Carlo Maley, 57, looks to nature for answers. The scientist, trained in evolutionary biology and computer science and head of the Arizona Cancer Evolution Center at Arizona State University, studies how tumors progress and how they can be halted, but from a very particular perspective: by observing and analyzing how cancer-suppression mechanisms evolved in large, long-lived animals such as elephants and whales.
“We think that nature has found ways of preventing cancer multiple times within animals,” he says. And perhaps we can learn from that: “The question is, what are all the innovations that evolution has discovered? And can we go find those and then try to use them in humans?”
Observing elephants and whales is not accidental. These animals present a curious biological contradiction that has sparked scientific interest —and debate— known as Peto’s Paradox. The theory posits that if tumors arise from a single cell that becomes rogue and begins to reproduce uncontrollably, the more cells an organism has, the higher its probability of developing cancer; and because cancers occur due to the accumulation of mutations, the more times a cell divides, the greater the chance of a mutation. By that logic, animals with larger bodies and longer life expectancies should have more cancer than smaller, short-lived animals. But that is not always the case.
Here is the paradox: elephants, for example, despite being much larger and having far more cells, have lower cancer rates than humans or mice. And that is, Maley says, because “evolution has given whales and elephants ways of preventing cancer that are better than humans.” The scientist visited Barcelona to take part in the annual Biomedical Research Conference organized by Pompeu Fabra University and to visit the Barcelona Beta Brain Research Center. He spoke to EL PAÍS shortly after his scientific presentation, in which he outlined a suggestive approach to fighting cancer resistance.
Question. How does nature suppress cancer in elephants and whales?
Answer. We are only at the beginning of studying it. In elephants we found that they have ways of sensing damage to their DNA, they’re very sensitive to detecting that, then they will kill off the cell that has the damage: they have 20 copies of their p53 gene, which is the most important tumor suppressor gene we know of, and it senses DNA damage and triggers the death of cells. As for whales, we don’t yet have as much of a developed story: they seem to repair their DNA better than humans, but they don’t do it through extra copies of p53.
Q. How can nature help us understand cancer?
A. If we look at the elephant story, nature is pointing us to using sensing of DNA damage as a really important way of preventing cancer. Joshua Schiffman, who worked with us on the elephant story, has founded a biotech company to try to use the p53 protein to see if we could use that as a medicine to remove damaged cells.
Q. Why don’t humans have mechanisms as sophisticated as those of elephants to protect us?
A. Natural selection only improves what is causing us to die or what helps us reproduce more. If a mouse with a thousand times fewer cells than us lives only two years, it doesn’t need much cancer protection. And so natural selection hasn’t built in a lot of cancer protection into it. Now, if many started to die of cancer in the wild, there would be selection for new mutations and variants that would prevent it. Essentially, there’s been more selection on elephants and whales to prevent cancer than there has been on humans, which is why we don’t have those extra protections.
Q. As a society, we have the goal and the desire to cure cancer. Is it more realistic to make it chronic than to eliminate it?
A. I think we have been misled by our obsession with a cure. The goal in medicine in general, but in cancer medicine in particular, shouldn’t be a cure, it should be extending life and quality of life. Cure is one way to achieve that, but we have become so obsessed with it that we haven’t thought about how to extend life and improve quality without a cure. So yes, we aspire to turn cancer into a chronic, controllable disease, like diabetes or HIV infection, which we do not cure but suppress and manage. We’re pursuing these ideas for how to manage the cancer so that we can live with it but not die from it.
Q. In some tumors, even if you make them chronic, the person still ends up dying from cancer.
A. Not necessarily; we’re hoping that we can keep control over it for the rest of your life, and that you die of something else. But I would be happy with just adding decades of life, good quality of life. That would be a huge win. Currently, in practice, if life is extended by a few months it’s considered a great success. I find that pathetic. A few months… We should be talking about years or decades!
Q. In precision oncology, the goal is to understand tumor biology and to look, for example, for treatments targeting the tumor’s driver mutations. What do you think of that approach?
A. I think it’s reasonable to analyze the tumor’s biology if it has a particular mutation and we have a drug for that mutation. But it doesn’t solve the problem because even if all the cells have that mutation, they will develop resistance to the drug fairly quickly.
Q. In the end, is resistance the problem?
A. Actually there are two big problems. One is simply getting any response: often we take a drug and it does nothing to the tumor. The precision oncology I mentioned is a way to find a drug that gives some response, but the next big problem is that even after getting a response, resistance to the drug will develop.
Q. You propose using the lowest possible dose. Can you explain?
A. The observation is that the greater the selective pressure —the more cells you eliminate— the faster resistance develops. One way to look at it is that all tumor cells compete for resources like oxygen, glucose and amino acids. If you eliminate 99% of the sensitive cells and the remaining 1% are resistant, they are freed from competition. They no longer have competitors. They have much more space and resources and tend to proliferate rapidly and aggressively. If you use a lower dose so that only some cells are eliminated, many competitors remain and it’s harder for the resistant cells to expand quickly. That is the essential intuition: the less drug you use, the lower the pressure for resistance to develop. Therefore, it takes longer to develop.
Q. What is the level of evidence for this approach?
A. In cancer there have been six mouse experiments showing this is an effective way to delay resistance or even prevent it. And one clinical trial doubled the time until resistance occurred, and several clinical trials are underway, but there are no reported results yet. So it’s still very early. It’s not clear if it will work, but we’re very hopeful.
Q. Is this strategy valid for all cancer stages?
A. This is only for types of cancer you believe you cannot cure. If a cancer has not metastasized, if it is still contained in the organ where it originated, we can generally cure it with surgery. One vision of the future is that we would develop measures to estimate how likely is it we could get a cure. And if we think it’s unlikely, then we go to these kinds of adaptive therapy procedures.
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