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Trailblazing cancer–physics project accused of losing ambition

Physical oncologists complain that US National Cancer Institute programme has lost sight of its mission.

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Cell division and other cancer processes are being studied by physicists looking for fundamental insights.

An ambitious initiative that has deployed physics in the fight against cancer since 2009 has awarded a second round of grants. But some pioneers of the field, known as physical oncology, protest that the US National Cancer Institute (NCI) has lost sight of the programme’s original vision.

In June, the NCI announced that it would give each of four Physical Sciences-Oncology Centers (PS-OCs) around US$2 million a year for five years. But the funded projects are too unambitious to produce major paradigm shifts, argues Robert Austin, a physicist at Princeton University in New Jersey who helped the NCI to lay the groundwork for the programme, and whose centre was not funded in the second round.

The programme is “losing patience with those of us who want to understand the fundamentals”, says Austin.

NCI officials say that the latest awards, along with two rounds of funding planned for later this year or next year, show the institute’s continuing commitment to the interdisciplinary approach. “The fact that this programme is renewed, while it’s not in the same original form, is still an indication of support,” says Larry Nagahara, a former director of the programme who left the NCI for Johns Hopkins University in Baltimore, Maryland, this month. Officials insist that there has been no move away from physics, although the programme also embraces related fields such as engineering and applied mathematics. “We’re sort of agnostic on the spectrum of research that people are working on,” says current programme head Sean Hanlon.

The PS-OC programme was largely the brainchild of Anna Barker, who in 2007–08, as a deputy director at the NCI, set up workshops that helped to lay the programme’s intellectual foundation. She and other proponents pointed out that although billions of dollars of research investment into drugs and therapies have reduced mortality for some cancers, they have not produced a fundamental understanding of the disease. Programme leaders proposed to open a new front in the war on cancer by recruiting physicists to study cancer as a physical rather than strictly biological phenomenon.

A different perspective

In 2009, the NCI gave grants averaging $2.5 million a year for 5 years to 12 centres, each co-directed by a physical scientist and a cancer biologist. Some researchers attempted to re-envision cancer from the bottom up. For example, physicist Paul Davies of Arizona State University in Tempe, who along with Austin was involved in the initial programme workshops (see Nature 474, 20–22; 2011), has proposed that a cell becomes cancerous when it reverts to a primitive evolutionary state. He is investigating whether ancient genes become activated during cancer development (P. C. W. Davies and C. H. Lineweaver Phys. Biol. 8, 015001; 2011). Austin has explored the evolution of drug resistance by using micro­fluidic devices to expose tumour cells to chemical gradients (A. Wu et al. Proc. Natl Acad. Sci. USA 110, 16103–16108; 2013), and has suggested that cancer might result from environmental stress rather than from genetic mutations.

Others have sought to develop or refine mathematical or biophysical tools for cancer research. At the Dana-Farber Cancer Institute in Boston, Massachusetts, for example, researchers have built computer simulations to predict which genetic and cellular changes are most likely to lead to certain cancers, and which treatment approaches are most likely to succeed. Other centres have used advanced microscopy and spectroscopy. Such projects are valuable, but do not seek the kind of fundamental understanding of cancer that is the hallmark of the physics approach, says Herbert Levine, a physicist at Rice University in Houston, Texas, who studies cancer but has not received PS-OC funding.

The awards announced in June went to existing centres at Northwestern University in Chicago, Illinois, and Dana-Farber, as well as to two new ones — at Columbia University in New York City and the University of Pennsylvania in Philadelphia. Neither Austin nor Davies had their proposals funded. Those decisions may reflect the tangible results produced by less paradigm-challenging projects, Levine says. He thinks that projects seeking fundamental breakthroughs, such as Austin’s, need more time to achieve their visions. “The lofty goal of helping find a new set of directions in biology with the help of physicists, computer scientists, whatever — I don’t think they quite got there.”

“The lofty goal of helping find a new set of directions in biology — I don’t think they quite got there.”

Barker, who left the NCI in 2010 and is now at Arizona State, says that the PS-OCs have made progress in a number of areas, including understanding cancer evolution, predicting when a cell will become metastatic and developing biomarkers for cancer. But she agrees that five years was probably too short for the more ambitious efforts. “For these large consortia, it takes about the first three years to get them all working together, to get a common language in place, to get common core resources developed,” she says. “In terms of judging the programme, I’d like to have seen it a couple years hence.”

NCI programme managers say that the plan was always to reopen the funding competition after five years, rather than simply to extend existing sites. More researchers applied for the second round of funding, they say, and there was not enough money for everyone. But they point out that physical oncologists now have more funding options. “I think most people will find somewhere to have their work supported,” says Hanlon, whether through future PS-OC awards, other NCI programmes or external sources.

Levine, for example, has funding from the state of Texas and has been involved in a partnership between the US National Science Foundation and private donors. The Francis Crick Institute, set to open this year in London, promises to bring more physicists into biomedical research (see Nature 509, 544–545; 2014). Austin and Davies say they may look overseas or to private foundations to continue their work.

NCI programme managers say that the diversification of funding sources shows that the field is gaining support and recognition. They also point to the journal Convergent Science Physical Oncology, launched in June by IOP Publishing of Bristol, UK, and to standing sessions on physics and the evolution of cancer at the American Physical Society’s annual March meeting and at meetings of the American Association for Cancer Research. “Those types of sessions didn’t exist five years ago — now you can find them at several of these meetings,” says Nagahara. “That’s a sign of success.”

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  1. Avatar for Sui Huang
    Sui Huang
    This article is right on but could be more pointed. The truth is: this PS-OC program has been hijacked by engineers and computational scientists and modelers who have little desire to seek “understanding of the fundamentals of cancer”, as the physicists interviewed herein, univocally put it. Instead, they "mathematize" existing ad hoc concepts and emphasize the “translational” aspects. There is nothing wrong with translational research. But what do we mean by “fundamental understanding”? The NCI officials’ defense quoted here is devoid of epistemic clarity. One problem is that the current climate of obsession with “translational value” may have contaminated the purist view, and some physicists may have interpreted, perhaps in naive optimism, this PS-OC initiative as NCI’s bold and visionary attempt to promote the long due quest for the “fundamentals” of cancer. Indeed, we shall not forget that NIH’s mission is “to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health…” (1). But the emphasis on the latter, now called translational research, must not come at the cost of the “fundamental knowledge” lest we run out of knowledge that can be “translated”! This balance is reflected in the two ways in which physics can benefit life sciences. One is more mundane: to provide the tools for quantitative analysis, such as facilitating the use of mathematical models for processes that are too complicated to be explained by the biologists qualitative cartoonisch models. This use of “physical sciences” (to use the more fuzzy terminology of NCI) in cancer biology is not new and would not warrant a particular initiative, since biophysics, computational biology, bioengineering, etc. have long been in the business of offering support for quantitative analysis in cancer research and clinic. The other, less obvious, and more exciting way in which physics (notably theoretical physics) can help is: to bring its epistemic culture to cancer biology. This means, as said above, to get to a fundamental understanding of cancer. So what is ‘fundamental understanding’? While this article leaves it open, it is implicitly delineated in the outcome it describes, hidden behind an irony: Those teams who did not get funded by the PS-OC Program know exactly what ‘fundamentals’ of cancer means, and those who did get funded, most likely not – or at least do not explicitly propose to pursue it. Thus, the funding decision cut along a natural, preexisting epistemic divide. This means that NCI has missed an opportunity to deliberately steer the course of cancer research against the winds of the current intellectual climate and to try something new. This of course is almost unavoidable because the review panels (with few theoretical physicists in them) represent precisely that same climate of thought. The identification of genetic pathways and ensuing development of targeted therapy are significant achievements. But if, despite a clear-cut mechanistic rationale, they do not fully explain all our observations (without pushing aside inconvenient ones) or do not fully deliver (without hyping up short-term therapeutic successes), then we need to also dig deeper instead of simply doubling-down with an intensified quest for more genetic pathways and variations of therapeutic schemes and with the mathematization of existing concepts. Something that is so ubiquitous and inevitable and profoundly linked to evolution and development of our multicellular essence as is cancer, and that with its relentless progression so potently follows an arrow of time, defying the most rational therapies, must be addressed as a fundamental problem of nature. This requires development of a theory, not mathematizing the phenomena based on ad hoc concepts. A comment like this cannot duly answer the question of what “fundamental principles” really means in cancer biology. But to illustrate its complementarity with the “less fundamental” translational research let us for concreteness sake consider steam engines. In the early 1800s, George Stephenson, a self-taught engineer, made a fortune of building steam locomotives shortly after steam engines were invented –without any knowledge of the fundamental principles of steam engines. Now, that was useful translational research. But it was Sadi Carnot who in 1824 proposed the formal theory for the intrinsic limitation of the efficiency of steam engines based on first principles of thermodynamics. The impact of Carnot’s work reached far into the era of combustion engines. Every high school student learns about the Carnot process but few outside the UK know of Stephenson. Cancer biology is in need of a formal theoretical framework that is epistemologically (not conceptually) equivalent to the Carnot process and can nail down the inevitable “fundamentals” behind the arrow of progression in terms of principles, not pathways. I think we as a research community have this duty –and it would fit NIH’s broader mission (1). The discrepancy between the magnitude of the problem of cancer (soon to be the most common cause of death) and the fact that cancer biology remains an empirical science that lacks a theoretical underpinning but depends on descriptive concepts (mathematical or not) cannot longer be tolerated. My interactions with NCI program officials reveals that there exists a minority of leaders who are exceptionally knowledgeable and visionary and epistemologically aware, and who know that we need a change of culture towards an embrace of the fundamentals. But why does funding keep going to the same old familiar “superficial” ideas, now just wrapped in the new clothes of mathematical analysis? One reason is perhaps that time is simply not ripe yet for a broader “fundamental understanding” of cancer. By sheer arithmetic, if only a minority of scientists see the need for a change of culture, and as long as our peer-review system depends on the aggregate score of a large panel of reviewers, the pace of progress will be rate-limited by the colleagues who are just “average” in the facility to comprehend the broader epistemic landscape. Second, there is the factor a cognitive dynamics: Yes, modeling genetic pathways and tumor growth and therapy schemes is a good idea. But if we seek progress, shouldn’t GOOD ideas sometimes give place to BETTER ones, as Shakespeare reminded us (2)? Unfortunately (as said here before): we overestimate the rationality of human judgement, for psychologists observed that GOOD ideas do not yield to, but suppress BETTER ones (3). These two reasons impose an intrinsic limitation to the rate of progress of cancer research. No particular person, nor the NCI, is to be blamed – for it is, well, a fundamental feature of our system. But if we do not find ways to overcome it, in the foreseeable future we will continue to experience the prosaic manifestation of the proverbial definition of insanity (attributed to Einstein, politicians and football coaches alike): doing the same thing over and over again and expecting different results each time. (1) see: (2) W. Shakespeare (1599), Julius Cesar, Act IV/III (3) Bilalic, M., et al. Cognition 108, 652-661 (2008).
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