Running on Empty?

Many physicians can recall the period more than three decades ago when a plague emerged that appeared to selectively afflict urban men. As death tolls mounted, no one knew why the immune systems of these patients deteriorated, how to treat the illness, or how widespread the sickness might become.

Thirty-five years have passed, and today, in most developed countries, people don’t die of AIDS. Rather, they live with HIV. The same disease that was a death sentence in the 1980s had become a chronic condition by the mid-1990s. For the bench-to-bedside trajectory, this is light speed. Although pressure from patient advocacy groups certainly played a transformative role in the development and distribution of therapeutics, years of curiosity-driven, publicly funded basic research into retroviruses—organisms that were considered irrelevant to humans—had been aggregating a reserve of knowledge that spurred rapid and effective translational research.

This is not an iso­lated anecdote.

Treatments for chronic myeloid leukemia, multiple myeloma, and even high cholesterol provide other examples of life-saving drugs that began at the bench during searches for answers to basic science questions.

The United States has been the world leader in cultivating a spectacularly successful culture of basic science, one that forms the bedrock of modern medicine. Support from such entities as the National Institutes of Health and the National Science Foundation has, on average, accounted for more than 50 percent of the global total of governmental investment in science. Likewise, the U.S. share of life-science patents worldwide exceeds 50 percent, despite a slight decline throughout the past thirty years.

During the past decade, however, there has been a slow, steady decline in public funding for research, particularly in the life sciences. And that is not going unnoticed. In fact, it is raising eyebrows, even alarm, among senior scientists, junior scientists, and other members of the scientific enterprise. The difficulty is not in identifying the problem, it’s in constructing a solution.

The Numbers Game

Just look at the data. From 1994 to 2004, the NIH budget doubled from 17.6 to 35.6 billion, an average annual growth rate of 7.3 percent. From 2004 to 2012, however, the budget dipped to 30.9 billion, a negative growth rate of nearly 2 percent. Declines, in fact, appear to be the new normal.

In addition, there is an emerging sense that the scientific enterprise itself is caught in a kind of straitjacket. Decreased funding has caused a ripple effect throughout the system, perhaps nowhere felt more keenly than downstream among graduate students and postdoctoral researchers who may be looking at an increasingly uncertain future.

It’s probably safe to say that no one thinks public funding will return to pre-2004 levels. As a result, there is a growing realization among scientists that the enterprise itself needs to change some of its entrenched cultural practices to avert not only a brain drain of young researchers but a potential slowdown of critical discoveries.

If the problem seems difficult, the solution is a Gordian knot.

Double Trouble

Alfred Sommer ’67, dean emeritus of the Johns Hopkins Bloomberg School of Public Health, was attending a congressional luncheon in the early 1990s when the topic of discussion turned to the doubling of the NIH budget and whether institutions would be able to absorb such an infusion of support. Sommer recalls being uncharacteristically silent during much of the debate, until he could keep quiet no longer.

“I told them that doubling was not the big deal,” he says. “We would have no trouble putting that money to work. The problem, I said, was going to be when the doubling stops. At that point we would hit a brick wall. This was not rocket science.”

Not rocket science, but prophesy. With the exception of a momentary bump from the American Recovery and Reinvestment Act of 2009, public funding for the life sciences has been flat.

The problem is more than addition and subtraction. According to Marc Kirschner, the John Franklin Enders University Professor of Systems Biology at HMS and founding chair of the School’s Department of Systems Biology, the change in support has put the scientific enterprise under tremendous stress. Kirschner has teamed up with Bruce Alberts, former editor of Sciencemagazine; Shirley Tilghman, past president of Princeton University; and Harold Varmus, former director of the National Cancer Institute, to try to bring this issue into the forefront of public discourse. The group coauthored a perspective piece in Proceedings of the National Academy of Sciences in 2014 titled “Rescuing U.S. biomedical research from its systemic flaws.” In scientific circles at least, the article caused a stir.

The authors state that, for better or for worse, we have built a system predicated on indefinite expansion. In fact, many universities and research institutions have created infrastructures, even salary structures, that depend on a steady flow of grant money. And what happens when an enterprise founded upon steady increase suddenly slams against steady decline?

“Diminished funding leads to a hyper-competition where science is getting less creative and more risk averse,” says Kirschner. “The less risky an idea, the more likely it is to get funded; it’s obvious and a sure bet. But it’s the risky, nonintuitive ideas that have advanced science.”

Adds Sommer, “The less money there is, the more conservative the grant approvers get. They will fund things that advance linear thinking by a couple of microns. They will not fund right-angle turns. And most major medical breakthroughs are right-angle turns.”

Kirschner and company’s perspective article does make some recommendations, such as making budgets from public funding agencies more predictable, rectifying the imbalance of a peer-review grant-approval system that prefers large projects over those that are more imaginative, and changing policies that inadvertently promote unsustainable growth. But even more so, their intention was, and still is, to instigate public debate—and in this at least they have been successful.

Future Tense

Among the more notable public discussions is one driven not by individuals with storied scientific careers, but by an ad hoc network of postdoctoral scientists and graduate students in the Boston area who represent not only HMS and its affiliated teaching hospitals but also Boston, Brandeis, and Tufts universities; MIT; and the Whitehead Institute. The group has coalesced into an organization called The Future of Research. Last October, it convened a conference that brought scientists from both industry and academia together to discuss the current state of the scientific enterprise and how its culture should adapt to new funding realities. At the heart of their concern is the knowledge that the scientific enterprise increasingly requires a pool of trainees—postdocs and grad students—that is an order of magnitude larger than the job prospects that await.

“This system looks less and less attractive to young scientists,” says Jessica Polka, an HMS postdoc and a cofounder of The Future of Research. “We certainly don’t want young scientists to be counseled to stay away because research is an unstable career choice.”

“There is a general fear among postdocs about what comes next,” adds Kristin Krukenberg, an HMS postdoc and a cofounder of the organization. “We’re realizing that almost everyone has these same fears. Conversations among postdocs are less and less about science and more and more about the fear of not getting published or of not getting grants.”

Such conversations would have been alien to the young Kirschner who, like many of his contemporaries, received his first major research grant in his late twenties and tenure in his early thirties. Today, approximately four decades after Kirschner began receiving support for his research, the median age at which scientists first receive an independent research grant is 42.

Last November the conference organizers published their own perspective piece, “Shaping the future of research: a perspective from junior scientists,” in the online journal F1000 Research.

The authors, who include Polka and Krukenberg, write, “While scientists continue to advocate for increased funding, they must also create a scientific enterprise that is sustainable with the current resources.” Some of their suggestions include greater involvement by junior scientists and other stakeholders in shaping reform, increased transparency regarding career options and outcomes, a system of greater accountability for the quality of training, and the development of a funding system that allows trainees to be more financially independent and, therefore, less tied to particular principal investigators.

As important as any of these recommendations is the willingness to broaden the conversation. In that sense, you can say The Future of Research has syndicated. Similar groups of concerned postdoctoral researchers are planning such public conversations in New York City, Chicago, and in the San Francisco Bay Area.

“If we really want to change the culture of science,” says Krukenberg, “young scientists need to be made aware of problems in the system. They can change the culture from within.”

Kirschner and his team are also broadening the conversation. Recently they held a meeting at the Howard Hughes Medical Institute that brought together presidents of universities, CEOs of drug companies, and heads of NIH institutes, as well as other leaders from academia and industry. Other universities around the country are starting to host symposia as well. In 2014, Kirschner, Tilghman, and Varmus met with the president’s Council of Advisors on Science and Technology, which devoted most of its meeting to discussing the subject.

According to Kirschner, there is near unanimity on the notion that the scientific enterprise has the seeds of its own destruction baked into it. Although parts of the enterprise are healthy, other parts are less so; those unhealthy parts need immediate action before they get much worse.

“The situation is complex,” says Kirschner, “but it’s not politically complex. There’s not a lot of opposition. It’s just not clear yet how to move forward with all this.”

A Tale of Two Worlds

While not exactly a voice of opposition, Gilbert Omenn ’65, a professor at the University of Michigan Medical School and director of the university’s Center for Computational Medicine and Bioinformatics, adds words of caution to any sense of alarm.

“I think this is a Dickensian best-of-times, worst-of-times dichotomy,” he says. “Science has never been more exciting than it is today, with more knowledge and great technology platforms. The NIH still awards $31 billion per year, and other federal and foundation sources supplement that investment.”

As Omenn sees it, new opportunities are always emerging. He is wary of any tendency to measure the quality of investment in a particular area by how much we have historically invested in that same area. That, he says, is not the right measure: The focus should instead be on emerging opportunities and bold goals.

He also points out that, while the low percentage of grants funded is certainly discouraging, during the five years that the NIH budget doubled, the number of grants submitted also doubled.

“This ‘woe is us’ talk is overdone,” he says. “True, it is competitive, and it is a struggle. Nevertheless, we should encourage bright young people who have a passion for discovery and for making a difference to go into biomedical research. There is much to be accomplished in medicine and public health and much benefit to be achieved for society.”

Kirschner agrees that today’s scientific tools are very powerful and that in some ways new science is easier than it’s ever been. But he sees this as a cruel irony.

“Opportunities to investigate are deeper than ever, but the constraints on the system are worse than ever,” he says.

In the meantime, as uncertainties continue to obscure the path forward, Sommer offers some tried-and-true advice.

“Write your representative in Congress,” he says.

Image: Mattias Paludi