The Logic behind Genome Studies
Much research into the genetic contributions to common diseases has started with the seemingly logical assumption that DNA variants occurring frequently in the human population would be at fault. Some argue, though, that this reasoning is faulty.
Image: Bryan Christie
In Brief
- In the year 2000 leaders of the Human Genome Project announced completion of the first rough draft of the human genome. They predicted that follow-up research could pave the way to personalized medicine within as few as 10 years.
- So far the work has yielded few medical applications, although the insights have revolutionized biology research.
- Some leading geneticists argue that a key strategy for seeking medical insights into complex common diseases—known as the “common variant” hypothesis—is fundamentally flawed. Others say the strategy is valid, but more time is needed to achieve the expected payoffs.
- Next-generation methods for studying the genome should soon help resolve the controversy and advance research into the genetic roots of major diseases.
A decade ago biologists and nonbiologists alike gushed with optimism about the medical promise of the $3-billion Human Genome Project. In announcing the first rough draft of the human “book of life” at a White House ceremony in the summer of 2000, President Bill Clinton predicted that the genome project would “revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases.”
A year earlier Francis S. Collins, then head of the National Human Genome Research Institute and perhaps the project’s most tireless enthusiast, painted a grand vision of the “personalized medicine” likely to emerge from the project by the year 2010: genetic tests indicating a person’s risk for heart disease, cancer and other common maladies would be available, soon to be followed by preventives and therapies tailored to the individual.
This article was originally published with the title Revolution Postponed.
Already a Digital subscriber? Sign-in Now
If your institution has site license access, enter here.
Rights & Permissions
See what we're tweeting about
24 Comments
Add CommentStephen S. Hall is not correct to state that scientists, 10 years ago, were seriously overoptimistic about medical progress when the first rough draft of the Human Genome project came out.
Reply | Report Abuse | Link to thisFor example, Francis Collins, in a lecture subsequently reported by the New York Times (June 27, 2000), predicted only that by 2010 the genome would help identify people at highest risk of particular diseases. In fact, it can do this already now to some degree, the only catch being that the costs are still too high for most people to have their genome sequenced. But there is general consensus that within only another three years, this type of testing should be widely available to the public.
On the other hand, Collins was careful, in this same lecture, to point out that preventives and therapies suited to the particular patient (gene therapy, a much more ambitious goal) would take substantially longer. He stated that such a second step would emerge only gradually and take some 40 years, not 10. The process thus would be completed only by 2040.
An inherent assumption in the hypothesis that the Human Genome Project results could be used to diagnose, prevent, and treat most human diseases is that disease is related to one's genetic composition. While this approach garnered huge sums of money for scientific research, it could only solve those health problems directly influenced by genes. If just a few of the genome-wide association studies have correlated a specific disease to a particular gene or set of genes, we would be wise to reassess the validity of the assumption. This reawakens the question of how nature and nurture contribute to health.
Reply | Report Abuse | Link to thisThe root cause of disease is important to identify as our treatment approach for each cause will be different. Pharmaceuticals are likely solutions to genetic problems. Health issues related to the individual's environment, or non-genetic causes, respond successfully to a wide range of approaches.
A helpful research question: Given the known diseases of humankind, what proportion is attributable to genes and what proportion is attributable to environment? Knowing the answer to this will help us understand the scope of possible successes with the Human Genome Project.
The complexity of the concept of a gene requires analytic tools far more sophisticated than the naïve assumption that there exist a one-to-one correspondence rule between gene variation and phenotype traits. The DNA is not a “blueprint” in the simple metaphor borrowed from engineering drawings. A more fitting metaphor is a musical score, defining the timing and amplitudes of notes series expression by various organs in the assemblage. Each musical instrument produces different waveforms due to its unique note expression mechanism, but music is made when all are controlled by a single set of notes and playing instructions and synchronized by the conductor. The waveforms combine to generate something “higher” than just more complex waveforms – just as life is more than metabolism.) The musical metaphor suggests how to analyze the relationship between DNA and phenotype.
Reply | Report Abuse | Link to thisThe “holistic” approach to appreciation of music is based on subjective, human-centric psychological response to various harmonics, note sequences, tempo, emphasis, etc. No “reductionist” approach can grasp the essence of what make music a different experience from noise. However, we do not possess a similar mental capacity to analyze DNA expression, so we have to develop a reductionist approach to enable analysis based on mathematical rigor. This is where physics can point the way.
From the point of view of physics, music is a time varying complex waveform that can be broken into its simple components. By doing so, you move from the complex world of waveforms into the linear, “orthogonal” world of frequencies. You pay for this transformation by losing the ability to grasp the wholeness of the musical experience – a heavenly symphony become just flickering bars on your spectrum analyzer – but the technique of Fourier transform is essencial when you want the zero-in on an acoustic trait of a music instrument.
It is somewhat naïve to assume that the same transformation that proved so useful and central in physics (not just in acoustics. Where would quantum mechanics be without the Fourier transformation) will unlock the genotype-phenotype conundrum. But it’s a promising first step in injecting some more sophisticated mathematics into genomics. To gain insight into the rules of the game you have to start with an overarching paradigm: our aim is to uncover a many-to-many transformation (perhaps expressed as a matrix) between two complementary world-views, the genome (the vector of DNA bases) and the phenotype (the vector whose components are traits).
If the common approach telles us that genes only offer a 5-10 percent explanation of a disease, it seems most logical to me to assume a critical factor is missing, not that there are hundreds of other genes involved.
Reply | Report Abuse | Link to thisThe critical factor is most likely a trauma or an infection in an early development stage, a hidden persistent infection or reactivation of a virus. For example, Alzheimer patients have more than average antibodies to herpes virus. Viruses, bacteria and prion-like agents may all be involved. For research into the biochemical pathways you can look at rare events in genes, but also at extreme events in certain food interventions, like vitamin B and flavonoids (if they really have a significant effect).
Andre van Hooren, Netherlands
As suggested by this well-written and insightful article, the human genome project will turn out to be failure. It will be a failure because it is based upon a scientific model - materialism or naive realism - that is simply not true. This model assumes that the world outside of our minds - including the human body -exists independently of the mind and operates outside of its control. In different words, the proponents of the genome project (which admittedly includes a lot of authoritative figures) have confused cause and effect. They have assumed that human illnesses originate in the misalignment of microscopic bodily parts (i.e., DNA strands)when the opposite is more likely true: the DNA strands are a reflection of the internal states of the mind. This would seem to be a radical position, except that another article in the same issue of Scientific American, written by Stephen Hawking and Leonard Mlodinow, ("The (Elusive) Theory of Everything"), directly questions the independent world model of modern science. Hawking and Mlodinow write, "Most people believe that there is an objective reality out there and that our senses and our science directly convey information about the material world. . . The way physics has been going, realism is becoming difficult to defend." Although Hawking and Mlodinow make these observations within the context of pursuing a grand unified theory of the cosmos, it also applies to modern medicine's conception of the human body, which also appears to exist external to the mind. Indeed, the great flaw of modern, empirical science is that it has not yet realized that both body and the natural world exist independently of the mind and exist on the same level. The body does not have a privileged status. (This is one flaw of the Hawking/Mlodinow article). The human genome project is science's last attempt to show that the human body is nothing but a machine where if the parts become misaligned the person becomes sick. But as the author notes, many experts find the human genome project teaches us nothing about the cause of disease. This is not surprising as human diseases cannot originate in a physical body that is a relection of the mind. Diseases must originate internally and result from the misalignment of the mind with its true nature. In sum, science must find a way to broaden its horizons beyond the materialistic paradigm if it seeks to truly solve the problem of human disease.
Reply | Report Abuse | Link to thisIn the broadest sense, anything that affects an organism (human or any other life form) can be attributed to its genes. Disease (dis - ease) and parasites only affect organisms that are genetically susceptible in this broad sense. For example, humans are not susceptible to attack from Puccinia recondita (causes leaf rust of wheat) and wheat is not susceptible to infection by the herpes virus. This is not an environmental immunity, it is a genetic immunity.
Reply | Report Abuse | Link to thisMuch of the "Revolution Postponed" article discusses possible reasons for the failure (to a large degree) of the genome initiative and the common variant hypothesis and it suggests other approaches to using our knowledge of the human genome to re-start the revolution.
What I've described above (broad sense genetic background) exactly fits Nadeau's findings that "the function of one particular gene sometimes depends on the specific constellation of genetic variants surrounding it." The thing is, and this often happens in science, Nadeau hasn't said anything that hasn't been said before (it's sort of like rediscovering Mendel's paper 40 years later or McClintock's research on "jumping genes"). Plant and animal breeders have long known about this "happy home" concept of gene expression. There are even old technology words (vs. modern technology) for this phenomenon: epistatis, pleiotropy, penetrance, and expressivity are all involved in the happy home of a gene. A happy home in the genetic sense is a genetic environment that allows a gene to express itself fully. One might say that "no gene is an island."
This is quackery at it's finest...or worst, as the case may be. Human disease is because of "a misalignment of the mind with its true nature"? Yes, because bacteria ONLY infect people with misaligned minds. And Down's syndrome (trisomy 21) ONLY affects fetuses with misaligned minds. Think about that one for a second.
Reply | Report Abuse | Link to thisI'll give you another one: How about diseases like Huntington's? That one is 100% genetic. That means if you have the gene, you get the disease, otherwise you don't. It's called autosomal dominant. Kind of like brown eyes, except deadly.
Take your Bronze Age, Deepak Chopra inspired mysticism elsewhere. And for the love of science, quit trying to use physicists to argue for a reality governed by mental spiritualism. Hawking's comments about physical realism have NOTHING to do with the practice and science of modern medicine. We cure disease and sickness every day. And they are cured in people who represent the entire gamut of "mental alignment". To suggest otherwise is not only intellectually embarrassing but morally and factually bankrupt.
My above comment was solely in response to pmereton's absurd statements. I realized if one were scanning, they might believe I was stating the article was pure quackery. I was making no such accusation.
Reply | Report Abuse | Link to thisCertainly the general public was inspired by the general press and investment funding interests to understand that there was a simple correspondence between specific genes and many diseases, such that 'fixing' the responsible gene might eliminate the occurrence of or even cure the incidence of many diseases. It's now becoming clear to the general public, since much of the previously funded initial research has been successfully completed, that it's more complicated than that.
Reply | Report Abuse | Link to thisI just wanted to thank you all for your posts. There are obviously some very bright minds reading these articles. To be honest, I thought most of the comments were more insightful than the article at hand.
Reply | Report Abuse | Link to thisSome may have expected too much too soon, especially people who like to write articles. A man or woman is not a simple machine, to which the DNA code offers a simple manual. Life is incredibly complex, as science is uncovering every day. Even very simple organisms show complex behaviour, not that easy to figure out. This does not prove that the scientific enterprise as such is wrong, or that the quest for simple solutions as such is wrong. Instead the entire history of science shows that simple answers are only arrived at by hard work by a number of geniuses. So if anyone thought that the uncovered DNA-code as such would provide enormous medical opportunities they may have been both right and wrong. Wrong if they thought that magic bullets would fall out of an equally magical box of ammo against disease. To use this knowledge enormous amounts of rethinking and reconceptualization will have to be made. It will be like entering an entirely new landscape.
Reply | Report Abuse | Link to thisThat sounds interesting.Indeed altought gene is the basis for the feature of biology, many factors influence and then integated into a huge interaction. Gene sequence for present is still expensive for individual, not to say the technology is still not mature in market. But for patients, we could do find the bad gene that lead to this disease, yet for therapy, it still only relies on gene, and many other factors should be taken into accounts.
Reply | Report Abuse | Link to thisI have obtained considerable help in understanding my disease(s) from the Genome project. My Doctors, however, are stuck with trying to find the name(s) that have been given the disease(s)over the past 200 years and cannot seem to see the forest for the trees. In my case, A nominally Systematic genome association with tissue types can link 5 chronic maladies to squamous cell tissue plaques and plaque calcification.
Reply | Report Abuse | Link to thisThe question, then is not what name the diseases had been given, but what the trigger for the plaque formation is and how to block the elevated plaque calcification response associated with my BTNL2 double T risk markers.
There is a much simpler and less prosaic reason for this problem. It has to do with the type of speculations from Lovallo & Kahneman, 2003, Delusional Optimism, where they point out the obvious and propose it as a systemic failure in most major human systems. To get the big jobs funded and on the table (human genome project), they come at the expense of other equally worthy big jobs (aids cure, SIDs cure, renewable energy, poverty cure, addiction cure - whatever) the winner has to over-promise the results. The results have to be presented firstly at the most upper limit of possibility - the glorious outcomes - (without being consciously dishonest), these then become the middle ground expectations (when they are the absolute best outcomes possible) once the project gets underway and then everyone forgets that these were the upper limits of possibility and hence everyone starts talking about disappointments.
Reply | Report Abuse | Link to thisIn support of pmereton. Science is a search for truth and until that search is exhausted no possibilities can be ruled out. The truth for me is that my experience of reality supports pmeretons' view. If Science chooses to ignore such experiences or merely explain them away, it will become yet another dogma that has been forced upon society by people who claim to have authority in the determination of truth. I personally believe science can rise above that...
Reply | Report Abuse | Link to thisNew-age mumbo-jumbo. Disease does exist within the body. This is a fact. Clearly you have chosen to ignore evidence and cherry pick your facts to fit a particular world-view. You are welcome to your own personal beliefs, but flaunting this kind of attitude is simply offensive.
Reply | Report Abuse | Link to thisAlso a reply to pmereton...
Reply | Report Abuse | Link to thisI think it will turn out that you are applying the label of quackery to the wrong target. The reason why the human genome project will fail is because it is based upon the model of materialism, which modern scientists assume is necessary to practice science. A chief problem with this worldview is that one has to assume not only that matter burst from nothing in the moments before the Big Bang but that it then arranged itself into the natural world, including the human body, with no intelligent guiding force. The question of whether the world, including our bodies, is a product of mind or matter has been one of the great -- and unsettled -- questions in both Eastern and Western philosophy. Descartes, for example, reached the conclusion during his famous meditations that he had greater certainty over his mind than the independent existence of the external world, which he found may very well be a dream. (He appealed to God and convinced himself the external world really existed.) Many scientists over the past century have made note of dream-like nature of reality, particulary when viewed through the lens of quantum theory. For example, note Heisenberg's statement that "atoms are not things" and Sir James Jean's comment that the world looks more like a great thought than a great machine. See also The Tao of Physics, books by Fred Wolf and many others.) If the natural world is at its core "dream-stuff" then so must be the body. No one can deny, including me, the existence of physical illness or disease and the great achievements of modern medicine. But if the world is at its core mind-created, then we act at our own peril when we ignore this fundamental law. In other words, it helps to think through this alternate hypothesis, not so lightly label it quackery and jump back into the maze of materialism. (By the way, I also think that saying disease originates in a misalignment of the mind with its true nature, sounds mystical, but if the world is mind-created, that's probably where we need to go. And, perhaps unlike Mr.Chopak, I think any theory, whether mind or matter-based, must have a logical and rationale basis.) Given cosmology's radical speculation over the origins of the universe (see the Grand Design and its 10E500 universes) and events such as the failings of the human genome project, my point is that like true scientists, we have to open our minds and consider other viewpoints, not just those commandeered by materialism. If we do otherwise, we are not practicing science but advancing a system of belief.
Reply | Report Abuse | Link to thisWe seem to be getting somewhere. If the body (including the genetic code) is a reflection of the mind, then, like Emerson and others have suggested, the body is the mind made manifest, or in different terms, the body is the mind. It is not easy removing the materialistic lens when considering any new viewpoint. After all, we have all had the machine-world mindset drilled into us. And, the notion that the source of the body is the mind is indeed radical. But the question, after all the labels are removed, is whether it is right. Yes, physical ailments appear in the body and may be reflected in the disarrangement of genes. But what is the source of the gene? In quantum theory, modern science is not far from the conclusion that the mind at least contributes to physical reality. Is not the DNA molecule also composed of quantum "particles?" The point is that this alternative viewpoint -- that the mind is a dream in action rather than a giant, mindless machine -- needs to be examined scientifically, and not simply dumped overboard with simple labels. It is not as radical as it may seem.
Reply | Report Abuse | Link to thisIt seems that there is a mistake in perspective. Namely, the separation of mind and body. This seems oddly similar to the religous prognostications that our soul is independent of the body and eternal. Unlikely. Rather, mind and spirit are simply aspects of the body - the function of the form.
Reply | Report Abuse | Link to thisStephen S. Hall: I wonder, is anyone considering the ataxias? Like Huntington's disease they are rare and 100% inheritable. I have one - spinocerebellar ataxia type 1. It is clearly genetic and they found the marker gene on the sixth chromosome in 1993. It is a very large CAG repeat. I had the genetic test done in 1995 and started showing symptoms in 2005. Doesn't this show that the common variant/materialistic model works in some instances?
Reply | Report Abuse | Link to thisThe 'Revolution' can be (and should be) speeded up, by simply locating all (or most) centenarians, doing a full analysis on their genes. Combining them as the 'base data', all other comparisons will reveal the shortcomings of basically diseased individuals - caused by nature or nurture.
Reply | Report Abuse | Link to thisI think that there is a faulse assumption underlying much of the otherwise excellent work the authors and others have been doing on the human genome. There is an assumption that there would be some selective pressure involved in the frequencies of the SNP's for various diseases. The assumption for diseases such as breast cancer, adult diabetes, heart attack, stroke, altzheimers, etc. The fact is that there cannot be any selective pressure for two huge reasons.
Reply | Report Abuse | Link to thisFirst: The diseases all take effect after the normal period of having children.
Second: As the average lifespan for most of history and before was between 25 and 35 years, most of these "modern" diseases were never expressed.
My Genetics professor made this point about Huntington's Disease in 1965. I don't see that all of our advancements in genetics has modified this basic truth.
I think that there is a faulse assumption underlying much of the otherwise excellent work the authors and others have been doing on the human genome. There is an assumption that there would be some selective pressure involved in the frequencies of the SNP's for various diseases. The assumption for diseases such as breast cancer, adult diabetes, heart attack, stroke, altzheimers, etc. The fact is that there cannot be any selective pressure for two huge reasons.
Reply | Report Abuse | Link to thisFirst: The diseases all take effect after the normal period of having children.
Second: As the average lifespan for most of history and before was between 25 and 35 years, most of these "modern" diseases were never expressed.
My Genetics professor made this point about Huntington's Disease in 1965. I don't see that all of our advancements in genetics has modified this basic truth.