January 4, 2013

Recently a colleague asked to me contribute suggestions for a strategic plan being developed for one of the institutes of the NIH. The idea was to come up with bold new initiatives that could set the institute off on some new directions. The NIH has been facing harsh criticism lately from policy-makers, Congress and the biomedical scientific community, all concerned that the agency is losing its way. A growing number of researchers are beginning to feel that trying to combine basic and translational research is like crossing the “Valley of Death”: any new idea or approach in moving from basic to translational research is immediately quashed because the institutes and their scientific advisors and reviewers are too timid to try anything novel or risky.

Sharon Begley, a former science editor and senior science writer for Newsweek (now senior health and science correspondent at Reuters), argues that the valley of death is especially perilous for biomedical researchers. She reports that "from 1996 to 1999, the U.S. Food and Drug Administration approved 157 new drugs. In the comparable period a decade later—that is, from 2006 to 2009—the agency approved 74. Not among them were any cures, or even meaningfully effective treatments, for Alzheimer’s disease, lung or pancreatic cancer, Parkinson’s disease, Huntington’s disease, or a host of other afflictions that destroy lives" [1]. Begley claimed that

the chance of FDA approval for a newly discovered molecule, targeting a newly discovered disease mechanism, is a dismal 0.6 percent. Diseases are complicated, and nature fights every human attempt to mess with what she has wrought. But frustration is growing with how few seemingly promising discoveries in basic biomedical science lead to something that helps patients, especially in what is supposed to be a golden age of genetics, neuroscience, and biomedical research in general [2].

What’s going on here? Is Big Pharma the culprit? The NIH? or what? 

·   We have met the enemy and he is us

A widely noticed recent article in Nature [3] accuses the NIH of “promoting mediocrity” and “small science” rather than supporting novel and courageous studies with low probability of success but high potential. According to Nicholson and Ioannidis, between 2002 and 2011 it issued around 460,000 research grants totaling almost $200 billion. Yet when the Institute Director, Francis Collins, proposed a new National Center for Advancing Translational Sciences (NCATS), there was a tremendous hue and cry from many biomedical scientists that this would divert critical funds from basic research—despite the fact that NIH support of basic science over the last 50 years has led to few discoveries with direct benefit to patients.

I’m coming to believe that the NIH and other Federal funding agencies are not at the heart of the problem. It’s us—the scientists. On both internal and national study section reviews of research proposals, I’ve observed a growing tendency of the peer reviewers to focus on the small and petty rather than on the larger issues of whether the potential work is creative and innovative. Lip service is often paid to these last two factors, followed by a feeding frenzy to tear apart the work and find reason to reject, often based on technical “flaws” that could easily be corrected by a phone call to the applicant asking for clarification. All it seems to take to start this cycle is one person raising a criticism—rarely does anyone challenge the critic,

It has been my impression that the younger and less experienced reviewers are often the harshest and most unsympathetic to their peers. It’s as if they have to make their bones by shredding their colleagues, especially when, God forbid, anyone has the temerity to propose solving a scientific problem with a paradigm that differs from the reviewer’s own ideas. It may be understandable that in the face of very limited funding one has to be more selective about what gets funded, but this adversarial approach to reviewing research proposals has gone too far and is eroding the morale and productivity of the scientific community as more and more young people are turning away from research careers in disgust and frustration.

I can remember a time when Study Sections were actually very collegial, and not always on the attack. They often gave investigators the benefit of the doubt and suggested specific modifications that the PI could agree to do. Certainly, the awards were still very competitive, but for the most part PIs felt that everyone was part of the same scientific community.  

The prevailing adversarial trend is exacerbated by the continuing lack of vision in the strategic planning of the research universities—who continue to think that they can count on external grants and indirect cost returns to fund their research mission, all the while putting tremendous pressure on the investigators to “go where the money is” and find the funding to keep their careers alive. The mission is no longer about doing the research but about attracting research funding at any price. We all know this, but either we won’t openly admit it or we are in denial about the reality because we haven’t planned on what we’re going to do with all those research buildings, staff and faculty we’ve just thrown up all over the campus in the forlorn hope that the Feds will pick up the tab.

So where does all this leave us, especially as we face the prospect of ever-diminishing NIH and other Federal support for research? Where do we go from here? What kind of mess we are leaving for our next generation of students and biomedical researchers?

·   How can institutions foster out-of-the-box thinking?

As I looked over the strategic plan and the White Papers from various ”consensus” committees, they all seemed very déjà vu and plus ça change. I think this was apparent in the publically available materials. It was my impression that the paradigms behind these ideas continued to support the belief that if we can just map, record and classify everything, good things will emerge and somehow we will find answers. This idea is based on 18th and 19th century taxonomy with more modern tools and techniques. As famously expressed by Einstein and Frank Zappa, "information is not knowledge," no matter how much of it accumulates. Where are the "Bold Ideas" and themes that emerge from all the work, planning and White Papers of the consensus committees?  Here is the website—you can judge for yourselves: http://www.nih.gov/news/health/dec2012/od-07.htm

Over 40 years ago Thomas Kuhn theorized that as any given area of science approaches maturity, its paradigms become well established and are taught to the rising generation of new scientists. This stage of development—“normal science”—“often  suppresses fundamental novelties because they are necessarily subversive of its basic commitments” [4]. Thus most researchers throughout their careers are engaged in “mopping-up operations”:

The enterprise then seems an attempt to force nature into the preformed and relatively inflexible box that the paradigm supplies. No part of the aim of normal science is to call forth new sorts of phenomena; indeed those that will not fit the box are not seen at all. Nor do scientists aim to invent new theories, and they are often intolerant of those invented by others. (p. 24)

Long before Kuhn, Leo Tolstoy made the same point:

I know that most men, including those at ease with problems of the greatest complexity, can seldom accept even the simplest and most obvious truth if it be such as would oblige them to admit the falsity of conclusions which they have delighted in explaining to colleagues, which they have proudly taught to others, and which they have woven, thread by thread, into the fabric of their lives. [5]

If Kuhn and Tolstoy are right, it’s not surprising that we are now facing some very serious problems. In biomedical research, when you go to a major professional scientific meeting like the Society for Neuroscience annual meeting where some 15,000 posters are presented without any prior review, how much of that tremendous body of work is going to be anything more than small, “normal” science? Of the 20 million scientific papers published over the last dozen years [6], how many ever get cited? Who even reads them? Sooner or later we have to ask whether this is good use of increasingly limited financial support for scientific research. 

With this in mind, I looked over the priority items on the NIH list and selected the few that I thought most interesting, added my comments (below) and sent them to my friend.  

•   Develop more personalized, patient-centered medicine

This is a bold new idea? My generation grew up thinking that all medicine was personalized! This “novel” concept implies that we will go back in time to when physicians actually knew their patients and their history, and apply integrative diagnostic tools that take into consideration the patient as a person rather than a collection of diverse organs each attended to by its own expert. This paradigm is now getting some attention at my institution. Out of the hundreds and hundreds of physicians at Emory, I am pleased to report that two young doctors have been assigned to the new “Center for Personalized Medicine.” I was even more pleased to learn that a third will soon be added. This is certainly a step in the right direction. You can check it out at   http://www.emoryhealthcare.org/patient-centered-primary-care-clinic/providers.html.   

Maybe this is the cyborg wave of the future, but this integrated care is not data- or computer-based; it’s more like a marketing ploy than full-blown personalized medicine.

As practiced by genuinely innovative institutions, personalized medicine is described by Leroy Hood, founder of the Institute of Systems Biology, in this press release:

The vision of P4 [Predictive, Preventive, Personalized and Participatory] medicine is that each patient will be surrounded by a virtual cloud of billions of data points. Advances in science and technology will reduce this enormous data dimensionality to simple hypotheses about human health and disease. The ultimate outcome is to create individualized patient disease models that are predictive and actionable. The shift to P4 Medicine will also require societal changes. [7]

 Where does the physician fit into this scheme? Sounds like all we need to figure out what’s wrong with us is a computer with lots of memory (for the billions of data points) and maybe a new, subcutaneous USB connection into our bodies and everything will be revealed via an immediate printout we take to the pharmacy for our meds. Robotic surgery can no doubt handle the rest—as long as the patient stays connected to the computer terminal. Given the over-specialization of just about everything in academia and medicine, looking at the complexities of diseases and how they affect the organism as a complex system is very much a step in the right direction. Here's where all those tools and P4 tests can be used to generate a comprehensive, computerized avatar of the patient as he/she moves through the developmental spectrum from infancy to old age. Maybe the patient-centered care approach will also require new thinking along the lines of those now used at the Mayo and Cleveland Clinics—a team approach which is likely to be fought tooth and nail by health care systems whose primary concern is the practice of fee-for-service medicine. This paradigm shift is clearly something the National Institutes of Health should urgently discuss and make part of its policies in planning and supporting its research mission. Given the dissociative and often unsympathetic way patients are treated these days, promoting this aim would be a really BOLD step for the NIH.

•   Invest more in systems biology research

I like this idea because to me this means moving away from the paradigm of mechanistic reductionism where very complex events are reduced to the level of a single gene, protein, receptor or organ. Such reductionism as applied to behavioral and neuroscience research has its grounding in 19th century biology and phrenology. I believe it’s time to escape this outdated paradigm. It would be a VERY BOLD step for the NIH to devote more support to holistic approaches to the study of human development, diseases and behaviors. And I’m not talking about alternative medicine here, but rather about giving more attention to a different paradigm of holistic thinking about the causes and evolution of disease, brain function and other systems. Some of these initiatives will obviously include the reconsideration of all the other "omics," along with environmental and epigenetic changes and how the changes affect disease and the course of treatment.

•    Change the nature and mission of the Study Sections.

To move forward in scientific research and education, we have to come to grips with the unremitting silo-ization and micronization of research. This could mean changing the make-up and mission of the various NIH study sections AND providing more instruction and training about the specific mission to individual study section members. This change in the status quo will take a lot of courage on the part of NIH staff and the Director, but if you don't do this the NIH will continue to be seen by many as a "valley of death" for major breakthroughs in biomedical research. How many members of study sections even know what the missions of the different NIH institutes are? 

The focus on perpetuating the same small science driven by the latest gadgets is going to continue to restrict scientific advancement and the delivery of improved health care to the taxpayers footing the bill for research. We’re crippling ourselves with what we are doing. Working to change this situation could be the THE BOLDEST step of all for the NIH—to change the culture in which study section priorities are set and grants are reviewed.

•   More focus on plasticity

As a part of the effort to move to a systems biology paradigm, at least for the neurosciences (where I work), I think we need to precisely define what is meant by "plasticity" and how it can be applied to the study of health and disease. We have to get more serious (and scholarly) about this. What we have now, especially in the neurosciences, is nothing more than explanation by naming. There are currently 54,631 papers on PubMed with “plasticity” in their titles. Can we take it for granted that we all just know intuitively what the term means? Does anyone even care what it means as long as it continues to generate grant funding? I looked at the white paper on this topic and it’s still as unclear as ever. Given how it is used in the documents and in most published papers—what's NOT an example of plasticity?

I’ve discussed this question in a recent article because I think it has important consequences for teaching about how the brain works and for research resource allocations [8]. If we’re going to continue to allocate resources to this field, it would be at least a moderately bold step to actually ask those doing the work to come up with precise definitions of plasticity and what it means at the different levels of analyses (molecular, anatomical, physiological and behavioral). We've been batting the term around for a long time—but what has actually come of it that we didn't know before someone invented the term as a catch-all phrase? Even the new DSM-5 does better than this.

•   Re-evaluate how clinical trials are done

It would be a very big bold step for the NIH to come to grips with the question of whether the randomized, double-blind, controlled trial is the best use of public funding of clinical trials. Should we be using newer, adaptive design approaches which permit more fluidity in trial design and hypotheses, taking immediate advantage of the data as it unfolds rather than staying locked into a design until it self-destructs? Is this a better strategy for the patients in the trials and those to be enrolled in the trials? There is much debate about this but a BOLD step would be to address the question head-on and for the NIH to take the lead in the debate and planning of future trials.

•   Direct resources into making a scientific career more attractive to young people

Here are some very recent NIH remarks on helping young investigators remain in the field:

This is the key to the future of ALL the institutes and to the use of public funds to support education and research in the years ahead. I see so many signs that we are falling behind (and that paper from Nature confirms this) because we are simply not getting the kinds of students we need who want to pursue a career in academic research. It’s time to stop just talking about the issue and initiate specific programs (both financial and educational) that will bring young scientists to the field,  provide decent salaries and keep them engaged in their education and provide some stability in the funding process to keep them going through their early years. 

·   The average age of a first NIH grant recipient is 44                  

What is the point of cranking out PhDs if we can’t support their work in any reasonable way? This is why many students I talk to have no desire at all to pursue a university research career. This is totally nuts … we all know it and we keep perpetuating the system that leads to this. Again, I have to come back to the problem of how to overcome timidity over changing the status quo (the mentality of: “if it was good enough for me in my training—it should be good enough for them as well”). The community has to work harder to build those bridges over the valley of death if we are to succeed down the road.

Having been around the sciences for now more than 50 years, this is what I see going on now. It seems like we’ve come from a much better place in the recent past two decades to where we are now. If there are better alternatives, we ought to be discussing them in open forums and coming up with viable priorities instead of just writing form letters to our Congressional delegations telling them how important and wonderful we are and why we need support more than anyone else with claims on the Federal budget. If we do write, at the very least, we ought to tell them the truth.


1. Begley Desperately Seeking Cures http://www.thedailybeast.com/newsweek/2010/05/15/desperately-seeking-cures.html

2.  op cit

3.  Nicholson, JM and Ioannidis, JPA. Conform and be funded. Nature, Vol 492, 6 December 2012, 34-36. http://www.nature.com/news/2008/080611/full/453840a.html

•       Begley’s comment on it, http://www.reuters.com/article/2012/12/05/us-science-nih-innovation-idUSBRE8B412J20121205

4. Thomas Kuhn, The Structure of Scientific Revolutions 1962, University of Chicago Press, p. 5

5. Leo Tolstoy, What is Art, Chapter 14. Oxford University Press, 1930, trans. Aylmer Maude. Quotes.net.  <http://www.quotes.net/quote/36375>.

6. Nicolson and Ioannidis, p. 35.

7. Emory Health Now, “Personalized Medicine Day in Georgia,” September 9, 2011. http://www.emoryhealthsciblog.com/?p=5085

8. Stein, DG, “Concepts of Central Nervous system plasticity and repair and their implications for recovery after brain damage.” In Zasler, ND, Katz, DI and Zafonte RD (eds), Brain Injury Medicine: Principles and Practice, Chapter 13, p. 162. New York: Demos Publishing, 2012.


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