Thursday, August 15, 2013

Eco-evolutionary medicine: why cancer is different

At many universities, including McGill, every thesis defense committee must have a “pro-Dean”, who represents the Faculty of Graduate Studies and is responsible for ensuring that the defense is conducted in accordance with university rules and in fairness to the student. The pro-Dean must come from a different faculty than the student, which means that the pro-Dean usually has little or no experience with the topic of the thesis. I am not sure how they normally assign pro-Deans but every once in a while an email goes out asking for emergency pro-Deans. That is, a bunch of thesis defenses are coming up for which they do not yet have pro-Deans arranged – and the email is to ask who might be willing to fill in. The email request usually includes a listing of thesis/departments that need pro-Deans and we are invited to choose one from among them. This allows one to get exposure to different branches of thinking within the university – once I chose to be pro-Dean for a thesis about the spread of militant Islam in western Africa. This time, I could choose between defenses in chemistry, physics, religious studies, medicine, etc. The one from medicine caught my eye: “Translational cancer research: from the bench to the bedside – and back again” by Torsten Holm Nielsen. So I signed up – primarily in the hope of having the opportunity to ask a question that had been in my mind for about six months.


I had better step back a few years. My early research was part of the wave of studies showing that “rapid” or “contemporary" evolution” often occurs in natural populations. Through time, my interest in this phenomenon expanded into “evolutionary applications” – how rapid evolution relates to applied situations, such as natural resource management, agriculture, conservation biology, and medicine. I even wrote two papers about the topic, one titled “Evolutionary biology in biodiversity science, conservation, and policy: a call to action” and one titled “Evolutionary principles and their practical application”. I also enthusiastically joined the editorial board of the new journal Evolutionary Applications that was founded by Louis Bernatchez and Michelle Tseng. I am here interested specifically in medical applications.

Evolutionary principles are now firmly ensconced in medical research and patient treatment, especially in relation to the evolution of bacterial resistance to antibiotics and viral resistance to antivirals. In particular, the use of any new antibiotic is swiftly followed by the evolution of resistance to that antibiotic, which then necessitates the development of new antibiotics. If this weren’t the case, then penicillin might still be the treatment of choice. The same evolution of resistance is also true for drugs designed to treat HIV. For instance, genome sequencing studies have documented the course of mutations that arise and spread to confer resistance to a given treatment. In both contexts, then, the evolution of resistance alters pathogen population dynamics to allow “evolutionary rescue” in the face of a treatment that would otherwise cause its extirpation from the host. In short, the evolution of resistance by human pathogens provides a clear example of eco-evolutionary dynamics.

In each of the above cases, the first part of the eco-evolutionary problem is evolution by the pathogen population within a given host. To be specific, replication by the pathogen in the host is accompanied by occasional errors (mutations), some of which (by chance) show enhanced resistance to whatever treatment is being applied. As a result, the resistant pathogens show reduced mortality relative to the pathogens without the resistance mutation and, as a consequence, resistance spreads over time through the pathogen population. Eventually, the treatment is no longer effective. The second part of the eco-evolutionary problem is that pathogens that have evolved resistance within one host can spread to new hosts, meaning that a new infection in a new host starts from a position where resistance to the preferred treatment is already strong. This, then, is the two-pronged eco-evolutionary problem faced in the treatment of infectious disease – evolution of resistance within hosts and the transmission of that resistance to new hosts.


I have recently had occasion to re-consider this eco-evolutionary medicine problem from the perspective of cancer. Many years earlier, I had heard several talks about evolution and cancer but my renewed interest came from reading two outstanding books: The Emperor of All Maladies and The Philadelphia Chromosome. Both of these books openly discuss cancer as an evolutionary problem. That is, a tumor is a population of cells in which each (or many) of the cells are replicating out of control – usually as the result of a series of mutations that originally occurred in a line of normal cells. Chemotherapy and radiation therapy are designed to kill these aberrant cells but (hopefully) not normal cells. Sometimes these treatments work right away and sometimes they do not. Other times they work initially but the patient eventually relapses. Both of these limitations are the result of evolution by the cancer cells. During replication by the cancer cells, mutations arise that can (by chance) reduce the cell’s susceptibility to the treatment. As a result – and similar to the first prong of the eco-evolutionary problem discussed above for infectious diseases – the cancer cells without these resistant mutations decrease in proportion relative to the cancer cells with the resistant mutations. During this period, the tumors often shrink as the population of non-resistant cells dies and the patient recovers. Eventually, however, the resistant cells have increased in frequency to the point where they cause expansion of the tumor again.



Cancer biology now has the above evolutionary principles firmly in mind. In particular, tumors are often genetically screened to see what mutations predominate and then treatment is based on chemotherapies known to work best against those mutations – this is the so-called “personalized medicine.” In addition, patients that relapse as their cancer evolves to escape the original treatment are often given a planned subsequent treatment that might better target the newly-evolved resistant cells. Eco-evolutionary cancer medicine!

What struck me when thinking about these phenomena is that – in relation to evolution – cancer is both the same and different from infectious diseases. It is the same with respect to the first prong of the eco-evolutionary problem discussed above – evolution within a patient – but is entirely different with respect to the second problem – transmission to a new person. As far as infectious diseases are concerned, the human body is simply a vehicle for replication and spread to other humans. As far as most cancers are concerned, however, their life – and their genetic line – ends with the death of their host. For cancer then, each human is its own independent world – never to interact with other worlds and with a finite life span beyond which propagation will not be possible. As a result, resistance that evolves within one patient will never (with rare exceptions) be transmitted to another person – which by contrast is the defining feature of infectious diseases.

To me, this suggests that evolutionary applications to cancer treatment will ultimately be very different from those to treat infectious diseases.  In cancer, we can – in principle – design a series of effective targeted therapies for the common (and eventually less common) mutations. We can then use those treatments from the get-go, monitor new mutations and treat those with additional targeted therapies, and eventually cure the patient. The unique – and hopeful – part is that the same sequence of treatments should work in the next patient with the same starting mutations – because any resistance that evolved in the first patient will not have transmitted to the next. That is, evolutionary history is reset in each new patient. With infectious diseases, however, the new patient might well be starting from the ending point of the old patient – thus making the personalized treatment protocol much more difficult and the design of new therapies a never ending treadmill.

So this is the idea I wanted to raise at Torsten’s defense. As should be the case for a pro-Dean, I didn’t ask any questions during the defense itself but was encouraged to hear that Torsten and his examiners frequently invoked evolution as a problem faced by cancer therapy. Then, after the committee had asked all of their questions, it was time to ask mine. I gave short description like that above and asked the student if my thinking was crazy. Encouragingly, it seemed it wasn’t. It was also interesting to see – including in discussions later with the committee – that this wasn’t a distinction frequently discussed in cancer therapy. Presumably this is because cancer researchers are not also infectious disease researchers and so they have to deal with the first prong of the eco-evolutionary problem but not the second. Infectious disease researchers on the other hand have not had to think about the first prong in the absence of the second.

The committee was quick to point out some interesting applications of which I was not aware. One particularly interesting one was that some cancer therapies are apparently designed to drive the evolution of the cancer in a particular genetic direction – a direction that can then make it particularly susceptible to another treatment. Kind of like leading the lamb to slaughter or perhaps an evolutionary bait-and-switch. I don’t think this idea is yet in clinical practice but it is seemingly being discussed.

In reality, I suspect that the difference between cancer and infectious diseases probably has been discussed in the literature (perhaps readers of this blog can point out examples) but it was rewarding to have the realization all on my own – and to then have the opportunity to discuss it with the experts. Congratulations Torsten – and good luck in your future endeavors.


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An aside: In discussions with the committee after the defense, I mentioned reading The Philadephia Chromosome, which is about the development of the first serious targeted cancer therapy for a specific genetic mutation. One of the committee members told me that one of the protagonists of that story – Suzan McNamara – had done a PhD in the laboratory of Dr. Wilson Miller, the person sitting beside me in the defense and the major supervisor for Torsten. In 1998, Suzan developed chronic myelogenous leukemia (CML) and had heard about a targeted cancer treatment in development by Novartis. Novartis was taking the usual careful but glacial steps toward testing their new drug but Suzan and others would die before gaining access. In 1999, Suzan started an online petition that was one of the major pushes causing Novartis to speed up production and testing. Suzan was later featured on advertisements for the drug, which was eventually named Gleevec. Afterward – and I was not aware of this – Suzan decided to become a leukemia researcher, was awarded a PhD in Wilson Miller’s lab, and now works as a clinical trial coordinator at Jewish General Hospital in Montreal – where the defense was taking place. (As a further aside, my uncle also had CML and was enrolled in the early trials of the drug that would become Gleevec. He responded extremely well at first but eventually relapsed and passed away several years later. Nonetheless, Gleevec extended his life and greatly increased its quality.)

Additional personal reasons for an interest in cancer stem from multiple myeloma – on both sides of the family. My mother’s father died of the disease in 1965 and was told at the time that no suitable therapies existed. Then, last year, my father was diagnosed with the same disease, which was my main motivation for reading the two cancer books noted earlier. This time, however, a good targeted therapy existed – bortezomib (Velcade) – a proteasome inhibitor that works by acting on the myeloma cells and the cells with which they interact to inhibit plasma cell growth and reproduction and to promote cell death. In combination with cyclophosphamide (Procytox, Cytoxan), which interferes with the growth and spread of tumor cells, my father is doing very well. I am very grateful for this progress but I can’t help but wish it was present in 1965, in which case I might have been able to meet my grandfather.

A grandfather I never met: William Plumer Hooker.

5 comments:

  1. You would enjoy "Cancer: The Evolutionary Legacy" by Mel Greaves, from the London Institute of Cancer Research. Authoritative, readable, fascinating. Also, there was a fabulous conference in June at UCSF on evolution and cancer. Details and videos here http://cancer.ucsf.edu/evolution/conference-2013
    More links at The Evolution and Medicine Review http://evemedreview.com

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    Replies
    1. Indeed, yes. Wonderful stuff. Thanks for the hints.

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  2. Having taught evolutionary medicine for three years at Taipei Medical University, I am somewhat surprised that you have not mentioned the possible role of viruses and other pathogens in the initial stages of cancer, see:

    TED Book: “Controlling Cancer” offers bold plan to stop a killer
    http://blog.ted.com/2012/01/10/ted-book-controlling-cancer-offers-bold-plan-to-stop-a-killer/
    Ewald PW, Ewald HAS (2012) Infection, mutation, and cancer evolution. J Mol Med 90: 535-541.
    Ewald PW (2009) An evolutionary perspective on parasitism as a cause of cancer. Adv Parasitol 68: 21-43.

    Other excellent, more general texts, are:
    Gluckman P, Beedle A, Hanson M (2009) Principles of evolutionary medicine: Oxford University Press.
    Nesse RM, Williams GC (1994) Why we get sick. The new science of Darwinian Medicine. New York: Times Books.
    Stearns SC, editor (1999) Evolution in health and disease: Oxford University Press.
    Stearns SC, Koella JC, editors (2008) Evolution in health and disease. Oxford, UK: Oxford University Press.
    Trevathan WR, Smith EO, McKenna JJ, editors (1999) Evolutionary medicine. Oxford, UK: Oxford University Press.
    Trevathan WR, Smith EO, McKenna JJ, editors (2008) Evolutionary medicine and health: New perspectives. Oxford, UK: Oxford University Press.
    Nesse RM, Stearns SC (2008) The great opportunity: Evolutionary applications to medicine and public health. Evol Applic 1: 28-48.
    Greaves M (2007) Darwinian medicine: a case for cancer. Nature Rev Cancer 7: 213-221.
    Merlo LMF, Pepper JW, Reid BJ, Maley CC (2006) Cancer as an evolutionary and ecological process. Nature Rev Cancer 6: 924-935.
    Crespi B, Summers K (2005) Evolutionary biology of cancer. Trends Ecol Evol 20: 545-552.
    Campisia J (2005) Aging, tumor suppression and cancer: high wire-act! Mechanisms of Ageing and Development 126: 51-58.
    Campisia J (2003) Cancer and ageing: rival demons? Nature Rev Cancer 3: 339-349.

    Best regards, Bruno Walther

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  3. Sorry for the late reply. I realize that viruses can play a role in cancer, which then changes my main thesis that the evolutionary problem is different. However, it is also clear that many cancers do NOT involve viruses in which case my main thesis remains correct.

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  4. On the train today I happened to read an article about The Immortal Devil in Discover Magazine. It tells the story of a cancer that occurred in one Tasmanian Devil that evolved the ability to spread to other Devils, thus becoming a directly transmitted "parasite". This cancer/parasite thus breaks the above rule regarding "why cancer is different." That is, defensive mutations that arise in the cancer cells of one individual (one Devil) can, actually, be transmitted to other Devils. The cancer cell line has escaped the mortal coil of its host and become potentially immortal. Interestingly, this provides a potential route to evolved control. At present the cancer/parasite/infectious disease is much too virulent (killing almost every infected host) for its own good. Evolution should favor mutations in the cancer that reduce its virulence and perhaps lead to a permanent detente between the Devils and their new disease.

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