The Dreams of Geneticists

In a wiser world, we would see genetics research as we see astronomy: worth supporting, but without expecting practical benefit. In this world, however, genetics research is far better funded than astronomy and is expected to have practical benefits.

Unfortunately, the benefits have been slight. A New York Times article by Nicholas Wade makes this clear:

The primary goal of the $3 billion Human Genome Project — to ferret out the genetic roots of common diseases like cancer and Alzheimer’s and then generate treatments — remains largely elusive. Indeed, after 10 years of effort, geneticists are almost back to square one in knowing where to look for the roots of common disease.

“Largely” elusive? Completely elusive is more accurate, as far as I know. Not one treatment has come from this work.

In spite of ten years of failure, geneticists appear no wiser than before:

With most diseases, the common variants have turned out to explain just a fraction of the genetic risk. It now seems more likely [to prominent geneticists] that each common disease is mostly caused by large numbers of rare variants.

I know of no examples where a common (or any) disease has been shown to be caused by “large numbers of rare variants.” Perhaps these estimates of “genetic risk” are as misleading as asking what percentage of the area of a rectangle is determined by its width.

History repeats. Ten years ago, geneticists had zero examples of how mapping the human genome would help anyone with a common disease. Absence of any examples didn’t prevent such vast claims as human genome mapping will ““revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases”. From zero, they extrapolated to “most”.

It’s a sad comment on science journalism that, at the time, no one pointed out the absence of examples, as far as I know, and a sad comment on Wade, holder of a powerful and prestigious job, that he has not pointed it out now. He simply repeats a claim. At least he has noticed a gigantic failure after it happens, even if he inaccurately describes it (“largely” rather than “completely”).

Lack of examples of the practical value of genetic mapping didn’t keep a huge amount of money from being spent.

With the catalog [of common genetic variants] in hand, the second stage was to see if any of the variants were more common in the patients with a given disease than in healthy people. These studies required large numbers of patients and cost several million dollars apiece. Nearly 400 of them had been completed by 2009.

Ten failures would have been plenty; 400 failures shows the resistant-to-evidence nature of the whole enterprise. It’s an example of how a little biochemical-mechanism research goes a long way; a lot of biochemical-mechanism research goes a little way.

For geneticists, to acknowledge the lack of examples is scary. Their funding might be cut! So they don’t. But nothing prevents journalists from thinking for themselves and asking a supposedly “tough” question (“what’s an example?”) — although asking for examples is the most basic question there is.

Thanks to Alex Chernavsky. More about the cargo-cult nature of modern biology. If you don’t believe me, read this: “Of the roughly 50 companies at the conference, not one is focused on approaches related to tracking down new genes. . . . The one corner of the genome-focused biotech industry that’s thriving is the one churning out equipment and services to support researchers in their endless hunt for gene links.”

35 Responses to “The Dreams of Geneticists”

  1. Kevin Miller Says:

    I agree that this is a fascinating development, but I don’t think it’s one that would have been predictable (I certainly thought the Francis Collins’ party line made perfect sense). Furthermore, I suspect that 1) the people who espoused it really believed it. (Funding is nice, but they all spent decades of their lives on this that they’re *never* getting back); 2) the tools that they developed will prove to be critical in the kinds of approaches that are likely to be more powerful, such as understanding the genes of invasive organisms.

    This isn’t my area of work by a long shot, but I’m old enough that the article reminded me a bit of all the stories in the 1990s about how the microcomputer revolution hadn’t had any demonstrable beneficial effect on business productivity. I suspect that there will be really powerful effects of this technology as it proliferates, and I hope that most of them will be positive.

  2. seth Says:

    Kevin, you write this “wasn’t predictable.” I have been saying what I say here for more than ten years — that all common diseases will turn out to have big environmental causes that we can figure out and use to our advantage. Genetics won’t matter. And I had many examples, such as lung cancer, tuberculosis, etc., plus lots of other data. The geneticists had nothing to back up their big confident predictions. Not one example. They were reduced to saying stuff like breast cancer runs in families! So did pellagra. Their case has been weaker than weak for a long time.

  3. Dennis Mangan Says:

    The fundamental reason for the lack of results: our genes didn’t evolve to kill us.

  4. sadie Says:

    Cancer treatments that target a specific tumor genotype definitely exist. I don’t know how many are mainstream yet, but a relative with medulloblastoma just participated in a clinical trial that targeted the “hedgehog” gene. From the link below: “In 2004, a St. Jude team reported that an experimental drug called HhAntag, which inhibits Sonic hedgehog signaling, led to the deaths of medulloblastoma cells and the elimination of these tumors in treated mice.”
    http://www.stjude.org/stjude/v/index.jsp?vgnextoid=00ef921b911e8110VgnVCM1000001e0215acRCRD&vgnextchannel=3c9213c016118010VgnVCM1000000e2015acRCRD

    Our genes didn’t evolve to kill us, but every once in a while one of them mutates and makes a whole hell of a mess.

  5. Nathan Myers Says:

    I seem to recall a Quantified Self presentation where someone got a gene workup. From the particular markers found, it predicted his risk of heart failure in twenty years would be enormously greater (as I recall, 1.5% vs. 50%) if he continued gaining a pound a year. This was enough to get him focused on keeping his weight stable. That seems like a useful result, even if it didn’t cure an existing illness. To me quantifiable prevention seems just as valuable as a cure.

  6. Brice Says:

    Regarding “largely elusive” vs “completely elusive” – the second article in the NY Times series published today does give some examples – 1 drug just approved for treatment (supposedly based on genomics) and others in trials and potentially close to approval. They quote 1 company as saying 1/3 of their drugs in trials are based on genomics. So “largely elusive” seems about right.

    In 1975 or so, monoclonal antibodies were discovered. There was a lot of hype about them, magic bullets to cure cancer, etc. At one point and after many failures sentiment swung the other way – it was thought by many that monoclonal antibodies could not and would not work in humans. In 1998 (23 years later) the monoclonal antibody drug Rituxan was approved for treatment of cancer. It has grown to be the drug of choice for non-hodgkins lymphoma.

    So will genomics lead to many new successful treatments for many diseases? Or exactly zero treatments? I suspect somewhere in-between.

  7. seth Says:

    Brice, thanks for the update. Drugs are approved if better than placebo. They may be worse than other treatments. So drug approval doesn’t mean the new drug provides any benefit. It’s too soon to say. Drugs can be approved and priced too high. This is why I think it’s fair to say it’s still impossible to point to even one clear benefit of the human genome project. In case my point isn’t blindingly obvious, I think research funding should be spread more widely. Less spent on genomics, more spent on other approaches.

  8. ChristianKl Says:

    I don’t see something wrong with the measuring equipment branch of the industry growing.
    They make impressive progress by being much faster at cheaping DNA sequencing than Moore’s law.

    Maybe there a way to give that branch money more directly to develop better tools but in a few years we will actually be able to give everyone their genomic data.

    Monoclonal antibody aren’t only useful as drugs, they are also in the core toolkit of microbiologists to measure the concentration of a given protein or other molecule.
    I would think that most drugs that get developed today benefited from monoclonal antibodies somewhere in their development cycle.

    I think it makes a lot of sense to develop a better core toolkit instead of just evaluating the usefulness of a discovery by the fact whether it cured a specific illness.
    Hopefully someday the core techniques get cheap enough that the can be used for self experimentation.

    We even cured some children’s blindness with Gene therapy: http://www.nytimes.com/2009/11/03/health/03eye.html?_r=1

  9. Cameron Says:

    Implying that understanding the human genome has been a waste of time and resources is irresponsible at best. So is assuming that all disease is purely environmentally derived with nothing to do with genetics. That’s a really big assumption and scientists shouldn’t be in the business of assumption. Anyone, including geneticists, who assumed that once the genome was mapped, that we would enter a utopia of disease-free life, was clearly mistaken. Understanding the genome is just the first step. The next step is the cataloging of all of the products of those genes. Then attempting to build a network of how those products/genes interact with each other as well as how they interact with the environment is the larger goal. We are still a long way away from that but it is not only a valid goal, but a necessary one. I don’t assume that all disease is genetically based. I understand that our current understanding is limited and we simply need more information. We also need new and better tools for understanding complex interactions and complex networks. But to say that since genetics hasn’t yet cured the common cold, or cured cancer, that it did not deserve to have had all the money allocated to it as well as it being undeserving of it’s current and future funding, I believe, only demonstrates a lack of understanding of what genetics is and where it’s going. It’s already been demonstrated with epigenetics that the environment is capable of altering how genes are expressed and that those changes are heritable. Understanding how the environment interacts with our bodies necessitates a complete understanding of our genome, its products and their interactions. I would argue that you can’t assume what causes a disease (and therefor, what a disease even IS) until you understand the system which the “disease” exists in. Devaluing genetics is just as myopic as devaluing investigating environmental causes for diseases. We should seek to understand all possibilities. I don’t disagree that some scientists might oversell their gene to get funding. But that doesn’t and shouldn’t undermine the science as a whole. Overselling is an unfortunate side effect of the competition for funding.

    http://www.nytimes.com/2009/11/06/health/06gene.html

  10. seth Says:

    Cameron, you say my position is “since genetics hasn’t yet cured the common cold, or cured cancer, it did not deserve to have had all the money allocated to it as well as it being undeserving of its current and future funding”. I’m not just thinking of the common cold and cancer, I’m thinking of any common disease. But you’re right — I think that lack of promised results should reduce funding and that the money freed up should go to support other approaches. What would it take to convince you that genetics has been overfunded?

  11. Cameron Says:

    I would have to be convinced that the completion of genome was the end of the story and that all successes and failures should have been hinged upon its’ completion. I would have to be convinced that understanding how genes and the products of genes interact with each other and the environment is not a worthy funding prospect. I would have to see an argument detailing the specifics of what money was spent on what and exactly why that should be considered a case of “overfunding”. Furthermore, why those specific cases should be extrapolated to define the endeavor as a whole. You say that genetics has been overfunded because it hasn’t immediately produced what it was promised to. I think you have to convince me that the majority of science was convinced and so promoted that once the genome was completed, again, that would be the end of the story and we all could go home. And you would have to convince me that it was precisely that promise led to what can be easily defined as “overfunding”. I think anyone can make an argument that certain aspects of genetics (or certain genes) were and may have been oversold. But I think anyone can make that argument about any branch or endeavor of science if you try hard enough. You state in another response that “all common diseases will turn out to have big environmental causes that we can figure out and use to our advantage. Genetics won’t matter.” Well, even if it is determined that all disease ultimately exists due to outside causality, you still have to understand how the disease acts upon/within the body. It won’t even be possible to make that determination until you understand how our genes/gene products work and interact. So I would say that if you are convinced that outward forces are the ultimate cause for all disease, you should be lauding the efforts of science to understand the genome and its products to so prove your assertion. Since you are your genes, understanding how your genes work on their own, interact with each other and with the environment (for instance if some environmental agent acts to shut a gene on or off epi-genetically) is vital to understanding exactly what a “disease” even is. Once you understand that neither the body nor the environment is a closed system, ultimate causality begins to become more difficult to pin down and you realize how much more we really need to understand. Making grand statements like the one I quoted above is exactly the type of statement that you contend that genetics did prior to the completion of the genome. I am not convinced that science as a whole contended that the completion would by itself cure all disease. You seem likewise convinced that genetics will have nothing to do with disease with the same combination of promise and lack of evidence that you decry geneticists had prior to the completion of the genome.

  12. seth Says:

    Cameron, here’s some evidence for my claim that studying environmental causes will lead to useful progress on common diseases: 1. The discovery that dirty water can spread disease led to cleaner water and less water-borne disease. 2. The discovery that folate deficiency increases the rate of birth defects led to folate-fortified foods, which led to a reduction in birth defects. 3. The discovery that smoking causes lung cancer led to less smoking and less lung cancer. 4. The discovery that scurvy is caused by lack of Vitamin C led to less scurvy. 5. The discovery that pellagra is due to lack of niacin led to less pellagra.

  13. Cameron Says:

    Those are all fine examples. Not once have I said that there are not environmental causes of certain diseases and that studying that is a waste of time. I just don’t understand how you go from these examples to “genetics won’t matter” and that it is “overfunded”. Nor is any of this a reason to lessen the funding for things like gene therapy or the study of gene networks. Again, understanding the genome and its’ products will only enhance our knowledge of exactly how and when environmental agents are responsible for what we call “disease”. Understanding that smoking causes cancer is only a part of the story. But what do you do when someone has lung cancer that didn’t smoke? That’s a reason to understand the mechanism for why cancer is so hard to “cure”. Telling people to stop smoking isn’t going to “cure” cancer either. It’s just going to significantly reduce the problem… which is good obviously. But that doesn’t mean we stop there and don’t try and understand the molecular mechanisms of cancer. Any outside agent that would cause a disease still has to act upon a system to disrupt. If you don’t understand the system by which the agent acts upon, then you do’t understand the disease. To only focus on any one aspect (genetics or environment) is not good science.

  14. seth Says:

    “Nor is any of this a reason to lessen funding for things like gene therapy . . . ” Funding is limited. Less funding for genetics research means more money for other research, in particular study of the environmental determinants of disease. So when one area of study (how environment causes disease) turns out to be fruitful, and another area (genetics) turns out to be less fruitful than the predictions made to get the funding, it is a reason to change how much money the two areas get. I’m not saying genetics research should be eliminated or is worthless, just that it should be less well-funded and the freed-up money should go to study of how the environment causes disease.

  15. Cameron Says:

    That’s a much different statement than “genetics won’t matter.” It’s fine to have that opinion, but it’s the type of argument that can’t really leave the realm of opinion. I’ve already said why I think that the general realm of genetic science is vital to our understanding of disease.

  16. seth Says:

    It would be interesting to know why you think further study of genetics will help us 1. prevent common diseases and 2. cure common diseases — along with any evidence that exists to support your ideas. I can’t find any evidence in your comments about this. That’s the point of my post — the lack of evidence for all the claims.

  17. Cameron Says:

    I don’t know what you define as “common diseases” but that seems an arbitrary designation. Presumedly, once the mechanism of the genome and its’ products is better understood, yes it will lead to better medicine. We’ve got the genome, but as I’ve explained, there is still much to do. Once we understand exactly what a disease is, it will give us the best chance to combat it. You say you want more money to understand environmental causes for disease, but without understanding the mechanism, without understanding how any environmental agent acts on the body, all you are doing is establishing correlations. It’s a start, but it’s not the whole story, and correlations are certainly not going to cure anything. What you fail to understand is that annotating the genome takes a long time. Computers can annotate genes but annotation algorithms are inexact. So it takes a human to clean it all up. Science, especially genetics, is a slow, deliberative process. It’s not a reality TV show, it’s science, and it takes a while to get it right.

  18. alan Says:

    There are all sorts of diseases that have been linked to genetics The APOE-4 allele on chromosome 19 in particular has been linked to a lot of conditions such as alzhiemers as well recovery from traumatic brain injury. There are tons of other disorders and “diseases” which have genetic components that we can identify. The interesting, and I suppose you could say unfortunate, thing about the mapping is that it taught us about alleles which are basically like little switches that control the gene expression. These actually are largely influenced by the environment and the affects can be seen as far as 3 generations later (there were a lot of studies about how famines affected the grandchildren of the people who were food deprived on a genetic level). The point being genetics is just like the rest of science. We answered a very important question and it gave us more questions. How is that surprising? Science is always like that. Whether it’s physics, biology, psychology, etc. As long as it is breaking new ground, why would you really expect that to be the end. Last I checked we aren’t anywhere near knowing all there is to know in any of these fields. It is regrettable the answer wasn’t so easy (and yes a lot of very smart people thought it was) but they couldn’t see the whole picture because they didn’t know what they do now obviously. Point is, we have learned a ton from mapping the genomes, you are over-simplifying.

  19. seth Says:

    Cameron and Alan, your comments suggest evidence that more genetics research will help us prevent and cure common diseases is hard to find. Nothing wrong with “learning a ton” — just as there’s nothing wrong with astronomy research — but preventing and curing common diseases is even more important. I think the loud claims of geneticists have drawn attention away from actual progress made by other approaches.

  20. Cameron Says:

    No offense. But I think that just sounds like whining. Biology only started getting a disproportionate amount of money in the 70′s. Before that it was the physicists. Things go in cycles. It won’t be in biology forever. As the amount of data all this biology generates gets to a certain point, the processing of this information will become vital and then all of the biologists will complain that all of the computer scientists get all the money. The genome was only finished 10 years ago and the average FDA patent takes 15 years. So what does that tell you? Again, I think your expectations that once the genome was done that we would automatically start curing diseases vastly misunderstands the process of science. Isn’t that ultimately what your blog is about? If you want to being attention to other methods then write a book and start a blog… wait. You still haven’t answered the charge that even if you lock down environmental causality, you still have to understand the system that this environmental agent acts upon. External causality is not the end of the story. You are not a closed system!

  21. alan Says:

    It’s hard to find because using the genetic expressions to cure diseases is completely different from understanding that they are an underlying cause in pathology of the disease. Just like we understand cancer is caused by uncontrollable cell growth, it is one thing to know what is causing it and another to actually find a cure. But just for a second think about what you are expecting. That as soon as we mapped out the genes, you thought we would be able to change the expression of the genes in a living person/animal to treat someone. It turns out RNA and epigenetics are actually much more responsible for the physical expression of your genes. RNA is extremely more complicated due to the large number of types, mRNA, tRNA, rRNA , tmRNA, etc. The point is even when we understand what all these things do we still have to figure out how to actually affect single alleles on single genes which then get sent throughout the body to all the nuclei via RNA without messing up everything else. I can’t really imagine anything more complicated to be honest. But that doesn’t mean we are going in the wrong direction. It does seem to be extremely important. At least equally important as environment. I think environment plays a big, big role don’t get me wrong. But as complicated as changing the gene expression in a human being can be, I think changing the environment is even harder. There are just too many factors. I just think you are being too impatient.

    What other methods would you suggest that focus on environment?

  22. alan Says:

    or what other approaches are you talking about that biology has taken attention away from?

    I am trying hard to think of any and I think therapy and the attitude that people have play a big role. But just because people with cancer who have more positive attitudes are more likely to go into remission doesn’t make it a cure. In fact it needs to be coupled with actual medical treatment or else they most likely just die. Anyways I’m trying to see it from your side but I guess I just need to know more specifically what you are saying.

    The main problem I had with this article is just the giant sweeping generalized statement that genetics hasn’t made any progress in the last 10 years. You seem like an intelligent person. You even got your news from a reputable source, But that was still just that authors opinion, not fact. And you are allowed to have your opinion as well. But I’m trying to tell you that it has in fact made progress and just because you aren’t hearing about it doesn’t mean it isn’t happening. Scientists almost by necessity aren’t the type to step out in front of the world and make huge announcements. They are extremely dedicated to their work and about the only place they show it to other people is at science symposiums. The only way it makes it into popular culture is when we finally see the tail end of it being marketed to us as some new product or invention. They aren’t going to say ‘hey guess what we made a little progress’ and then get asked ‘what does that mean?’ and then answer ‘more research’ every time a new development occurs because they would have to spend all their time doing stupid interviews for newspapers, radios, television and internet bloggers instead of actually conducting research. Look up some scientific articles. They are out there I assure you. If you don’t see them you’re not looking in the right place. There are scientific journals solely dedicated to genetic research. In the those journals are published experiments some successes, some failures, and with each of those comes progress.

  23. seth Says:

    “Changing the environment is even harder.” I have changed my environment in six or seven ways due to the results of my experiments (about environmental effects). Lots of people have quit smoking.

    The emphasis on genetics has taken away from studying environmental effects.

  24. Cameron Says:

    “The emphasis on genetics has taken away from studying environmental effects.” If you say so.

  25. alan Says:

    http://en.wikipedia.org/wiki/List_of_genetic_disorders

    These are all genetic disorders that we’ve learned about since mapping the genome. There is also all sorts of other crazy stuff they can tell as well. Even trivial things like if you are a person who has wet or dry ear wax. No lie. It’s ridiculous but true. I just don’t understand how in the face of all this evidence you refuse to change your opinion.

    I won’t and I’m sure cameron wouldn’t hold it against you if you revise your opinion. But Sadie, Brice, Christian, Cameron, and I have ALL given examples as evidence that your opinion is based on faulty information and you are in fact wrong. There’s really nothing else we can do to change your mind.

    If you are a scientist who works on alternative treatment methods I could see how you would be bitter about not having funding. But the way you are so ill informed about the current research in genetics makes me sincerely doubt you are in any way at all involved in a related scientific field.

    And I am out. Good luck in the future. I hope someday you will be happy with amazing developments that come out of genetic research.

  26. seth Says:

    I don’t see how providing a list of genetic disorders (all rare) helps prevent or cure any common disease. “You are so ill informed about the current state of genetics research . . . ” Let’s put it this way: I knew of no examples where recent genetics research has helped cure or prevent a common disease. I asked for examples but none were given by defenders of that research.

  27. Cameron Says:

    You also fail to listen to anything that doesn’t support your view. You ignore the reality that the genome is only 10 years old. You ignore the reality that getting a patent in the US takes 15 years. You ignore the fact that no one ever said that mapping the genome would, by itself and without any follow-up research, cure disease. That’s why we are saying you are ill-informed and don’t understand genetics. Genes-protein-networks-environment. All of those components are required to understand disease. You only talk about one while you accuse “the other side” about talking about one of those. The problem is, “the other side” is not ignoring proteins and networks (OR environment)… you are. Not only are you ill-informed about genetics, you are ill-informed as to the scientific process.

  28. Cameron Says:

    http://www.npr.org/templates/story/story.php?storyId=126396839

    http://www.hhmi.org/genetictrail/g100.html

    http://www.npr.org/blogs/health/2010/04/francis_collins_dna_may_be_a_d.html?ps=rs

    Decent articles that give a basic view of the state of the science. We haven’t “cured” disease yet because the genome is really really really complicated. All we have right now is some strings of correlation. But that isn’t enough. And that’s why we need to know a lot more.

  29. Cameron Says:

    http://seedmagazine.com/content/article/the_once_and_future_genome/

  30. Cameron Says:

    http://www.economist.com/node/16349358?story_id=16349358

  31. Cameron Says:

    The above articles are pretty good perspectives (especially the last two) and I’m going to try and express my opinion in a less confrontational way. It’s understandable that people expected a lot more from the genome project immediately. There was a misunderstanding on all sides about what was expected. But as the I am learning more about this history all the time, science was and still is, in fact, surprised by the incredible complexity of the genome. This complexity has really let us know how much we still don’t know and how much promises of utopia (or dystopia) where naive. Our knowledge is still nascent. If you think about it, believing that we would understand the complexity of disease once the genome was mapped is roughly equivalent to thinking that once a child is able to understand the alphabet and maybe a few basic words, that child can go immediately to reading and comprehending James Joyce.

  32. seth Says:

    “Science was surprised by the incredible complexity of the genome.” Perhaps it would have been better to wait a while — until after that complexity was grasped — before making promises? The main alternative to studying how genes cause disease is to study how the environment causes disease. If the first route (genes) turns out to be more difficult than expected, it argues for paying more attention to the second route (environment).

    Thanks for the links.

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