A Conversation with OPASI Director Alan Krensky

The recently established NIH Office of Portfolio Analysis and Strategic Initiatives (OPASI) is taking hold just as NIH enters its fifth year of budget doldrums amid rising financial anxieties in the research community. OPASI is located in the Office of NIH Director Elias Zerhouni, as part of the Division of Program Coordination, Planning and Strategic Initiatives (DPCPSI). Its role is to help implement the NIH Roadmap for Medical Research — a Zerhouni innovation that began several years ago to support cross-cutting research that warrants attention from multiple institutes — by identifying gaps in research and promoting interdisciplinary and multi-institutional research. OPASI projects now receive 1.7 percent of the NIH budget, some $495 million, and will ultimately reach 5 percent. OPASI’s first director, Alan Krensky, a pediatric nephrologist from Stanford Medical School, formally took office in July 2007. Krensky discussed OPASI on January 23 with Washington journalist Daniel S. Greenberg. Following are edited excerpts from their conversation.

The NIH community has a tradition of being wary of change. OPASI is potentially a big change. Have you encountered this wariness and what do you do about it?
Changes involving collaboration among institutes were occurring before OPASI was created, and people were becoming accustomed to it. Different institutes at NIH were working together in dramatic ways. The Genome Project is a case in point. The underpinnings for almost every disease have involvement there. Or the environment, which we’re understanding more and more about now. So this cross-cutting nature was going on, and I think OPASI is really about trying to get some institutional structure to it. But I think that the change actually preceded OPASI.

Why was an institutional structure necessary for what’s already happening?
To try to bring some degree of coordination. Many of the different groups are already doing things, but in a large organization like this it’s hard to know what everyone is doing. So one function that I hope we will develop within OPASI is to have web-based bulletin boards that say: If you’re interested in programs designed for a cure, people can list them there. If you’re interested in informatics systems, that particular function, we can list them there. Just having that codified function of making lists is something very useful to an organization like this. But that’s doesn’t negate being very much cutting-edge and innovative. Take an idea like portfolio analysis for evaluation — the concepts sound very straightforward but the science is just developing. How do you really go about evaluating something? What are the metrics? These are things that businesses have done for a long time; we’re just starting to ask the questions. People always thought, well, writing a paper is good. But, not every paper is good. So what’s important about a paper? What’s its impact? Do we get a drug? Do we get a cure? Is there a patent? Is there a new company that comes about? We want to start asking questions about the portfolio as a whole, what we’re doing, and what we’re not doing. And once again, this isn’t top down. We’re not telling the community what to do with the data, but we’re going to make data available, which will be very powerful. So I just view this as a function for the whole.

Are you getting good feedback from people?
Oh yeah. Among the people who are using it already, there are very interesting things happening. There’s a recent publication just out, looking at schistosomiasis, which is a worm which affects kids largely in sub-Saharan Africa. Researchers at Illinois State University, in collaboration with people here at NIH, have made small molecules that are blocking the disease and will go into clinical trials to be tested. So that’s very rapid for progress. I think that’s a real positive area.

The Clinical Translational Science Awards (CTSA) is another [program] that’s incredibly positive and grew out of the Roadmap and the Roadmap process. We’re expending $90 million dollars towards it this year, and it is now run by the National Center for Research Resources. It has done profound things. It has already been truly transforming. It got people to start talking to one another who weren’t talking to each other. And this is really the idea behind the Roadmap — that the clinical and translational sciences needed a jumpstart and needed a home in the academic institutions. And that we needed to codify this interdisciplinary area. Just like OPASI within the NIH, there needed to be a home in our great universities where, not just the people doing clinical trials, but the epidemiologists, the computer scientists, the imaging people and the geneticists could all come together. So we built this tremendous platform. Right now it’s only a platform — government money can only do so much — but these institutions can build upon it and philanthropy can build upon it. It is a real stage for the connection we talked about, how you go from this basic science, from an experiment, to getting a drug in a bottle to impacting human life. And that continuum is what the CTSAs are about and it grew out of Roadmap. Once again, it all predated me. I can’t take credit for it, but the concepts and the process are the proof of the Roadmap.

The Pioneer Awards [also set up by the Roadmap] are also an experiment — basically asking for ideas outside the box, trying to recognize people who do things that wouldn’t have gotten funded the old way. Now, is that what we’re doing? We don’t know. We have to test. The Pioneer Awards were one of the first parts of the Roadmap. The idea here was, “send us your ideas that wouldn’t normally get funded. Think outside the box. Think cutting edge. Think about what, in this incremental world, would be a quantum leap forward, a transforming experiment.” And so it’s been going [for four years]. And it’s an experiment. We’ve gotten terrific people, there’s no question about the quality of people. But will these people end up doing different things? Will Nobel Prizes come out of it? Will whole new areas of sciences come out?

Didn’t the peer review system recognize these people in the past?
The community’s concern is that, with the flattening of the budget, people tend to get conservative. So the old way — the grant system and the peer-review system for extramural research — was very much about what your specific aims were and what the feasibility was. And your specific aims and feasibility moved science forward. No question about it. But if there was a big question there, if there was something you didn’t or couldn’t answer or if you didn’t have the preliminary results, you were at risk in the old system. And so recognizing this, in this new system, you might not need preliminary results, and the idea may not be incremental. Peer review often focused on the feasibility. Now peer review is a very complex approach, so some people were more understanding of this cutting edge than others. But clearly as the dollars went down relatively, the system did become more conservative and this is in part a response to that.

Now every institute and center here on their own, separate from OPASI, has recognized this, and are trying. There’s a new Eureka Award that the National Institute of General Medical Sciences has started. Several other institutes have gotten on board with it, so they’re very interested in this idea of new approaches. The community has really insisted upon it, and NIH has been responsive in recognizing that innovation is important. We just had an innovation workshop here that was asking these questions about how we [foster new research]. And that’s not an attack on the old stuff, because science is also incremental. This is not that we all have to do one hundred percent crazy things. We’re really looking to balance the portfolio.

The Common Fund, how does that work?
The Common Fund was Zerhouni’s idea. The concept was that each of NIH’s 27 institutes and centers (ICs), based on their own size and own budget, would pay into it and it would be something shared. The institutes, centers and directors would work together to decide how to expend the money each year. The NIH Reform Act of 2006 codified the Common Fund. For this year and last year, it was a line item in the budget. The ICs no longer pay into it and now they’ve got that money back, so it was a relative increase for them. But we have maintained that the ownership belongs to the 27 institutes and centers; the deciders in this process are the 27. So once again our function is to coordinate this, but at the end of the day it is groupthink.

What’s the amount of money in it now? What’s the expectation?
It is currently 1.7 percent [of the budget which is] $495 million dollars; it was 1.7 percent last year, which was $486 million. It can grow to 5 percent of the budget, but that can only happen if we are growing above inflation. In the current financial situation, I don’t see us growing to the 5 percent very quickly.

It seems to be far off the way things are going.
That would be one interpretation. But I think we’re having a big impact already, and that’s just what is in the Common Fund. When the ICs recognize something is good, like the Pioneer Awards, they’ll do it on their own.

Both Congressional Appropriations Committees asked for reports on the behavioral sciences. Where do things stand with those reports?
The Reform Act asked that the Office for Behavioral and Social Sciences Research [OBSSR] and the Division of Program Coordination, Planning, and Strategic Initiatives (DPCPSI), which is the Reform Act’s larger OPASI, work together. And in many ways I view it as a test of the construct of OPASI within DPCPSI. And so that’s the process we’re in the middle of. In general for NIH, the basic sciences are informing the translation to clinical. In behavior it’s actually been the reverse. There’s been less basic science and more of the clinical. Of course, it depends on the definitions. What these new reports to Congress are really aimed at, and what DPCPSI and OPASI are aimed at, is this concept of speaking with one voice, rather than sounding like several voices. And that’s really what we’re doing in this process of not just talking about just what’s going on now, but [talking about] where we should be.

How does OPASI relate to DPCPSI?
DPCPSI [was created by] the Reform Act. It basically has the functionality of OPASI. The difference is that it includes the other programmatic offices in the Office of the Director — AIDS, Women’s Heath, Behavioral Science, Prevention. These are very large, important areas. We’re just getting OPASI up and going; we have not yet transitioned to DPCPSI. Zerhouni is acting director of DPCPSI but the functionality in the Reauthorization Bill is very much like OPASI. It is about strategic coordination, the Roadmap and the Common Fund. So we’re in a transition stage, from getting OPASI up and going, but the ultimate goal is that it will be DPCPSI; the only difference is that DPCPSI does include other offices.

Does it eventually get folded into OPASI?
It’s the other way around. Right now, OPASI is an office within DPCPSI. And whether OPASI merges into DPCPSI or stays in an office in DPCPSI is not yet defined, because we’re trying to get this organization to stand up first.

How does the Council of Councils function?
The Council of Councils [which was organized to advise on proposals to be funded by the Common Fund and of which I am the Chair] is brand new. I was sort of amazed when I hit the ground running that we said we had to get this going very quickly. It has representatives from the councils of all the institutes and centers. They each have their own advisory councils, and they make recommendations to us. I put together the membership based on a variety of things. We had our first meeting last November, and it was really quite exciting. I think almost everyone sent back very positive feelings about it. The Council is not meant to represent your own institute and center; it’s meant to come together as a whole to talk about “trans-ness” within NIH, but from your own background and perspective. So we talked about innovation. We talked about a lot of interesting trans-NIH initiatives in the first meeting. Because not everyone was signed up as a government advisor at that point, it was called a planning meeting. So the first live meeting is actually going to happen March 31st.. At that meeting we’re going to explore the Council of Councils and the organization of OPASI as it is now.

What are the roles of OPASI’s three divisions?
The Division of Resource Development and Analysis (DRDA) is for portfolio analysis, the Division of Strategic Analysis (DSC) is for strategic initiatives, and the Division of Evaluation and Systematic Assessments (DESA) is the evaluation branch division. People from each of those are going to present to the group as a whole. The 30 members of the Council of Councils have selected interests in each of the divisions. They’re going to have breakout groups and are going to start to explore issues. The DSC will examine what new programs are coming in for the Roadmap, determine which make sense to them, advise us on the Roadmap initiatives, and even generate new ideas. For the DESA, the real issue is the science of science, which is going to be metrics. What are the measures that we should be judging science by? Is it just the number of papers or where they’re published, or is it whether there’s a drug, a patent, or a company? DESA will also try to build databases and have an understanding of what we’re doing and what the metrics should be. We are going to be much more businesslike about that. And the portfolio analysis [at DRDA] includes a variety of things, but it’s a new science too.

It’s not just a new computer system we’re working on. Our goal is to have one transparent system, RCDC, which stands for Research Condition and Disease Categorization. This is one system, reproducible and transparent for all of NIH. I’m not saying that this new system is any more real than the current system, and it’s going to have growing pains. [Communication will be crucial while] building this new system and working with it over time, seeing what works and doesn’t work. It will be an iterative process with the ICs, understanding that if the results aren’t coming out right, it is only a computer system. It’s a new computer system — it’s not artificial intelligence. It doesn’t think, so it’s going to depend on the people. There will be a lot of pressure for this system, because one system for NIH hasn’t existed before. So that lies within this division, but there are other branches making new tools. What are the ideas of portfolio analysis? How do we test the waters? How do we define gaps? How do we find new opportunities out there? Not just within the NIH, but within the whole world, and the scientific [community]. Where are the scientific opportunities? These are not new questions, but we’re looking for new approaches, new tools, and analysis.

And the other part of this office is what’s been called the burden of disease, or public health branch. And there the idea, expected by the American people, is how do you decide what to fund based on the burden of disease? It sounds like an easy question, but it never has been. [Former NIH Director] Harold Varmus had written a very important paper on scientific opportunity versus the burden of disease. We have always wrestled with that, and this is a new opportunity now, forward thinking, using information systems and the like to try to mesh that and understand where you get the bang for your buck. But the question is not always just what do more people have, it’s what the scientific opportunity is. It’s pretty easy to get numbers [of how many people suffer from a certain disease], although they don’t always agree. But the impact [of the numbers] is not well understood. These are economic and social science questions.

The organizational structure you’ve described strikes me as enormously cumbersome. It’s got many new components that are being attached to an ongoing organization.
NIH is a huge, complicated organization. In OPASI, we’re trying not to be cumbersome, although some people feel that we are. We have done a lot of streamlining. Since there are 27 institutes and centers and they are the people in the decision-making process, that part is more complicated than just one person making decisions. But that is what this whole experiment is about. What we’re wrestling with now is how to make that as streamlined as possible and get the best end result. And as we’re growing — I told you we don’t even have [all of] our three division chiefs in place — I’m hoping that the top priority of those thought leaders who are the division chiefs is to make this as simple as possible. Unlike a lot of other areas, which have all these ongoing programs, we don’t. We have this churn space. And we’re 1.7 percent of the budget. So we can be sort of light on our feet, I think. But to do that for the institution in the best way, we’re putting a lot of time and effort into it. And it’s a major thing that the division chiefs are working on.

What kind of a reaction have you received internally here?
People had agreed to do this before I came. It is a matter of change. I’m learning on the job and listening and hearing from people. They have given us advice of how to do this in the best way. I think it is heartfelt by everyone now. It is understood that OPASI is going to be here. It’s going to be part of NIH. And the real issue is to bring value and make it something positive for NIH. And that’s the part I’m trying to figure out on the job — how to not be cumbersome and not be burdensome, but to help things along that wouldn’t have happened otherwise. So it’s been an incredibly interesting opportunity.

In the relatively brief time you’ve been here, what do you feel has been accomplished of importance in this start-up phase?
Well, I think the most important thing is yet to happen, which is to get those three division chiefs in place. The progress since I got here? It’s hard to say, because that was a very short time ago. I started on July 8, 2007. The molecular libraries, which took small molecule technologies available in industry and made them available to the academic community; the Pioneer Awards; and the CTSA’s are big things that had already happened. I can’t take credit for any of those. I would say that our progress is just interacting, getting out there, listening to the environment, figuring out where we can bring value. I certainly think there are so many possibilities for this office, there’s no reason for us to be divisive at all. That’s what we’re working on, and I think it’s going well.

You bring up the word ‘divisive.’ Why does division occur?
Well, it doesn’t occur. It would only occur if I come up with an agenda that’s off the mark of the agency. So, I don’t want to do anything that would be viewed as not adding value to the agency.

But to be harmonious with the organization.
Absolutely. So you’re right. It’s about change, but it’s about a complex organization working together.

Do you think Craig Venter [who quit NIH in frustration and successfully carried out a privately funded genome project] and the Genome Project would have been perceived differently if OPASI had existed at that time?
Well, it’s a really interesting question. I think the whole experience of the Genome Project has opened up a lot of people’s eyes. It’s very easy to say no when there are naysayers about a big plan. And now they always say, well look at that. Our new areas like the epigenome and microbiome, which are brand new in the Roadmap, are both examples of what was built upon the Genome Project. The technologies that grew out of that, being able to sequence rapidly at lower and lower costs in large, high throughput, is why we’re able to do microbiome now. So we’re going to be able to look at the microbes inside and outside your body, even though we can’t grow them. We’re going to be able to use those techniques. The epigenome is about [gene expression]. You have your constellation of genes, but how they get expressed is more complicated than that. What is important is how these work in health and disease, and how your environment, or your mother’s and father’s environment can determine your own disease.

So we’re becoming more complex, but these are huge problems, each one of them. The Genome Project gave the whole system the feeling that you can take on these big topics and make quantum leaps forward.

Well, does this suggest that we are on the road to the virtual disappearance of the individual PI, the solo researcher?
There are people who are concerned about that; we call them the R01 community. And a lot of the pushback of the Roadmap came from the concern that they were going to disappear. I don’t think that at all. The people involved are still the individual scientists and their brain power is what science is all about. Is infrastructure more important than ever? Yes. Are teams more important than ever? Yes. Science is changing, but the individual investigator is still the coin of the realm. Their brain is what makes science.

But, aren’t individual investigators members of a team?
Not necessarily. That’s why the amount of money we have to spend is very important because no one can presage the next big finding, and it is generally born in one person’s mind. So these big teams and this infrastructure are important, but the idea comes generally from one person. Sometimes they don’t even get the proper credit for it, but we need to have enough people going into science. Pipeline [training of new scientists] is a big deal. The people in science are getting older, the pipeline is at risk, with dollars not increasing, and we need those minds. We need people to choose to go into science instead of investment banking.

What responsibility does OPASI see for itself in regard to the pipeline?
It is much broader than that. It’s not even clear what the lead institute is for it or what the lead body is for it. I think it’s the Office of Extramural Research now. But we’re actually talking about a new office. It’s so important — there are discussions going on that perhaps there should be an office in the Office of the Director for the pipeline. When I spoke recently at the Institute of Medicine, it was one of my three topics because I think it is so important. We’re not the responsible party but if we’re interested in science and science being better, we have to be part of that discussion. Everyone does. Just like the peer review process which is under review at NIH now. OPASI is not responsible, but these are really fundamental questions that we hope to participate in.

Some are very skeptical of the idea of a scientist shortage.
It is a very complicated question, because it’s not just the numbers of scientists, it’s what they’re doing, how they’re trained, etc. I saw these young people in the [budget] doubling. Then, with what has been called by some “the undoubling,” these people are leaving. So it’s really problematic.

Do you think OPASI can make the system more responsive? The complaints or the warnings about the advanced age of first grant recipients go back 20 or 30 years and there has really been scarcely any change.
You’re absolutely right. Zerhouni, looking at the last five years, decided last year that there should be 1,500 new R01 investigators. There actually were almost 1,600. So we are doing that. We’re figuring out what the problem is and trying to modulate the system. But at the end of the day, we can’t really tell. And so the issue is, if we make a move this year with almost 1,600 new R01 investigators, what happens to them over the next 5 years, and then what happens in 10 years and 15 years? If the curve moved back a little bit because of this, that would be important. It hasn’t.
And the other big part of this aging population is that the baby boomers are in there, and the Vietnam War era was in there, so there was a big blip of investigators over about a 10-year period that I was at the very tail end of. People came to NIH during the draft era and brought a lot of brain power and tremendous expertise. So there are ups and downs, but I do think what’s most important is that we not turn these valves. They should be dialed slowly up and down. [We should not make] brisk changes, which has sometimes happened if you look at the history of NIH. There are big ups and downs. Those have huge impacts, and it would be nice if there were some stability. ♦