Genetic Information: Its Significance
for Patients, Families, Health Professionals,
Ethics, and Policy Development

Remarks by NANCY WEXLER

I am honored to speak here today.

I am delighted that the President’s Council on Bioethics is taking on the serious challenge of newborn screening and genetic testing, in general. This is a critical area in which we need to tread cautiously and with your advice. What we do today will have repercussions for many years to come.

I also appreciate your willingness to broaden your mandate to include “genetic information and knowledge, whether obtained before or after birth, and in terms of (1) its ‘existential’ significance for individuals, families, and society at large and (2) its implications for policy (e.g., insurance and employment.”

In the interest of full disclosure, my grandfather, three uncles and my mother all died of Huntington's disease. My father established the Hereditary Disease Foundation in 1968 when my mother was diagnosed, and our entire family has spent our lives seeking treatments and cures for the disease.

Dr. Alexander and colleagues argue that the “’dogma’ governing newborn screening—i.e., do not screen unless you can effectively treat—should be discarded.”

The completion of the Human Genome Project 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, microarray technology, and genetic technologies which we have not yet fathomed. We need to be ready for these advances.

I would like to use the Huntington's disease story as an example to address these questions and others posed to me.

In 1968, my father began the Hereditary Disease Foundation when my mother was diagnosed with Huntington's disease. He held small, interdisciplinary workshops to interest scientists in the field and to stimulate new knowledge. In October, 1979 – 27 years from next month – the Hereditary Disease Foundation held a workshop entitled, “Can You Use DNA Markers to Find the Huntington's Disease Gene?” Organized by David Housman of MIT and Allan Tobin, UCLA, the workshop included Ray White and David Botstein, at the beginning of their careers, as well as other genetic pioneers. It had taken Ray almost two years to develop one human restriction fragment length polymorphism, or RFLP, as they were called, and no articles had yet been published describing how DNA markers might be used to find human disease genes.

There were many heated arguments over methods and madness. Ray White and David Botstein felt strongly that the whole human genome must be mapped first before we could look for a marker segregating with the HD gene. David Housman argued even more vociferously that we should look for the HD gene segregating within an HD kindred, so we might get lucky before the genome was completed. Besides, he had a special graduate student named Jim Gusella equal to the task. Everybody in the room was a believer that this technology could work, albeit perhaps in a hundred or so years. There were calculations about how many post-docs years it would take to map the human genome. Housman advised me that finding the right family was critical and encouraged me to go to Venezuela for the research as the Lake Maracaibo area was home to the largest known kindreds with Huntington's disease.

In 1981, I began going with a team to Venezuela, collecting pedigree information, clinical data and DNA. Shockingly, in 1983, together with David Housman, Jim Gusella and Mike Conneally, we discovered the DNA marker, 4 million base pairs beneath the HD gene on the top of chromosome 4. The jubilation and elation that flowed around the world was not only for cracking Huntington's disease, but also for the proof-of-principle that this strategy could work to find all genes, deleterious and healthy.

The Hereditary Disease Foundation organized a collaboration of many of the early pioneers in the genetics world to find the Huntington's disease gene itself - David Housman, Jim Gusella, Francis Collins, Hans Lehrach, John Wasmuth, Peter Harper, Bob Horvitz, and many talented post-docs and graduate students. It took a decade of arduous work finally to isolate the Huntington's disease gene. Its abnormality turns out to be an expansion of a CAG repeat that makes too much of the amino acid “glutamine” in a gene encoding the protein “huntingtin.”

When the research looking for the HD gene began, the equipment used were very old fashioned gel boxes with paper towels held together by paper clips, subjected to jolts of electricity and radioactivity. Many of these machines for manipulating DNA had never been used with human DNA until the HD patient samples were applied to them. PCR had not yet been invented. The gene sequencing machine had just been invented – it was a gorgeously aesthetic machine, whose beam of multicolored light and insides were visible.

When the Human Genome Project began in earnest in 1990, it required innovative technology in order to succeed. It also necessitated worldwide collaboration and cooperation in both public and private sectors. It demanded informatics on a previously unknown scale, and, as astonishing as it was, the Project came out ahead of schedule and under budget!

After the Human Genome Project was finished, many of these groups collaborated again to set up a Haplotype Map Project to look at human variability. An example of the genetics of the future is the Broad Institute Center for Genotyping and Analysis of MIT and Harvard. The Broad Institute provides new technology to sequence entire genomes in a matter of weeks. There are chips made by Illumina, Affymetrix, and Sequenom containing 100,000 SNPs or Single Nucleotide Polymorphisms. The SNP is the latest version of the RFLP that we used 27 years ago to search for the HD gene.

I will use HD again as an example of how rapidly the fields of human genetics are improving and changing. In 1993, when we isolated the HD gene, we observed that the size of the expansion of the CAG repeat was tightly correlated with the age of onset of the disease - the larger the repeat size, the earlier the age of onset. With a repeat size of 40 CAGs or more, the disease is fully penetrant; if you live a normal life span, the disease will inevitably appear. And it 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 and severe psychiatric problems such as depression, suicide, and even hallucinations appear.

The typical age of onset is in the 30s or 40s. The disease can appear as early as 2 years of age and as late as the 80s. If a person inherits a repeat size of 60 CAGs or greater, the disease will inevitably appear at age 20 or younger and has a much more aggressive course with seizures and other disabilities. Once we had discovered the HD gene, we learned, to our surprise, that some individuals with repeat sizes between 35 and 39 CAGs evidence variable penetrance – that is, some individuals get sick while others do not. People with repeats in this range usually produce the so-called new mutations – a parent who is never symptomatic produces an offspring who develops Huntington’s disease. The HD gene has a tendency to expand when it is passed from generation to generation. This is particularly true in sperm cells, for unknown reasons.

HD is one of the most fully genetically determinant diseases known. If you carry an expanded allele of a certain size, you will get sick and die. And yet there is tremendous variability in when the disease appears. The HD community – researchers and families - is very interested to find modifiers that could provide additional therapeutic targets – pushing the disease to beyond the normal life span.

We analyzed data from the huge kindreds in Venezuela whose cooperation had permitted us to find the HD gene. Astonishingly, we discovered that in some families in which the CAG repeat size is 44, the average age of onset is in the 20s. In other families in which the repeat size is also 44 CAGs, the average age of onset is in their 50s. There is a 30 year difference in age of onset, even with precisely the same CAG repeat length!

We felt that this difference must be influenced by genetic modifiers and began our search for these modifiers. Using the same DNA and clinical data that enabled us to find the HD gene, we sent the materials to the Broad Institute Center for Genotyping and Analysis for analysis with their SNP chip looking for linkage.

After only a month, the data came back. We have clear evidence of the presence of modifying genes which influence the age of onset of HD. The analysis points to certain regions on chromosomes as “hot spots” which most likely contain modifying genes. And even more amazing – we can look on the computer at the database of these regions and see what genes might be the crucial ones to pursue.

These shocking advances are entirely due to the Human Genome Project. The Project mapped and sequenced all the genes which appear in these data bases that you can now just dial up. But as important, the Human Genome Project was a unique catalyst for the most extraordinary technological revolution.

It will still take time to sort out which HD modifier genes to pursue and how to go about it – but the process should take months or years – rather than lifetimes.

In a mere 27 years we have seen a scarcely imaginable change. Walking through the Broad Center in Cambridge and comparing it to the labs at MIT and Harvard where much of the search for the HD gene took place – you would think that you are on a different planet.

The driving motivator behind the Human Genome Project is the search for new diagnostics, and treatments and cures for human disorders. And that push is the same for technological advances in genetic diagnostics. I think we can assume that future tests for diseases will be DNA-based and accurate. 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 dramatically lower the cost for accurate diagnostic testing.

The world which welcomed the completion of the Human Genome Project will certainly welcome its increasing medical relevance. But 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 touch on some of these challenges – again, using HD as a model since I am most familiar with these questions.

One of the first questions raised regarding newborn screening in general is the accuracy of the test, including false positives and false negatives. We have learned that there are often “phenocopies” of diseases like PKU in which a baby tests positive but would be harmed by the special diet. With more testing of different diseases, the likelihood is that we will see even more complex relationships between genotypes and phenotypes. CF is an extremely good example. There are huge differences in the severity of symptoms, differences which do not accord with particular mistakes in the CF gene.

Without the HD gene in hand, we never would have known that there is variable penetrance and new mutations. We also would not have known about a phenocopy of HD that looks identical to HD even pathologically but is a mutation on another chromosome entirely. Called HDL2, this disease is more prevalent in African-Americans and in Africa (on chromosome 16 in a gene called junctophilin-3).

I always recommend individuals getting two independent diagnostic tests – either twice at the same institution or two different institutions. The implications of these results are so dramatic that it is crucial that genetic tests be accurate.

It is critical to have testing go hand in hand, as much as possible, with research to capture the variability which is bound to occur probably in all diseases – if we look closely enough. It is also essential to try to predict where advances may lead to new health crises. Again, PKU is our guide. At every phase of this success story, investigators were asking research questions like “How long does the diet need to be given?, etc.” As much as possible, animal research could be utilized to answer questions in a predictive way, in addition to gathering the human data. As soon as it became apparent that normal, treated women could be reaching child bearing age, scientists could be asking “Does increased phenylalanine levels damage the fetus?” All human testing programs should be seamlessly integrated into basic and clinical research programs to learn the most, avoid harm and take advantage of the benefits.

One of the confusing issues of diagnostic testing is how results are described and interpreted. With HD, the diagnostic DNA test is 100% accurate – barring human error. At conception, the presence of the normal sized or expanded repeat can be detected. This does not mean that the embryo has HD. Later in life, the same expansion can be detected. But there is a big difference between having an expanded repeat at the DNA level and having a clinical diagnosis of HD. At the DNA level – they are all the same, but in practice they are vastly different. Many families and even counselors are extremely lax in how the test results are given. As a result, people say they were “diagnosed with HD” when they only had an expanded repeat on a genetic diagnostic test. There has to be a tremendous amount of additional education at every level – from medical personnel to families – to avoid permanent harm with profound ramifications – which I have observed personally.

The Human Genome Project is providing us with an opportunity to have personalized medicine. This is one of the extraordinary benefits of the information gained. But to me, we are not ready yet to take full advantage of these new discoveries.

My personal view of personalized medicine may be slightly idiosyncratic, but I think we must look at each disease, as well as each person, in an individualistic way. In other words, each disease has its own distinctive “personality,” based on its symptoms, prognosis, treatment or lack thereof, prevalence, age of onset and other characteristics. And each individual in society is distinctive.

Again, let me use HD as an example. We now know precisely the nature of the molecular mistake and have an extremely accurate test – barring human error – which could easily be given at any time from conception to death.

But where do we stand clinically in being able to treat HD patients? We are no different today than when my mother was diagnosed, almost 40 years ago. We have some better medicines to treat the psychiatric complications of HD. Tetrabenazine – the drug of choice in Europe, Canada and elsewhere for almost 40 years for treating chorea, the abnormal movements of HD – has not yet been licensed by the FDA for use in the U.S. There is nothing to prevent, retard or cure the disease – only the most meager symptomatic relief. We are really not that different today from the mid-1800s when George Huntington first described the disorder.

We need a tremendous amount more research and research funding at every level – particularly the federal NIH level which has the magnitude to make a difference – to develop new treatments and cures. Certainly having the HD gene in hand has radically changed our research. There are in vitro and in vivo systems – cells, yeast, worms, flies, mice – containing the HD gene, which allow us to make progress inch by inch – but we are not there yet, by any means.

So what do patients and families do in the meantime, while science is working hard at its slow, unpredictable pace? For families, the appearance 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 organization of families, the International HD Association, and the international body of scientists and health professionals, the World Federation of Neurology Working Group on Huntington’s Disease. The committee was composed equally of HD family members - persons at risk, parents and spouses - and scientists. The Guideline Committee recognized that having a DNA test that could definitively diagnose HD in a symptomatic person had major ramifications for the rest of that individual’s family and only should be done with caution and counseling.

But we also realized that we were in a unique, unprecedented situation. The HD DNA marker test could diagnose accurately, both presymptomatically and prenatally, the appearance of a disease decades before its onset – a disease which inexorably ravages body and mind. Some suggested that perhaps the test should never be given until some treatment could be found. Others said that the test could help in family planning and potentially in resolving ambiguity. We should try to develop guidelines responsibly, to anticipate problems and make suggestions.

The Guidelines were published by the Journal of Neurological Sciences in 1989 and the Journal of Medical Genetics in 1990. When we discovered the actual location of the Huntington's disease gene in 1993, the guidelines had to be revised and the final guidelines were published in Neurology. [“Guidelines for the molecular genetics predictive test in Huntington's disease.” International Huntington Association (IHA) and the World Federation of Neurology (WFN) Research Group on Huntington's Chorea. Neurology. 1994 Aug; 44(8):1533-6.] The guidelines are set forth by members of HD family organizations throughout the world, as well as by medical communities as guidelines to protect individuals at risk.

The guidelines explicitly reject the notion of including testing for HD as part of newborn screening.

The guidelines state that, “the test is available only to individuals who have reached the age of maturity (according to the laws of the respective country).”

The committee and the family and professional organizations adopting these guidelines felt strongly that the choice to take a test only should be made when a 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 it was not acceptable.

A related guideline said “the decision to take the test is solely the choice of the individual concerned. No request from third parties, family members or otherwise, shall be considered. The individual must choose freely 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 should also not be permitted since the child to be adopted cannot decide for his or herself whether to be tested.”

Privacy of children is an area as crucial as the confidentiality of adults, with respect to insurance and employment, but it is not discussed as much. The groups developing testing guidelines discussed these issues at great length. The committee felt after age of 18 years old, individuals should be mature enough to give truly informed consent and understand the tremendously serious repercussions such information can have for their lives forever. The guidelines also recommend that no one else can test a minor, including the minor’s parents. Minors are burdened for their lives with unwelcome information not sought by them. Once in an insurance system, school system, or employment, minors have to deal with the negative consequences of that information forever. You cannot “take back” such information, once it is revealed.

The guidelines specifying that minors not be tested for the HD gene breaks with precedent in family law. Ordinarily, parents are given a great deal of license with respect to their children’s health.

The guidelines were modified appropriately when the HD gene was isolated and discovered to be an expanded repeat – which influences the way in which the test is given and interpreted. But essentially these guidelines have remained the same since 1983. PROCEED WITH ONLY EXTREME CAUTION!!!!!!

And what has been the experience of people using the guidelines to be tested? Only a tiny minority of people worldwide has chosen to utilize the test – fewer than 20% of individuals at risk in countries where the test is offered. This includes using the test prenatally.

Here are some of the voices that we have recorded talking about their experiences:

• When you ask, “What’s it like?” you can prepare for testing cognitively, you can have a support person that you talk to for 23 hours out of the 24 each day and that’s the only thing that you’re thinking about. And you can go to counseling to get prepared for testing. And that can go extremely smoothly and you think that you have your ducks in a row. But when you’re 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 whether you are or not. …You have this horrible traumatic experience that you have to internalize. You have to zipper your trauma up. I’m sorry, I just was not that good at that, you know.

…initially I was prepared for the fact that this would be very difficult should I receive the results that I was positive, so my husband and I anticipated that I might need a period of time where I’m not accountable. That we’d play it by ear. So we cognitively prepared for that. What we didn’t prepare for, though, was that the weight of that would be so grave. So, I think I went for a period of going through the motions and making sure I had my ducks in a row before I was really able to let my guard down and let this information be internalized. But it was a huge struggle. I was trying to put on a good front for my daughter. And I really thought it was a very personal decision to be tested and that I largely did it for myself. But an awful lot was done for my family and what I could offer. I was hoping to say [to my 10 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 that I was getting tested. And we had all kinds of scenes of where we were going and why we’d be away for the day and what have you.

But what wore down my energy was trying to keep up a front in front of my daughter after receiving this result…I come home and try to be a normal, happy mother for my daughter not to worry about me. Which is my big fear from childhood. I did not want my child taking care of me ever, and I still feel very committed to that. If nothing else, I do not want my child to have to do anything but live her life in a natural progression as much as possible. I don’t want her to have to give up her childhood or her early adulthood for me. So I wanted to spare her this grief. And that just really wore me down. And it was quite dysfunctional in my family to try after we had been such an open unit before that. Very honest. To think that I could possibly pull off this act, you know, and of course that didn’t work. She held me hostage one afternoon and said, I know something’s wrong. Are you getting divorced? Are you dying? Is grandma dying? Do you not love me anymore? I mean, it was horrible. So I thought...it very obvious that this was the time to tell her that I had been tested and that my results were positive. And I really wasn’t prepared for that conversation either but it was such a relief to do that. And I, at that point, had no choice but to just give up my life for six weeks and I did nothing. I took a leave. I did not get paid for six weeks. We relied on my income completely. Not completely, but it was a large part of our budget. My husband worked three jobs, did laundry, cooked dinner. I walked the dog, I went to the beach...and I went to therapy three times a week. Probably like twice individual and once with my husband. And that’s what I did for six weeks. I did nothing else. Nothing else. And that was an accomplishment to get up and walk the dog on the beach, read and go to therapy. That’s all I did for six weeks because that’s all I could do. And [cry all day.]

And I just felt that a part of me completely vanished and that I 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.

My dreams [were over]. I really thought after living in the dysfunctional household that I lived in that I pulled myself up from my bootstraps. It was high time for me to live the way I wanted to live. I put myself through school. I moved away. And I was on my road. I was marching in my parade and, you know, the conductor stopped. I really thought that I had worked very, very hard to be able to offer myself and my daughter a life that we deserved to live. And here we are challenged with something that was much, much, much more devastating than I can possibly ever imagine. I knew that whether I was gene positive or gene negative it wasn’t going to be over. It didn’t matter to me...it mattered to me, of course, that I was gene positive in terms of my aspirations and what my future was and what I would do with my family, but if I received the information that I was gene negative it certainly would not be over. And I was very scared to be gene negative, too, because I know what it’s like to take care of my mother. So how much more would I be expected to be this strong. So, there’s no good news with testing. And I certainly don’t think it’s for everyone. But I think, truly, if you need to know, there’s no two ways about it - you must know. And I don’t regret that.

Question: When you were walking on the beach, at any point did you ever think, gee, I wish I hadn’t pursued this thing?

Answer: No, never.

Question: Ever like to take it back?

Answer: Maybe that.

• I was as very, very, very prepared as possibly you could be. I mean, years of being in different functions and having a lot of information. All the information possible and making a choice and still, still, at the point when the information was real it was still painful. It was a deep...it was almost like a death. But yet not totally. It was like a loss, a really big - a loss of dreams.

The opportunity to do prenatal testing has been an extraordinarily beneficial and unique outcome of having the HD gene in hand, even though no new treatments have yet been forthcoming.Several options exist for prenatal testing. The HD gene can be tested for through amniocentesis, either at the usual time or earlier through chorion villus sampling. The HD gene can also be tested for using Pre-Implantation Genetic Diagnosis (PGD). This procedure involves selecting a single cell from the embryo when it is at approximately the 8 cell stage and testing the cell for the HD gene. If the gene is found to be normal, that embryo is implanted or frozen for the future. If the HD gene in the cell contains an expanded allele of over 40 CAG repeats, the embryo will either be discarded or, with permission, used for research. PGD has already been successfully used in some instances.

PGD permits a critically important variant on prenatal testing, which is very appealing to many HD families: non-disclosing PGD. Many at-risk individuals do not want to know their own genotype, but they also do not want to pass on this horrific illness to the next generation.

Non-disclosing PGD provides an excellent solution to this dilemma. People at risk for HD have embryos carrying normal huntingtin genes implanted, without knowing the genotypes of any of their embryos or even their own genotype. This means that IVF physicians performing the services are instructed not to reveal the genotypes of all the embryos they test, whether normal or carrying an expanded HD allele. It is also imperative that they not provide the number of embryos that are available for implantation since the number itself might reveal the parent’s genotype: few embryos means HD; many means normal. At one center, the lab tech performing a sonogram told a woman who had chosen not to know her own genotype, “It’s a good thing your expanded repeat isn’t a giant size to produce juveniles.”

With all the advantages that PGD can provide, there are some external disadvantages that must be overcome before all can enjoy its benefits. IVF is required for PGD and IVF is still expensive. It is also not covered by insurance, even if it is being utilized to avoid a lethal genetic disease. In the UK and Canada, a certain number of IVF trials are covered by national health insurance, for indications of infertility, as well as for genetic disease.

Privacy is a critical issue for HD families, as well for families affected by other genetic diseases.In health insurance, disability insurance, and life insurance, people suffering from or even at-risk for HD are, in the words of the insurance industry, considered “uninsurable,” unless they are part of a large group insurance in which no questions are asked. Since employers are usually insurers, many families do not want their employers to know about their actual or potential illnesses. The Medical Information Bureau (MIB), in Boston, is an information network for insurers to provide the industry with health information. If one person is denied insurance due to HD in the family, other family members can be linked by name and may be denied as well.

One egregious difficulty since isolating the HD gene is that the testing protocol that was developed with assiduous attention to detail is only a guideline and has not yet been established as the standard of care with any enforceability. Juvenile testing and presymptomatic testing raises other dilemmas as well. Who is to be the gatekeeper and enforcer of following the guidelines? The clinicians should do it but often even they are unaware of the guidelines. Should the laboratories do it, since they are the actual provider of the test and are in a position to review how the process prior to receiving the sample was conducted? At one point in history, the laboratories were the enforcers. But then they ran into trouble with their laboratory chiefs because they potentially caused the laboratories to lose money if they refused testing. Another area where confusion reigns is if the test is for a symptomatic or presymptomatic individual. Again, the laboratories were sometimes in the inappropriate position of trying to determine this as well.

Genetic testing for Huntington’s disease is one of the very first molecular genetic tests offered at the dawn of the molecular genetic age. The harsh consequences of error, either technically or psychologically, are so profound that they united a community of academic scientists, family members, health care professionals, laboratory professionals, testing companies, and others in striving to develop procedures, protocols, guidelines and advice to bring the test into fruition. And mistakes do occur since, for the most part, apart from laboratory requirements in CLIA-approved labs, these are only guidelines with no strength of enforcement.

The driving push behind finding the HD gene was to illuminate the pathogenesis of the disease in order to develop new therapeutics and cures. Diagnostic testing was a byproduct of isolating the gene – useful to some, destructive to others. Once new therapeutics are developed, there will be a great change in people’s motivation to be tested, since testing will be linked to therapies. Testing for HIV/AIDS changed, as did testing for colon cancer, breast cancer and other illnesses for which there are some interventions, inadequate as they may be. Some at-risk individuals have even stated they would be willing to take an experimental therapeutic without being tested, the prospect of testing is so onerous.

Even in the best of circumstances, when the guidelines are in place and utilized, mistakes can occur. My cousin decided to get tested for the HD gene in order to clarify the genetic risk for her children before they started families of their own. I call her one of the “altruistic testees” since she would not have done it on her own but did it for her children. Part of the guideline protocol calls for having a neurological examination. She was told the neurologist would not provide feedback after the exam and she went alone to see him. The neurologist immediately diagnosed her with clinical symptoms of HD and told her to skip the expense of the DNA diagnostic test since she already had evident clinical HD. She dropped the test. A year later she decided to complete the testing for the sake of thoroughness. The DNA test result revealed a normal sized HD gene – no HD!

Many people who are worried about potential loss of insurance and employment if they are found to have the certainty of developing HD in the future will get tested anonymously, using a pseudonym and paying for the test with cash out of pocket. And sometimes the testing center calls a follow-up number and the anonymity is broken by accident.

Sometimes people will go to their general practitioners – who are all too often unaware of the existence of HD testing guidelines – and request the test, using a pseudonym. One woman called me up in a panic and would not reveal her name as she provided the sole support for her small son. Her GP told her to call a genetic counselor because her HD gene test had come back with “two Al’s – one big and one little.” He didn’t know what an “Al” was or what it meant to her. I had to tell her, over the phone, that the test meant that she had inherited an expanded repeat. You never want to give this information over the telephone, especially when you can’t follow-up.

Much of people’s concern with respect to acquiring genetic information is often driven by their concerns about its impact on their insurance and also on their employment – which usually provides their insurance. When I was the Chair of the Joint NIH/DOE Ethical Legal and Social Issues Working Group, we established a Task Force on Health Insurance to look carefully at these issues and make recommendations. Many of these same observations and suggestions are relevant today. It is often difficult to document discrimination because people are exceedingly careful to hide a genetic risk, get insurance through another family member, or even, in some instances, not be truthful on applications.

During the ELSI years and during Insurance Task Force meetings, I was very public about the fact that I am at risk for Huntington’s disease. I said many times that as a person merely at risk, I am in a category of person who is, by definition, uninsurable. If this was not true, insurance commioners and any of the number of experts present would have contradicted me. I get health insurance currently because I am part of a very large group at Columbia University. And some insurance companies have begun offering insurance at extremely high rates. But what was true then is still true now.

Until issues of universal access to affordable insurance and genetic privacy are guaranteed, and until insurance and employment discrimination is banned, the public will not 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 for our citizenry.

I would like to try to answer some of the specific questions raised by Dr. Davis is his letter.

• I do not believe that we should be guided by dogma, but rather that each disorder should be reviewed on a case by case basis. It is critical to involve family members who suffer from and are familiar with the ramifications of these diseases in the decision making process. In 1983, some doctors immediately wanted to proceed with testing for HD, almost delighting in their new technology. The HD family members said, “Go slowly and carefully.” The fact that this position has been maintained for more than 20 years suggests that the combined group made the right choice.
  
• I personally do not believe that “failing to screen for currently untreatable disorders will a) deprive both child and family of numerous potential benefits and b) doom us to continued ignorance and unavailability of treatment.”

We are not doing a sufficiently good job in screening for the diseases for which we can treat or following up on diseases for which we can either intervene medically or socially.

I think we can do potentially more harm by including at the moment all diseases for which we can test – especially if they have a very late onset. Families are often extremely concerned about some other entity having exceedingly personal information about them. In the case of the state, even if it is the state public health department, there is little confidence that this information will not be misused, if it is no longer under the control of the individual. There is also the concern that the diagnosis of one individual immediately diagnoses a family. My mother’s diagnosis of HD makes my sister and me at risk. Other medical diagnoses, without such strong genetic ties, do not necessarily have this expanding pool of influence.

It can also be extremely problematic to have your entire life from birth clouded by an early diagnosis of HD and then have a treatment or cure intervene before the disease actually appears. You have suffered needlessly for decades. We know that many people at risk in HD families often are subject to depression, alcohol and drug abuse just from the stress of the possibility of suffering from HD. The HD test may relieve the anxiety for some but for others it is dooming them without hope.

To include the HD test as a part of newborn testing adds to the tortuous aspect of the disease without offering a medical benefit.

• I disagree that the “default position should be to include rather than exclude.” If dogma is 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 this cannot be done and cannot be revised appropriately as the science changes.

I would recommend that late onset diseases such as Huntington’s disease and the hereditary forms of AD, PD, ALS, CJD (a hereditary disorder similar to Mad Cow disease) and other similar disorders should be excluded from newborn screening programs. In fact, I would suggest that these disorders merit being treated as genetic tests, rather than genetic screens. A genetic testing program provides the individualistic approach and care that is necessary when dealing with all of these horrific disorders for which there is now little or no treatment or cures. Utilizing the HD testing guidelines might be appropriate if families and organizations so choose.

• I definitely think that multiplex genetic screening of newborns is likely to become standard of practice in most states. I also believe strongly that diseases should not be routinely included in the multiplexing, just because it is more economical to include them. HD, the presenillins – a hereditary form of Alzheimer’s disease, and familial ALS, should not be lumped together with PKU and other disorders treatable at birth.

A more complex problem may be whether or not to include screening for CF. Early diagnosis, treatments and other interventions have improved greatly since the identification of the CF gene.

CF testing is another example in which, at least in some circumstances, we have an approach distorted by economics. In some medical centers, the CF genetic test is not paid for until a pregnancy occurs. This limits a couple to either continuing or terminating the pregnancy. If the CF test was paid for prior to pregnancy , more options would be available to a couple, including PGD, sperm or ova donation, or adoption. There is also insufficient counseling given to couples identified as carriers to discuss the results with other relatives who might also be at risk and of child bearing age.

• · There may be certain disorders which are routinely screened for in 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 spend 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 discussion of the “right to remain ignorant” mischaracterizes the situation. The word “ignorant” has pejorative connotations 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 the genetic test for HD, they are often choosing not to cloud years when they are young and healthy with foreknowledge of their doom. If they develop symptoms, they take a genetic test and also get an appropriate clinical diagnosis. It the disease never appears, they will know that. Sometime people consent to a genetic test after death to confirm the lack of genetic risk to offspring. Having a one-in-two risk of developing HD is sufficiently high to guide people to plan appropriately financially and to lead their lives in a healthy, careful manner.

Testing involves timing. There are different developmental stages when testing can be relevant and others when it may not be. Jim Watson once told me that he would not like to know if he was going to develop Alzheimer’s disease, for example, and not be able to do anything about it. And Jim is probably the most intellectually curious and rigorous person I know. People’s individual autonomy requires that they be given the choice to receive information or not. This specifies nothing about ignorance or knowledge.

An elderly gentleman – very sophisticated and a business scion – went to his doctor for a checkup. He asked his doctor not to perform the PSA test since he did not intend to treat the illness if it appeared. His doctor said, in closing, “And your PSA test was normal.” The man was shocked. He was relieved that the test was normal but furious that his doctor ignored his wishes and disobeyed his orders. What if the test had been positive?

We are in severe danger of running over the abyss in terms of our ability to provide the kind of meaningful genetic services that are required to deliver on the promise of the Human Genome Project. Even in the 1990s, there was a lack of appropriately trained personnel. There were only approximately 1,000 trained genetic counselors and 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 great deal 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 would be tragic if our choices as a society are merely guided or 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.

We currently have a unique opportunity to develop today the policies and procedures that should be in place in the future to help people benefit from genetic information and minimize harm. We know we need trained personnel to interpret the data and we currently have a dramatic paucity of these individuals. We know that insurance and privacy concerns are blocking people even now from taking advantage of the existing genetic information that could be advantageous to their health, for fear of discrimination and retribution. We know that people are resisting even taking part in genetic research for fear of genetic discrimination in the future. We know that there is timing to diseases and we need to respect an individual’s decision-making about when or whether to acquire genetic information.

We also hope that research on diseases is a moving target. In the HD field, we hope that research will lead to new breakthroughs in treatments and cures. For example, some proming studies are now being carried out using RNA interference to prevent the abnormal protein from even making its toxic product. This could be a cure for HD, as well as for many other disorders. Probably the earlier that treatment is delivered, the more chance it has of working to prevent the disease, rather than counting on the treatment to reverse an already existent disease process. Treatment itself could be deleterious, however.

We may need to genetically test for the HD gene earlier in the lifespan if a treatment is developed that requires early delivery. So it will be important to be flexible in setting and observing guidelines about testing. We hope to have a reason to change, but it is still difficult information to receive. I would like to end with a letter I received from a family member which underscores why we must maintain caution, vigilance and optimism. And why we need your help.

“Those of us who have been told we have the gene 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’ve 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 am used to looking at my life and seeing nothing after age 50 or 55 because I will have ended my life by then.”