THE CANCER MOONSHOT : LOOK OUTSIDE THE BOX (the 9-9-9-9 — proposal)

Cancer research is in stagnation. We cannot stay the course and double-down on exiting approaches with just more clinical trials and more data sharing. Instead, we need to promote contrarian approaches to overcome group-think. But how can we do so without being too disruptive?

Unfortunately, I fear, the well-intended Cancer Moonshot initiative is on the verge of being hijacked by the establishment of cancer research. As in politics, the establishment opposes any concerted efforts to change the system to the better. There are too many stakeholders who will suffer from attempts to fix the system. They want to stay the course, THEIR course. Of course, there is honest desire to advance cancer research and to help patients — but only “my way or highway”. The Cancer Moonshot Summit last month (June 29, 2016) confirmed this mood: it was a festival of circular back patting among the members of the cancer research establishment, a celebration of the already achieved and a call to stay the course: just at higher intensity, with more resolve, thanks to more funding. There was not a shred of an original new scientific idea about the nature of cancer, not even the glimmer of a path in science policy that would lead us towards such. But we do need new bold ideas. Current approaches do not work as desired. The major proposals for how to spend the big dollars to be allocated to cancer research were not bold but same old, same old! They essentially focusing on these four areas: (1) more targeted therapy and immunotherapy, (2) more clinical trials, (3) more collaborations, (4) more data sharing. All areas that we have been hearing from NCI over the past decade.

Not that we should abandon immunotherapy and targeted therapy, or redcue clinical trials, avoid collaboration and eschew data sharing. But these are NOT the critical rate limiting factors to be addressed if we are to overcome the current quagmire in cancer research, and if we expect some sort of breakthrough that could lead to a cure. We need new biological insights and cannot stay the course and double-down on existing approaches. To shake up the establishment, I propose that these focus areas must be complemented by their very OPPOSITE — which is likely to sound backwards and unromantic and will anger some folks. But if we are talking about a path towards a cure of cancer all options should be on the table.

So how do we complement the same old, same old with something bold — but without disrupting? I propose that to each of the four focus areas listed above, just 9% of funds goes to doing the opposite of what the establishments desires:

(1) More targeted therapy, more immunotherapy: These are two big domains that big pharma bets its money on. Fine. But there is already a mono-culture of thought that sees no alternative beyond these two types of treatments and billions of dollars are already being spent and made in these two segments. Despite the cases of spectacular success, these therapy strategies famously work only in a subset of patients and in most cases do not achieve durable remission. But instead of beefing up efforts with more potent drugs, or of pushing success rate by finding out whether there exist predictable subsets of patients that are helped by these new therapy (“Precision Medicine”), which won’t help those that do not possess the “responsiveness markers”, let’s figure out WHY there is an INTRINSIC LIMITATION to such therapies, as opposed to denying the existence of such a limitation and double-down on these therapeutic strategies. This is like with improving fuel efficiency of the internal combustion engine: We can either blindly try to push the limits of gas mileage by more tweaks to the engine, or we look for outside-the-box and solution: electrical cars.

PROPOSAL (1): Reserve 9% of the research funding intended to support targeted and immunotherapies and divert it to projects that are explicitly not about improving existing therapy strategies but take fundamentally outside-the-box approaches. (Ideas are not lacking, just suppressed).

(2) More clinical trials: Don’t forget that drug trials are not science and will not lead to breakthroughs. Clinical trials are merely institutionalized rigorous trial-and-error attempts to best deal with our scientific ignorance. Sure, trials are necessary but they are driven by monetary incentives and guided by safety issues — they are not motivated by scientific curiosity. No new insights (except rare surprises) come from trials. They do not “figure out” new principles — only human minds can. Randomized clinical trials (RTC) have become de facto gold-standards in establishing “biological facts” but they have their methodological flaws. And they are agnostic of a very particular human individuality that defies the statistical variability on which they are based.

PROPOSAL (2): Reserve 9% of the funding that goes to clinical trials and funnel it to basic research on the inherent flaws of such studies caused by the unfathomable individuality of patients (high-dimensionality, non-ergodicity,…) and on alternatives to RCTs

(3) More collaborations: Yes, collaborations — they sound quite romantic. But we have heard that before: When Broadway musical composers started to collaborate in networks in the 1960, the creativity of the golden 1940, 1950s sank drastically. In fact, in cancer research we have been collaborating all the time! What’s new? All the larger NIH grants require collaboration between multiple principal investigator. We have created a culture of intellectual free-riding and band-wagon jumping, promoting scientists specialized in collaborating but lacking originality. In this climate, original ideas have no chance. What if THE key insight that would lead to a breakthrough lies in a profound idea that crystallizes only in the depth of the undivided mind, undisturbed by the endless meetings with collaborators? This is the type of fundamental scientific insight that has given us the laws of mechanics, the theory of evolution, the laws of genetic inheritance or the theory of relativity. This type of insight has not happened in cancer biology.

PROPOSAL (3): Set aside 9% of all the funds for these big collaborative projects to go to strictly single investigator proposals to give the lone crazy scientist with unconventional but well-argued ideas a chance.

(4) More data sharing: We are swamped in data on cancer, and the internet has drastically facilitated access to them. In the history of science there were times when we had lots of ideas and no data. Then there were times when we had lots of data and no ideas. I think we are in an era of the latter. If we have tons of data and do not understand the data, will sharing them and collaboratively looking at them afford new fundamental insights? In the best case scenario, perhaps a new drug target may emerge. But this is not the kind of fundamental novelty we need. No, most targeted drugs do not work as desired. Petabytes of data cancer genome and other omics linger in huge databases, readily accessible or soon to be so (NCI’s cancer cloud) but the vast majority is not used to test new biological hypothesis. Instead, cancer data have so far become a digital playground for computational scientists with little knowledge of cancer biology to play with and test machine learning algorithms. Such playful activities are always welcome but are too diffuse and inefficient in generating fundamental insights. The over-embrace of computational sciences has killed the culture of hypothesis-driven research.

PROPOSAL (4): 9% of all funds that go to building new platforms for sharing data shall be allocated to the classical type data analysis driven by a carefully framed hypothesis that comes out of rigorous and profound understanding of cancer biology.

OK, I know these are highly unpopular ideas and in direct opposition to current enthusiasm of mainstream and of those who want to stay the course and just accelerate it. But diverting just 9% of funds away from the unbounded promise of targeted and immunotherapy, the solid certainty of clinical trials, the magic of collaborations, and the altruism of data sharing — all good stuff — may still be worth it. This will disrupt herd mentality, overcome group-think and give outside-the-box ideas chance. In the grander scheme, numerically, this is actually quite a conservative proposal, yet could shake up things.

Not sure where I got the numbers 9–9–9… from ;) but it may help to make cancer research great again ;). Without a deliberate, forceful but controlled promotion of contrarian approaches, cancer research will advance only at the rate at which establishments cancer researchers die out … The patients cannot wait.

Institute for Systems Biology

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