In cancer research, high risk is the new black

Following the Gates Foundation’s lead on global health, many critics fault play-it-safe research for the failed war against cancer. Will upping the dose of risk in research bring about new cures?
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Richard Klausner: the grant system is not working

Following the Gates Foundation’s lead on global health, many critics fault play-it-safe research for the failed war against cancer. Will upping the dose of risk in research bring about new cures?

The war on cancer, perhaps the largest scientific undertaking in human history, has failed. Why? Timidity, according to a growing number of critics. The New York Times recently examined the 40-year, $100 billion war and headlined its conclusion: 'ꀜGrant System Leads Cancer Researchers to Play It Safe.'ꀝ

The Gates Foundation said the same thing about global health research more than a year ago. Keying off an unavailing, 25-year search for an HIV vaccine, the foundation criticized a process that mostly funded projects that 'ꀜavoid controversy, and have a high probability of success, if 'ꀘsuccess'ꀙ is defined as the production of a meaningful but limited increase in knowledge.'ꀝ

The Times reporting highlights a nearly identical view of cancer research as risk-averse and 'ꀜonly likely to produce incremental progress.'ꀝ The grant system is broken, according Richard Klausner, who served as director of the National Cancer Institute (NCI) from 1995 to 2001. He told the Times: 'ꀜThere is no conversation that I have ever had about the grant system that doesn'ꀙt have an incredible sense of consensus that it is not working.'ꀝ Many of these conversations took place at the Gates Foundation, where Klausner served as the first head of global health after leaving NCI. Gates tasked Klausner with devising a completely new system of goals and grant-making known as the Grand Challenges in Global Health.

The program funds projects considered too "far-out" and risky for traditional National Institutes of Health (NIH) funding. Gates predicted that 'ꀜ80 percent of these are likely to be dead ends.'ꀝ Not yet satisfied with progress, the foundation launched its Explorations program two years later in 2007. The Explorations seek ideas that directly defy scientific consensus. More than 95 percent of them are expected to fail.

Actual data for this experiment on science will arrive soon. Phase I of the Explorations concludes this fall when the 105 grants from the inaugural round are renewed or dropped. Much as in a clinical drug trial, the foundation plans a 'ꀜrigorous analysis'ꀝ of the program. But meanwhile The New York Times appears to be administering the experimental medicine to the National Cancer Institute already.

Yet both the design and momentum of the Grand Challenges might have only just begun. Last February, Elias Zerhouni joined the foundation as a senior fellow. Previously director of NIH from 2002 to 2008, Zerhouni is now the architect of the Grand Challenges. Who better to modify the blueprint of life sciences research to achieve more rapid breakthroughs in global health?

But research practices beyond the global health sphere might also change, and not only in cancer but throughout NIH, whose granting practice 'ꀜactually discourages innovative work,'ꀝ as the Scientist recently commented.

Risk might be the new black. And perhaps the trend-setting Bill Gates will break up a government monopoly guilty of stifling innovation.

The Gates Foundation talks of funding up to a thousand Explorations projects — but compare that to the NIH portfolio of some 50,000 grants. Also, with a budget of $28 billion, NIH spends in a year an amount equal to about half of the Gates Foundation'ꀙs total assets. If big breakthroughs require taking big risks, it might not only be fashionable but compellingly rational for NIH to follow the Gates Foundation'ꀙs example. With the biggest chip stack, NIH can better afford to gamble — and win big.

Is risk the cure? Or a passing fashion? No one faults the grant system when things are going well. In the fall of 1996, during Richard Klausner'ꀙs tenure as head of NCI, it looked like the cancer tide had turned. A New York Times article quoted Klausner as saying: 'ꀜThe 1990s will be remembered as the decade when we measurably turned the tide against cancer.'ꀝ The paper also reported on hemlines in the fall of 1996, concluding that 'ꀜThe Right Skirt Is a Long Skirt.'ꀝ Now both Klausner and the Times are calling for more exposure.

But the 40-year, $100 billion war on cancer has not been short of clever, unorthodox, risky ideas: It has devoured them. More than one million scientific papers have been published on cancer. The disease has bested two generations of scientists, with the most recent one based on the incredible powers of DNA sequencing technology. Yet in terms of mortality, we'ꀙre at a standstill.

The Explorations are premised on there being sizeable inefficiencies in science and major undiscovered ideas, like a massive arbitrage opportunity in financial markets. Yet the first round of Explorations turned up precious few fundamentally new, radical notions for an HIV/AIDS vaccine. Significantly, the aggressiveness of HIV/AIDS research was recently dialed down, all the way 'ꀜback to basics,'ꀝ because of a shocking failure of a trial vaccine.

Our scientific grasp of both HIV/AIDS and cancer is remarkably tenuous, even as their risk pendulums seem to be swinging in opposite directions. The outcome of the Grand Challenges Explorations will have consequences beyond, for example, curing tuberculosis. In guiding biomedical research, the results will shed light on the 'ꀜscience of science.'ꀝ


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