FALL MEETING IN NEW YORK CITY AND BIOETHICS FORUM Ethical Issues in Human Genome Research Dr. Thomas H. Murray Click here for Dr. Murray's bio I’m going to talk about three great challenges that we are facing today. Number one, the avalanche of genetic information. Now in 1988 there were a few small pebbles cascading down the hill of genetic information. As you have just seen in Jeff Friedman’s presentation, we’ve got some fairly good-sized boulders working their way down the mountain. The real avalanche hasn’t arrived yet. But, it’s coming. Predictably it will be here in the relatively near future. So, the first great challenge of the genome project is how to responsibly handle the ethics of law and public policy of this avalanche of genetic information. The second great challenge will be what I call the technologies of genetic manipulation. I’ll say a bit more about this later. I understand there’re some people here who share my interest in the Olympics and high-level sport. We already see some early signs of what the challenges will be in our dealing with technology in genetic manipulation. And the third is something I’d like to call the temptations to genetic apology. I’ll have to explain what that means in just a moment. When you think about genetic information, when the genome program first began, a working group was established for the ethical, legal, and social issues working group and as punishment for having suggested that we pay attention to these issues early on, I was named a member of the working group. We talked to lots of folks, and the thing they were mainly concerned about was the possibility of discrimination against them because somebody knew something about their genes which predicted that they would be susceptible to a certain disease. So, we established a task force of genetics and insurance because that turned out to be the most important one to really go into. And one of the first things we discovered in this ethical, legal, and social issues working group is that the conception that most of carry around about genetic diseases, diseases like Huntington’s, is correct about Huntington’s, but is misleading for the great majority of diseases that will be connected to genes. Huntington’s—Jeff did a beautiful job of sort of explaining how genes work. I actually use a literary metaphor which helps me as a humanist understand it. Imagine an alphabet with just four letters; where every single word in the alphabet and every single punctuation mark was exactly three letters long. But of course we don’t care about letters and words, we care about the units of meaning—the sentences. Well, in the genome, the units of meaning are the genes. Do you know what the shortest or longest are, Jeff? Yeah, very short would be a hundred or fewer letters long to sentences of Faulknerian length that might run on for tens of thousands of words. Those are all genes. Those are the units of meaning. And the different mutations, sometimes you replace a letter, that’s the mutation. Sometimes you just drop the letter so everything shifted over and the genome reading device is kind of stupid. It continues to read three at a time, even if there’s been a disruption. Or sometimes an entirely new kind of mistake we didn’t know about—you get a stutter at the end of a sentence. That’s the problem with Huntington’s disease. You get three letters that just repeat too many times. We all have a stutter, but most of our stutters are relatively short. In Huntington’s disease, the stutter is quite long. And that is enough to disrupt the function of the gene. So that’s Huntington’s. Now, exactly as Jeff said, when we’re talking about the connection between genes and risks, we’re talking about probabilities not certainties. Huntington’s is a virtual certainty. If your stutter is very short; you’re not going to get it. If it’s very long and you live long enough, you will get it. Diseases that are directly caused by a gene; they are a function of interaction between genes and environment. The two breast cancer genes, and I gather there’s quite a Utah connection with this group. The Utah firm Myriad Genetics has licensed a test for BRCA1, BRCA2. And again that test does not tell a woman that you either are certain to get breast cancer or you’re certain not to get it. If the test is negative, you’re back to the population risk which is about 10 or 11%. If you have one of the clinically significant mutations, it may be a lifetime risk. Most of it is compressed in the later years of life; it arises in the 60s or perhaps higher. The Hastings Center has a current project right now looking at what’s going on in newborn screening. In the US there are roughly 4 million babies born each year. Newborn screening—if any of you had children born in the past 20 or 30 years or even longer, your children have been screened. You may not know it; you may not even have been told it was being done. But a little prick was made in your child’s heel, two capillary tubes of blood were drawn and put on a little card called a Guthrie card, named after its creator. Those little dry blood spots can be used to test for a variety of diseases. PKU. Jeff mentioned PKU. Have you ever drank a diet beverage? It says phenylketonurics shouldn’t drink this, because they can’t tolerate one of the amino acids that’s in phenylalanine, a synthetic sweetener. Newborn screening has been low profile. Most people aren’t as much aware of it, but it’s widely regarded as a very successful public health screening program. What I want to emphasize to you today is that the menu of tests has just been expanded within the past couple of weeks. The recommendation has been made and some states are testing for a mere handful of conditions. The recommended list is now 30. And this is a state-run program by the way. Each of your states has a different screening program. For those of you who are former governors, all of your states have them right now, and there’s numerous variations in how many things they test for, and what happens afterwards. But the recommendations of this panel are that every state will test for at least 30. As we were doing our work, we began talking to the people who make gene chips, particularly Affy-Metrix, which is predominant manufacturer of the so-called gene chips, and they’re made just like computer chips. Same technology so they can be mass produced later. I was talking with the president of Affy, and some of his senior staff, and he said we could, for 4 million a year, we could deliver a gene chip at essentially pennies per chip. A gene chip can run a few thousand variations or it can run hundreds of thousands of variations. Cost goes up as you increase the number. But the same drop of blood can be used to test for 3 conditions, 30 conditions, or 3000 conditions. The cost of the test itself will not be that different. What has to go on to gather the sample and to run the sample won’t be that different. The difference will be how much information is generated, how much useful information, how much information that makes people scared as hell that their kid is going to die of something, how much money will be spent following up for these conditions. I spent 15 years as a professor at medical schools, and my experience is that the senior and most respected clinicians invariably recommended fewer rather than more tests. Don’t request a test unless you really think it’s important and you’re prepared to follow up if you get an abnormal reading. Much medical care is following up on these kinds of abnormal findings. They may lead nowhere. What’s happening with newborn screening is that ethical principals that have underscored it are being challenged. In the past you only tested for diseases that you can detect early, that you couldn’t detect otherwise, that you can detect early with this kind of genetic screening test, and that you could treat early on and make a difference in the child’s outcome. The press is on now to do more tests just to find out—just out of curiosity to see if they might have something, even if there’s not a thing we can do about it today to help the child. So the principles are under challenge. Genetic manipulation, second category of worries. I grew up in Philadelphia and I’m sorry it’s from my old days of playing basketball on the street, and it’s where I ruined my knees—fake left, go right is what you did if you were successful. Many years ago we began to worry about genetic manipulation, and they were mainly worried about gene transferal also known as gene therapy. But in fact, we have an eminent gene transfer researcher here today. The FDA asked me to come about 20 years ago to talk about anabolic steroids, the Hastings Center in the very early 1980s did a project on ethics and drug use in sport. So, they asked me to come and talk about anabolic steroids. They didn’t make it clear why I was being invited; they just wanted me to talk about its use in sport. It turns out they were trying to decide whether to modify that little piece of paper with all the risks of everything that goes inside the package. And before I left I said biosynthetic genetically engineered human growth hormone is on the way. When that hits the market you’re going to see many people who think it’s a good idea to make my child taller than he or she would otherwise be. At the break in that hearing, a physician came up to me, she introduced herself as a pediatric endocrinologist, and she said she had already had that request. She thought for a minute and she said it was all physicians, now that I think of it. But I think that just tells me two things: one is they have the prospect of affording it because it’s going to be tens of thousands of dollars a year and that they knew about. Most people couldn’t afford it and didn’t know about it anyway. Since then, other biosynthetic drugs have come a long way. EPO, do you know what that stands for? The long chemical name is Erythropoietin. It’s a hormone that encourages the bone marrow to make red blood cells. If you are an athlete, if you are a long distance runner, a road cyclist, a Nordic skier, you want to have some more red blood cells. Not too many more because you could kill yourself. Your blood would turn to sludge, which appears to be what happened to somewhere between a dozen or a dozen and a half cyclists in Western Europe almost immediately after EPO first hit the market. They just dropped dead suddenly—these were well conditioned young men. The Atlanta Games—anybody here from Atlanta? The Atlanta Games were known in the Olympic community as the EPO games. The drug was widely available; there was no test for it. The athletes said it worked. EPO and other substances have the potential the change the way we do sport. HDH growth hormone has the potential to change the way we deal with our children. We think about generally how to handle enhancement technologies, which these are. Memorex, I guess there was a product called Memorex, but this is a fictional product that improves your memory. Is there anyone here wouldn’t love to have their memory improved? Imagine Memorex existed or imagine even more ambitious and effective—it didn’t just enhance your memory—and this is one of the world’s great researchers on the brain here—(Dr. Greengard). So imagine it enhanced your executive cognitive functions. Imagine there was such a drug. There’s no question it would be developed but for enhancement purposes it would be developed for people who have deficits, for people who are developing Alzheimer’s dementia, for people with other kinds of cognitive deficits. But it won’t take long for the rest of us to cotton on to the fact that, hey I’ve got this report to write, it’s late at night and I’m tired. I’m sort of caffeined out, but there’s something better that might help me stay awake, stay focused, think clearly, remember what I need to do. What an impact when that happens. The Olympic movement is deeply worried right now about gene transfer in sport. There are researchers, including one here today, who are doing research on gene transfer in muscle. Now again, they’re not doing this for athletes, they’re doing it for people with muscular dystrophy in this case, and other muscular diseases. But, if we come up with these technologies to enhance muscle growth and function, it won’t take long for athletes to come up with it. I’m frequently asked to talk about this subject. I’ll only say one thing about it—reporters always want to know, when’s it going to affect the games? I don’t know the answer to that, what I do say is that there will surely be people offering soon, if they aren’t already offering, gene therapy, gene enhancement for muscles. I know enough about the world of sport. There are plenty of charlatans out there who will offer it, and there are enough gullible athletes, coaches, and trainers who will give it a try. Will it actually work? Probably not for a long time. Will it do some harm? To a number of people it probably will, but to most of the others it will be either completely ineffective or a placebo. But someday, some year, I can only hope that it’s some point in the distant future, but we will have to deal with the issue of gene transference. I mentioned genetic apology. I have a rough thesis here. The thesis is: the more we exaggerate the power of genes, the power of genetic information, the more we underscore the power of genetic apology. And I borrow this from an historian Robert Proctor, who wrote a brilliant book called Racial Hygiene: Medicine Under the Nazis. It’s a disturbing book. Proctor looked at this thesis that the scientists and doctors who did the horrendous experiments under the Third Reich that we’ve all read about and that were held up as the absolute paradigms of evil, and the extortions and perversions of science and its treatment of its subjects. Well, Proctor found that indeed some of the scientists who did this were the dregs of the German community. But not all of them; some of them were leaders, internationally recognized leaders who were seduced for a variety of reasons to align themselves to the Nazi powers. And the party began to use this theory of racial hygiene as pretext for its programs of racial eugenics, racial elimination. Well, we don’t face that kind of danger at this time, but we do face other kinds of dangers of genetic apology. You will, if you haven’t already, seen people who will plead, I’m not guilty of this criminal offense because it was my genes. I didn’t choose to do this, my genes made me do it. Those of you in sport remember the popularity of steroid “roid rage,”—people claiming that because they took anabolic steroids to enhance their sports performance, they couldn’t control themselves and therefore they beat the hell out of somebody. Another useful excuse will be in policy positions, where the claim will be that the reason these people are not doing well is not because they’re treated unfairly in some way, but it’s because their genes just don’t fit them as well to succeed in the social economic environment that we’ve created. I’m going to end with talking about genetic exceptionalism. And I’m culpable—I coined the phrase as far as it’s known. This came out of this task force of insurance. People were worried about who wants to know my genetic information, and what are they going to do with it. We got insurers to work with us; we got people at risk of disease to work with us, and some experts. The insurers describe the moral principal they call actuarial fairness. Actuarial fairness says you should pay as a customer according to your risk. Now that makes perfectly good sense if I’m an employer, and I have a very hazardous workplace. My premiums ought to reflect the fact that I don’t have a well-kept workplace. On the other hand, if I’m virtuous employer, my premiums should be low because my employees are safe and my workplace is safe. Is actuarial fairness a proper standard to apply to healthcare? The apotheosis in theoretical and actuarial fairness is a system where all of us are insured for diseases we’re not going to get; if however you have the mutation of BRCA1 and you get breast cancer, it’s been nice knowing you, you’re on your own. Jeff had an interesting example of potential employment; this was the Long QT syndrome case. Well there is a real example. Burlington Northern Railroad was surreptitiously testing—well this is the claim—it was said that the EEOC of a relative had settled, so I guess there’s no precedent, so the true facts are unknown. Here are the facts that we’ve heard. Burlington Northern began surreptitiously testing some of its employees for a rare genetic anomaly that is associated with Carpal Tunnel syndrome. The apparent idea was that Burlington Northern could claim, well, it wasn’t the workplace environment that caused this person’s disability, it was their genetic predisposition. I’ve talked to some medical geneticists about this. They said if you have this particular abnormality, you would not have been running a jackhammer for 25 years, you would have had Carpal Tunnel syndrome early in life and from relatively minor stresses. Someone figured it out. One of the workers’ spouses was a nurse. Suspicions were aroused and she tracked them down, so it was ultimately settled. The interesting thing here is it looks like the medical advice in this so-called scientific case was absolute bogus. The Long QT case we were talking about would be a much more serious issue since you would have to have public policy to deal with it. I want to reinforce a point that Jeff made. I’m going to ask a question. I’m going to ask that all Nobel Laureates in the room please refrain from answering the question, because I’m sure they know the answer only too well. This task force that I chair on genetics and insurance was given the job of thinking about what would be the implications of this avalanche of genetic information in the long term. We tried very hard to distinguish genetic information from other health-related information. Ultimately, I realized we have two buckets. Now you have to help me. Imagine a bucket here that’s labeled “Genetic” and the second bucket is labeled “Non-Genetic”. I’m going to give you something and you tell me which bucket it goes in. Huntington’s disease? (Answered by group) Genetic. Getting run over by a taxi crossing Broadway to this meeting? (Answered by group) Non-Genetic. A tougher one now—a risk factor, cholesterol level? (Answered by group) Genetic . . . Non-Genetic. Tell me, does anybody here see a bucket labeled “Both”? You see the problem—it is in fact both. Your actual cholesterol level is some complex interaction between genetic factors and environmental factors. When you go see your doctor as I have with high cholesterol, what does your doctor tell you? You cannot change your genes, but eat better, lose weight, there’s a variety of things, take Lipitor, and other things that help reduce cholesterol level. The problem with the two-bucket theory is that while it works well enough for things like getting hit by a taxi or Huntington’s disease, the overwhelming mass of human conditions that cause the great bulk of medical expense, misery, and premature death is in the middle. It’s the dreaded normal curve. There’s stuff on the two ends but almost everything is here in the middle. We realized that the charge to our task force was an impossible charge. Either you had to take such a narrow definition of genetic information as to leave almost everything of interest out. Or else you had to admit what the real question was this combination of genetic and other risk factors—all-health related risk factors. So, we ended up rejecting the two-bucket theory and recommended that genetic information be treated as all other health-related information. This was a heretical stance we’ve taken in the early 1990s, and I think it’s less heretical today. The eminent law professor, George Annas and his team at Boston University, drafted a model genetic privacy act. And you don’t need to read this whole quote, just get that first phrase. They described your DNA as coded probabilistic future diary. They also noted that you didn’t write it, you can’t read it, and somebody else might be able to. It’s a pretty scary image. They go on to say, to the extent that we accord special status to our genes and what they reveal, genetic information is uniquely powerful and uniquely personal, thus merits the privacy act. The message I want to give you is, they’re right only if we in fact grant genetic information this kind of mystical occult power. If we come to see genetic information as just another kind of health-related information, we can deprive it of that power and begin to use it intelligently in medicine and public health. I think I’ve gone on long enough so I’m going to skip what I have left and leave time for conversation. These are just a series of responses to the complaints against my point of view. So what’s the task before us? To try to anticipate the implications of this avalanche of genetic information. To prepare ourselves and our public policies for the technologies of genetic enhancement. And to, at all costs, avoid the temptation toward genetic apology. Thank you very much.