision or an understanding
that the morality is a combination of concepts and beliefs?
This is a very difficult question, and I don't envy your task
as Council. If you were to take a fertilized egg and reprogram
a nucleus, create an embryo out of that to make stem cells, that's
not so technically different than just simply programming the nucleus
to go through all of those steps to create stem cells, and it's
one of an intellectual process coming to grips with a moral stance,
a belief. It's going to be difficult to separate those two,
So technically I think there's great hope to program the genome
in a way that would lead to an embryonic stem cell that's pluripotent.
The prototype of that is nuclear transfer technology, and that is
the technology that's going to give you those steps to get from
Point A to Point B without creating the embryo.
DR. HURLBUT: Within the constraints of existing policy,
do you think we could if we funded it properly find a way to do
DR. PALMER: It could happen tomorrow or it could be years.
It will happen offshore regardless.
CHAIRMAN KASS: Thanks to our four panelists for your presentations,
your forthcomingness. Thanks to the Council members for enduring
a long, but very interesting day.
We meet again tomorrow morning at 8:30, and we meet again at 6:30
for convivial repast.
The meeting is adjourned.
(Whereupon, at 5:40 p.m., the meeting in the
above-entitled matter was adjourned, to reconvene at 8:30 a.m.,
Friday, September 5, 2003.)