How do we challenge prevailing wisdom?

by Andrew Thorburn, Ph.D.
Interim Director
Associate Director for Basic Science
Grohne Chair in Basic Cancer Research

Last week, I said that one of the reasons cancer increases with age is because the longer you live, the more chance you have to accumulate mutations in genes that control cancer.

I was careful to put the word “one” in there but even using that modifier, my statement gave the impression that this “conventional” view, which you’ll find in textbooks, is the most important thing.

Was I right last week? DeGregori says no.
One of the best things for me since I’ve been doing this job is getting feedback about these messages. So it was gratifying that shortly after last week’s message went out, I got a message from Dr. James DeGregori (co-leader, Molecular Oncology Program/SOM Molecular Biology) telling me that I’m wrong.

James thinks the “more time for oncogene mutation” idea probably does contribute a bit to age-related cancer, but it’s not the most important thing. James doesn’t think the “more time” idea can really explain the exponential increase in cancer with aging. Instead, James has been developing a radically different idea that he calls “adaptive oncogenesis.”

Adaptive oncogenesis and stem cell fitness
Cancer is a fascinating area to work in for many reasons, but one of them is that cancer is Darwinian natural selection in action (we’ve talked about this before in the context of treatment but it’s also true for cancer development). So, think back to your basic biology education and the fact that as Theodosius Dobzhansky said in a famous 1973 essay “nothing in biology makes sense except in the light of evolution.”

Adaptive oncogenesis proposes that, as we age, cancer development is driven by changes in the relative “fitness” (in a natural selection sense) of our stem cells.

James proposes that long-lived organisms like us have evolved stem cell populations with high fitness that prevent selection of cells that have acquired mutations in cancer genes. The idea is that, just as an animal population that is well-adapted to its environment will not change much (i.e. mutations will tend to be weeded out), stem cells with high fitness will tend to be stable. So, if they acquire a new mutation, the status quo will be favored and mutations will tend not to be selected for.

James thinks (and has direct published data) that as we get older, our stem cell fitness declines. And so, now we can get selection for adaptive mutations especially those that confer a cancer advantage. So, the adaptive oncogenesis hypothesis proposes that the high fitness of young stem cells acts against selection for oncogenic mutations, but as we age and fitness declines, this allows selection for cancer to occur.

But what about gene mutations?
James doesn’t deny the importance of mutations. He just thinks that their effects (in our case the development of cancer) can’t be manifested unless the overall fitness of the stem cell compartment is compromised as occurs during aging (or in response to other stresses like radiation exposure).

This is a radical re-thinking of how cancer develops that might provide new perspectives on what cancer is and how to prevent it. If James is correct, the key may not be preventing the acquisition of mutations but rather preserving the fitness of stem cells to ensure that these mutations can’t drive tumor evolution.

Game-changer
This idea didn’t just come out of the sky. Good ideas never do. They come about by putting together other pieces of information and making them into something better.

Others have influenced the adaptive oncogenesis idea, but I think it’s fair to say that James DeGregori is the person who has developed this concept.

So, one of UCCC’s investigators has an original idea that challenges a reigning paradigm about a central aspect of cancer—a really central aspect, how it comes about! And, if he’s right, adaptive oncogenesis could be a game changer that might even lead to strategies to prevent cancer that would never have been considered in the absence of the new idea.

Big money needed
Radical new ideas are not accepted with open arms. The scientific establishment is always saying that we look for innovation. However, the truth is that people are wary of new things.

Add to that the concepts here are not intuitively obvious (and people need to grasp ideas from evolutionary biology) and you see the problem: The reviewers will tend to go for a safer option, which fits with the ideas in the textbooks.

In our system, if he’s going to make real inroads in getting adequate funding (i.e. a big grant from the NCI), James needs to go beyond having the idea. He needs to be halfway down the road of demonstrating its validity.

James had a couple of pilot project grants through a UCCC Cancer and Aging Program grant in the early days of developing his idea. He needs much more, but even that small amount of funding has helped solidify his ideas and get some publications.

However, and I quote him, “The problem has been getting big money. NIH reviewers don't get it.”

What James didn’t tell me was Plan B—what if the next set of NIH reviewers are still too cautious to get behind a guy with a radically different take on things? Should we let an idea die because it’s too original or too hard to get your head around? Should we let it die because it goes against textbooks?

This is why we need funding (mostly from philanthropy but also from grants like the lung cancer SPORE or that Cancer and Aging grant) to start new projects.

And, sometimes, we need more money to keep those ideas alive while we build an argument that is persuasive enough that even risk-averse reviewers will approve the big money that it takes to do the big test.

That’s why the UCCC supporters who provide that funding are just as important a part of our team as the investigator with great ideas that challenge paradigms. Ideas aren’t enough when you’re in the business of changing prevailing wisdom; you need dollars too.


Want to read more of Dr. Thorburn's articles? Read the Director's Newsletter Online: www.uccc.info/dnl