Thursday, November 16, 2006
Session 3: Overview: Genetic Research and Clinical Applications
Robert L. Nussbaum, M.D.
Holly Smith Distinguished Professor of Medicine,
Chief, Medical Genetics
University of California, San Francisco
DR. PELLEGRINO: As you all know, we've been having discussions over the last six or eight, nine months on various aspects of screening of newborns. We're going to continue that discussion this afternoon, looking at some of the broader aspects than we've engaged before and the clinical aspects and some of the social aspects.
Our first speaker is Dr. Robert Nussbaum of the University of California at San Francisco, and again, Dr. Nussbaum, our custom has been not to provide a long curriculum vitae, so you won't have the schizophrenic experience of saying, "Who is it they're talking about?"
(Laughter.)
DR. PELLEGRINO: But we do have your curriculum vitae in the book. It's in the book and you can all refer to it.
Dr. Nussbaum is going to address us on the clinical aspects of gene medicine, genomics.
DR. NUSSBAUM: Thank you all for inviting me. It's really a great pleasure.
So what I'll be talking about briefly and trying to leave plenty of time for discussion of, is a broad overview of just one aspect, one particular application of the Human Genome Project, and that is a public health application in an area that is often referred to as personalized medicine.
Before I begin, I did a search on this, and it's interesting. The first time that I could find anyone use the term "personalized medicine" — I'm sorry it's cut off at the bottom as we have Macintosh PC problems. It's a different kind of PC — in that it was back in 1990, and it was a paper called "Rewarding Medicine, Good Doctors and Good Behavior."
And what they said was we need to choose persons for medical careers who will find patient-centered care rewarding, and we need to provide those persons the training and socialization and underscore the value of personalized medicine. That was 1990, but that was also the time that the Human Genome Project was just getting off the ground.
Fifteen years later, when the Genome Project was pretty much complete, personalized medicine took on a very different tone. This is a quote from my former boss, Francis Collins, NHGRI. "At its most basic, personalized medicine refers to using information about a person's genetic makeup to tailor strategies for the detection, treatment or prevention of disease," and it is in this context, in this definition of personalized medicine that I'll be referring to for the rest of this talk.
So I also want to say what my sort of bedrock supposition is here and one that I think we should all agree upon, and that is that gene variants are not completely determinative of disease or phenotypes of various kinds; that we're dealing with an interaction between genes and environment.
In some diseases, environment is a minor contributor. For example, in cystic fibrosis your genotype is the predominant determinant of whether you're going to get this disease or not, although, of course, there's variation in your genotype, which particular mutant alleles can have an effect on the severity of disease, and there are also clearly environmental factors.
On the other end of the spectrum, we have a disorder like AIDS where the environmental impact of the virus infection is the overwhelming factor, but there's still a strong genetic contribution, for example, whether or not one has a mutant allele for a cell surface receptor that blocks the ability of the AIDS virus to get into the cell.
And in most disorders, for example, Type 2 diabetes or Type 1 diabetes, we have an interaction between environment and genes in some very complex way that we are just now starting to try to dissect out, but it is a very difficult and challenging job to dissect out the environmental and genetic contributions.
But I'd like to point out that these are not mutually exclusive; that if we can understand, for example, the genetic contributions to disease, that will make us much smarter in being able to ferret out what are the environmental factors because we will then have some context.
As hard as it is to find these genetic contributions, we do have only about 25,000 genes, but the environmental impact, the environmental factors are broader. They occur over time, and it's actually in some ways a much more challenging problem.
Okay. So variation between two chromosomes. We have these variants. The most common are polymorphisms that are called SNPs or single nucleotype polymorphisms, and so here's an example of three polymorphic SNPs on a stretch of DNA.
On average, we have about one SNP for every 1,250 nucleotides. We're talking about close to three million between any two chromosomes that one inherits from a father and a mother.
But if you look through all of humankind, we're talking about a lot more SNPs, already identified, ten million SNPs that have been found. These are single-based changes in different populations across the world.
So there's a significant amount of variation, and of course, one of the challenges is how many of these SNPs actually have functional significance. Some are going to be in neutral areas, and some are going to affect gene expression in extremely subtle ways. Some of them may be actually in the coding regions of genes and change the amino acid that is encoded by that gene. Others will change the way the gene is spliced. Others will change the way the promoter works, and others affect the function of the gene in ways that we do not understand at this point.
And of course, the non-coding parts of the genome are the vast majority of all the DNA. Only a very small percentage of all of your DNA actually has the triplet code that codes for amino acids.
So the other important point I'd like to make about these SNPs is that as a result of the genome project and the catalogue of SNPs, we are starting to be able to trace the history of DNA variants: where they come from, and in particular, that there are groups of variants that stay together and have stayed together for tens of thousands of years.
And so that if you carry one variant in that location, you are very likely to carry other neighboring variants, and what location are we talking about? Well, that's all over the genome, and it includes regions that are perhaps anywhere from 2,000 to 3,000 base pairs up to 10,000 or even 50,000 base pairs, depending on what part of the genome you're talking about and what population you're talking about. The population history plays an enormous role in this degree of what we call linkage disequilibrium, that is, having multiple variants that are nearly always found together on a single chromosome.
So the idea here is that a variant may arise on a certain founder chromosome, and this would be in a small group of people. Then as the population expands, and of course, we as human beings are actually quite recently developed as a huge population. We started from a much, much smaller group of people in Africa.
So you have population expansion, and what happens of course is that every time you make eggs or sperm, chromosomes cross over with each other. So you end up with this shuffling of parental chromosomes in the offspring.
But what happens is that when these regions are close together, the chance of shuffling gets lower and lower and lower to a point where these yellow bars represent regions of genome that have stayed together over hundreds of generations, and so all of the variants present here will be found together on a given chromosome in what's called linkage disequilibrium, the importance of which I'll bring up in a minute.
So let's talk about, first of all, the basic science. You start with DNA sequencing, and you identify variation. The next question you want to ask is to what extent do those variants contribute to susceptibility to disease. That's really the basic science questions.
The basic tool for trying to understand that is association analysis. It's an epidemiological tool, and it's very simple in some ways, and in other ways it is very challenging.
You take a group of people and you ask simply how many of them have the disease and how many of them don't or how many will develop the disease and how many don't develop disease. If you follow people over time and you ask among those what fraction have the genetic variant that you're interested in and how many of them don't have it, and this variant can be two copies of a variant allele on both chromosomes or one copy on one chromosome.
This is essentially what epidemiologists call the exposure. You're either exposed to the variant or you're not, and you divide up the population in this way, and the fundamental question when asked is: what is the relative risk? What is the fraction of people with a variant who get the disease versus the fraction of people without the variant who get the disease?
And what is that? Well, here's our two-by-two table again for association study, and this is the basic issue, the relative risk. This would be A over A plus B. It's the fraction of people with the disease who have the variant. That's the people who have the variant, divided by the fraction of people with the disease who don't have the variant. Okay? That's the relative risk ratio.
When it's greater than one, and it's statistically significantly greater than one, there's an association between the variant and the disease.
Now, you can have a variant that's highly associated with a disease in a population for a number of different reasons, some of them biological and some of them artifactual.
What are the biological reasons? Well, the first is the variant you're testing for association is actually responsible for the susceptibility. It's because of that variant affecting the way the gene is being regulated or expressed or the way the protein looks that you're actually affecting the function and, therefore, the susceptibility.
It could also be as I described, that the variant you're asking about is in linkage disequilibrium with the variant that's actually responsible for the susceptibility. The association will still be there, but not the functional connection.
And it's also possible that this association that you see is actually an artifact, an artifact of the way you put the study together. You can have what's called stratification artifacts, and I don't want to go into any of the details, but this is one of the reasons why with association studies people have repeatedly said with good reason that an association needs to be replicated. You need to see it happen in more than one population and make sure that it's not either a statistical quirk or actual artifact of the way you put your study together.
So here is, I think, an example of a recent association study that has been quite interesting and replicated and, I think, important, and that is this gene called TCF7L2. It's a transcription factor. It's expressed in the beta cells of the pancreas, the cells that make insulin.
About the common variants in introns associated with increased risk: now this is not in the coding part of the gene. This is in the spacers between the coding part. Common variants in introns are associated with an increased risk of Type 2 diabetes, and this was found through a study by DeCode Genetics, which is the company that's working in Iceland comparing genetic information and clinical information obtained through medical records in the country of Iceland.
What's interesting is the effect appears to be pan-ethnic. So once this was found in Iceland, obviously a number of other people jumped to look.
Oh, excuse me. This is the extent of the relative risk. So if you have no copy, that's defined as being one. If you have one copy of the variant, your relative risk is one and a half times, and if you have two copies of the variant, it's about 2.3 or 2.4 times.
So that's the degree of relative risk, and I want to stress that this is a very significant finding, and yet its effect on relative risk is moderate. We're not talking about if you have this variant you're 100 times more likely to develop Type 2 diabetes than if you didn't have the variant. We're talking about one and a half to two and a half times.
Okay. So this has been repeated now in Indian-Asians and Afro-Caribbeans, and these numbers are not relative risks. They're actually odds ratios, which are very similar to relative risks, and I'm happy to explain what the difference is, but it has to do with the way the study is designed.
But the important point is that all of these numbers are greater than one. They're all significantly greater than one. They all increase when you go from one copy to two copies. So I think that this is a real finding, that variants in this gene in the entrons are associated with Type 2 diabetes in more than one ethnic group.
So what are the basic science questions? Are the entronic variants the actual functional variants responsible for susceptibility or are they an LD, linkage disequilibrium, with the responsible variants? Those questions are being answered.
Whatever the variant is that's responsible for the positive association, what effect do the responsible variants have on gene function? Why do these variants increase your risk for Type 2 diabetes?
And finally, how does this effect on gene function increase susceptibility?
Okay. So future progress. You certainly want to know what are the susceptibility variants for a variety of common disorders. Type 2 diabetes is one. There are many others. We'd like to know what those variants are.
In addition, there's a whole other area which I'm very happy to talk about, and that is identifying the variants that don't increase your susceptibility for diseases, but increase your risk of an adverse drug reaction or increase your risk for not having effective drug therapy.
And so this whole area of pharmacogenetics now is becoming extremely interesting and important, and the search for such variants is ongoing.
Okay. So we talked a little bit about the basic science. We want to find the susceptibility variants, but how do you use them? And that's really where I'd like to spend the rest of the time.
Clearly, if you can identify susceptibility variants, what's the translational science? Well, you certainly would like to be able to do individual risk assessment, in other words, test patients that come to your office for these susceptibility variants who may not have any disease at all, but would allow you to identify people who are at increased risk for developing disorders so that you could prevent it, intervene in some way either medically, behavioral changes, life style changes, whatever.
Also, if you can identify susceptibility variants, it may help you understand how to treat people better who actually have the disease. If we understood why that transcription factor alteration affects Type 2 diabetes, we might be able to then treat people with Type 2 diabetes more effectively and more rationally.
And this, of course, is something that people talk about a lot, have talked a lot about, and I'm not going to in this context.
Okay. So what are the translational science questions for the TCF7L2 variant Type 2 diabetes? How can we use knowledge of susceptibility variance and devise new drugs or behavioral therapies? And what does having a positive test for a variant mean to an individual person whether they have the disease or not?
Let's talk first of all about the ones who don't, and this leads us to this basic area, which I call the three "-itys": analytical validity, clinical validity, and clinical utility of any genetic test. You want to try to analyze these. What are they?
Analytical validity I'm not going to spend any time talking about. It's essentially the technical aspects of "Do you get the test right?" Do you know how to do the test? Can you find the variant that you think is there through the laboratory test?
Clinical validity is, all right, suppose you've got the right genotype. You know what variant the person is carrying. How well does that predict the phenotype, the disease?
And then finally, if you successfully predicted phenotype, what's the usefulness of it? What's the clinical utility? Does it result in an improved outcome to that person?
Clinical validity. How predictive of disease is a positive test for any one patient?
Well, for that you really need these basic pieces of information, what's called the positive predictive value. That's the fraction of people with a test who have or will develop the disease, and the negative predictive value, the fraction of people who are negative on the test who will not have the disease.
In other words, you can rule out or reduce their risk by doing the test and find they have a negative test.
Well, this is a busy slide, but it is, I think, the best way for me to demonstrate this. You've got three factors you need to take into account. One is how frequent is the variant in the population. Is it a rare or common variant?
Number two, how common is the disease in the population? So that's disease prevalence. So here I've got one in 1,000 people have the disease, one in 100 people have the disease, one in ten people have the disease. That would be obviously very common.
Here's the genotype frequency, one in 1,000, one in 100, one in ten.
And then finally, what is the relative risk conferred by having that variant? And I've generated these relative risks, everything from 1.5 or two, which is where we were for the Type 2 diabetes variant, up to 100, which would be a very substantial relative risk.
And what I've plotted here on the vertical axis is the positive predictive value, and I think that what you can see here is until you are at very high relative risks and common disorders, having a positive test has very little positive predictive value.
I mean, down here, for example, if you have a relative risk of, let's say, one and a half or two with a disease that affects one in 100 people and with a variant that is present in one in ten or one in 100 people in the population, we're talking about positive predictive values well below ten percent.
In other words, out of every 20 people or so walking into your office and you test them and they test positive, 19 out of 20 will not develop this disease. Only one in 20 will.
So for most multigenic disorders that we're dealing with, these are common disorders where the disease prevalence is high, relative risk ratios are modest, one and a half, twofold. Positive predictive values are very low, and the non-genetic factors are going to be very important.
So these are clinical validity issues. So how about for the Type 2 diabetes? These are the calculations that I did for preparing for this. Disease prevalence, about six percent I think is a reasonable assessment for Type 2 diabetes. The allele frequency for this variance has been found. It's about.28. So 28 percent of the population will carry either one or two copies.
The positive predictive value of carrying one copy is 7.5 percent. So 92 and a half percent of people who carry one of those variants won't develop the disease. And for two copies, 11 percent, or 89 percent won't develop the disease. Eleven percent will.
So you can see from a clinical usefulness point or I should say from a clinical validity point of view, this test is not very good at predicting your chance of developing disease.
Okay. But now that leads us to the other issue, which is suppose even so, you do the test and you find people have this genotype. How useful is it? So this is an interesting quote from Kari Stefansson. He is a CDO of DeCode. "It's terribly important to know if you have this gene variant. It gives you an added incentive to exercise and eat right."
And so the question really is: given that people might carry this variant, how is that going to change what you actually tell the patient sitting in your office about what that person should do?
Now, there are a number of common variants and common diseases that have been identified, and I put these down because they really in some ways cover the gamut. One is ApoE4 for Alzheimer's disease, the disorder for which we can do susceptibility testing, but we can't intervene in any way. We don't have any way of trying to suppose you identify someone with increased susceptibility.
On the other hand, we have Factor V Leiden, which is an alteration in one of the coagulation factors; it increases your susceptibility for deep vein thrombosis and possible pulmonary embolists, clots in the lung. That's something you can intervene on. You can intervene with anticoagulation.
And down the list, these all vary to a greater or lesser extent. Hemochromatosis, you can intervene by removing blood and taking iron off of people, et cetera.
Okay. So this leads us of the clinical utility. Assuming the result is interpreted properly, is having an individual's test results useful or harmful? That's really the essence of clinical utility. What good is knowing the information?
And is that utility evidence-based? Do you actually have retrospective data at a minimum, prospective data preferably, i.e., data that affects health outcome and economic and also has a beneficial effect on economic factors?
Of all the areas where this sort of genetic testing seems to be closest to really coming to use is in pharmacogenetics, and probably the number one area that people are looking at this very carefully now is in the use of the cumadin or warfarin, the blood thinning drug.
This is a drug that has a very high rate of adverse events. We're talking about significant bleeding occurring per year in a few percent of people on this drug: three to five percent of people on this drug, some estimates as high as ten percent will have a significant bleed per year that they're on it.
A lot of people are on it: people with atrial fibrillation, people with deep vein thrombosis, a variety of other people that are at risk for clots going to their lungs are on this drug.
The drug is metabolized through a variety of enzymes that have variants in the population, that are common, common variants, and depending on what your variants are, the proper dose for this drug can vary by as much as fivefold.
So that it is possible for someone to sit in your office, two people. You see them back to back in your office. You give them the same dose of warfarin, and one is going to bleed and the other is going to clot because one dose isn't enough.
Now, what do you do? Well, what physicians who use warfarin do is they start the drug and then they monitor people closely. They look at their anti-coagulation by doing what's called an INR. It's the degree of blood thinning.
And people have gotten very, very good at following the INRs and adjusting the dose. Despite that, we still have a significant level of harmful outcomes from coumadin use or warfarin use, and so the question is: do we have any actual evidence that if we genotype the people for the variants that affect warfarin metabolism, would it improve care?
And it's sort of amazing that the FDA is right now in the process of thinking about changing the labeling for warfarin, and yet we actually don't have any clear prospective evidence that it actually affects outcome and very little retrospective evidence.
There is excellent evidence that if you genotype people you can get their INRs within range more quickly and more stably. So if your outcome is the blood test, the degree of blood thinning, pharmacogenetic analysis is helpful. If your outcome is serious bleeding, we don't know.
The same is true for other drugs. For example, there's a chemotherapeutic agent, arinatikan (phonetic), which is metabolized by an enzyme that has some significant variation in the population. You can give people this same drug and one person will drop their white counts and get bone marrow suppression. Another person won't. That is now on the FDA label.
Another drug, mercaptopurine used in leukemia chemotherapy, also a tenfold difference in the proper dose of that drug depending on what your genetic makeup is.
So I think from the science, clinical utility point of view, pharmacogenetics is right at the top, and it's what we are going to see coming into clinic now.
Once you step back from that and you start asking, all right, well, what difference does it make to an overweight patient who is at risk for Type 2 diabetes whether they have the variant or not in that transcription factor if the positive predictive value is ten percent or eight percent? First of all, what harm would you do that person by genotyping them at that locus? One question.
What harm would you do by labeling people as being a "susceptibility carrier" if they actually are never going to end up getting diabetes? Would you then draw back and say, "Well, it's not so important for you to lose weight and change your diet and your life style because you don't carry the variant." What other sorts of problems might you be then allowing this person to suffer?
How good are we at using genetic information to motivate patients? Would it actually motivate patients? There's very little information about this.
There's one interesting study that was done by my former colleague, Colleen McBride who looked at variants in an enzyme that metabolizes some of the constituents of cigarette smoke, and she did this study among an African American population in North Carolina where they genotyped them for these variants and then tried to use that information to try to intervene and convince people that they should stop smoking because they're at greater risk for bad outcomes.
At six months after instituting this prospective study, the people who had gotten genotypic information had a better rate of quitting smoking. By 12 months it was gone.
And so our ability to intervene with behavior modification is questionable as to whether this genotype information is going to help or not. I am not one of these people who says it's useless because I just don't think we know. It has never really been put to the test.
So in summary: We're in the era of personalized medicine. Common genetic variants increase susceptibility rather than cause disease. Genetics empowers the basic science investigations and drug discovery in a very important way, and I do not want to downplay the significance of this for basic science.
The direct application to patient care requires evidence of validity and utility, and this has to be done on a case-by-case basis, disease by disease and locus by locus.
And with that I'll stop and be happy to answer questions and discussion.
(Applause.)
DR. PELLEGRINO: I'll ask Dr. Janet Rowley to open the discussion. Will you do this for us, Janet?
DR. ROWLEY: Thank you, Doctor Pellegrino.
Well, I'm sure I speak for all of my colleagues, Bob, when I thank you for a thoughtful, logical, but very sobering primer related to genetics. I wasn't here for the last meeting. So I've likely missed some of the pertinent discussion then which has, I believe, led to some of this afternoon's presentations, but it seems to me that much of what Bob Nussbaum discusses is tangential to some of our earlier discussions on prenatal genetic testing.
Therefore, at present as far as I know, although Kathy may disagree, PGD is done for single gene disorders with a clear association for a particular disease, usually one with a sufficiently serious or fatal outcome so the parents with to avoid having a child with that disorder, realizing, of course, as Bob pointed out that the accuracy of the test and the degree of penetrance certainly makes clear-cut associations difficult.
When we come to the era of personalized medicine, the decision to have any kind of genetic testing is complex, and it depends on the individual, on social factors, particularly the family, and the information regarding the disorder and the genetic complexity of the disease.
But I think that it's important to separate out single gene disorders, such as Tay-Sachs, with high penetrance from some of the others that we've been talking about, and I'm sure that there are good data available, though I don't know.
What's the proportion of individuals at risk of Tay-Sachs, say, amongst the Ashkenazi Jewish population? How many of those patients were screened, and what kind of impact did it have?
You've indicated that related to smoking the long term impact was little. My impression is in Tay-Sachs with a very educated and committed and concerned population, maybe the answers are somewhat different.
You also raised the question of the interaction of environmental factors and also the interaction of other genes with a particular gene in question, and these are critical factors that we don't know.
So I think that — and this is something that we've discussed in the past — that genetic testing is going to be very unlikely for determining a person's height, athletic prowess or pulchritude, but the screening is going to be limited, in general, to serious genetic diseases.
And I think that one of the other issues is whether therapy is available, and we can test for Huntington's disease, but many very intelligent individuals who are at risk for Huntington's disease don't want to know whether they've got the disease or not or are at risk of having the disease because there isn't any treatment for it in any case.
So this goes back to your question as to what is the utility of this, and we had some readings under Tab 60 that you provided, Bob, that have different points of view. Holtzman and Marteau are relatively negative about the impact of genomics on medicine, whereas Guttmacher and Collins are quite understandably more positive.
I think it's worth noting that the former was written in 2000 and the latter in 2005, and given the rapidity with which the field is moving, I think the difference is critical.
And you raised linkage equilibrium. Certainly the development of the HapMap, which really defines how these blocks of DNA — not defines, but gives us information about these blocks of DNA and their inheritance in different populations — is going to be extremely important because rather than asking about a single genetic variant, one can say for a particular disease or group of patients who have, say, heart disease, are certain blocks inherited more frequently in the affected population than in those that don't have the disease?
And whereas it doesn't give you the gene because as Bob indicated, some of these blocks can be rather large, they certainly narrow down regions that we should be paying attention to.
And I think we also have to remember that some genes are associated with decreased susceptibility rather than increased susceptibility so that we're really a mixture and a balance, if you will, of those that decrease or susceptibility with other genes that increase susceptibility, and this just goes to confirming the complexity of complex diseases.
If every factor accounts for one or two percent in an individual, you know, you have to have 50 or 60 factors, probably not that many, but a large number of factors that are going to be involved.
So I think that Bob's points about genetic variance may increase the susceptibility rather than cause the disease is a very critical one, and then going to the question of whether the variants are functionally involved in the disease and if so, how their altered function is associated with the disease is very critical.
Now, my own view is that personalized medicine already has an impact on cancer treatment, and it isn't one you mentioned, Bob, but in part I think it's because we're further along in our understanding of the genes or genetic changes that are associated with cancer.
So you know, we know not all of the individual genes that increase the risk, but also regions that are gained or lost that are associated with malignancy. So I disagree with Francis' statement in his paper at Tab 8 that in the future we're going to sequence tumors. I think instead what we're going to do is for large classes of tumors, breast cancer, prostate, et cetera, we'll have a series of known genes or chromosomal segments of interest, and we're going to monitor them in the tumor from the individual patient and then tailor treatment depending on what the answer is.
I do think in the future that we're going to do the same for common diseases, and then partly the question isat what age should monitoring begin. The simplest thing is as you're drawing blood for Guthrie test and others, you draw blood for at least a HapMap.
Francis' dream is that we're going to have the $1,000 genome sequence, but then whether it's worthwhile spending $1,000 on every newborn to get the sequence, I'm not sure that we're there, but I can see reasons for doing a HapMap on children, and it certainly is going to depend on the disease. And only time is going to tell whether personalized medicine really can fulfill some of its promises.
but I think in some areas it has already shown that it's important.
DR. PELLEGRINO: Thank you very much.
Dr. Nussbaum.
DR. NUSSBAUM: Well, I thank Janet very much for underscoring what I think is really a very important distinction, and I chose not to talk about single gene disorders of extremely high penetrants, such as Tay-Sachs disease.
There the relevant risks are infinite. I mean, you essentially get the disease if you have two copies of defective gene. The effect on a population screening, heterozygote carrier in Tay-Sachs has been among, for example, a targeted population, a self-targeted population, Ashkenazi Jews, has been very high. The rate of Tay-Sachs in the last ten or 15 years has dropped to, I believe, somewhere around five percent of what it was before based on carrier detection and people either choosing prenatal diagnosis or in some cases the arranged marriage is disarranged.
So this has had a very serious effect, a very significant effect. I was really trying to focus much more on the multi-factorial complex disorders and the issue of really the validity and utility of that sort of testing for common disorders, and it's really a different area.
DR. PELLEGRINO: Thank you.
DR. NUSSBAUM: I was going to say the other thing is that I think the effect of genetic analysis in cancer has been profound, but once again, I'd like to make a distinction. I think most of what's been done has been on the cancer cells, and so it has allowed us a lot of information and is going to provide even much more information about how to treat a cancer.
And in some ways that's a lot like what we have already been doing since the discovery of sulfa and penicillin, and that is studying the microbe to see what they're sensitive to and susceptible to so that we pick the right treatment. That is where the cancer treatment is going, and I think it already is having a significant effect.
What hasn't happened in cancer yet, I think, is a screening where we are finding people who are constitutionally susceptible to cancer and then intervening in some way.
You know, there are people that are carriers for atxitillangetasia mutations, Bloom's Syndrome mutations that have a significant increased risk for various cancers, but in the modest range, similar to what I showed you before, quite different, for example, through BRCA-1 and 2 where we have a highly penetrant gene depending on what study between 50 and 80 percent of people who carry this gene will develop breast cancer and/or varying cancer, and there personalizing the medicine for that family, identifying the mutations and counseling people on an individual basis I think is already having a very substantial effect.
So there's a difference between the single gene and the complex is one that's worth keeping in mind.
DR. PELLEGRINO: Thank you very much.
Janet, do you want to respond? Your light is on.
DR. ROWLEY: I agree with him.
DR. PELLEGRINO: Open for general discussion now.
PROF. DRESSER: Thank you very much. That was elegant and very clear to a non-scientist.
You mentioned that finding out more about genetic susceptibility would help discover environmental factors, but isn't it always going to be very difficult?
I mean, cellular Type 2 diabetes susceptibility, so that you've narrowed it down some, but you still have a huge percentage from environment.
DR. NUSSBAUM: I mean, for example, something near and dear to my heart and that's Parkinson's disease and trying to understand Parkinson's disease. We have already identified single gene defects which cause a small percentage of Parkinson's disease. By understanding the pathway that's affected, we can now look and see, all right, well, what does this pathway interact with, and is it involved with how pesticides are handled? Is it involved with the way reactive oxygen species are dealt with?
So I think that the genes will shed light on pathways that they will help be smarter about asking about environment because as a non-epidemiologist, as a geneticist, I find environment very, very daunting. It is not like the Genome Project where 25,000 genes and ten million variants. I mean, that's a lot, but you can get your hands around it.
DR. PELLEGRINO: Other questions? Gil.
PROF. MEILAENDER: Well, this is sort of a quirky question. So make of it what you will, but as I was thinking about what you said, you know, the example about the smoking case that after I think it was 12 months the information seemed to have ceased to affect behavior.
But it also strikes me that even if for many of us information like that would cease to affect our behavior, if without it costing us too much because, say, our insurance paid for it or something, the information were available, lots of people would want to know, and those are strange things to try to put together, kind of. You know, a lot of us would want to know this information, and that it wouldn't make a lot of difference in the long run in our behavior.
Now, I don't have any evidence really, but does that strike you as true? And what, if anything, should one conclude from that?
I realize this goes beyond the kinds of sort of technical questions you were raising, but I'd just be interested in hearing you talk about that.
DR. NUSSBAUM: Yeah, I'd be happy to. I think it's really a very interesting point.
Some people, and I think there are differences between different people in terms of their personality, are very big into control. They like to feel like they're in control and to be told, for example, that they can't be tested for a susceptibility to cancer from smoking. Whether it affects their behavior or not, what they will say is, "I want the information, and then it is up to me to decide whether I want to act on it or not and how I want to act on it," and it's a matter of personal control.
I remember very clearly when the BRCA-1 gene was first cloned, first identified, and some of the first mutations were found. We really didn't have a good handle on what the penetrance was. So if you carried one of these variants, how likely was it you were going to develop breast cancer?
And so that the push came from NIH and from other areas that we need a study to find that out before people got tested, and I remember very clearly there was a letter to the editor from a breast cancer survivor saying, "Don't patronize me. I don't want that sort of paternalism. I want to know and I should be able to go get the testing now."
And I think that there is some validity to that approach that people have.
On the other hand, you do have to be careful because information can be dangerous. It can hurt people. It can hurt people's self-image. It can hurt them in terms of employment, insurance, and a whole variety of other ways. So if they're being tested for genetic variance and increased susceptibility, they have very little positive predictive value. What are you doing to — what good are you doing for them?
So you have to balance their feeling of "I want." You know, it's about me. It's my body, my DNA. I want this information.
On the other hand, what is having that information going to do from a negative and positive point of view? My view of it is that it's not clear cut at all and that it's going to vary from person to person, just in the same way as Janet brought up. Even with a disorder like Huntington's disease, there are people that say, "I want to know."
I mean, I counseled a man two months ago who had through a research study gotten the information. He wasn't supposed to get the information back, but he insisted, and in fact, the researchers couldn't deny it to him, that he was a homozygote ApoE4 carrier for apoepiprotein E, and therefore had an increased risk for development Alzheimer's somewhere between 15 to 25 years earlier than the general population, and he demanded to know that information. He wanted the information because he was making life decisions. He knew that there was nothing he could do to intervene, but you know, should I sell my house and buy a condo? You know, there are certain things he wanted to know and had to do if — having control over his life by knowing this information.
So that's my view of it.
DR. PELLEGRINO: On this point, Gil?
PROF. MEILAENDER: Just to follow it up, I mean, that was a nice and helpful response.
If we had some kind of national health insurance program and we put you on the committee to decide how we should rank, what sort of a lexical ranking we should come up with even though we can't fund everything in the world, how high would — sort of how important would be paying to test for some of these multi-factorial diseases that you talked about. I mean, obviously they're of interest to you. You've studied them, but now we've put you on this committee that's got to make this other kind of decision. Where would it come?
DR. NUSSBAUM: I hope I don't get put on that committee, but if I were and since you've just put me on it, I would try to test for those variants that reasonable clinical validity, and that they have utility. Can you intervene so that you can improve the outcome of this person? Can you benefit economics? Is it going to in the long run save us, save society money by knowing?
And so, for example, very high on the list, I think my personal feeling would be everybody who comes in for the routine physical at some point is going to have a complete pharmacogenetic survey done. That information only has to be done once. It goes into that person's record, and then it will inform all drug therapy after that.
So that in the long run adverse drug reactions are an enormous source of morbidity and mortality and cost in this country. Billions of dollars a year are spent because of adverse drug reactions. If we could understand what the genetic basis for those are and prevent them prospectively by knowing the genetic information, I think we could have a major impact on well-being and economics. So that would be high on my list.
So I think things with decent validity and demonstrated utility.
DR. PELLEGRINO: I have Drs. Lawler, Kass, and Carson, in that order.
DR. LAWLER: So, for example, diabetes, it would seem to pass the two tests but in a relatively trivial way, right? For example, as a physician, as someone comes into your office, how would you judge, for instance, the diabetes? Would it be the genetic test or the fat gut?
I think the fat gut test would be much more telling, especially if it's fat in a certain way, as you know. So this diabetes information, I think, by itself just wouldn't be striking enough to me, the genetic information, to cause me to exercise more, and my doctor could tell me to lose weight without that genetic information.
So the genetics goes two for two on the test. Nonetheless, if you were on this committee, would you bother?
DR. McHUGH: I'd like to actually make two comments. One is that one should not forget what is probably the single biggest personalized medicine intervention that we've had for years, and that is the family history, and so a family history of diabetes, I think, would play a role, and there is information that people's behavior can be motivated to some extent by a family experience.
See, family history has two effects. One is it demonstrates that there is a low susceptibility variance in that family that your patient is at risk for inheriting, but the other is the social aspect of it, which is that this person will have known somebody who has had this disorder and may have seen Uncle Joe end up with an amputated limb.
And so family history is a major effect. I'm not sure at this point that the variant for Type 2 diabetes make it at the clinical utility level. I mean, we really don't know that.
On the other hand, I'd love to see some well funded, decent prospective studies that really go at it. I mean, that study with the genetic variants on the glutationous transferase that was done by Colleen McBride is one of the fe studies I can find in the literature where people have actually tried to do it and actually put it to a test, in essence, a randomized trial of genetic information to affect behavior. We need more of those sorts of trials because for one thing, it may teach us how to do it better.
DR. ROWLEY: Can I just intervene here? So if you had ten or 15 factors for diabetes, and actually there are a few additional genes that I guess are more of Type 1 than Type 2, what would your answer be to Peter?
DR. NUSSBAUM: Yeah, so the answer would be twofold. One is if you had a constellation of variance that raised the relative risk very substantially, then I think the positive predictive value and the clinical validity would go up.
However, what has to be factored in is that the more variance you have, the rarer you are in the population, and so that the impact from a public health point of view is probably reduced. so that's the tradeoff.
DR. PELLEGRINO: Leon. Dr. Kass.
DR. KASS: Thank you.
And thank you for that wonderful presentation.
I want to, I guess, continue on this theme of clinical utility, which I think you presented quite admirably, and it is sort of of two parts. The study that you cited, and I don't know how many such studies there have been, it seems to me it would be interesting to replicate these things to see what the comparison is between the fear that might be generated by a genetic risks factor from other sorts of things that could be held up as a way of providing changes to the incentives to change behavior.
It's not enough, I think, to sort of simply look at does this genetic knowledge somehow lead to a greater incentive to quit smoking and displaying, you know, photographs of cancers and taking someone to visit, you know, the hospital.?
Since in so many of these things which are not single gene disorders with high penetrants, where the environment plays a large role, it seems to me that it would be very desirable to have some kind of well thought out, prospective disorders to see what is the efficacy of genomic knowledge compared to other sorts of things.
And I wondered if you could comment on that, and then I guess second — well, a footnote to that. The change of behaviors that would be required will differ a lot. I mean, it's one thing for someone who for a variety of reasons likes to eat and likes to eat to excess. The loss, the calculations of present pleasures versus future risks, very different. Much harder to motivate certain kinds of people to exercise than others.
And so it would seem to me that to really do this study right, you would a great deal of multi-variables in terms of the environmental things, and not all diseases are going to look the same.
The other thing is I wondered if genomic knowledge and genetic knowledge — maybe this will change — still has a kind of mystique about it, not necessarily to the scientists who work on it, but to lots of people in the public, and you can tell them till you're blue in the face this is not a determinant. This is part of a susceptibility.
They hear this as there's a certain element of fatedness about this, and I wondered to what extent that is beneficial or misleading in the source of doing your own sort of clinical counseling, especially when you're dealing with things with the penetrants as low and the meaning of this genomic knowledge to you will differ from its meaning to the people to whom you give it.
There wasn't a clear question in there. I'm sorry, but it sort of circles around the questions of how do the people receive this kind of knowledge in contrast to other sorts of knowledge, and if you're interested in clinical utility, how will a profession that might come, notwithstanding all of your caveats, to regard the genomic element as very high? How are we going to know that that really is the best way to try to begin to influence the behaviors that would make for really clinical usefulness?
It wasn't as clear as I would have liked, but you nod. So maybe you can do something with that.
DR. NUSSBAUM: No, I think those are all very useful and important points that you're making. In terms of the first part, I'm not a behavioral scientist, and I just think we need to do a lot more work. I can put a small plug in here for my former colleagues, Colleen McBride and Larry Brody at the National Human Genome Research Institute in the intramural program, that are undertaking now, I think, a very interesting prospective trial where they are typing people for variants that are thought to affect things like bone density and so for a risk of osteoporosis and a variety of other such complex disorders.
From the point of view of trying to really study how do you communicate that information and what do people remember about it and how do they use it and do they used it, I just think we need a lot more of that.
The other point you're making is actually one of the areas where I was told in my charge that I was supposed to particularly identify areas that are of ethical issues, ethical dilemmas, and I think you put your finger on a major one, this issue of genetic determinism and what negative effects that will have or could have on society.
So in terms of thinking about genetic variants that increase susceptibility to disease, there have been a lot of studies done looking at do people take a fatalistic point of view or do they take a sort of empowerment point of view.
And the answer is yes. Different people, different perspectives, different responses, and it's really quite fascinating. The genetic counseling literature has a lot of such studies.
Unfortunately the vast majority of them are sort of hypothetical. You would go to someone and say, "Suppose we had genetic variants that increase susceptibility for alcoholism. What do you think about that? Would you want to be tested?" et cetera, et cetera, et cetera.
Once we start actually finding variants, then I think those studies are going to take a very different kind of tone.
The other area, I think, is in genetic variants that change our susceptibility not so much for type 2 diabetes, but things like alcoholism, drug addiction and other sorts of traits that have a disease component, but also have more social effects.
And there I'm very concerned about over stressing of genetic determinism for traits that have, you know, major social impacts. And so I think it's really incumbent upon everyone who does genetics and people that are interested in genetics to continue to repeat the message that a complex trait is a complex trait with environmental effects that can be intervened in through environmental ways, and that if we were at the end of the day to have a situation where people thought they could be tested and then this would make a prediction as to whether they would have violent behavior or whether they would or would not become alcoholics with high positive predictive value, that I think would be a serious disservice.
DR. PELLEGRINO: Dr. Carson.
DR.CARSON: I'd like to add my thanks for that clear and interesting presentation. My initial question was really along the same lines as Leon's and you sort of answered it to a degree.
But one question or I assume that you're quite pro, you know, genetic testing. It certainly seems like a worthwhile thing to do, and yet it's really in my opinion not that different from many things we've been doing for decades, you know, some of the enzymatic testing, for instance, that we do on newborns. You know, every man when he has his annual physical gets a PSA, which is not necessarily 100 percent predictive, but certainly can provide some guidance in terms of clinical utility.
Doesn't it seem to you like we could use very much the same type of argument for genetic testing? It's just maybe perhaps a little more sophisticated than what we've been doing in the long run, but in principle it's no different.
DR. NUSSBAUM: So I think you're making an excellent point, and to use that old, hackneyed phrase, the devil is in the details. So in newborn screening, for example, if we successfully identify a child at risk for PKU, that child will develop PKU, and it's not a matter of having a low positive predictive value. It's a screening test that obviously needs to be followed up, but I'm talking about the whole system, not just the one Guthrie test, but the whole system or the one tandem aspect, the whole system results in a test which is very predictive and which we can intervene on, an enormous clinical utility, enormous clinical validity.
And so that, I think, is in a different pot. I shudder to talk about PSAs with someone with the kind of experiences that you've had as a surgeon, although I guess prostate surgery is probably not your area — well, yeah, the other end.
(Laughter.)
DR.CARSON: But my understanding is PSA testing also is an issue, and to what extent should it be done and at what age, and what really is the clinical utility and validity of testing people over age 60 or 65 with PSA?
And so in that sense I think they're very similar and the same kinds of questions should be applied.
The argument, and I think Dr. Kass brought this up, too, which is this genetic exclusivity or the specialness of genetic testing. I think what it comes down to, to some extent, is that a lot of the testing that we do is to test for the early signs of a developing phenotype like abnormal glucose tolerance or an elevated blood pressure, well before there is any disease from it, but at least there's a measurable change in the phenotype of that patient.
With genetic testing, there is no phenotype yet, and there may never be, and so I think that's the area where we really have to apply real critical thinking and decide.
In some situations I'm absolutely convinced that genetic testing is going to be life saving. It's going to reduce economic cost. It's going to reduce hospitalization. As I said, I think the top of the list is pharmacogenetic testing from my point of view, although even that requires more demonstration.
In other areas, until the science changes, and of course, what would I be saying sitting here five years from now if within the next five years we develop an effective treatment that prevents the onset of Alzheimer's? then I think whether one would test for ApoE4 or not becomes a very different question.
DR. PELLEGRINO: Dr. Hurlbut.
DR. HURLBUT: I appreciate your emphasis on the utility of the single cause model and the causal web and the polygenic nature of many traits. What I want to ask you is sort of a slightly different angle on the clinical utility question.
Am I right in thinking that when it comes to recombination events that there are hot spots, that it isn't just simple random recombination?
DR. NUSSBAUM: It depends on the scale. So if you're looking at the whole chromosome level or even down to a few megabase level, it's quasi random. There are some differences. The tips of chromosomes have a higher recombination area than the area around centromeres, but in general it looks pretty uniform.
But just like with a digital picture, once you get up really close and start seeing the pixels, then you start seeing very different recombination frequencies, and there is some evidence that the linkage disequilibrium blocks that have been detected as statistical associations have biological reality in that the boundaries between those blocks have been at least in some cases demonstrated to be areas of high recombination.
DR. HURLBUT: The reason I ask that is because it strikes me that it would be very clever of nature to have several genes contributing to a single trait, segregating together consistently. That way you could select for the trait, and that's the reason I wanted to ask you the question.
Because in an earlier report we worked on preimplantation genetic diagnosis, and we pointed out rightly in that report that selecting for traits for most things we care about wasn't very likely; that it's much easier to select for a gene that's a broken link in a chain and, therefore, cause of a disease, but for positive traits or desired variations, that's a lot harder.
But now what you're saying implies that there might be haplotypes that could be selected for, in which case the idea of doing genetic testing for reasons other than disease analysis might have some attraction here.
PARTICIPANT: It becomes more realistic.
DR. HURLBUT: Yeah. Do you think there's anything to that?
DR. NUSSBAUM: I guess I think that the element that's missing from that picture is that it's very likely that it's going to be multiple haplotypes distributed throughout the genome rather than one single one.
DR. HURLBUT: But 50,000 base pairs could still subsume quite a few genes.
DR. NUSSBAUM: Yes, in the area where we already know that there's linkage disequilibrium and significant effects over long ranges in the MAC, the HLA region where there are alleles that move together, and for reasons that are unclear that may not have to do with whether recombination is random or not, but have to do with selection for certain alleles being kept together.
And so I don't think we really know. I think you're raising an important scientific question, is that certain alleles in regions in multiple genes may have been kept together for reasons other than failure of recombination to occur.
DR. PELLEGRINO: Dr. George.
PROF.GEORGE: Dr. Nussbaum, I wanted to follow up — oh, was somebody ahead of me? — on some of the comments and questions of Professor Meilaender and Kass, and really the question I have is one that people in your business probably ask very frequently. It's the forbidden knowledge question.
And here what I have in mind is not whether an individual is better off not knowing something about himself or a family is better off not knowing something about a family member, but rather the more general question: are there some questions about genetics that we, in general, are better off not asking? Is there genetic knowledge that we are better off as a society not knowing about?
And we divide those two questions along another axis. If there's anything to the idea of forbidden knowledge, are there some things that, for example, it's better off not knowing absolutely, that there are no circumstances in which a decent society would really want to know because of the bad things likely to happen if we do know.
And the other would be a category of things that we're better off not knowing now because knowing it is dangerous, potentially harmful before we know other things. Now, maybe after we learn other things, the possession of the first body of knowledge would not be dangerous.
Now, I ask this not as a rhetorical question. I myself have a strong aversion to the very idea of forbidden knowledge, but you're working right smack in the area, and I bet you've asked yourself the question, and I'll bet it is kicked around. So what are your own thoughts and what do people say about this?
DR. KASS: Are you going to give an example?
PROF.GEORGE: Yeah. Do you have one, Leon? Maybe if you have one.
DR. NUSSBAUM: I'd love one.
PROF.GEORGE: Things having to do with links of genetics with crime. There's a term, but is it called criminogenic, a criminogenic basis for behavior, that kind of knowledge?
DR. NUSSBAUM: So I can approach this two ways.
PROF.GEORGE: Or even just your own — sorry to interrupt again —
DR. NUSSBAUM: Sure.
PROF.GEORGE: — your own example that you were talking about with alcoholism. I think you were getting near raising a question about whether we really are better off as a society knowing about it, knowing about a genetic link with alcoholism or a predisposition to alcoholism because of the nature of alcoholism is not simply a disease, although there is a disease component to it, I guess, by the prevailing account.
DR. NUSSBAUM: Major account.
PROF.GEORGE: But there's so many other things connected with it, social factors connected with it.
DR. NUSSBAUM: Right.
PROF.GEORGE: I wish I could think of a better example. If somebody has a better one, toss it in, but this is the general thrust of my question.
DR. NUSSBAUM: Right. It's a very difficult question. It's actually one that bothers me at two o'clock in the morning when I wake up and I'm having trouble sleeping.
So is there such a thing as forbidden knowledge in genetics? I approach it sort of in two ways. One is I can kind of assuage my concern by just reminding myself that we're not talking about genetic determinism. We're talking about susceptibility variants, which are going to be, as Dr. Rowley pointed out, probably balancing acts of various kinds. Certain variants that might increase one's relative risk for certain things and others that would decrease it, and so that knowing those at an individual locus-by-locus or gene-by-gene way might not necessarily have a major impact on the individual. There's going to be a mixture of these things.
So there's that. However, I still personally have concern about what I think is the major challenge facing complex genetics now, and that is what are we learning about human origins and, in particular, human geographic origins, and what is the overlap between the science of human genetic origins and the social construct that we call race.
That, I think, is a major, significant, serious societal issue, and one could imagine — and this has already happened to some extent. Janet brought up the question about Tay-Sachs disease among Ashkenazi Jews. Ashkenazi Jews were very fast to promote heterozygote screening. Ten, 15, 20 years later, a very different attitude among quite a few Ashkenazi Jews about the breast cancer gene. It was actually quite different, even though they have a significant allele frequency for certain variants that predispose to breast cancer. The feeling that this was a variant that was stigmatizing them as a social group.
DR. PELLEGRINO: Dr. Foster.
DR. NUSSBAUM: Is that even close to addressing?
PROF.GEORGE: Yes. Indeed, it is, and the only follow-up I would have is what about the potential uses. Do you ever worry about potential uses of genetic knowledge, for example, in a military context that could make matters worth — what weaponizations that are made possible by virtue of advances in genetic knowledge? Is there anything there to worry about?
DR. NUSSBAUM: That has not occurred to me, and I can't imagine it, but I mean, maybe someone could convince me, but I don't know of it.
PROF.GEORGE: It sounds like Janet knows something about it.
DR. ROWLEY: I don't, but you didn't really ask the question of forbidden knowledge or answer the question, and I'm curious as to what your thoughts are on that matter. Are there some things — say, take the example of alcoholism — are we better off not knowing about susceptibility to alcoholism or drug abuse as a society rather than understanding that?
That's just one example that was tossed out.
DR. NUSSBAUM: So my answer to that is that I think that those are not examples where we should — those are not examples of where we should not go. I'm sorry to do the double negative, but I think those are examples of where we should go, but the individual autonomy of being able to choose whether one wants to be personally tested or not, needs to be absolutely protected.
But I think that that knowledge of susceptibility to alcoholism, drug abuse, other sorts of traits that have societal impact is valuable. I'm actually not that worried about that.
I guess the example I come back to often is, I mean, I'm an Ashkenazi Jew, and there are, quote, Jewish diseases. There are rare carriers of rare disorders for a whole host of disorders, Gauche disease, Canovan disease, Tay-Sachs disease. You can go down the list.
My own personal feeling is I'm grateful to have that knowledge so that we can do something about it. I don't feel stigmatized because I know that every group around the world has their own sect, and it's just to some extent we've discovered them. In many situations we haven't discovered them. So we're all in the same boat together. It's just that we're sitting in different places in the boat, but we're all in the boat.
DR. PELLEGRINO: Dr. McHugh.
DR. McHUGH: On the forbidden knowledge thing, you have to remember that sometimes the very study of the possibility of a connection to behavior and genes has provoked many people to be beset by anger about this.
The XYY study, you remember, we were looking to see whether young children with XYY were criminal, and I think quite rightly we said that was perhaps stigmatizing them right at the start and putting before them the possibility that might not be there if we weren't, in fact, studying it.
So it became a forbidden form of study. Fortunately, it turned out that they weren't.
DR. NUSSBAUM: Well, I should say that my very close friend and actually my mother-in-law —
(Laughter.)
DR. McHUGH: That's pretty close.
DR. NUSSBAUM: Yeah. — was involved in the study in Denver run by Arthur Robinson, which was a prospective study of newborns looking for SEC (phonetic) chromosome abnormalities, and as opposed to what happened with the Walter study, that study was allowed to continue, and they ended up following 40 or 50,000 newborns, and it was done as a therapeutic interaction between social workers, geneticists and the families.
And what it demonstrated was that knowledge could be used for intervention, particularly in the area of education for the children who actually have learning disabilities which are not the 47 XYYs, but the 47 XXYs nd the 47 XXX females.
DR. PELLEGRINO: Dan, you've been waiting very patiently. Thank you.
DR. FOSTER: Well, that's right. I want to just make a brief comment that's not meant to be amusing or anything about it, but there is another form of genetic terminism that is rampant in clinical medicine, and you know, it really is in the old phrase that, you know, my genes made me do it, and probably the most important generalized disease in the world right now has to do with obesity and Type 2 diabetes. When you get the metabolic syndrome you might — I can't remember whether I said this last meeting or not — but the leading cause of liver disease in the world is non-alcoholic fatty livers. It gives you more cirrhosis than you get with alcohol and so forth.
If you take care of patients with diabetes, as I do, and Type 2 is the common thing, and all are overweight, and it's an absolutely curable disease right now. You don't need a kidney transplant. You don't need anything. You prevent the eye disease. It's an environmentally cured disease, but they always say they see this new gene for Type 2 diabetes and said, "I always knew that the reason that I couldn't lose weight was because of this gene."
And as a consequence, a defense against the cure of major diseases, like lung cancer and smoking, coronary artery disease, almost all of these things have a huge environmental component.
Now, we learn other things about doing the genes. I've been involved in the discovery of an effect on the insulin fairly recently in Asian Indians, which gives you the metabolic syndrome without obesity. It's a very interesting thing. There's a little review coming out fairly soon about that.
So you learn these things, but a very great amount of the disease that we deal with right now can be controlled without the genes, and this is not to say that, you know, endocanibinioid receptors and hedonic pleasure networks are not important, you know. I mean, we now think that the eating signals are hooking up with the same place marijuana goes and so forth so that there are things that drive you.
But these are curable diseases, and so we have to — I think we have to be careful to not give an excuse to do the things that we can do is the minor point that I want to make.
Mike Brown, who works at our place, always tells the medical students that disease is a consequence of both genes and environment, and he said, for example, a person that was just hit by the car out in front of the medical school and broke his hip had a genetic disease.
And the students all say, "Well, wait a minute, Dr. Brown. How can you say that? I mean, that's a pure environmental disease. The car hit you and he broke the thing."
And he says, "Well, if you had better hearing or better seeing, you know, you would have gotten out of the way and you wouldn't have had it."
But I do want to say we have to be a little bit careful about a defense against things that we can do right now on a genetic basis because of the assumption that these polymorphisms and whatever they are are going on are true, and we need to do all of those things, I think. I mean, you're going to learn how to maybe do specific treatments in that.
DR. NUSSBAUM: I think it's a fascinating question in behavior science to ask the question does knowing that information make one more motivated to act on it or retreat into a fatalism and say, "Because of my genes there's nothing I can do about it."
I think it's an open question. It's probably different for different people, but what I think is really a fascinating question is can we now build on that to do behavioral science research and figure out how better to get people to intervene in the environmental factors and cure these diseases that they're susceptible to.
DR. PELLEGRINO: Other questions?
PROF. SCHAUB: Do you have views on direct to consumer genetic testing, given your concerns about misapplications or misunderstandings of the information?
DR. NUSSBAUM: Yeah, I do have strong issues about it, and actually I was at a meeting that Dr. Hudson organized quite recently precisely on that topic.
So I think there are some potential benefits of certain kinds of testing in terms of empowering people, is what I was speaking to Dr. Meilaender about, which is people want to know information and perhaps use it.
On the other hand, there's a lot of direct to consumer testing that, first of all, is false in terms of clinical validity. It is without any clinical utility, and on top of it all, in some situations is bound together with completely unproven neutroceutical interventions that I think are essentially something that the Federal Trade Commission should look hard at in terms of false advertising.
So, yeah, I do have strong feelings about it.
DR. PELLEGRINO: Leon.
DR. KASS: This is an indulgence, but I don't see other hands. So if you'll indulge me, this is back to the subject of dangerous knowledge. Just an anecdote.
I was a young staff person on an NRC committee just like this one in 1970 to 1972, and I was stunned when the report review committee of the academy decided to censor the report that our little committee had produced on the grounds that if people read that document they would cut off all funds for biomedical research. That was dangerous knowledge, number one.
(Laughter.)
DR. KASS: But the more interesting one was it was coincident with another example of self-censorship, one which I applauded, when William Shockley proposed that the academy come out in favor of a study of race and IQ, then I don't think was anything like the genomics studies, which now could in principle at least be undertaken, but Dubjanski was appointed the head of a serious committee, and it was a model, just a model of prudence saying that there was absolutely no good that could come from this kind of a study, and we ought not to give it our blessings.
And it seems to me — and you've touched on this already — we may yet face certain kinds of difficulties. The African American community did not take to the proposals for routine screening for sickle cell disease the way the Jewish community did over Tay-Sachs partly because of all kinds of other concerns about what this meant in terms of stigmatization, absence of care, and I think not without cause.
DR. PELLEGRINO: Dan.
DR. FOSTER: All racial things are not problems at all. I hope you didn't mean to do that because it would be just like the sickle cell thing. Helen Hobbs has discovered a new gene that means that if you're carrying it if you're an African American, you don't get coronary artery disease for the same level of cholesterol and so forth.
I mean, this is a terrific thing that came out of the Dallas heart study. I mean, you know, and the Dallas heart study was deliberately aimed at why African Americans have more heart disease than other things.
You know, we measure blood pressures in barber shops. I mean in other words, what they — I don't have anything to do with this, except it's at my school — and the whole community, not only the religious community, but it turns out if you want to get your blood pressures checked regularly, go to the barbers for men. It's the men that are a problem, you know, to do that.
And so we have these little things all over town, and the enthusiasm of the community because things are coming out that may save their lives and so forth. So it's one thing to talk about — I mean I agree with you wholeheartedly about minor changes in intellect that might say that somebody who lived in Texas was going to be more stupid than somebody who lived in Massachusetts or something, you know, but these other things, I don't want to leave the impression that racial studies in and of themselves are dangerous or should not be done.
DR. KASS: I agree with you completely. I didn't mean to imply otherwise.
DR. FOSTER: Well, I was sure you didn't mean to imply that.
DR. KASS: I'm glad to have it on the record.
DR. PELLEGRINO: I think it's time for a break until 3:45. See you all then.
