From 1958-78,29 very funny British 'Carry on' movies, with titles like 'Carry on nurse,' were produced. It's a British phrase that a boss would say to an employee, but in this case, no matter how bollixed up the situation was, the idea was that people just 'carry on' regardless. The movies parodied British institutions and their behavior.
Well, though it's neither satirical nor funny, the same is often the case in science, where the thing-to-do is what's done regardless of whether it's the best thing or is working very well. We cling to our flotsam if it's all we know or seems the safest.
On July 14, we wrote about a Nature paper describing the results of a genome-wide association study (GWAS) of the genetics of schizophrenia, published online. This and two accompanying papers appear in the journal this week, reinforcing the story of schizophrenia as a polygenic trait, with many genes involved, each with very small effect. The papers suggest that the immune system may somehow be involved, as genes in the HLA system are found to have a significant, if limited effect, as well as some aspects of brain development, cognition and memory.
This is potentially very interesting because if GWAS are finding anything it may be that immune or inflammatory system genes are involved in a wide array of traits, perhaps not always previously suspected as such. Could infectious or autoimmune causes be more widespread than we have suspected? If so, it may say a lot. Partly it could be the things that go wrong over a life that's decades long, in terms of exposures and/or mutations that attack self.
But this and a host of other GWA studies have had minimal findings--hyped to death, perhaps, but usually accounting for only a minor fraction of all causation, even the known genetic component as revealed by the family cluster of disease. Each study finds one or a few genes that contribute detectable amounts to the trait. Some of these have been replicated and begin to be believable for that reason (though many if not most have no a priori plausibility as causes of the mapped disease).
This should be providing geneticists with plenty of targets for real genetics, real in the sense of figuring out what the genes do and how to attack them therapeutically. Modest they may be, but they're the strongest candidates we have.
So why, then are new GWAS still being done all over the place on the same diseases? Even strong proponents of this method have acknowledged that they are finding many genes with small effect. The same traits are being studied over and over again, often finding different genes, but which almost invariably explain very little risk.
It's time to stop paying for ever more of this, and to demand proof of principle. The principle is that (1) we can show how, why, and when these candidates (and their many mutations and regulatory sequence variants) are involved in disease, and then (2) that we can do something about them. Yet, because many investigators are set up for mapping, which is after all a rather mechanical button-pushing kind of enterprise (and very grant-able), one often hears investigators saying that 'mapping is what I do' .
That's a very poor excuse, even if in a careerist society that depends on the grant system and on intellectual inertia. What we need now is some accountability: to show that the fruits of GWAS labor to date are worth it and do, after all, have important biomedical use.
That being done, we'll know better whether we should continue down the reductionist mapping road, or whether better, more effective approaches to causation, even genetic causation, are the proper course.
In the 'Carry on' movies, things muddled along despite all the confusion, and in science we'll muddle along, too. Nobody can say that persistence with GWAS or other tactics is useless, even if it's inefficient and we know better what would be better. But biomedical science can do better, and we think that it should.
Thursday, August 6, 2009
Cornered!
At a very nice reception after the Bar Harbor meeting, I (Ken) was approached (or one might say, eventually cornered) by two people who had attended and who wanted to talk about how evolution was consistent with religion. One, indeed, wanted to argue that evolution was consistent with literal interpretations of the Bible.
This may have been occasioned by questions at the Q&A that had to do with whether there is any new evidence for evolution, or whether humans are still evolving. Or, perhaps these two asked those questions. We mentioned this in an earlier post-meeting post. As I said in reply, every day my mailbox has at least one or two new journal issues that provide, implicitly or explicitly, evidence more consistent with the idea of evolution than with any other current theory about biological diversity. If there's another explanation, it will take something pretty dramatic to be discovered! Indeed, as I said, the flood of consistent evidence is all post-Darwinian, that is, is new evidence not available to Darwin or many decades of researchers after him. Confirmation is one of the most convincing kinds of evidence, because it does not require manipulation of the original evidence on which a theory was based.
Of course, it is well known that we in science (as in other areas of human endeavor) work within frameworks of accepted ideas (or ideology), and we do tend to try to force new evidence into our comforting belief that we understand things. But this fact does not undermine the consistency of countless kinds of evidence of every kind that evolution as a historical process of descent with modification from common ancestry is our best evidence of the nature of life. What is at issue is the details, the relative importance of selection, chance, sampling, stasis, and so on that have generated any given trait of interest.
There's plenty of room for debate about that--but it can give no solace to those who pine for simple, comforting religious explanations. Even Darwin was a kind of Deist, who accepted the possibility of a God who set things in motion and let them go on their (to him) predicted course. Even that undermines the idea of selection and drift as processes as we understand them, because if such a God knew in advance what would happen, then chance and competition are in some senses illusionary. Nonetheless, this is not the same kind of God who is said to intervene in human affairs, and who cares about out daily lives.
Nobody who is aware of the facts as we know them, both observational and experimental, should these days have illusions about life as an historical process. That so many do is a reflection either of our educational system and/or of the power of human thirst for solace. If there are some kinds of spiritual truths that involve some kind of deity, they are experiential rather than scientifically demonstrable at this point, and don't relate to evolution as we understand it.
The latter possibility, however, should tame militant atheism, because what we cannot deal with directly in science cannot be disproven accept by assumption. Militant atheism is a kind of arrogance in that sense. That doesn't gainsay the horrors that have been and are still the consequence of religious fervor, or the things people can be made by demogogues to do in the name of 'God'.
However, it is of little use to try to discuss this with believers who, even if scientists, cling to the hope that a very large shoe-horn can force what we know about the foot of evolution to fit into the shoe of received Truth. It is a profound question why on earth beings who are supposedly characterized by their rational cerebral cortex should be so immune to the facts of life. That emotions rather than reason had higher survival value is a standard response, but it's only a speculation (especially since there are so many willing martyrs!). At the same time, we in science have our own dogmas that we only reluctantly shed, so the phenomenon of belief-frameworks is a broader, and in that sense more interesting, issue in human life.
This may have been occasioned by questions at the Q&A that had to do with whether there is any new evidence for evolution, or whether humans are still evolving. Or, perhaps these two asked those questions. We mentioned this in an earlier post-meeting post. As I said in reply, every day my mailbox has at least one or two new journal issues that provide, implicitly or explicitly, evidence more consistent with the idea of evolution than with any other current theory about biological diversity. If there's another explanation, it will take something pretty dramatic to be discovered! Indeed, as I said, the flood of consistent evidence is all post-Darwinian, that is, is new evidence not available to Darwin or many decades of researchers after him. Confirmation is one of the most convincing kinds of evidence, because it does not require manipulation of the original evidence on which a theory was based.
Of course, it is well known that we in science (as in other areas of human endeavor) work within frameworks of accepted ideas (or ideology), and we do tend to try to force new evidence into our comforting belief that we understand things. But this fact does not undermine the consistency of countless kinds of evidence of every kind that evolution as a historical process of descent with modification from common ancestry is our best evidence of the nature of life. What is at issue is the details, the relative importance of selection, chance, sampling, stasis, and so on that have generated any given trait of interest.
There's plenty of room for debate about that--but it can give no solace to those who pine for simple, comforting religious explanations. Even Darwin was a kind of Deist, who accepted the possibility of a God who set things in motion and let them go on their (to him) predicted course. Even that undermines the idea of selection and drift as processes as we understand them, because if such a God knew in advance what would happen, then chance and competition are in some senses illusionary. Nonetheless, this is not the same kind of God who is said to intervene in human affairs, and who cares about out daily lives.
Nobody who is aware of the facts as we know them, both observational and experimental, should these days have illusions about life as an historical process. That so many do is a reflection either of our educational system and/or of the power of human thirst for solace. If there are some kinds of spiritual truths that involve some kind of deity, they are experiential rather than scientifically demonstrable at this point, and don't relate to evolution as we understand it.
The latter possibility, however, should tame militant atheism, because what we cannot deal with directly in science cannot be disproven accept by assumption. Militant atheism is a kind of arrogance in that sense. That doesn't gainsay the horrors that have been and are still the consequence of religious fervor, or the things people can be made by demogogues to do in the name of 'God'.
However, it is of little use to try to discuss this with believers who, even if scientists, cling to the hope that a very large shoe-horn can force what we know about the foot of evolution to fit into the shoe of received Truth. It is a profound question why on earth beings who are supposedly characterized by their rational cerebral cortex should be so immune to the facts of life. That emotions rather than reason had higher survival value is a standard response, but it's only a speculation (especially since there are so many willing martyrs!). At the same time, we in science have our own dogmas that we only reluctantly shed, so the phenomenon of belief-frameworks is a broader, and in that sense more interesting, issue in human life.
John Hawks invades our blog!
Thanks for the mention, John. We appreciate it. Though, the link that sent John here misrepresents us a bit. Lisa Miller, writing in Newsweek in support of the Francis Collins appointment to head NIH , says
Secondly, it's a problem when, if you've got a hammer, everything looks like a nail. These days everything looks like a gene. As regular readers of this blog know, our view has been that not everything is genetic, and yet genetics has had a growing or even predatory corner on research funds in the last few decades, largely due to Collins' prowess at convincing Congress of the importance of genes in explaining, preventing, and curing disease. That prowess will serve him well at the NIH, but his faith in genes, perhaps more disturbing than his faith in a personal god, is less likely to serve the rest of us as well.
We know, for example, that the health disparities in this country, not to mention the world, have almost zero to do with genetic susceptibility (except that which all humans share), and more to do with life styles, nutrition, infectious disease prevention etc. Most of the common diseases which our flesh is heir to can be prevented or delayed by lifestyle changes. If that were done, which should (we think) be Priority One at NIH, then the residuum of those diseases would be the cases that really are genetic.
Lifestyle changes are hard to mandate and research on relevant social behavior has failed us. Whether it's worth investing in that kind of research is a separate, debatable, question. Short of outlawing McDonald's and television, Americans probably would rather be fat and out of shape. Many of our fellow citizens still smoke, after all.
We have many reservations about the way things are being done in genetics and genomics these days, relative to the problems we know are 'out there', which are separate from the relative priority issue. We think very large amounts of funds are being spent to maintain the status quo even when we know it is not working. That's another way that systems, of all sorts, resist change. It is not a view against genetics, but one that would see genetics done in a better way, and one more relevant to the state purpose of health-research funds.
If Dr Collins takes a broader view of health rather than health research, as NIH Director, he may use his administrative skills to make excellent contributions to our country's and the world's well-being. But if his presence just encourages every university seeking grants and grant overhead, and so on, to continue to go for the gene, even if Dr Collins doesn't explicitly push them to do that, then his stint may be less sanguine. Time will tell.
On a blog, anthropologist Kenneth M. Weiss complained recently that as Human Genome Project director, Collins "directly or indirectly intimidated other NIH agencies to get into the genome game … That did, and still does, co-opt funds that could be used for other things instead." The concern of some scientists, in other words, has nothing to do with religion. It's that his view of legitimate science doesn't extend to them.No, the concerns are two. First, it is in the nature of bureaucrats to go for what they think will protect their portfolios, and that often if not usually means following the latest fads and fashions. It is not that genetics and genomics are unimportant, but that they had momentum and that attracts 'me-too' ers. It is certainly debatable whether committing so much money and energy to genetics was the best way that funds could or should have been spent to the extent they were.
Secondly, it's a problem when, if you've got a hammer, everything looks like a nail. These days everything looks like a gene. As regular readers of this blog know, our view has been that not everything is genetic, and yet genetics has had a growing or even predatory corner on research funds in the last few decades, largely due to Collins' prowess at convincing Congress of the importance of genes in explaining, preventing, and curing disease. That prowess will serve him well at the NIH, but his faith in genes, perhaps more disturbing than his faith in a personal god, is less likely to serve the rest of us as well.
We know, for example, that the health disparities in this country, not to mention the world, have almost zero to do with genetic susceptibility (except that which all humans share), and more to do with life styles, nutrition, infectious disease prevention etc. Most of the common diseases which our flesh is heir to can be prevented or delayed by lifestyle changes. If that were done, which should (we think) be Priority One at NIH, then the residuum of those diseases would be the cases that really are genetic.
Lifestyle changes are hard to mandate and research on relevant social behavior has failed us. Whether it's worth investing in that kind of research is a separate, debatable, question. Short of outlawing McDonald's and television, Americans probably would rather be fat and out of shape. Many of our fellow citizens still smoke, after all.
We have many reservations about the way things are being done in genetics and genomics these days, relative to the problems we know are 'out there', which are separate from the relative priority issue. We think very large amounts of funds are being spent to maintain the status quo even when we know it is not working. That's another way that systems, of all sorts, resist change. It is not a view against genetics, but one that would see genetics done in a better way, and one more relevant to the state purpose of health-research funds.
If Dr Collins takes a broader view of health rather than health research, as NIH Director, he may use his administrative skills to make excellent contributions to our country's and the world's well-being. But if his presence just encourages every university seeking grants and grant overhead, and so on, to continue to go for the gene, even if Dr Collins doesn't explicitly push them to do that, then his stint may be less sanguine. Time will tell.
Wednesday, August 5, 2009
Monday, August 3, 2009
Thoughts from a meeting: Honoring Victor McKusick, and looking to the genomic future
We spent a foggy, drizzly but perfect morning at one of the most beautiful places we know, Pemaquid Point in Maine, a few days ago, a good excuse to post this photo. We're now at the dairy goat farm in Vermont that Anne's sister runs with her husband, being kept very busy milking goats and making cheese, so here is a rambling tour of the Bar Harbor symposium--we don't have time to make it short. The meeting was interesting. Even without Francis Collins, who couldn’t be there because of his upcoming confirmation hearings to head the National Institutes of Health. The event was in celebration of the Short Course in medical genetics that has been offered by Jackson Labs for 50 years, started by Victor McKusick, one of the first physicians to be interested in human genetics in the modern era, and often called the “Father of Medical Genetics”. He and his wife attended every Short Course for 49 years; he died last year, but not before he helped to organize this commemorative day. (Actually, to be fair without in any way diminishing Dr McKusick’s contribution, the British physician Archibald Garrod is generally said to be the founder of modern biomedical genetics, back at the beginning of the 20th century. He studied recessive metabolic diseases in close relatives, showing that human inherited disorders followed Mendel’s principles.)
Most of the speakers at the Bar Harbor meeting had a personal connection with Dr McKusick, so his presence was strongly felt throughout the day. The talk we thought was most interesting, perhaps because it was about a subject that we know something about, was by Richard Axel, a neuroscientist who won a Nobel Prize in 2004 for his work on smell. He talked about the neuronal connections that stretch from the odor receptors in the olfactory epithelium in the nose to the olfactory bulb in the brain, the only neurons that single-handedly, so to speak, connect the external world to the brain without synapsing with another neuron along the way. But, that’s largely because it’s a short path twixt nose and olfactory bulb.
Axel’s main thrust was that understanding how the brain interprets messages about smell that are delivered to it from the nose is still poorly understood. It’s clear that single odorant receptor genes (ORs) are expressed in each cell in the olfactory epithelium, although we have about 900 genes that code for ORs and each cell picks up a different odor. Most odors trigger a combination of ORs and it’s that combination that has to be interpreted in the brain.
What happens next is called the “binding problem”, a problem not restricted to the sense of smell, but one that applies to all our senses. How does our brain put together the many different pieces of information our
eyes absorb (color, angle, form, etc), how we build sound from all the bits of information our ears take in (frequency, loudness, timber, and so on) into a single sound, sight, or odor? Axel demonstrated the binding problem with this picture by Salvador Dali—do you see the head of Voltaire or two nuns? How and why we see one and only one at a time is not at all clear.Odorant detection reflects an intriguing but unsolved problem that is much more widespread. Of the 900 OR genes (actually 1800 since we have two copies), each cell picks only one of the two copies of only one of the 900 genes to express. These genes are located on almost all human chromosomes, so some form of communication among the chromosomes, and among genes within clusters of them on the given chromosome, must take place to exclude 1799 genes, differently, in each olfactory receptor cell. Many other genes also manifest what is called allelic exclusion, and this appears to be similar to the process that inactivates genes on one of a female’s two X chromosome (a phenomenon that’s long been known but still is only partly understood).
Another talk was about stem cells, and how iPS (induced pluripotent stem cell) technology has rapidly advanced the field, and it’s now possible to envision stem cell therapies using any patient’s cells as progenitors. But, according to this speaker, the understanding of how to direct differentiation of stem cells into any cell we want is in its infancy. And, cloned animals will never be normal, thus he’s not sanguine about human reproduction through cloning. Never is a long time, but at least the point is that the great promise of stem cell research is being worked on but not yet here.
Yet another speaker does research on epistatic processes—changes in DNA that aren’t in the DNA sequence itself, but instead in the chemical properties of DNA. Methylation is the most well-studied of these, and this speaker suggested that aberrant methylation may explain most cancers, and other diseases.
Ken talked about evolution as more of a cooperative process than a competitive one, and suggested, as we have in this blog and in our book, that natural selection is a less powerful force in evolutionary change than most people believe. He talked about the weakness of the link between genotype and phenotype, and the many ways to get to a single phenotype. Some simulation work was presented from Ken’s and Brian Lambert’s ForSim simulation program, that showed why connections between specific genotypes and phenotypes is likely to be weak, with poor predictive power, an important point both in relation to evolution and in the biomedical context of assigning genetic causation (a subject we’ve dealt with many times in this blog, and will again when we have time).
Joe Palca, a science reporter for National Public Radio, moderated panel discussions with the speakers at several points during the day. Ken was asked if he could give 2 examples of traits that have evolved, which was a rather surprising question from an audience of scientists, since the journals are filled with such examples. He was also asked if humans are still evolving. Even Darwin shared the misconception that humans are no longer evolving because, as he said, they have culture, and culture overrides evolution. But, as Ken pointed out, there are always mutations in DNA, the stuff of evolution, and in humans, the fact that we have culture may moderate the effects of change (infertility is treated, or previously fatal diseases treated), but it can’t prevent it. We have evolved, from the beginning, to adapt with and to an environment that includes culture (language, tools, fire, clothing and shelter we make, cooperative hunting and gathering, and so on). It’s not new, and it may not be of exactly the same kind of adaptive evolution found in other species, but it’s evolution in every meaningful sense of the term.
Eric Lander, head of the Broad Institute in Cambridge, MA, summed up the events of the day in an after-dinner talk. He summarized each talk briefly, and then went on to predict where genetics will be in the next 50 years. He had worked closely with McKusick, who was a great believer in catalogues. He initiated the catalogue of human diseases called Mendelian Inheritance in Man, now OMIM (Online MIM). Lander believes that, in the McKusick tradition, all genetic diseases will soon be catalogued and we now need to move on to cataloguing all cell states—“whether 500 or 5000”. He’s more optimistic than we would be, and indeed we think humans cannot eliminate all diseases. If we could eliminate all currently known or named diseases, then whatever was left that we didn’t like would come to be viewed as ‘disease’. Or society would find new ways to identify its fringe states or members.
We think elimination of ‘all’ diseases is unrealistic and probably not a responsible thing to hint at. But that’s not the same as saying, which we don’t, that the assault on major biomedical problems won’t have major, even wonderful positive successes. The amount of effort being made, barring major social catastrophe that pulls the research plug, can safely be predicted to have such successes. The debate is, or should be, about what approaches are best to take to have the most or best success. And there’s plenty of room for that debate.
But now we have to go help milk the goats.
Thursday, July 30, 2009
Darwin's Rubbish
We're in Maine for a few days for a meeting in Bar Harbor. It's a celebration of the 50th anniversary of 'short courses' at Jackson Labs, an organization that focuses on genetic research, primarily having to do with health. They've developed and maintain numerous model mouse strains for research -- diabetic mice, obese mice, mice susceptible to cancer, and so on. If you work in a mammalian genetics lab, you've ordered mice from Jackson Labs.
The meeting tomorrow is the culminating day of the "Symposium celebrating the 50th Annual Short Course on Medical and Experimental Mammalian Genetics", with a focus on the future of genetic research, and an emphasis on personalized medicine. Speakers are charged with addressing the question, "What are the scientific, technical, social and legal implications of 21st century medicine?" Mario Capecchi from the University of Utah will be talking on "The Future of Development", Janet Davison Rowley on "The Future of Cancer", Richard Axel on "The Future of Neurogenetics", Francis Collins on "The Future of Individualized Medicine", and so on. Ken was asked to speak on "The Future of Evolution", but has changed the title (to "Darwin's "Rubbish": 150 Years of Evolution and Counting"), as the future of evolution seemed obvious (it will happen, but its course is unpredictable) and wouldn't fill a half hour.
Ken's new title refers to a letter Darwin wrote to Asa Gray on Sept 5, 1857, upon completion of The Origin of Species. Gray was a famous botanist at Harvard, and long- time correspondent of Darwin's. In the letter, Darwin wrote,
“This sketch is most imperfect; but in so short a space I cannot make it better. Your imagination must fill up many wide blanks. Without some reflection, it will appear all rubbish; perhaps it will appear so after reflection.”
More to come.
Monday, July 27, 2009
Ethical issues in personalized 'genomic' medicine
Ken was just at a very interesting conference on ethical issues that will pertain to the use of genomic data to 'personalize' medicine in the 21st century. Of course, all such conferences are presumptuous in the sense that nobody can really know what things will be like. The record of pundits and experts (scientific, economic, or political) is so poor it's a wonder there is employment for any of us. In biomedicine and genetics, we've made so many false promises that if we were Pinocchio we'd all be sprouting giant Sequoias for noses.
Nonetheless, using individual genotypes to try to predict or diagnose disease is going to be a fad for at least some years until it either proves to be a bonanza for health care, or a bust with little definitive power. So much effort is going to be invested in the effort, that if it doesn't pay off it will be for good reasons -- that is, we'll have learned a lot about biology in the process of not improving medicine very much.
Likewise, if individual genotypes do prove to be of high predictive or diagnostic value, that will mean we know the genes and hence will be able to figure out why they lead to disorders and then, presumably, we'll be able to engineer some prevention or therapy.
'Personalized medicine' is a lobbying phrase in that medicine has always been personalized, and adding the term 'genomic' is also a lobbying phrase for support to attempt to boil your and my health (and who knows what else?) to estimable, powerful genetically based effects. The fact that's it's a catch-phrase to sell personal direct to consumer genetic advice, or other clinical or commercial products, does not mean it's bad or won't work. But at this stage, we need to be aware of the vested-interest component. In principle (but not in America), we could keep quiet until we actually knew it would work before we started selling predictive genomic services.
In fact, there are many traits for which an aberrant gene is indisputably known. Many investigators are working on trying to understand them. They are the 'Mendelian' diseases that are almost always due to aberrant function in the same gene (like cystic fibrosis or sickle-cell anemia), and fractions of more complex diseases in which some cases are due to a single gene (like breast cancer associated with mutations in the BRCA1 and 2 genes) but most cases aren't. Personalized medicine, whether predictive, diagnostic, or clinical is quite important in these instances, and the main ethical issues are things like whether prenatal screening or abortion are justified, etc.
Ethical issues abound, however, in the case of most traits, where genotypes are only vaguely known or have weak predictive power. There the question is what the relationship between a known genotype and actual risk is, and at what level of risk something should be done about it. Or whether, if nothing can be done about it, it is useful to worry people.
Who gets to see the information in either case is important. Can or should it be used to force treatment or preventive measures on people as a condition of insurability? Or to adjust health insurance premiums? Or to screen relatives? Or decide about employability?
Weak predictive power often means such incomplete knowledge that the genotype may not, in fact, make reliable or replicable effect on risk. The problem here, which we are already beginning to see, is that genotyping leads people to confront their physicians with diagnoses that the physician may or may not agree with (or understand, since much of this area is quite complex), but may feel obliged to do something about.
In a country in which the health care system is already overburdened, and will become even more so as the population ages, personalized genotyping can lead to large-scale over-diagnosis, new and unnecessary testing, and lifelong costly maintenance such as multiple screening checkups, preventive medication, and so on. Much in the way of profit to the system, much in the way of distraction for lawyer-wary doctors, but not much in the way of additional health. Indeed, overdiagnosis leads to overtreatment and hence actual increase in risk.
These and other issues, like the value (or not) of 'racial profiling' in medicine, were discussed at this meeting. There aren't answers, exactly, but at least the issues are being raised. Whether the issues are being examined deeply enough -- for example, as to ask whether some of these activities should be legal, or how much research money should be invested (or wasted, depending on your viewpoint), get less discussion, because our system places vested interests across the spectrum of people from commercial to academic to clinical.
Certainly, as everyone agreed, the genomics perspective is here to stay at least for a while. Probably, much of the promise and hype will prove to be false and will simply fade away. What is discovered that is useful will become part of standard practice and a source of better diagnosis and treatment. It is usual that most of what people claim at this or any time proves to be rather worthless. That's likely to be the same in this instance. But, as is also usual, some gains are made and they set the stage for the next wave of ideas about how genes work and how health can be improved.
Nonetheless, using individual genotypes to try to predict or diagnose disease is going to be a fad for at least some years until it either proves to be a bonanza for health care, or a bust with little definitive power. So much effort is going to be invested in the effort, that if it doesn't pay off it will be for good reasons -- that is, we'll have learned a lot about biology in the process of not improving medicine very much.
Likewise, if individual genotypes do prove to be of high predictive or diagnostic value, that will mean we know the genes and hence will be able to figure out why they lead to disorders and then, presumably, we'll be able to engineer some prevention or therapy.
'Personalized medicine' is a lobbying phrase in that medicine has always been personalized, and adding the term 'genomic' is also a lobbying phrase for support to attempt to boil your and my health (and who knows what else?) to estimable, powerful genetically based effects. The fact that's it's a catch-phrase to sell personal direct to consumer genetic advice, or other clinical or commercial products, does not mean it's bad or won't work. But at this stage, we need to be aware of the vested-interest component. In principle (but not in America), we could keep quiet until we actually knew it would work before we started selling predictive genomic services.
In fact, there are many traits for which an aberrant gene is indisputably known. Many investigators are working on trying to understand them. They are the 'Mendelian' diseases that are almost always due to aberrant function in the same gene (like cystic fibrosis or sickle-cell anemia), and fractions of more complex diseases in which some cases are due to a single gene (like breast cancer associated with mutations in the BRCA1 and 2 genes) but most cases aren't. Personalized medicine, whether predictive, diagnostic, or clinical is quite important in these instances, and the main ethical issues are things like whether prenatal screening or abortion are justified, etc.
Ethical issues abound, however, in the case of most traits, where genotypes are only vaguely known or have weak predictive power. There the question is what the relationship between a known genotype and actual risk is, and at what level of risk something should be done about it. Or whether, if nothing can be done about it, it is useful to worry people.
Who gets to see the information in either case is important. Can or should it be used to force treatment or preventive measures on people as a condition of insurability? Or to adjust health insurance premiums? Or to screen relatives? Or decide about employability?
Weak predictive power often means such incomplete knowledge that the genotype may not, in fact, make reliable or replicable effect on risk. The problem here, which we are already beginning to see, is that genotyping leads people to confront their physicians with diagnoses that the physician may or may not agree with (or understand, since much of this area is quite complex), but may feel obliged to do something about.
In a country in which the health care system is already overburdened, and will become even more so as the population ages, personalized genotyping can lead to large-scale over-diagnosis, new and unnecessary testing, and lifelong costly maintenance such as multiple screening checkups, preventive medication, and so on. Much in the way of profit to the system, much in the way of distraction for lawyer-wary doctors, but not much in the way of additional health. Indeed, overdiagnosis leads to overtreatment and hence actual increase in risk.
These and other issues, like the value (or not) of 'racial profiling' in medicine, were discussed at this meeting. There aren't answers, exactly, but at least the issues are being raised. Whether the issues are being examined deeply enough -- for example, as to ask whether some of these activities should be legal, or how much research money should be invested (or wasted, depending on your viewpoint), get less discussion, because our system places vested interests across the spectrum of people from commercial to academic to clinical.
Certainly, as everyone agreed, the genomics perspective is here to stay at least for a while. Probably, much of the promise and hype will prove to be false and will simply fade away. What is discovered that is useful will become part of standard practice and a source of better diagnosis and treatment. It is usual that most of what people claim at this or any time proves to be rather worthless. That's likely to be the same in this instance. But, as is also usual, some gains are made and they set the stage for the next wave of ideas about how genes work and how health can be improved.
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