2012 Panel Discussion - Questions and Answers

Genomic Screening (Eugenics, Insurance, Privacy)

How long until newborn screening by whole-genome sequencing becomes (1) available, (2) routine, and (3) useful?

The question is excellent because it highlights the concern that availability, routine application, and utility are often poorly correlated features of medical practice. This test is already available in specialized settings and is not even extraordinarily expensive relative to many other diagnostic procedures routinely applied to newborns with abnormal characteristics. We hope that the method will become routine under appropriate circumstances. However, experience tells us that many medical tests are used routinely just because they are available, not because of any clear evidence of utility. Hence, I think that routine use is imminent for significant numbers of newborns but am apprehensive that use will outstrip utility.

If we could sequence every embryo before implantation, would that be a good thing?

This prospect is too much of a “Brave New World” idea for my tastes. Do we really want in vitro fertilization, followed by pre-implantation diagnosis, to become the standard means of human reproduction? I doubt it, now or ever. Since all of moral philosophy is about trying to define “a good thing,” I will not try to enunciate general rules about the circumstances under which this procedure would qualify.

Can personal genome sequencing and health insurance co-exist?

I think there are real issues about the ability of genome sequencing and common forms of insurance to co-exist. These issues differ from those surrounding the clinical utility of genome sequencing. Clinical utility requires there to be a substantial likelihood that the data will improve the health care of an individual. This is a much higher bar than simply differentiating an individual’s risk from that of the general population. I suspect even our limited current knowledge of the effects of genetic variants on health would support substantial risk stratification. In the years ahead, I am confident that this goal will be readily achievable long before there is widespread clinical utility. I doubt that society wants to go down this path. Federal law already prevents most uses of genetic data in setting health-insurance premiums. Long-term-care insurance and life insurance pose more difficult questions. Simple genetic-privacy principles are unlikely to resolve the resultant dilemmas. Individual insurance has been giving way for years to risk-pooling strategies that average risks over large groups. Perhaps the “socialists” will win this one, with genomics being just one driver of a needed change.

Where should we draw the ethical bounds of exploring genomic techniques? Should people be allowed to genetically modify their children during fertilization to eliminate genetic predisposition for disease? What about GM your kids to be stronger, smarter, faster?

No one wants to live in Huxley’s dystopia. On the other hand, education always works better than prohibition. Consider, for example, the slow trend toward equality in male and female births in India despite greatly improved options for carrying out pre-natal sex selection. Furthermore, when there is no social consensus about the underlying moral issues (e.g., in the ongoing conflict over abortion in the U.S.), a strong case can be made for leaving decisions to individuals. There is no possibility of enunciating general rules about the management of hypothetical social risks. Having said that, I am worried about the “stronger, smarter, faster, more beautiful” part of the question. Issues surrounding human enhancement, by genetic or pharmacological means, are likely to take a steadily more central place in discussions of bioethics. I prefer to think of this arena less as a slippery slope than as one of innumerable grey-zone distinctions.

Given that genomic data would be so large that it must reside on computers, and that computer systems are vulnerable to security breaches, how can privacy concerns be adequately protected for any progress to be made? If the genetic sequences of everyone on earth were known today, what changes or improvements would be possible (1) immediately; (2) in 5 years; (3) in 20 years?

I am no longer preoccupied with the privacy issue. If someone posted my identified genome sequence on the web, I would be unhappy. However, I would be even more unhappy if Google posted a list of all the web sites I have ever visited. We need to move away from “genetic exceptionalism,” the idea that genetic data are intrinsically so different in character, and so much more sensitive, than other data that we need to develop a whole zone of specialized laws and moral rules to curtail abuses of genetic information. For example, consider the question of whether the results of an HIV test pose more or less of a privacy concern than a genome sequence.

On the question of what we would learn from having comprehensive data on billions of genomes, the answer is “not much” unless these sequences were accompanied by detailed phenotypic data. Assuming we had sequences of a vast number of people that were linked to phenotypic data—and particularly phenotypes over time, including medical histories—the data would be a research bonanza. The goal of understanding human genotype-phenotype relationships, across a broad range of genotypes and phenotypes, poses perhaps the greatest challenge ever to inductive science. The only possibility of long-term success lies in attempting to overwhelm the problem with data. I believe the imagined difficulties of managing and analyzing these data are overrated. The big difficulty is finding a socially and technically acceptable path toward collecting them. By the time we solve this problem, we will be in a good position to manage the data and start the needed analyses.

With medical treatments and fertility medicine, what are the current selective pressures on the human genome? Is the prevalence of deleterious mutations increasing? If so, what should we do about it?

The main selective pressures acting on the human genome today have nothing to do with expensive medical procedures. Differential birthrates around the world—and within all individual societies—are huge, and these differentials provide the basic machinery of selection. We know very little about what, if any, genotypes influence differential birthrates. However, it seems unlikely that genotypes are wholly irrelevant: to the extent that they play a role, selection currently strongly favors whatever genotypes are associated—by whatever mechanisms—to high birth rates.

In rich countries, there undoubtedly is an increase in the prevalence of deleterious mutations that would interfere with reproduction without medical intervention. Infertility treatments are a good example, as are many of the measures that have so successfully decreased maternal and infant mortality. For example, the widespread use of Caesarian deliveries must have altered selection on pelvic anatomy in rich countries in just in a few generations. It would be surprising if genetic influences on myopia and other easily corrected visual defects were not increasing in frequency. These points are all abstract because it is difficult to identify examples, other than extremely rare ones, of specific deleterious genotypes that are becoming more common as a result of medical interventions. We will learn much more about this issue during the decades immediately ahead as our understanding of genotype-phenotype correlations increases.

With respect to the long-term health of the human “gene pool,” the obsession of the 20th century eugenics movement, there are some grounds for theoretical concern. Estimates of the number of deleterious mutations that occur in each generation, and the strength of selection against them over evolutionary time, are getting better as a result of genomic analyses. These estimates suggest that negative selection has played a major, ongoing role in human evolutionary history. Affluence is undoubtedly leading to weaker selection, at least among the privileged. History speaks with a loud voice about what we should do about it: nothing. This is a good question to revisit in a few centuries. Even then, my advice to posterity is “proceed with caution.”

Do you think the American public tends more towards the dystopian/genetic determinism side or utopian/personal medicine/no disease model? Do you think one viewpoint is more harmful to society, especially marginalized groups?

I will let someone else speculate about the American public’s ambivalence about the future. Utopian and dystopian visions permeate attitudes toward every manner of human activity. Mostly, these discordant visions co-exist peaceably. I consider utopian views to be far the more harmful extreme, particularly when articulated by self-serving scientists and their spokespeople. Utopian outbursts distort expectations, lead to unwise resource allocation, and undercut the real potential that science has to build a better future. They achieve the latter effect by promoting a fanciful conception of what science is, how it is done, and how it achieves its occasional major successes. I also think utopian views pose the more dangerous for marginalized groups, who have always been victimized by utopians under one banner or another. Dystopianism is primarily a device that artists use to remind us of our potential for murderous folly. We all benefit from these reminders.

The people who said “yes” to knowing about a fatal gene were young – perhaps they want to plan to have or not to have children. The people who said “no” were older – perhaps they want to protect their own hearts from fearing for their children. This future belongs to the young?

I think this question was motivated by a poll Jim Evans took of the audience during the panel discussion. This university-community audience was not representative of the general public. In Huntington’s families, most children choose not to be tested when they come of age. My guess is that the trend in academic communities will be toward the position adopted by the younger members of the panel audience. In the general public, I think the uptake of genetic tests will be tightly tied to the availability of effective, pre-symptomatic interventions.

When will an understanding of our genome reveal our personality disorders, and how can we protect our privacy on this matter?

We are just starting to identify genetic variants that predispose to, or even cause, various severe “personality disorders” such as autism and schizophrenia. Earlier work in this area was largely unproductive for several reasons that are now coming to light: new mutations are an important source of sporadic cases (i.e., those that occur without a family history of the disorder) and mutations in many different genes can contribute to these disorders. Both of these effects undermine traditional family-based studies. Not surprisingly, there has been the most scientific progress in analyzing patients with severe phenotypes. In these instances, the privacy issues seem similar to those surrounding other facets of the medical records of patients undergoing psychiatric treatment.

The more distinctive issues will arise if and when genetic variants are convincingly associated with a broader range of personality traits, not all of which are “disorders.” Examples would include introversion/extroversion, aggressiveness, and impulsiveness. While everyone has elements of all these characteristics, psychological testing suggests that some people lie at extremes of these distributions and maintain their position stably over time. I doubt that privacy, however achieved, will provide a long-term solution to the resulting dilemmas. Within a generation or two, I suspect the whole concept of “genetic privacy” will seem quaint, at least in affluent, educated communities.

Of course, behavioral phenotypes are already the basis for many of our judgments of other people. The new risk is that we will all be exposed to guilt by association with particular genetic variants. There is no reason to expect that genetics will ever achieve a GAATACA-like ability to predict phenotype from genotype. Each individual will have his or her own idiosyncratic combination of unusual genetic variants, and environmental influences are obviously important. However, it is likely that we will recognize correlations between behavioral phenotypes and genotypes that have some predictive power. Simply stated, the risk to me is that I might be a nice guy but have a genetic variant that has developed a bad reputation. If I am right that genetic privacy will be a declining source of protection from resultant prejudices, the best hope is public education. People’s worst fears about genetic determinism are not going to be realized. We need to aim for broad understanding that genetic stereotypes are sure to be just as unreliable and destructive as other stereotypes.