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Ingber: Lecture on U.S. R&D Agenda on Capital Hill

Testimony delivered by Dr. Donald Ingber, Wyss Institute director, on March 2, 2009, at a conference on Capitol Hill for Congressional staff and Washington leaders, called "Toward an R&D Agenda for the New Administration and Congress: Perspectives from Scientists and Economists." The conference, organized by the National Bureau of Economic Research, brought together some of the nation’s top experts on innovation and economic growth to discuss priorities for federal research and development. 

I’m here speaking to you as a voice from the trenches.  I have worked for the past 30 years with funding support from multiple different Institutes at NIH, as well as from NASA, DOD, DARPA [Defense Advanced Research Projects Agency], and other government funding agencies. I have watched as drugs and other therapies moved from the bench to the bedside, through clinical trials. I have started two companies, and I consult for others, both large and small. And probably most pertinent, I was recently appointed as the founding director for the Wyss Institute for Biologically Inspired Engineering at Harvard University.  It was founded two months ago with the largest gift in Harvard’s history – $125 million from a single donor – explicitly to fund high-risk research that government funding agencies don’t fund today. So there is a problem here in terms of how the U.S. government currently funds research and development, and it’s recognized worldwide.

Given the stimulus package and the huge influx of funds into our R&D budget, it’s an important time to reexamine where we are, what we have been doing in the past, and where we want to be in the future.   There is no doubt that government funds for scientific research, and particularly fundamental research, have been severely limited over the past few years.  And thus, the current increase in funding for NIH and the other science agencies is badly needed and greatly appreciated by the research community.  However, there is considerable concern that with the emphasis on allocation of funds that can be spent out rapidly, that we are not being as strategic as we can be or considering the full implications of this short-term move.   Science does not do well when funded in fits and starts, and an ephemeral huge influx of cash could potentially be more detrimental than constructive in the end.  The other question I would like to address today is whether our existing R&D funding structure is optimally designed to produce the major scientific and economic breakthroughs we all so badly desire.

In terms of the existing R&D funding mechanisms, there are reasons to be skeptical. Fred Sachs, who is a biologist at SUNY-Buffalo, recently published an article in The Scientist in which he analyzed the number of scientific articles published over the time the NIH budget doubled, and there was not even a hint that this rapid, but short-lived, influx of funds had any impact on productivity.  He did this analysis various different ways, and examined its impact for multiple years out, but he always obtained the same results.  Meanwhile, over the same time period, scientific publications by Chinese scientists went up 40 percent.  In short, if you use publications as a measure of scientific productivity and the effectiveness of NIH R&D funding, doubling the budget had no effect.

I think it’s fair to say that Congress and the nation expect transformative change in return for providing a huge increase in funding for science and engineering. They expect cancer cures, cures for heart disease, and major advances in energy as well as healthcare.  As we now move to rapidly increase R&D funding, do we have the right structures in place to funnel these funds? Is throwing money at the problem an end in and of itself? There are many reasons to be concerned.

Currently NIH and many other science funding agencies are structured to sustain the status quo.  That’s their job: to ensure success by minimizing risk. What is probably most worrisome is that there’s a natural selection process — we don’t submit grants to support science, we submit grants to get funded. These are two very different things. For example, most of the work I have published was never described in any grant application because it was too adventurous to suggest, if I expected to be funded by peers.  Most scientists write grants for the things they know will get funded, and then they do what they want. We all strive to get multiple grants so that we can then work between the seams. Virtually every successful scientist will tell you that. We write the grant applications that we know will be valued by critics so that we can get the funding that will keep our labs running. Once we have the funds, we then try to pursue the work we need to do, regardless of its relevance to the original grant application.  We basically advance science in spite of the system.

So one of the potential problems we face is that if we throw more money at these agencies, such as NIH, then we will fund more of the same. This is guaranteed to some degree because NIH is now planning to quickly siphon much of the newly available funds into existing grants. There is no doubt that there are many grant applications not funded in the past due to financial limitations that warrant funding based on quality. It is critical that more of these grants now be funded, even if just to maintain our scientific work force. However, if we truly want transformative change, then funding grants explicitly designed to meet the expectations of a system that supports incremental advances more than innovation might not get us where we want to be. In other words, we will be funding grants that were self-selected to be competitive based how grant selection is carried out, rather than seeking out the high-risk adventurous work that our best scientist truly desire to pursue based on their understanding of the challenges we face.

These concerns once again raise the question of whether we currently have right measures of success. Let’s consider publications and patents, for example. When you have an NIH or other grant, at the end of the three- to five-year period, you are required to notify the funding institution regarding the published articles and submitted patents that resulted from the work. But I know firsthand that it can take many years for a discovery to go from the bench into the clinic. For example, I discovered a drug in 1985 based on a fungal contaminant I found in my culture dish; it took five years before the finding was published in Nature paper in 1990, in 1992 it went into human clinical trials, which is really fast. In 1998 – 13 years later, the first report of a complete remission of a human metastatic cancer induced by this drug was published in New England Journal of Medicine. But to this day, it still isn’t FDA approved because of complexities with companies and issues relating to potential toxicities. This is standard.  We know that one out of 10 or 15 drugs will fail, but we don’t take this into account when we fund research. If a high failure rate is the reality, then why do we expect near-term success when we fund research grants?

When it comes to the limitations of our current grant funding system for scientific research: "We have seen the enemy and it is us." It is my firm belief that is true at many levels. The peer review process at NIH is incredibly rigorous, but we are all reviewed by our competitors, and we are all competitors of those who we review. To ensure objectivity, the current funding process requires that we fund very high quality work that will lead to multiple excellent scientific publications in the world’s most outstanding journals. This is ensured because investigators must have completed most of the work they propose to do before they submit their application, and oftentimes, these ‘preliminary findings’ have already been submitted or accepted for publication before the grant is funded.  But these advances are often only incremental in nature, and projects that validate existing paradigms or explore them in greater detail, are usually the ones most likely to be funded. Of course, if you fund enough grants and support investigators who have natural curiosity, by chance, important new observations will fall out, and those are the ones that will always lead to new advances.

Unfortunately, the current funding process does not as easily support truly innovative new ideas or unconventional paths of inquiry. If the original proposal were exciting enough to be truly barrier-breaking, it could easily be threatening to the people who are reviewing it. In a sense, it is a conflict of interest. So a proposal under review that could potentially bring about a major paradigm shift which would cause the current field to no longer exist is likely not to get funded. This is the reality, and everyone successful in science knows this and goes around it. They write the grants that their peers and government agencies want to fund, the ones that do ‘safe science’ and ensure incremental advances driven by a rigorous focus on details.

NIH recognizes this problem and is trying to work around it by scoring applications for ‘innovation’, but it’s limited by the rigidity of the system.  NIH is trying to diversify, for example, by attempting to fund the most adventurous and innovative scientists (with Pioneer Awards), but they are still reviewed by the same peer review system. So the people who already do well in the conventional grant scoring process by applying existing approaches and paradigms (in a highly rigorous and elegant manner) often get these grants too.  In general, most scientists tend to write the same kinds of proposals regardless of whether the funding agency explicitly requests innovation or risk-taking research because that’s the only thing we’ve trained them how to do.

Let’s contrast this with the old DARPA (as opposed to the new DARPA), which was a wonderful place if you appreciate innovation.  DARPA program managers used to show graphs at their meetings that weren’t about science, but about transformative change. They would explain that if you truly want to fund paradigm-shifting research, then if you don’t fail at 80 percent of your attempts, the entire enterprise is a failure.  What DARPA did to make this work is something that NIH would consider horrible: they gave relatively low level program managers a lot of independence to make selections.  The concept of a few individuals making decisions about how to distribute large amounts of research funding goes against the fundamental concept of the peer-review process at NIH.  Yet this is what was found to be necessary to fund the paradigm-shifting research that led to the Internet, microcomputers and optical communications over the past 50 years.

The people in the trenches at DARPA have a track record of taking chances.  They organized small meetings with the best people they could find who would then work together to identify a high value problem, and to define potential research trajectories that might just solve the problem. The program managers did not tell the researchers what to do, and they didn’t expect them to solve the problem in two years. They recognized the importance of providing the most innovative people with full creative freedom, and they often tried to network them with other visionaries who were similarly motivated and passionate about the challenge at hand. DARPA expected individual scientists to collaborate, even if located at different institutions and in entirely different fields, if they believed it would advance the science.  Essentially, they sought out the best and brightest, but also those who were passionate enough that they are willing going to go outside their comfort zones, and to work with others with a similar vision, regardless of their expertise. 

This is the sort of thing we’re trying to do at the Wyss Institute. Our vision is based on the idea that in the past bioengineering used engineering principles to solve medical problems. But we’re now at a tipping point where there’s an equal melding of the life sciences, engineering, physics, computer science, architecture, and many other fields, such that the boundary between living and nonliving systems is beginning to break down. We can now manipulate an atom, a gene, a molecule, a cell one at a time to build things that we design.  We are essentially beginning to uncover how nature builds, manufactures, and controls. As a result, we believe that we are going to discover entirely new engineering principles that will transform medicine and nonmedical areas that were never before touched by the biology revolution.  For example, we have a platform in adaptive architectures in which we are trying to go beyond the simplicity of constructing buildings that open and close with sunlight to develop fully responsive multiscale architectures with multiple bioinspired functionalities that adapt to their environment the way the living cells and organisms do.  Imagine buildings covered with layers of microlenses that mimic how sea creatures concentrate light deep under the sea, but then focus this light on bacteria that have been genetically reprogrammed to convert light into energy with high efficiency.  Or rain gutters that feed into microcapillary systems that work to raise water to the roof of the building without requiring pumps or energy, using capillary action and evaporation like leaves in plants.  This is an example of NIH funded work coming back to advance architecture and environmental sustainability.

We have four other platforms at the Institute that range from Anticipatory Medical Devices and Programmable Nanomaterials to Biomaterials Evolution; in the latter platform, we evolve new materials rather than synthesize them. But even in this endeavor, the silo structure is a problem. It’s a problem at Harvard, MIT, Boston University, and all the hospitals I work with, just as it is in government agencies. I believe that you have to set up something outside these silos that provide a pull or push to facilitate cross cutting research and leverage all the siloed investments, for this to be a success – and this is exactly what we have done by forming the Wyss Institute for Biologically Inspired Engineering at Harvard.

Now if we return to the government’s current plan for infusing new funds into our nation’s R&D infrastructure, we see that the newest legislation requires that most of these new funds must be spend out within two years, and there is no guarantee that funding will continue into the future.  Having fits and starts of funding is a terrible thing because it turns away the young: this a major problem in ‘research sustainability’.  In an environment where we don’t allow immigration from outside, we are allowing natural selection to define the end of our own technological superiority.  In this country, the economy is driven by science and technology.  If you read the news or watch television, scientists are these little guys who work alone in a lab.  I don’t know anyone who works alone in a lab.  The disconnect between how we communicate what science and technology are, their impact on business, and the lifestyles scientists have is creating an endgame that is difficult to get out of. I think if someone at the national scale doesn’t take a hold of this huge problem soon, we could easily relinquish the scientific, technological and economic leadership position we have held internationally for the past half century.

The rapid funneling of $10.4 billion into the existing research infrastructure is terrifying to me. More of the same is guaranteed.  I think the $800 million that is going to be poured into work that has to be completed within two years, by definition, will not do anything meaningful because you can’t do anything that quickly.  You can’t easily hire multiple new staff in less than six to nine months, and anyone who’s done a start-up knows it takes a year to a year and a half to put new strategy together.  And then the funding ends. You can’t support a graduate student for their entire time in the lab.  You can’t even recruit them if you don’t know that these funds will continue.  Moreover, if a technology is truly two years away from having a major clinical impact, then it should be funded by industrial partners who know how to carry out manufacturing, clinical testing, and distribution to key end-users, and not by fundamental research support provided by the government. If you funnel all of the funds into existing grants, then by definition you are guaranteed to get more of the same.

I think we have the potential to miss out on a huge opportunity: We need to learn how to fund science and not agencies. We have to identify big problems, and we have to give incentives to people who are passionate about going after these high-risk/huge payoff applications so that they collaborate with others who will carry out the fundamental work required to enable the development and translation of transformative new technologies. We need experts from many fields involved in different stages of the technology and translation pipeline, and we need to assure them all the funds will be provided for the entire initiative. If we fund ten major projects, and nine fail but one cures cancer or makes blind people see, we’re going to be okay.  That’s what we need to do if we want to retain our technological superiority, to restore our economy, and to meet the huge challenges our nation and our entire planet will face over the next century.

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