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Big Biology is Here to Stay

Why R01-funded biologists should throw their support behind large-scale research projects.

By | August 1, 2008

One of the favorite complaints of biologists is that we spend too much money on large-scale research projects. Grousing about big science, however, is nothing new. I remember in the early 1990s when the NIH announced its intention to sequence the human genome. NIH funding was tight at the time, and the idea of throwing scarce resources at a project of dubious feasibility, and without a clear scientific objective, seemed ludicrous. Many of my university colleagues wrote protest letters to stop the perceived boondoggle, to no avail. I personally thought it was a waste of money. We were all wrong.

The success of the Human Genome Project, in part, helped convinced the public that biologists' work was worthy of more public funds, and it helped justify the doubling of the NIH budget. It also started a push towards big science at the NIH, exemplified by the "Roadmap" initiative, started in 2002. This initiative included projects such as translational clinical centers, molecular screening centers, and large-scale bioinformatics and technology development projects.

The stated intent of the Roadmap initiative is to remove traditional bottlenecks in biomedical research and more quickly apply research results to the diagnosis and treatment of disease. But the Roadmap also has the unstated purpose of convincing Congress that NIH is serious about using its increased funding to improve human health. Why is this necessary? Because Congress and the American public have a different measure of success than biologists.

From biologists' perspective, NIH research has been a tremendous success. We now understand the fundamental architecture of cells, how genetic information is encoded, and many of the molecular details of metabolism and signal transduction. From the perspective of the American public, however, we don't know much at all. We can't cure most cancers, and although we have identified the genes that cause Lou Gehrig's disease and other disorders, we still can't do much about them. There is a feeling that we will find cures someday, but the public is anxious that the cures won't come soon enough to help them. Congress, which votes for the NIH budget, responds primarily to the voters.

Considering this situation, it was unrealistic to expect NIH to use the budget doubling to simply increase the number of R01 grants. If R01 grants had not cured cancer in the past, why would one expect them to do so in the future? Instead, NIH used a small part of the extra money to create big, visible programs that were directly targeted at what Congress explicitly expected as part of the budget doubling - clinical results.

Let's face it: The business of the NIH is to fund research that improves people's health, not fund our personal research projects. Starting new, large-scale research projects was a clear demonstration that NIH was willing to try new approaches to accelerate biomedical research. It was critical to show Congress that the NIH was serious about this responsibility and that new money would be used in innovative ways. Of course, this means that if these new, large research programs fail, Congress is unlikely to look favorably on future requests for more money. Thus, trying to shift funds away from these large projects will ensure that they do fail, and will be self-defeating in the long run. We'd better hope these projects are successful, and we should do all we can to help them.

The big centers started by the Roadmap initiative have also created new research opportunities for other biologists. The purpose of many of them, in fact, is to provide resources to the scientific community that can be exploited to enable new research ideas and directions. If you have an opinion about the most useful types of projects to fund, let the agency know. But just complaining about big science is not helpful. The success of large, high-profile NIH projects is the best way to get increased funding for all of NIH, and to accelerate scientific advances in biology in the process.

Steven Wiley is a Pacific Northwest National Laboratory Fellow and director of PNNL's Biomolecular Systems Initiative.

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Comments

Avatar of: THOMAS DECOURSEY

THOMAS DECOURSEY

Posts: 3

August 5, 2008

Steve Wiley?s function seems to be to present ill-conceived, blatantly ridiculous propositions, evidently intended to stir up controversy. I was sucked into his latest absurdity ?Big Biology is Here to Stay? (The Scientist, August, 2008, p. 27), although I suspect (and hope) it is a joke.\n He claims that the Human Genome Project helped convince the public that supporting research was worthwhile. This statement is a fabrication with no evidence to back it up. The public has always favored increasing support for biomedical research. I doubt if 10% of the public could explain what the Human Genome Project is or name one disease cured as a result.\n He touts the ?Big Biology? Roadmap initiative of 2002 as a means to convince politicians to support the NIH. He neglects to mention that NIH funding has stagnated since 2002, and therefore this attempt to secure funding has failed miserably. We are worse off than when the Roadmap started.\n The tortured logic in the following statement is painful to contemplate, ??it was unrealistic to expect NIH to use the budget doubling to simply increase the number of R01 grants. If R01 grants had not cured cancer in the past, why would one expect them to do so in the future?? The NIH squandered the extra money on the ?Roadmap? boondoggle, but according to Wiley?s own logic, this has failed because cancer remains uncured.\n The premise of Wiley?s argument is that we have to trick Congress and the Public, and we can do this best by diverting scarce NIH funding into Roadmap-style research projects. It is high time that scientists stop shooting ourselves in the foot by this kind of chicanery. Let us recognize several truths:\n1) Big science, with very few exceptions - one being the Human Genome Project, is a waste of money. Big science is grossly inefficient, and is designed to impress non-scientists (including university administrators). Anyone who has experienced the difference between forced collaborations (big science) and real collaborations (spontaneous, as-needed interactions) knows this is true.\n2) Scientists certainly do need better PR with Congress and the Public. However, we can make a stronger case with the truth. Basic research does lead to cures for diseases as well as other improvements in quality of life. Big science enriches a few empire builders but produces nothing.\n3) Contrary to Wiley?s claim, Congress does not respond to the voters. The voters have said for decades they want more money spent on medical research. The voters are screaming today to end the 3 trillion dollar war in Iraq. I have no doubt that 90% of the public would support a one-month moratorium on the Iraq war in order to double the NIH budget. Congress responds to lobbyists and they respond to money. We need better lobbyists.\n4) Biomedical research in the United States is now in a state of crisis from which it may not recover. The most important single indicator of the future of biomedical research is the funding rate of the R01. Diverting money from real science into flashy projects may fool a few politicians for a few years, but the real cost will be the destruction of American science. As is a direct result of 10% R01 paylines, virtually no American student selects traditional academic-track basic biomedical research as a career. They see top scientists struggling to keep their labs afloat or leaving science altogether, and they would be insane to choose this path. Research needs continuity, and this is what we are in danger of losing.\nWiley does a great disservice by writing a frivolous piece when genuine basic biomedical research is on the verge of extinction.\n\nThomas E. DeCoursey, Ph.D.\nDepartment of Molecular Biophysics and Physiology\nRush University Medical Center HOS-036\n1750 West Harrison\nChicago IL 60612\n\nPhone: 312-942-3267\nEmb: tdecours@rush.edu\n
Avatar of: ROBERT HURST

ROBERT HURST

Posts: 31

August 12, 2008

While Thomas Decoursey makes several important points, I must disagree with several others and agree with Stephen Wiley. However, let me make clear at the outset that nothig said below is intended as a criticism of Dr. Decoursey. \n\nBasic biomedical research is not facing extinction because of the "Roadmap." It is in trouble because the system has an unlimited capacity to absorb resources and because of over-reliance on one model of science. From the viewpoint of Congress, they just doubled our budget, and we are complaining about not having sufficient support. In fact, during the doubling, many institutions expanded facilities on the anticipation that steady increases would follow. If I remember correctly there were many warnings from both the political system and those inside science NOT to expect steady 7% increases. Now there are too many scientists chasing a constant budget, \n\nThe other problem is that with the maturation of molecular biology in the 70's came an over reliance on "bottom up" science, aka "hypothesis-driven research." I believe this is why cancer has not been cured. The favored bottom-up system depends upon an eternal chaining together of hypotheses to assemble the larger picture one gene or protein at a time. Thus knowledge about a previously unknown protein emerges only when it is connected to a known one. There are two major problems with this approach. First, as became painfully evident with the emergence of transgenics, the "pathways" were actually networks. When scientific experimentation could only be done one gene or protein at a time, the cellular system did resemble pathways. An effect was predicted, and if it was seen, QED. What was not evident was that the predicted result could have been an indirect rather than a direct result of intervening in the system. Likewise, what else might occur was also not seen except by serendipity. Thus, a very simplified version of what is now turning out to be a very complex system was accepted as the only legitimate way of doing science.\n\nThe second major problem is that while the bottom up approach may work in the end, the time scale likely is very long. Steven Weinberg in his classic 1972 book "Introduction to Systems Thinking" pointed out this very problem. To paraphrase, the problem with top-down science is that it could be wrong. The problem with bottom-up science is that it is slow. "Wrong" is usually cured quickly. There is no cure for slowness. Congress and the public are beginning to react to the problem of slowness, which, interestingly, is not viewed as a problem by most scientists.\n\nNow it is commonly thought that our knowledge base includes most of the important systems. Whether that assertion is true is not immediately clear. It is true that the role and control of cell cycle is well understood, but that likely reflects the use of cells grown on plastic as the major model for investigating cellular phenomena. Unfortunately, cells grown on plastic represent a very poor model for cells in vivo because most cell-cell and cell-matrix interactions are not represented in the model. The human genome consists of something around 35,000 genes, more or less. The number is many times larger if splice variants are counted separately. The proteome may be as large as a million proteins if splice variants and post-translational modifications (which can have profound effects on activity) are counted separately. An amazingly large fraction of the genome is unannotated or poorly annotated, meaning the functions and interactions are little understood. Only half of the genome is associated with more than one publication. Fully one-third are not associated with any publications and therefore represent completely unknown functions. Worse, many of the papers describing much of the genome are omnibus papers describing the cloning of thousands of genes. Thus, in fact, quite little is known about how cells and tissues function as a system. No more than 1,000 genes have been investigated in any detail in breast cancer, probably the most studied of the cancers. To claim that these are the most important genes flies in the face of reason, as does the belief that the functions of the other 34,000 or million genes and proteins will emerge in finite time with the bottom-up model. A case can be made that if the cure for cancer were within this very limited knowledge base, it would have been discovered already. That it has not suggests that the cure for cancer and other diseases lies within the vast portions of the genome and proteome that are not annotated or understood or that understanding how all the parts function as a whole is incomplete.\n\nThe question arises as to what is the most efficient means to focus our efforts on understanding the larger picture. Unlike the past when genes or proteins really could only be studied one or two at a time, a choice now exists. "Big Biology," which few appear to really understand, offers the possibility of quickly providing a low-resolution picture of how the unannotated portion of the genome and proteome might function as a system that certainly includes the more or less well-understood portions. Yes, it is true that errors will result, but the resulting picture will serve as a guide for the generation and testing of hypotheses and errors will be quickly corrected. Thus, bottom-up and top-down science are really not incompatible; they are complementary. Alone, the bottom-up approach is extremely inefficient. Failed hypotheses are rarely presented and likely are tested over and over again. Yet, without mechanistic hypothesis testing, the top-down approach never reaches certainty. \n\nI think it is true the public and Congress want more money spent on health research. While the scientific establishment has tried to make a case that bottom-up science is health research, I think that a certain disenchantment with this connection is emerging. Thus, I agree with Stephen Wiley. Big Biology is here to stay, and we should welcome it because it will allow us to focus our efforts on significant societal problems. I wonder if perhaps that is threatening to many in our community who have come to view the public's largesse as a right, not a privilege. \n\nDr. Decoursey certainly is correct that biomedical research is in deep trouble, and this engine that drives a growing portion of our economy as well as providing improvements in health care (I am very thankful for simvastatin, myself) is placing our entire nation at risk. It is not clear to me, however, that the reason is "Big Biology." Perhaps we do need to keep some rational connection between the number of scientists and the level of support available, and perhaps some refocusing to better integrate top-down (aka "Big Biology") and bottom-up science. \n\nRobert E. Hurst, PhD\nProfessor of Urology\nAdjunct Professor of Biochemistry and Molecular Biology\nMember, Oklahoma University Cancer Institute\nOklahoma University Health Sciences Center
Avatar of: anonymous poster

anonymous poster

Posts: 9

August 12, 2008

Let me add my two cents..\n\nI don't think doubling of the NIH budget was wasted. This money funded a lot of new research (read peer-reviewed ideas that deserved funding). Research needs new people and ideas. We need to diversify our investment in ideas and people, not promote a monoculture that "big science" produces. \n
Avatar of: anonymous poster

anonymous poster

Posts: 18

August 13, 2008

I don?t know the meaning of ?big biology,? but this old-timer senses a very disturbing trend. In the 1980s, I was a scientific climber with a multi-grant lab starting to border on big science (~20 people and growing). I realized I had lost contact with my trainees, and was unable to monitor their research or professional development. I cut back to half that size and have enjoyed myself immensely since. Thus, I think I have a balanced perspective on Wiley's position with which I substantially disagree. \n\nBig biology promotes colossal labs. While these may attract the best post-docs and students, most of these labs provide a survival-of-the-fittest, not a training, environment. The value of scientific ethics, methodological rigor, correction of wrong publications, and scientific openness are some of the casualties. Worse is the competitive spirit that rewards getting there first, not getting there right or thoroughly. Who in their right mind today will talk about unpublished data knowing some large lab would crank out a paper in no time with no concept of crediting the originator of the idea. When there is a disagreement among labs, how often is the issue resolved in the literature (e.g., by exchange of techniques or reagents and joint publication)? \n\nSome rare projects are technology-focused and need big science (HGP, Manhattan Project, etc.). On the other hand, big biology may tend to submerge individual creativity. We ignore past lessons of undue centralization shown by inefficiencies of central national planning or central management of large corporate conglomerates. Big science may appear to succeed because it has the resources and therefore attracts the best and the brightest, but it is quite an open question about whether it maximizes the use of those fiscal and people resources. A second casualty may be that big science will lose some of the next generation of talented scientists, many of whom are at universities and colleges where they will have more limited access to research experience. \n\nThere is no doubt that there are benefits of big biology if that means promoting collaboration and providing access to key resources. On the other hand, I suggest that it is time to give critical scrutiny to the NIH-funding of megalabs and national centers. Optimistic economic assessments are for cutting half-trillion dollar deficits to the several hundred billion range. Can we realistically expect much NIH growth in such circumstance? Will both science and the public be best served by huge projects?\n
Avatar of: JOHN HAMLYN

JOHN HAMLYN

Posts: 1

August 13, 2008

We don't NEED Big Biology or little biology per se. Both biologies have well understood scientific, financial and political consequences. Some problems simply need massive resources others not. But whether big or small we can all agree on the need for good science. Many of todays key discoveries, insights and technology were unthinkable 10-20 years ago. The same statement will be equally valid 20 years from now. The real trick is getting the right balance and then letting big and little biology do what they do best.
Avatar of: anonymous poster

anonymous poster

Posts: 27

August 13, 2008

I tend to agree with Wiley. Big Biology is here to stay. But, of course, there has to be balance. Big Biology alone is not the best way to advance the field. Just like R01s alone are not the best way to advance NIH funded research. \n\nTo say that the ONLY/BEST way to do science is by R01 (or the equivalent) funded scientists toiling in a lab with a couple of students and a post doc is just as bad as saying that BIG science is the best way to make breakthroughs. \n\nI have no problem with big science as long as it clearly provides a benefit to the whole scientific community.
Avatar of: anonymous poster

anonymous poster

Posts: 5

August 14, 2008

At this point, I only know a few students and post-docs that are going to pursue the traditional academic path. Even those with K awards are not assured positions or continued funding. The pay is awful, the conditions are ridiculous (capricious reviewers for grants and papers) and the methodology for advancement haphazard and somewhat guild-like. Tenure these days grants you nothing at a biomedical research institution (20% of salary = who cares?). The only ones staying in the system are MD/Ph.D.s that can bring their salary in treating patients. Honestly, due to the time constraints they have, they are not very good scientists.\n\nI love science, especially the theoretical work that ties into our more clinically relevant work, but how could any logical person enter this system? I need to know I can feed my children.\n\nI think we are better off building skills that are applicable in the real world, and bouncing between companies, than dealing with this system. My naive view of doing science to help people and for the good of humanity is gone, and it appears to have never even developed for many of the students I know.\n\nI am sure a dedicated immigrant will gladly take my place, but I am not sure they will do as good a job as I would have.\n\nWhat a waste of 10 years of taxpayer training dollars.\n\nOff to industry I go...\n\nI won't even bother getting into the Big Science vs. RO1s since the debate is pointless - congress doesn't understand either, and we simply need a lobby like everyone else.\n\n\n
Avatar of: anonymous poster

anonymous poster

Posts: 1

August 22, 2008

To Robert Hurst:Steven Weinberg in his classic 1972 book "Introduction to Systems Thinking" pointed out this very problem.\n\nDid you mean Gerald Weinberg book "Introduction to General Systems Thinking" or I am missing something?

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