Friday, September 8, 2006
Session 6: Genetic Information: Its Significance for Patients, Health Professionals, Ethics, and Policy Development
Nancy Wexler, Ph.D., Professor of Clinical Psychology, Columbia University, New York City
CHAIRMAN PELLEGRINO: Our next topic will be on genetic information. And we have the opportunity and the pleasure to hear from Dr. Nancy Wexler, who is Professor of Clinical Psychology at Columbia University.
I told her and for the benefit of those of you who haven't been here before, we do not provide extensive autobiographies. The people who come here are distinguished by their very presence and by their titles. And so we find it unnecessary and gilding the lily to go into the rest of it. I hope that's a good excuse for not going into it. Dr. Wexler, will you please take over? We're at your service.
DR. WEXLER: I am honored to speak here today and delighted that the President's Council is taking on the serious challenge both of newborn screening and potentially genetic testing in general. This is a critical area in which we need to tread cautiously and with your advice. I give you my biases right up front. What we do today will have repercussions for many years to come.
I also appreciate your willingness to consider broadening your mandate to include genetic information and knowledge, whether obtained before or after birth in terms of its existential significance for individuals, families, society at large, its implications for policy, particularly insurance and employment.
I was asked to answer some specific questions in Dr. Davis' letter, which I will address somewhat throughout the presentation and come back to at the end. Particularly I was asked to look at the question posed by Dr. Alexander and colleagues at your last meeting, whether the so-called dogma governing newborn screening — that is, not to screen unless you have a treatment, an effective treatment — should be discarded. And I was also asked to really focus on the impact of the completion of the Human Genome Project.
The completion of the Human Genome Project I believe has placed us in a hitherto almost unimagined era of possibility, responsibility, and liability. There will certainly be affordable gene chips, customized gene chips, beads, micro array technology, and genetic technologies which we have not yet fathomed, even nanotechnologies. So I think that fits with one of your other topics. We need to be ready for these advances.
In the light of public acknowledgement of my own biases, I would like to also say that my grandfather, two uncles, and mother died of Huntington's disease. And my family has been very invested and involved in trying to find a cure for this particular disorder. So I would like to use some of the experiences from our Huntington's world to address some of these issues specifically.
In 1968 — I would like to actually talk about finding the gene and how that reflects on where we are now with respect to the human genome and the future.
In 1968, my father began the Hereditary Disease Foundation when my mother was diagnosed. We held small interdisciplinary workshops because at that point no one was really interested in looking at this tiny disorder.
In October 1979, 27 years from next month, we had a workshop entitled "Can You Use DNA Markers to Find the Huntington's Disease Gene?" This was organized by David Housman of M.I.T. The workshop included Ray White and David Botstein at the very beginning of their careers. If you can imagine, remember back to that time. There was nothing yet published about using DNA markers to find human diseases, that you could even find a marker.
We were talking about whether this was method or madness. There were heated arguments, scribbles of calculations on the board, how many postdoc years it would actually take to even consider mapping the human genome. And David Housman said he had a very talented graduate student named Jim Gusella and we should do it in Gusella years.
Now, at that point, there was a ferocious argument about whether or not we should actually look for the HD gene or wait until the human genome was finished. Ray White and David Botstein felt strongly that the whole human genome had to be mapped first before we could look for a marker segregating with the HD gene. They felt, in fact, it was unethical to do it any other way because we were over-promising. That's how far away. It had taken Ray about two years to find the first marker.
David Housman, on the other hand, said, "Look, why don't you look for markers segregating in a family? Maybe you will get lucky. You won't have to wait until the entire genome is mapped. You'll be ahead of the game. And every time you find a new marker, run it through a family."
In fact, David Housman encouraged me. I had already been in Venezuela in a small study. He encouraged me to go to Venezuela to study what turned out to be the largest kindred known anywhere with Huntington's disease to look for a marker segregating with the HD gene.
In 1981, I began traveling to Venezuela, which, unfortunately, still has many families living in the most unbelievable poverty, to collect pedigree information, clinical data, and DNA.
Astonishingly — this was in 1981 we started — in 1983, together with David Housman, Jim Gusella, Mike Conneally, we actually discovered a DNA marker which was 4 million base pairs beneath the Huntington's disease gene on the top of chromosome 4.
The jubilation and elation — you can remember that, Paul, right? Remember that? Nobody could believe that. It was just shocking. So the jubilation and elation were not only for Huntington's, which is an appalling disorder, but really that this was a proof of principle that you could use these strategies to find any genes, deleterious or not.
The Hereditary Disease Foundation then organized a collaboration of many of the early pioneers of the genetics world to go from this linked marker to actually finding the gene because without the gene, we still were sort of in Never Never Land.
David Housman; Jim Gusella; Francis Collins; Hans Lehrach; the late John Wasmuth; Peter Harper; Robert Horvitz, Nobel Prize winner; and many talented postdocs and graduate students worked for a decade of really arduous work to isolate the gene itself.
Its abnormality turns out to be an expansion of a CAG repeat that makes too much of the amino acid glutamine in the protein called "huntingtin." When the research began, looking for the gene, the equipment — if you went to anybody's lab at that time, the equipment were these gel boxes literally put together with massive giant clips like that, paper towels, jolts of electricity, and radioactivity. The thing just looked like a death trap.
And at that time, there was no PCR. And the first gene-sequencing machine had just been discovered, which was almost like a kind of aesthetic work of art. That's the technology 27 years ago, not that long ago.
So when the genome project began in earnest in 1990, it required innovative technology in order to succeed. It also necessitated worldwide collaborations, cooperation in both public and private sectors, informatics previously unheard of, an unknown scale. And, astonishingly, the project came in ahead of schedule and under budget, which astonishes everybody.
So as soon as the genome was finished, all the same groups got together to set up a HapMaps project to look at human variability. So an example of the genetics of the future is now at the Broad Institute Center for Genotyping and Analysis at M.I.T. and Harvard.
The Broad Institute has brand new sequencing capability. In a matter of weeks, you can put your DNA in. They have new chips with 100,000 SNPs, which are sort of the RFLPs of today. And the difference is shocking between where we started and what the capability is now.
So let me say a word again about some of the advances in HD to just talk about what is happening now, not only for Huntington's but many other different diseases.
In 1983, when we isolated the gene, we observed that the size of the expansion correlates extremely closely with the age of onset. We also learned that the larger the repeat, the earlier the age of onset. If you have about 40 repeats, the disease is fully penetrant.
If you live a normal life span, this disease will inevitably appear and is invariably fatal, over a course of 10 to 20 grueling years of loss of physical and mental capacities. Uncontrollable movements envelop the body. Cognition is profoundly impaired. Severe psychiatric problems, such as depression, suicide, even hallucinations and delusions, appear.
The typical age of onset is the 30s or 40s, but the disease can appear as early as 2 and as late as 80. If a person inherits a CAG size of 60, the disease starts at 12 or younger.
So once we had discovered the HD gene, we learned, much to our surprise, that some people with repeats between 35 and 39 may or may not get sick. Sometimes they do. Sometimes they don't. But those people invariably give rise to new mutations. When you pass on the gene from generation to generation, it expands, particularly in sperm. Why this happens we don't know.
Huntington's is one of the most fully genetically determinant diseases known. If you carry an expanded repeat of a certain size, you will get sick and die. And, yet, there is this tremendous variability in when the disease appears, from 2 to 80.
So we were very interested to see whether or not there were modifiers that affect when the disease shows up because these could also be therapeutic targets pushing the disease out of the life span.
We went back to our Venezuelan data and started looking very closely at different families. We found that in certain families who had 44 repeats, they had an onset in their 20s. Other families with 44 repeats had an onset in their 50s, same repeats. So obviously there was something else besides repeats.
We took the DNA. We took this information. We sent it off to the Broad Center. And just a couple of weeks ago, after less than a month — the Broad Center sends you back all of this data. And we have clear evidence of the presence of modifying genes which influence the age of onset of Huntington's.
The analysis points to certain regions on chromosomes as hot spots, which most likely contain modifying genes. And, even more amazing, we can dial up the computer and actually look at the area in the chromosome and say, "Well, what genes should we pay attention to?"; which is astonishing.
I mean, when you start out in 1979 thinking that there's no way you're going to actually find this gene and you're dialing up to say, "Hey, can you just get that little tip of the chromosome a little bigger because that's the gene that's causing it to be starting at 2 or starting at 80?", that's shocking. I mean, that is so mind-boggling that it's almost beyond comprehension how fast this field is moving.
Now, it's entirely thanks to the Human Genome Project that we're in this happy position. And if Huntington's can be unraveled in the same way, if the rate of change is happening so rapidly, there's no doubt about what we can anticipate in the future.
Whatever our wild imagination about what could happen, it is going to happen. And if we stop until it happens, we are going to be totally missing the boat. We are going to be in serious, serious trouble.
I mean, if you walk down in the Broad Institute now, in the old labs where we were doing the work, you think you're on a different planet. The driving motivator behind the Human Genome Project was to look for new diagnostics, treatments and cures for human disorders. And that push is the same for technological advances in genetic diagnostics.
So I think we can assume that future tests will be DNA-based and accurate. That was one of the questions posed to me. I think we can posit that the same drivers that forced the cost of sequencing to tumble sufficiently to make large-scale sequencing feasible will also be dramatically lower, will lower the cost for accurate diagnostic testing, making it possible, not only throughout the states but probably throughout the world, to take advantage of these new technological advances.
The world, which welcomed the completion of the Human Genome Project, will certainly welcome its increasing medical relevance. In my opinion, we are woefully unprepared as a society to deal with these changes.
The challenges span the range of issues from scientific to social to ethical. Unless we prepare now, we won't be ready to take advantage of the benefits of technological advances. We are like a freight train on a collision course with our future.
Let me try to get at some of these examples. Certainly there's a huge amount of variability when you actually start looking at any of these diseases. They're much more variable than you thought, even with Huntington's. It turns out to have another disease, looks exactly like it, called HDL2, which is present in Africa and African Americans, another chromosome entirely.
So I always recommend that somebody get two genetic tests. Everybody yells at me and says, "Oh, no." You know, they're impugning the labs if you actually say, "Get one blood test and send it to this lab and another blood test, send it to that lab and make sure you get the same result because the importance of the data is much, much, much too critical."
One of the other problems we really have also is how the results are described and interpreted. So with Huntington's, if you have an expansion at the DNA level, that can be picked up if you have newborn screening. It's exactly the same when you have an embryo as when you have somebody that is actually diagnosed.
When people are given their diagnostic information, it's usually extremely unclear. They say to somebody who is in their 30s, "You have been diagnosed with Huntington's disease," meaning that when they looked at the DNA, they found an expanded repeat but not that the person clinically had symptoms. And so there is a huge amount of just lack of clarity and necessity for education about what actually these diagnostic terms mean.
The Human Genome Project is providing us with an opportunity to have personalized medicine. I think that's one of the benefits of the information gained, but for me we're not ready to take advantage of these discoveries.
My personal view of personalized medicine is rather idiosyncratic. I think that we look at each disease in an individualistic way as if the disease itself is a person. In other words, the disease has its own personality based on symptoms, prognosis, treatment, or lack thereof, age of onset, and other characteristics. And each individual in society is also distinctive.
Let me again use Huntington's as an example. We know precisely the nature of the molecular mistake. We have an accurate test, could be given at any time from conception to death. Where do we stand clinically? We are actually no different now than when my mother was diagnosed almost four years ago. We have better medicines to treat the psychiatric aspects but really not very much else.
Tetrabenazine, which is the drug of choice, used for chorea for 40 years and Europe and elsewhere, has not yet been licensed by the FDA. And we don't know whether it is going to be. So there's nothing now to prevent, retard, or cure the disease, only the most meager symptomatic relief.
We are not really that different from when George Huntington described the disease in the 1800s. So we need a tremendous amount more research, funding at every level, particularly at the NIH level, where it is being cut, which has the magnitude to make a difference, to develop new treatments and cures.
But having the gene in hand, you know, certainly has changed research. We have in vitro systems, in vivo systems. But, really, we don't know when any kind of really therapeutic breakthrough is going to happen.
And so what do patients and families do in the meantime while science is working hard at a slow, unpredictable pace? For families, the experience of the expanded repeat means definite inexorable death.
When we discovered the HD marker in 1983, families and health professionals alike realized that we needed guidelines to help define how the test should be given.
I was part of a committee to develop guidelines formed by the major international organizations of families at the International HD Association and the major scientific group, the World Federation of Neurology.
We published a series of guidelines. And it had to be revised slightly when the gene was found. In fact, I think that the latest guideline publication is at your table. We sent it around. That was published in Neurology in 1994.
We realized that we were in a unique, unprecedented situation. The HD DNA marker test could accurately diagnose, both pre-symptomatically and prenatally, the appearance of a disease decades before its onset, a disease which inexorably ravages body and mind.
Some even suggested we shouldn't give the test until there was a treatment, but others felt that it would be helpful to have it in order to help people, particularly for family planning and to resolve ambiguity.
The guidelines explicitly reject the notion of including Huntington's as part of newborn screening. The guideline states, "The test is available only to individuals who have reached the age of maturity according to the laws of their respective country."
The committees and family professional groups adopting the guideline felt strongly that the choice to take the test should be only made when the person has the capacity to fully understand all of the ramifications and implications of the knowledge on his or her life. For an individual to be tested prior to the age of majority was an invasion into the privacy of the child. It violated the child's confidentiality and was not acceptable.
A related guideline states, "The decision to take the test is solely the choice of the individual concerned. No requests from third parties, family members, or otherwise will be considered. The individuals must freely choose whether to be tested and must not be coerced by family, friends, partners, or potential partners, physicians, insurance companies, employers, government, or others.
"Testing for adoption purposes will also not be permitted since the child to be adopted cannot decide for his or her self whether to be tested. The privacy of children is an area as crucial as the confidentiality of adults with respect to insurance and employment."
So the committee felt that by the time you were 18, you were able to make some of these informed choices and to understand the tremendously serious repercussions that this information can have. You cannot take back information once it's revealed.
What has been the experience of some of these people who actually have been tested? So let me read a couple of excerpts from some of the people who have actually gone through testing. And then I want to address some of the specific questions, and we'll stop.
"When you ask what it is like to be tested, you can prepare for testing cognitively. You can have a support person that you talk to for 23 out of the 24 hours each day. And that's the only thing you think about.
"You go to counseling to get prepared for testing. And that can go smoothly. And you think you have all of your ducks in a row. But when you are delivered that information, you know, you have to remember to breathe again. And then you have to figure out how to go on. And for me, it was extremely difficult to assimilate that information while the world continues to go on.
"Initially I was prepared that this would be very difficult should I receive the results I was positive. So my husband and I anticipated that I might need a period of time where I'm not accountable. We would play it by ear.
"We cognitively prepared for that. What we couldn't prepare for, though, was that the weight of that would be so grave. So I think for a period, I was going through the motions and had my ducks in a row, but it was a huge struggle. I was trying to put on a good front for my daughter.
"I thought it was a personal decision for me to get tested. I largely did it for me, but an awful lot was done for my family, what I could offer. I was hoping to say to my ten-year-old daughter, 'Sweetheart, you don't have to worry. We're going to end this right here,' but I didn't choose to tell her I was getting tested. We had all kinds of scenes about where I was going and why I would be away. That wore down my energy keeping up a front for my daughter.
"I came home, trying to be a happy, normal mother so my daughter wouldn't worry, which is my big fear from childhood. I didn't want my child ever taking care of me and having to do what I did for my own mother. I didn't want her to deal with Huntington's. I didn't want her to give up her childhood or early adulthood for me. I wanted to spare her that grief.
"It was quite dysfunctional in my family after we had been such an open unit not to talk about it, very honest before. So, of course, that didn't work. One day she held me hostage and said to me, 'I know something is wrong. Are you getting divorced? Are you dying? Is Grandma dying? Don't you love me anymore?'
"I mean, it was horrible. So I thought 'It's obvious I needed to tell her what had happened.' I had been tested, and my results were positive. I wasn't really prepared for that conversation either, but it was a relief.
"At that point, I had no choice but just to give up my life for six weeks and do nothing. I didn't get paid for six weeks. We relied on my income entirely. My husband worked three jobs, did laundry, cooked dinner. I walked the dog, went to the beach, and went to therapy three times a week. I did nothing else. And it was an accomplishment just to get up and walk the dog on the beach. That's all I did for six weeks because that is all I could do. And cry.
"I felt that part of me completely vanished and that I had died. I was stuck in my dead body to figure out how to pick up the pieces and go on because it wasn't over, but a large part of me was.
"I really thought after living in the dysfunctional household that I had grown up in, that I had pulled myself up by my bootstraps. It was high time for me to live the way I wanted to live.
"I put myself through school. I moved away. I was on my road. I was marching to my parade. And, you know, the conductor stopped. I really thought I worked very, very hard to offer myself and my daughter a life we deserved to live. And now we were challenged with something that was much, much, much more devastating than I could possibly ever imagine.
"I knew whether I was gene-positive or gene-negative, it wasn't going to be over. If I were gene-positive, in terms of my aspirations and my future, what I would do with my family, that would be terrible. But if I received the information that I was gene-negative, it certainly would not be over either.
"I was scared of being gene-negative, too, because I know what it is like to have to take care of my mother. So how much more would be expected of me to be even more strong?
"So I think there is no good news for this testing. I don't think it's for everyone, but I think truly if you need to know, there are no two ways about it. One must know. And I don't regret that."
I asked her if she ever wished she hadn't pursued it. She said, "No, never."
I said, "Would you ever like to take it back?"
She said, "Maybe that. I was as very, very prepared, as possibly you could be. I mean, years of being at different functions, having a lot of information, all the information possible in making a choice. And still at the point when the information was real, it was painful. It was deep. It was almost like a death but not yet totally. It was like a loss, a really big loss, of dreams."
The opportunity to do prenatal testing has been extraordinarily beneficial, a unique outcome of having the HD gene in hand, even though no new treatments have been forthcoming.
There are several options for prenatal testing through amniocentesis, chorionic villus sampling, or also through pre-implantation genetic diagnosis, PGD. This procedure, as you know, involves selecting a single cell from an embryo at approximately the eight-cell stage. PGD permits a critically important variant on prenatal testing, which is very appealing to many HD families, called non-disclosing PGD.
Many at-risk individuals don't want to know their own genotype, but they also don't want to pass on this horrific illness to the next generation.
Non-disclosing PGD provides an excellent solution to the dilemma. People at risk for Huntington's have embryos. They're guaranteed to be having a normal size allele implanted without knowing the genotypes either of the embryos or themselves. This means that the IVF physicians performing the services are instructed not to say how many embryos there are since that could give it away.
One woman was also diagnosed inadvertently by a lab tech doing the sonogram who said to her, "Gee, isn't it good that your expanded repeat isn't so big?" She was doing non-disclosing. She didn't want to know her genotype.
With all the advantages that PGD can provide, there are some external disadvantages that must be overcome. IVF is required for PGD, and IVF is still expensive and not covered by insurance, even if it's being utilized to avoid a lethal disease.
Privacy is a critical issue for HD families as well as families affected by other genetic diseases. Health insurance, disability insurance, life insurance, people suffering from or even at risk from Huntington's are, in the words of the insurance industry, considered uninsurable unless they're part of a large group.
There is a Medical Information Bureau in Boston, which is a bank, which keeps a lot of health information. And people have been denied insurance by having somebody in the family with Huntington's linked in the database and denied.
One of the problems about having these guidelines is that they are just guidelines and there is no way, really, to enforce them. Who is to be the gatekeeper and enforcer?
The clinicians should know about the guidelines, but they don't. The laboratories had been actually very helpful to enforce the guidelines, but they were chastised because they were losing money because they were not accepting certain samples. So, really, one of the problems, even if you have beautiful guidelines, is who is actually going to enforce them?
Another problem is that the people's motivation to be tested is so great that sometimes they want to take the test but they do it anonymously. And there is a protocol for being able to be tested anonymously. If you just give a false name, sometimes the center will call up a telephone number. And, all of a sudden, the anonymity is suddenly violated.
In one instance, a woman who was the sole support of her young son went to a general practitioner to get tested because the general practitioners haven't a clue about guidelines and just said, you know, "Test me for Huntington's disease."
When the results came back, she called me up in a panic. And she said, "The doctor said to me, 'You have two als. One is big. One is little. I don't know what this means. Call for help."
What do you mean two als? Well, an al was an allele. And it turned out she had an expanded allele, but the GP didn't have a clue what that was. And I had to tell her over the phone that she was going to get Huntington's in the future. And I didn't know her name, and there wasn't any possibility of follow-up. And doing that over the phone is a definite violation of any guideline.
Another problem, even in the best of circumstances, part of the guideline is to have a clinical examination, a neurological examination. My cousin had two growing-up children, had two children who were in their teens. She decided that she wanted to get tested just to clarify the risk for her children. Left to her own devices, she wouldn't have gotten tested. So I call her sort of the altruistic testee.
When she went to the center, part of this evaluation is the neurological exam. They said, "No, you won't get feedback. That's not part of the guideline."
She went on her own. The neurologist took one look at her and said, "Why are you bothering to pay for a DNA test? You obviously have clinical Huntington's disease. Go home. And don't see me."
After a year, she decided maybe she would go back and get the DNA test since she had given the blood just for completeness' sake. And the result came back perfectly normal. So mistakes happen. And these are in the best of circumstances.
Some of the people's concerns were with respect to acquiring genetic information. Is this concern a valid impact on their insurance and employment?
When I was chairing the Ethical, Legal, Social Issues Working Group, we established a task force on insurance, health insurance, to look at these issues. Very often in the course of those discussions, I would say very openly as a person at risk for Huntington's, I'm uninsurable, that uninsurable category. People at risk even for one of the BRCA1 genes, that's an uninsurable category.
Now, if that were not true, you can believe me that nobody would want to have gone on record having that blur, that slight on the health insurance industry. So it is definitely an issue which is chilling people's participation in research, people's participation even in the genetic testing, which potentially could be beneficial for their future health.
This is not just that people are concerned that there is going to be discrimination. There actually is discrimination. Sometimes very often it's very hard for people to be honest about it because they're getting insurance in other ways.
So until issues of universal access to affordable insurance and genetic privacy are guaranteed and until insurance and employment discrimination is banned, the public won't be able to take advantage of the benefits of the Human Genome Project. We have created social and economic barriers that impede the way to improved health care for our citizenry.
Let me just in closing try briefly to address a couple of the other points raised by Dr. Davis. I do not believe that we should be guided by dogma but that each disorder should be reviewed in a case by case basis.
It's critical to involve family members who suffer from or are familiar with the ramifications of the disease in any decision-making process. In 1983, some doctors immediately wanted to go ahead with HD testing, but because this was such a delightful new technology. And the family members said, "No, no, no. Put on the brakes." And I think that the guidelines have stayed in place.
So I personally do not believe that failing to screen for currently untreatable diseases will deprive children or family of benefits. We're not doing a sufficiently good job in screening for the diseases for which we can treat. We're following up on diseases for which we have some remedy.
I do think we potentially do more harm by including at the moment all diseases for which we can test, especially if they have a very late onset. Families are concerned about some other entity, like the state or even the state Public Health Department, having confidential information about them that they cannot control, that this information will be misused.
There is also the issue that diagnosis of one individual with a genetic disease spreads. It would be extremely problematic to have your entire life from birth clouded by an early diagnosis of Huntington's and then have a treatment or cure intervene before the disease actually appears.
You suffered needlessly for decades. We know that in many of these families, there are already issues of depression, alcohol, and drug abuse just from the stress of being at risk. So to include HD tests as part of newborn screening, which was suggested, I think only adds to that torture.
I disagree that the default position should be to include, rather than exclude. If the dogma is going to be broken, each situation must be evaluated on its own merits. There should be no default position. There are not so many diseases that we can't look at them one by one.
I would recommend that late-onset diseases, such as Huntington's, the hereditary forms of Alzheimer's, Parkinson's, ALS, and others be excluded from any newborn screening programs; in fact, that these disorders merit being treated as genetic tests, rather than genetic screens. So a testing program provides a more individualistic approach.
I definitely think that multiplex genetic screening of newborns is likely to become standard of practice. I also believe strongly that diseases should not be routinely multiplexed just because it's more economical. You can't lump Huntington's and Alzheimer's along with PKU because it's cheaper. A more complex problem might be CF.
There are certain disorders that can be routinely screened for newborns and for which informed consent is not necessary. It may be more beneficial to protect the health of the child from a treatable disorder than spending time acquiring informed consent from a parent. But exempting informed consent should be the exception for genetic tests, not the norm. Truly informed consent is not a luxury item.
I think that the discussion, the quote "right to remain ignorant" mischaracterizes the situation. The word "ignorant" has a pejorative connotation in our culture and society.
Ignorance is not well-regarded. And, really, the choice often involves when to know a piece of information. If people choose not to take a genetic test for Huntington's, they are often choosing not to cloud years when they are young and healthy with foreknowledge of their doom. If they develop symptoms, they will take a genetic test and also get appropriate clinical diagnosis. If a disease never appears, they will know that, too.
Sometimes people consent to genetic testing after death just to confirm the lack of a genetic risk to offspring. Having a one in two risk of developing Huntington's is sufficiently high to guide people to plan appropriately financially and lead their lives carefully.
Testing involves timing. There are different developmental stages when testing can be relevant, others when it's not. Jim Watson once told me that he would not like to know if he was going to get Alzheimer's in the future if there wasn't anything he could do about it. I would not call Jim somebody who lacks curiosity.
We're in severe danger of running over the abyss in terms of our ability to provide the kind of meaningful genetic services that we're required to deliver on the promise of the humane genome project.
Even in the 1990s, there was a lack of appropriately trained personnel. There were only approximately 1,000 trained genetic counselors. Medical education was sadly lacking in teaching the kind of sophisticated genetics and probability theory necessary to help families cope with genetic decision-making.
There is still a severe shortage of genetically trained individuals at any level: physicians, nurses, counselors, allied health professionals. Even the general public still has a huge amount to learn to avail itself of the latest genetic information. They need guidance and training to integrate new genetic risk factors and decision-making into their lives.
It will be tragic if our choices as a society are merely hijacked by the technological imperative. We can predict that more and more diseases will be able to be accurately diagnosed, often prior to being able to treat or intervene. We will be flooded by more and more genetic information, but our capacity to interpret and handle that information is strained, even today, as Floyd would say.
We currently have a unique opportunity to develop the policies and procedures that we need to have in place in the future to help people benefit from genetic information and minimize harm. We know we need trained personnel. We have a tremendous paucity of them.
We also know that research is a moving target. You know, people are looking at RNA interference as a cure for Huntington's. Well, obviously when the disease becomes treatable, then you reconsider when you want to introduce testing because it may be a good idea to prevent a disease, rather than trying to backtrack after it has begun. So we need flexibility. We need to look at all of these things.
I just want to end with one note from someone who also was tested, who I think is a spur to both having these kinds of mechanisms in place. "
"To those of us who have been told we have the gene, we are facing such a black, uncertain future. The worst part about testing positive is the uncertainty. When will the symptoms start? And what will they look like? We're talking about suicide. For us, suicide isn't an if but a when and a how. We plan the logistics and whether it should be staged as an accident. The big question is, how do you (or your designated loved one if you even enlisted help) know when it's time.
"What is shaking up my frame of reference is the idea that a cure could be possible. If that happens, then I have a future. That's a little spooky. I'm used to looking at my life and seeing nothing after age 50 or 55 because I will have ended it by then."
CHAIRMAN PELLEGRINO: Thank you very much, Dr. Wexler. We have among the Council members Dr. William Hurlbut to open up the discussion. And then we'll have a general examination of the issues. Bill?
DR. HURLBUT: Well, I think, actually, most of what I wanted to say has been said, explicitly or implicitly. Let me maybe put a couple of words on labels on categories that I think we should be concerned about.
First of all, I want to thank Nancy for her typical penetrating and poignant comments. I've known Nancy a long time and just want to say how extraordinary her contribution has been to this whole field over the years. She has come to my classes at Stanford and again today showed how humanly sensitive her comments are.
I am struck again by the deep human significance of this subject. It just goes to the core, I mean, where we come from and where we're heading. I am also struck by the immense positive value of the Human Genome Project and its implications, this exciting opportunity to step in, understand more deeply the significance of where disease comes from and our new possibilities for intervening. Just wonderful possibilities lie ahead.
Just to put a few labels on the potential problems that have been mentioned by Nancy in this whole realm of knowledge, the word "toxic" knowledge was used for this years ago. It captures the potential problem here.
Knowing kind of more than you wanted to know or more than you can handle is summed up by that term. I don't need to go into it because it was so clearly stated.
Well, just to put one further explication on it that Nancy had in her writings, some people may actually kill themselves when they find out this information. And it puts an imperative on our society for managing the playing out of this kind of testing and the danger that this will be mismanaged, either in a commercialized context or just misunderstood by individuals, in spite of our best efforts. And Carl has pointed out the danger of informed consent, which implies the difficulty of even communicating to people what is actually at issue or what the meaning of it is.
It is obvious that, as Nancy implied, this is going to go from very powerful and compelling autosomal dominance all the way down to what they call multi-trace loci, the complex interweaving of numerous genes with only statistical probabilities of what goes from disease all the way through just human variation and what we will be tested for and what will come forward, as I said, only as a statistical probability.
That blends over into the second label we might give, which is the problem of what has been called micro-eugenics, the one at a time individual choice. If we have been well-warned about letting the state take over guidance and governance of our genetics, we might be persuaded by our ignorance or by our false ambitions to take control over family lineages in ways that could be tragically inappropriate.
The question of pre-implementation genetic diagnosis is not a simple one at all. You put into the hands the future of not just the individual lineage but to some extent the species itself. And whereas this has some powerful ramifications for specific diseases, it also has implications for the broader prevailing — what they call flavor of the month preferences for what people should be like.
There's a very interesting historical moment where — I'm trying to remember who it was now — Haldane or maybe it was Mueller, one of the two, called for programs of eugenics where people would be made more and more like ideal members of the society.
And, first, he was a communist at that time, like many intellectuals in America. And he called for making people more like Lenin and Stalin. And then he got disenchanted with it. Who was this? Was this Herman Mueller — have I got that right — or J. B. S. Haldane? In any case, he said, "Well, we should make people like Lenin and Stalin." And then he got disenchanted, and he retreated to Lincoln and Pasteur.
So not that we will easily do this, but there could be a lot of misunderstanding, which I think is the other side of it, immense human ignorance about the meaning of this knowledge and over-interpreting, over-determination of human existence.
I know of a case of Huntington's disease where identical twins have manifested the early symptoms of the disease at a lag of ten years. So even where the genetics are identical, the individual manifestation is dramatically different.
And then just one final comment on this. The amazing complexity of this is not just a complexity in the biological level but on the social interpretive level. I'm good friends with Baruch Blumberg, who discovered hepatitis B. He and I taught a class together. He used to say, "For the most part, there are no good genes, bad genes. The biology is an immense balance." And Nancy pointed that out well.
Let me, just for the interest of it, highlight one what I see as kind of a poignant problem. You take an allele like the sickle cell allele, which everybody knows has a balancing benefit in the carrier state and a disease in the homozygous state. And you ask yourself, "Well, we're doing selections now for traits like that."
And who knows? Cystic fibrosis may very well have some balancing benefits, too. There are theories that it is there in our genome in such a high density, the CF trait, because it may have conferred some benefit during cholera epidemics or — there are a variety of theories on this.
Well, the image of selecting either prenatally through pre-implantation genetic diagnosis, pre-implantation or prenatally, and then eliminating the individual who is the homozygous or even the carrier, is sort of a poignant problem. If the gene confers some benefit to the society as a whole, the individual who got the homozygous state is, in fact, an unfortunate recipient of a problem that occurs because there's also a benefit.
I bring this up because it seems to me in all cases but especially, as pointed out, by those where the individual has a disease because there's a benefit to society, we owe something to the person who carries the burden of genetic disease. We owe something because they're part of our human family for which the balance of genes is not a simple issue. It's not like there's good genes, bad genes.
We should be very, very careful before we endorse projects that, either explicitly or implicitly involve an agenda of purifying the genome.
Well, I think that says it all, says enough. Just to end with one statement, I think this is a level of knowledge at a profoundly fundamental level biologically. And at the same time, it raises very fundamental ethical questions worthy of our council.
CHAIRMAN PELLEGRINO: Thank you very much, Bill.
Dr. Wexler, would you like to respond?
DR. WEXLER: One of the potential inequities about using PGD is that only people who can afford it are going to be able to ensure that their children aren't suffering.
I mean, I take your point that we don't really know what these genes do and we sort of struggle with "Is there a benefit to Alzheimer's or Huntington's or these genes?"
On the other hand, the person that's suffering is really devastated, the person who is watching them suffer. And so if there is an opportunity, at least so that that person who kind of has a double dose by accident or is suffering the manifestations doesn't have to, then I think that gives us an opportunity to ease the burden.
However, most people can't afford it. And so that is going to be putting, again, too much of it — I mean, we already were talking before about just people who have insurance, people who are afraid of losing their insurance because of genetic discrimination, people who are totally uninsured, and then people who can pay cash out of pocket for genetic tests so they won't lose their insurance, some people who can pay cash out of pocket for IVF and PGD so that their children won't suffer.
I think we need to have a better equity about these issues.
CHAIRMAN PELLEGRINO: Open to Bill unless you want to say anything further. Dr. Hurlbut?
DR. HURLBUT: Well, just one little comment on that. Sometimes I think maybe you're lucky if you're poor in some ways in this field. That's a strange statement, but you may not get drawn into some of the errors that the rich might get drawn into. And you may accept some fundamental human realities that are in the large play of things meaningful human experiences and don't place you in what may be called the options glut.
I have students who — I have a set of twins I taught who have cystic fibrosis and who are genetic counselors now at Stanford Medical Center ten years after my classes. And I'm not saying I got them there, but that was a very interesting experience.
When I first met Francis Collins, who discovered the gene for cystic fibrosis, I said to him, "Francis" — he was a practicing clinician. Most of you know that. And he had been working with cystic fibrosis patients. And I said to him, "Francis, have you ever taken care of a patient with cystic fibrosis who said they wished they had never been born?" And he said that he hadn't.
So along with whatever we think about this subject, let's remember that genetics is not going to solve all the problems. Genetic knowledge is not going to solve all the problems of human suffering and that in the mix of thinking about what to do with this, we need a more profound understanding of the meaning of human suffering and what it calls us as a society to do by way of solidarity amid suffering, not just cooperative efforts to eliminate it.
CHAIRMAN PELLEGRINO: Thank you, Bill.
Now we open it up to general comments of the Council members. Does anyone wish to? Dr. Carson?
DR. CARSON: I just had a question, actually. Has it been considered by the committee making the guidelines for the molecular genetic testing to advise people not to have testing done unless they have non-terminable health and life insurance?
CHAIRMAN PELLEGRINO: Dr. Wexler?
DR. WEXLER: In fact, that is part of this specifically. And all of the genetic counselors or other people in the advocacy groups are all really instructed before they even begin testing, have done the testing protocol, to talk to people about their insurance.
People have put the testing on hold, in fact, so that they could work out issues of insurance. And that's either, implicitly or explicitly, exactly your suggestion. Some people do that.
CHAIRMAN PELLEGRINO: Thank you very much.
Further comments? Further comments? Dr. McHugh? Dr. McHugh?
DR. McHUGH: Hello, Nancy. It's wonderful to see you. I do have a question. Before I get to my question, I want to reinforce what Bill has said and why you are such a heroine to all of us, Nancy. I think many of us in the group know that Nancy has been the spirit behind the development of so much in the science, the practice, and ultimately in the ethics of Huntington's disease and the care and treatment and understanding of those patients.
You know, I've known Nancy since the '70s, when our Huntington's program got started, but she always was a sharp and contributing leader for the field and led us to see things more deeply than we would have otherwise.
Just take, for example, her point about not letting testing be done on people before they're [age of] majority. If only other scientists in other conditions, like, for example, children born with ambiguous genitalia, had followed a similar thought process that Nancy illuminated for all of us, a great deal of suffering in later life for those people would have been avoided.
And so, Nancy, I just reiterate everybody's theme that it's wonderful to see you here and have us get a chance to thank you and with deep gratitude for the energies and spirit that you brought to our understanding of Huntington's disease.
Now, when I know that and say that, I appreciate, of course, as well that as you're thinking of Huntington's disease, you think about the other genetic disorders and the ones that surround us.
As it turns out, Huntington's, of course, is a very specific disease in more senses than one. I mean, it's a dominant genetic disorder. It's fully penetrant.
We now understand a lot more, not completely yet, about the biochemical mechanisms that direct the development of it and the timing of it in life. And we are making steady progress towards the understanding of Huntington and things of that sort.
The lessons that we have learned here, are they completely translatable into our understanding and management of the polygenetic disorders who are much more common, certainly amongst our psychiatrists?
I mean, our Department of Psychiatry turned to Huntington's disease because of the things that Nancy has pointed out, including the fact that these patients, a very sizeable number of them, suffer from clear mental disorders and the like. And from that, we had thought it would be an easy step into understanding schizophrenia, manic depressive disorder, and the like. It has turned out to be a lot harder.
What lessons from a single genetic disorder are there for us to appreciate in relationship to polygenetic disorders? And if possible, what ethical principles do you want to translate in that way, Nancy?
CHAIRMAN PELLEGRINO: Dr. Wexler?
DR. WEXLER: Thank you. Well, first, I just want to thank you for all of your kind words. I am also glad that you are feeling better and that you are here today. And I salute you.
DR. McHUGH: Thanks.
DR. WEXLER: I can always count on Paul to ask me an impossible question. I think it's a really crucial question. In fact, one of our hopes for looking for modifiers, even at the genetic level, is to look at some of the families where there are tremendous psychiatric problems, OCD, depression, hallucinations — you know, people say, "Our family, we go crazy" — to see if we can't find genes, actually, even in the Venezuelan Huntington's families that produce that kind of psychiatric characteristics.
I think that there is a lot of generalizability because the problems given the fact that there isn't a treatment other than the psychiatric treatment for Huntington's, the problems for the families are very, very similar. A lot of Huntington's families have sort of some of the apathy, the negative kinds of schizophrenia.
So some of the family members are constantly trying to figure out in terms of taking care of the patients. They're almost always with other people with psychiatric problems, rather than neurological problems. I mean, I think it's really a false distinction. You know, we talk about neuropsychiatric, but it really is one brain.
Since I think there is also a tremendous misunderstanding in the general public about how predictive genes are — you know, even recently I was with somebody with Alzheimer's disease who had two doses of apoE4. And she was crying about how obviously her children were doomed because it was so predictive.
And I said to her, "It's not predictive. It isn't predictive." And it was the first time anybody actually had talked to her about the genetics, that sometimes you yourself can — if you have these genes, they can be more diagnostic. But if you pass them on, they're not predictive.
People, even in cancer, if you say, something is hereditary or something is genetic, it means something totally different because genetic can be just some surprise explosion in a cancer cell, but it isn't passed on to your children. But since people sort of interchangeably will use hereditary and genetic, everybody is completely panicked that they now are passing down these genetic diseases to their children.
Certainly there are many genetic influences in psychiatric diseases, some clearly more than others. So we need to do a tremendous amount of educating in families. In genetic counseling, really, what is the risk if people want to have children or if people have a child with autism, what is the risk to other children in allaying people's anxieties.
There's a tremendous amount we could do with collecting pedigree information that people will often have huge family histories and nobody even knows about them. So getting a lot of that information just accessible in a way helps people even understand what is going on, though, in family, sometimes for research but also just in terms of family counseling.
Destigamatizing. All of these diseases have a horrendous stigma. And if they're hereditary, there is a kind of a peculiar sort of — in a certain way it becomes, you know, not stigmatized. You can't help it because it's in your genes.
On the other hand, it's even more stigmatized because it's considered a stain. I mean, some of the social Darwinism, some of the laws, which actually permitted people to be sterilized if they had schizophrenia, epilepsy, Huntington's disease, they weren't so long ago. And I think that many of the families kind of carry this notion that "There is something wrong with me."
I think having the idea of genetic variability is very helpful because I say to people, you know, "Your DNA got too enthusiastic, you know, just got fancy and expanded" because people feel that "There is something wrong with me. I have a bad gene. I am a mutation." And I think that also generalizes to other diseases in general.
So in terms of the genetic counseling, in terms of the research issues, in terms of having these diseases included, much more integrated into family practice, and understood, I think we have a huge amount, you know, a ways to go.
CHAIRMAN PELLEGRINO: Dr. Meilaender?
PROF. MEILAENDER:I want to sort of take a risk. I don't wish to underplay what is new in the challenge that this kind of knowledge faces us, but I would like to think just a little about it.
I am conscious of the fact that there may be a certain kind of teutonic temperament at work here, and I apologize in advance for that.
At least if one has a certain kind of philosophical bent, we live every day toward death. In order to be a parent, I have to know that my children are all doomed. I have no idea how much of a future I have. I may walk out of here and keel over. This may be the day I make a foolish left turn. I've made one of those in my life, but I survived it.
And we all at different points — again, it may be different depending on what sort of philosophical bent we have, but we may begin to notice declining powers. People make jokes, but they're not just jokes about forgetting where their car keys were and things like that. You know, we don't know where life is headed.
One of the things it leads me to conclude is that knowing where life is headed isn't so important or special, that life has to be lived in a certain way toward death, toward oblivion, but without certain knowledge of what that is.
And I just wonder. As I say, I mean, I don't wish to deny that there is something new and special going on here, but I just wonder if we might not let the amazing possibilities that increasing genetic knowledge offers us to know certain things about the future cause us to forget what human life well-lived is actually like. And if we didn't forget it, it would seem to me it would reinforce some things that you said that the best life is lived with a great deal of uncertainty and that there are a lot of things that we think we might like to know but that, actually, we don't need to know in order to live well.
Now, as I say, I don't know. And if that is unnecessarily gloomy, I am sorry. But it just seems to me that this is a very focused problem and a really dramatic one, of course, for people who face it, but I'm not sure that it's so different from what life is like once we really start to think about it.
I don't know if that makes sense to you or not.
CHAIRMAN PELLEGRINO: Dr. Wexler?
DR. WEXLER: It absolutely makes sense to me. And I think that our capacity to have those choices be our own is very crucial. Somebody that I know recently, very, very sophisticated, sort of a scion of business, went to see his doctor. And he said to his doctor, "Please don't do the PSA test because I don't intend to do anything about it," got thoroughly worked up.
And at the end of his visit as he was walking out, his doctor said, "By the way, your PSA was normal." Now, on the one hand, he was delighted it was normal. On the other hand, he was furious because here was a person who had thought extremely carefully about his therapeutic options and didn't want to be tested and didn't want his doctor overruling how he chose to live his life.
So I think that and I know that people are saying, "I don't want to take the Alzheimer's test because my mother has Alzheimer's."
"Oh, you know, the apoE4 test."
So people are constantly sort of going into their doctor's office and having genetic conversations of some sort. They are asked, "Do you want to take the BRACA1 test? Do you want to take this test? Do you want to take that test?"
And so the fact that as we have more and more knowledge and as that knowledge is more and more predictive, I mean, it's not going to all be like Huntington's, but there will be things. For Alzheimer's disease, I mean, there is certain autosomal dominant Alzheimer's disease or autosomal dominant ALS, which is just exactly like Huntington's and no treatment, 1 and 2, and if you have the gene, you get it and you die.
Now, we need, I think, to as a society be able to educate ourselves about these genes and what they do but also educate ourselves about the choices and that — I mean, when we first started having the Huntington's test, there was a lot of, you know, press interest in it. And so people would call up and say to me, "Well, so are you going to take the Huntington's test?"
And I said, "Well, you know, that's personal."
And they would say, "Well, my editor told me that I had to ask you."
And to that I would say, "Don't you have anything genetic in your family?"
"No. My family is perfect."
"Well, what did your parents die of?"
"Oh, they died of cancer and heart disease."
"So you mean you don't really have anything genetic in your family?"
So there's like a gradual sort of understanding of, you know, what really these genes can and can't do. And if we want to live our lives so that we're taken out by the next Mack truck, that's our prerogative.
But one of the difficulties I think is that for certain diseases, if they get lumped into, for example, prenatal screening, about which you have no choice, cystic fibrosis — I mean, in certain ways it makes a lot of sense to have an early indication of cystic fibrosis because you can treat better, you can intervene, you can do therapies.
On the other hand, cystic fibrosis can also be a disease for which people are concerned at least about losing their insurance. So they don't want people to know that they have it in the family.
They have a sort of schizophrenic attitude toward in my institution, they require you to be pregnant before they test you for CF. So the only option you have is termination if it turns out that, actually, you and your husband have a baby that's affected.
So why don't they pay for it prior? Well, the insurance is really basically driving the whole pregnancy because the insurance won't pay before you get pregnant.
Then the genetic counselors don't say, "Hey, you have a CF gene. Talk to your parents. Talk to your brothers and sisters. Talk to your cousins." Nobody discusses it.
So everything is just kind of happening in this little vacuum and void except that on occasion somebody will write down, for example, you know, "She told her doctor 'Don't talk about Huntington's' because I don't want to lose my insurance."
But you want to be candid with your doctor so you can have an intelligent conversation. So the doctor wrote on the outside on a manila folder "Huntington's in the family." When it got returned to this woman's work, somebody noticed that there was something written on the outside, Xeroxed the piece of paper, put it inside. The woman lost her insurance.
So these things happen all the time. Someone whose wife was pregnant, at risk for Huntington's, wanted to get insurance, was told they couldn't get insurance, discovered, in fact, that what was in his family wasn't Huntington's, another disorder very similar. So he called up the insurance agency and said, "If I test negative for Huntington's, will you insure me and my wife?"
They said, "Yep." So he tested negative for Huntington's because it wasn't in his family. And then in the meantime, he also tested for what was in his family, and he was positive.
So people are forced into these kinds of distorted relationships that I think a lot of it really has to do with the question that you were talking about earlier, you know, what kind of health care system do we want to have for our nation as an ethical nation. And how does this get perverted and distorted by information, by gaming the system? And I think it is something that it is being distorted for us so that we are not able to make the kinds of choices that I agree with you we ought to be able to make ourselves.
CHAIRMAN PELLEGRINO: Thank you, Dr. Wexler.
I have two requests for speakers. And we are running close to the end of our time. So may I ask for brevity and conciseness. I first have Dr. George and then Dr. Bloom. And may I, Dr. Wexler, ask them to provide the questions in sequence and then you respond to both. Dr. George?
PROF. GEORGE: Dr. Wexler, thank you for your presentation, which was not only informative but very moving. I'm grateful, as I'm sure the other members of the Council are, to you not only for sharing your expertise with us but also your very personal reflections.
I hope you will excuse me for raising the very sensitive question of eugenic abortion. I ordinarily wouldn't do it in this context except for the fact that in the guidelines, which you have kindly provided us, there seems to be a recommendation at 7.2, together with a comment at 7.2, that relates directly to it. And I would like to ask you about those.
The recommendation says that the couple requesting antenatal testing must be clearly informed that if they intend to complete the pregnancy, if the fetus is a carrier of the gene defect, there is no valid reason for performing the test. And I think it's clear that by "complete the pregnancy," that means not have an abortion, not do something that will destroy the fetus.
And then at 7.2 in the "Comments" column, there is an indication that testing a fetus carries with it a small additional risk of miscarriage and possibly of congenital abnormality.
Is it correct to conclude from the combination of the recommendation and the comments here that the test carried out on the fetus couldn't benefit the fetus, himself or herself, in any way? It would either be positive, in which case the expectation would be that an abortion would be performed, or it would be negative, in which case the fetus is carrying a small additional risk imposed by virtue of the test but no benefit, therapeutic benefit, to the fetus himself or herself.
Is that right? Have I understood this correctly? Oh, yes. Okay.
CHAIRMAN PELLEGRINO: Thank you.
PROF. GEORGE: And then the second point, second question, is that obviously on the question of abortion in the case of fetal defect, there is a wide descensus. There is a dispute in the society. Americans and others are divided over the question of the legitimacy of that, whether that is a legitimate option.
And I wondered if the committee that put together the ethical guidelines that you have shared with us had a spectrum of views sort of reflecting the broader society on the question represented or whether all of the members of the committee or the overwhelming majority of members of the committee took the view that abortion for fetal defect, leading, quite possibly, to a serious disease, such as Huntington's, was a legitimate option.
CHAIRMAN PELLEGRINO: Thank you.
DR. BLOOM: I will try to be very brief.
CHAIRMAN PELLEGRINO: Dr. Bloom?
DR. BLOOM: It is always inspiring to hear Nancy speak, as it was when she and her dad came out of the Congressional Caucus and said, "What is good for neuroscience will be good for Huntington's disease." It was the first disease-focused agency to make that kind of generalization.
In the early days of HIV, we said since we can't treat it, there's no point in testing for it. Eventually we recognized that there were people who were HIV-positive in whom there was no disease.
Your mentioning of the Broad Institute's finding of modifier genes at least creates the possibility that someone could be HD, Huntington, mutation-positive, and, yet, never show the disease. Would that change your attitude towards prenatal screening, antenatal screening?
CHAIRMAN PELLEGRINO: Thank you very much.
DR. WEXLER: Let me try to address the first question. If I am not understanding your question, please correct me. There was a lot of discussion about the issue of prenatal discussion — I want to answer your second question first — and what it actually meant.
There was as an international group a tremendous range of different beliefs, philosophies, religions. And, again, I think having family members as well as professionals made a real contribution. And there were people who felt very strongly for religious reasons that they did not in any way support abortion or terminating the fetus.
There were other people who felt that just as an at-risk person, they didn't want to feel that someone would choose to end the life of someone like them. So there was a whole, really, an array of different points of view.
The intent of the guideline — it may not be that clear the way it is expressed — is that if some people just one said, "I want to have a baby, but I also want to know if it is going to have Huntington's disease."
And the point of view of the guideline was to say, "That is an invasion of the privacy of the child, of the minor in the same way that testing somebody under the age of 18 is an invasion. That baby in utero is not giving informed consent. And so since you intend to keep the pregnancy and there is no medical benefit, we can't treat in utero" — I mean, obviously, if there was a treatment, it would be different.
But since there is nothing you can do and there is some potential risk of harm by doing any kind of amnio, then there wasn't a cause for testing the fetus in terms of the well-being of the fetus and the child to be, that if they wanted to have the child, that was fine, but the position of the guideline was that the only reason, really, that someone would have the test prenatally was if they then intended to terminate that pregnancy, if they find that the fetus is carrying expanded repeat and they wanted to terminate the fetus.
So it wasn't that people were saying, "Yes. I promise to do this." And obviously people change their minds all the time. And you can't say, you know, "You promised. We did this test. And now you're keeping the baby. If people change their mind, they change their mind."
Sometimes, interestingly enough, people change their minds. Sometimes if they were pregnant and they went home and visited a relative who was sick, just seeing the reality of the disease, they said, "Well, you know, I am not going to carry this pregnancy without testing" or the husband got diagnosed with a repeat the size of a juvenile. So they knew that the baby would be affected as a juvenile. And they decided to terminate.
So people have very varied reasons for doing it. For the most part, HD families are just having children. They're not testing themselves. And they're not testing the children. And I think partly this is because, by and large, the testing centers, many of them, don't advocate abortion. They don't even suggest it.
And sometimes people who have had multiple terminations because they are trying not to have children who will carry this terrible disease, but they can't afford IVF and PGD, so they're having multiple terminations, they finally just say, "I can't stand it anymore. I can't bear. I want to have children." You know, they're not people who want to terminate. They just don't want their children to suffer.
And, finally, they just give up and say, "Okay. I'm not going to test the baby. I'm just going to have a baby." And then very often they are absolutely castigated by the health care system that says, "How could you be so selfish? How can you do it?" They don't even know, you know, what they went through to even get to that point.
So that has been, really, a difficulty. And, again, I think for people for whom PGD is an option, that that helps some of the stress of that.
Did I answer your question or not quite?
PROF. GEORGE: Yes. It is quite clarifying. And, if I have understood the answer correctly, it sounds as though the committee is working with just a very difficult problem because you're trying to protect the rights of the baby in utero, who may very well become a person who would like to decide for himself or herself whether these tests are performed. But you are trying to protect the rights of the baby in utero while you don't know whether the baby will be terminated or not as a result of the testing.
So it's difficult. I see the dilemma that the committee is in.
DR. WEXLER: What we are asking the couple is, "Do you" — I mean, the couple has to say to us, "Our intention is to terminate if we find that that baby is positive. Our intention is not to continue the pregnancy and to try again."
If they don't have that intention, then there's no reason to test the fetus because it is an invasion of privacy. So the couple has to come to us saying, "This is what we intend to do."
Now, the couple can always change their mind if the baby tests positive and they say, "Well, we're going to keep it anyway."
PROF. GEORGE: Well, just to be clear, the invasion of privacy is the invasion of the privacy of the child.
DR. WEXLER: Exactly.
PROF. GEORGE: And the invader, who is violating the rights of the child, is the parents.
DR. WEXLER: Exactly. Yes, you are exactly right.
PROF. GEORGE: This is a real paradox here.
DR. WEXLER: That's right. That's right. But that's why, you know you wouldn't even begin to take on the challenge unless the parents are coming to you and saying, you know, "Our option at the moment is to try not to have a baby that is going to suffer in the long run."
To go to Floyd —
CHAIRMAN PELLEGRINO: Dr. Bloom's question.
DR. WEXLER: Right. I think that we were extremely enthusiastic when we found out about both the HIV, that there could be people that had these protective factors that would enable them to never develop AIDS. It also gave a kind of window on the cause and the treatment for AIDS because you could figure out how were they getting protected.
It certainly is our hope that with these modifiers, that — I mean, there are people who get the disease and it's almost unnoticeable. They get it in their 80s, in their 90s. And it's usually completely misdiagnosed because the people just think they're kind of old until it is passed down. And then the younger generations get it earlier often.
So it certainly is our hope to find these modifiers. Now, whether that would make enough of a difference, you know, I am open. I think that is why we need to take a flexible attitude, both towards what we are going to find as modifiers, you know, doing RNA interference or any other kind of small molecule treatment. The likelihood is if you don't intervene early, it's going to be much harder to reverse the process.
I mean, certainly there is a mouse that had Huntington's and got sick. And the gene was stopped. And it got reversed and got cured. So there are examples in mice of the brain being able to handle this kind of toxic load as long as has toxic information. Probably it would be better to prevent the disease than to have to reverse it.
So then, of course, you would absolutely say, "Let's start over from scratch and figure out what is the best thing for patients, to protect them."
So that's why I think what you are doing is so crucial because you can raise these as issues of how you would introduce them flexibility, how would you introduce these kinds of protections, and also the kinds of research that really needs to be pushed because this research is going to change the future of all of these diseases.
CHAIRMAN PELLEGRINO: Thank you very much, Dr. Wexler.