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Does Cancer Build Anything New? A Response to Josh Swamidass

Ann Gauger

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As Evolution News has noted, Professor S. Joshua Swamidass raises some interesting points at the BioLogos Open Forum page (“Cancer and Evolutionary Theory“). He recently published a paper in Nature Genetics on a new computational means to identify “driver” mutations involved in the progression of cancer. In commenting on his own paper he makes the argument that cancer evolves, which “does not in itself prove evolution is true” but “casts serious doubt on the [intelligent design] arguments from molecular biology (vis-a-vis Doug Axe and Kirk Durston, etc.).”

His argument:

…[I]f (1) evolutionary genetic tools correctly infer the progress and history of cancer, (2) cancer regularly innovates with proteins of novel function, (3) regularly exhibits convergence at a molecular level, and (4) all the mathematical of machinery of neutral theory works so well, THEN what magically prevents all these things from being true at the species level?

This all cannot be true for cancer, but false for evolution. That is the real inconvenience [for intelligent design theory] here.

Let’s take his points one at a time.

1. “Evolutionary genetic tools correctly infer the progress and history of cancer.”

Yes, cancer evolves. So do lots of things on a small scale. And genetic tools predict it well. No dispute here. Greaves and Maley write in a well-respected Nature review cited by Swamidass himself:

In 1976 Peter Nowell published a landmark perspective on cancer as an evolutionary process, driven by stepwise, somatic cell mutations with sequential sub-clonal selection. The implicit parallel was to Darwinian natural selection with cancer equivalent to an asexually reproducing, unicellular, quasi-species. The modern era of cancer biology and genomics has validated the fundamentals of cancer as a complex, Darwinian adaptive systems….

A classical or Darwinian evolutionary system embodies a basic principle: purposeless genetic variation of reproductive individuals, united by common descent, coupled with natural selection of the fittest variants. That is, natural selection of those rare individuals that fortuitously express the traits that complement or thwart the contemporary selective pressures or constraints. It’s a process replete with chance. Cancer is a clear example of such a Darwinian system.

2. “Cancer regularly innovates with proteins of novel function.”

Cancer evolves by mutating DNA. Some mutations are in genes that code for proteins. There can be tens to thousands of mutations in a particular cancer tumor, and each cancer is unique in its mutations. Most mutations are presumed to be neutral, having no effect on cellular behavior. Some are loss-of-function (LOF) mutations, meaning the mutation breaks a protein or reduces its expression, causing it to have little or no function. However some mutations can be what are called gain-of-function (GOF) mutations, where the mutation does not eliminate function, but causes aberrant “new” function. The key is, what does “new” mean? In the case of the genes I have examined, it means a point mutation (single nucleotide change) that changes a protein’s binding preferences to DNA or to other cellular proteins. In the case of p53, one of the first proteins identified as mutated in many cancers, the protein can lose its ability to bind its original DNA binding site, but can still bind other factors it is involved with, thus disrupting their function. Or it can bind new factors, causing them to interact inappropriately with their targets. Or it can be over-expressed, meaning there is now too much of it, which causes other abnormal interactions. These mutations change cell behavior, making them more prone to metastasize and invade other tissues, for example, and because of that change they are called GOF mutations. But is it really a new function or merely a monkey wrench in the finely tuned works of the body? The mutation certainly is not constructive.

Oren and Rotter write in their article titled “Mutant p53 Gain-of-Function in Cancer“:

The term “gain-of-function” seems to imply that mutp53 [mutant p53] acts through mechanisms that are totally uncharted by wtp53 [wild-type, or unmutated p53]. However, this is not necessarily the case. Rather, at least some of the biochemical activities of mutp53 might stem from its having lost sequence-specific DNA binding while retaining the functionality of other domains. For instance, cancer-associated mutp53 proteins typically retain an intact transactivation domain (TAD), which may still operate exactly as it does within the wtp53 protein, but can now be targeted to different sites on the chromatin. Furthermore, given the high concentration of mutp53 protein in tumor cells, relatively weak molecular interactions, which are marginal within the wtp53 protein, may now be amplified by mass action and reach a threshold that allows them to exert a measurable impact on biochemical processes within the cell. When expressed at sufficiently high levels, tumor-associated mutp53 isoforms can exert profound effects on gene expression patterns, thereby promoting specific biological outcomes while disfavoring others. … In particular, given that mutp53 can interact with a variety of transcription factors (see later), often in a signal dependent manner the subset of genes affected by mutp53 is likely to vary greatly among different cell types and cell contexts.

Most mutations are neutral (probably the vast majority), some are LOF mutations, and some are GOF mutations, what Swamidass calls “proteins of novel function.” But are these GOF mutations constructive or destructive? Do they carry out a new reaction or merely an old one in the wrong context or the wrong way? It’s definitely not to the benefit of the organism in question. Imagine that the oil in your car’s engine turned to sludge. The finely tuned machine will not respond well, even if the sludge is “novel,” an “innovation” in the system.

3. Cancer “regularly exhibits convergence at a molecular level.”

Cancers evade control — they lose their normal inhibitions on cell growth, and eventually they leave their tissue of origin and spread. This sounds simple but it is not. There are many ways to disrupt the finely balanced milieu of cells. This can be seen by the latest research results, such as in Swamidass’s paper. Greaves and Maley summarize it this way:

What has now emerged in genomic screens is a portrait of just how complex cancer genomes usually are. Individual cancers can contain hundreds or hundreds of thousands of mutations and chromosomal alterations, the great majority of which are assumed to be neutral mutations arising via genetic instability. Chromosomal instability (amplifications, deletions, translocations and other structural changes) is a common feature of most cancers Additionally, the data vividly confirms that each cancer in each patient has an individually unique genomic profile. It may be that only a modest number of phenotypic traits are required to negotiate all constraints and evolve to full malignant or metastatic status but the inference is that this can be achieved by an almost infinite variety of evolutionary trajectories and with multiple, different combinations of driver mutations. [Emphasis added.]

And in another place:

Clonal evolution involves the interplay of selectively advantageous or ‘driver’ lesions, selectively neutral or ‘passenger’ lesions, and deleterious lesions…’Driver’ candidature is supported by independent observation in multiple neoplasm beyond what would be expected by the background mutation rate, association with clonal expansions, and type of mutation (missense, nonsense, frame shift, splice-site, phosphorylation sites, double deletions, etc.), particularly if the gene involved has a known role in cellular processes relevant to oncogenesis.

Some mutations are more potent than others in their effects; these drive progression of the cancer. Any cell with that sort of mutation will outcompete its neighbors and take over. Since there are key checkpoints in the cell cycle, and key regulatory interactions, mutations to these systems will have a strong effect, and likely be a driver of cancer progression, like mutp53 above. These kinds of driver mutations are found over and over in many different tumors precisely because they affect key checkpoints or regulatory processes in the cell — hence convergent evolution.

This is no challenge to ID. It’s simple population dynamics. Very large numbers of tumor cells, coupled to a very high degree of instability and mutation rate, mean that many, many mutations are sampled. The most potent ones, “drivers,” cause increased cell proliferation — though they are a small subset of all possible mutations, their appearance is strongly selected for. As a result these drivers appear “beyond what would be expected by the background mutation rate,” because it is the successful drivers that produce cancerous malignancies.

4. “All the mathematical of machinery [sic] of neutral theory works.”

Neutral evolutionary theory works well, in the sense that mutations accumulate over time, and the successful ones are propagated over time, and that there are passenger neutral mutations that come along for the ride. They happen to be present in the successful cells, and even though they have no effect on the cancer, they are carried along as the successful mutations sweep away their competition. I have no dispute with neutral theory.

I also have no quarrel with the evolution of cancer — it involves step-wise positive selection for proliferative, invasive clones. No intelligent design advocate ought to deny that kind of process.

What I do object to in Swamidass’s argument is this: cancer is chaotic with incredible rates of mutation and chromosomal instability. That’s part of its destructive nature. What kind of constructive evolution can be accomplished that way, on the organismal level?

In fact, I would argue that cancer is an argument for intelligent design. For multicellular organisms to survive, it is essential that their cells behave cooperatively and not grow out of control. A complex layering of multiple pathways, checkpoints, and fail-safe mechanisms exist to maintain the balance. Without this regulation our lives would not be possible. I would argue that the existence of such complex regulation is due to design.

The Darwinian imperative is to multiply without limit; there is no Darwinian advantage to surrendering that potential. Cancer is proof of what happens when the Darwinian paradigm takes over. Yet our cells do maintain a balanced behavior in the face of so many ways to fail. That we exist at all, and that the balance is maintained nearly all the time, is in fact a wonder of design.

Photo credit: © Kurhan — stock.adobe.com.

Ann Gauger

Senior Fellow, Center for Science and Culture
Dr. Ann Gauger is Director of Science Communication and a Senior Fellow at the Discovery Institute Center for Science and Culture, and Senior Research Scientist at the Biologic Institute in Seattle, Washington. She received her Bachelor's degree from MIT and her Ph.D. from the University of Washington Department of Zoology. She held a postdoctoral fellowship at Harvard University, where her work was on the molecular motor kinesin.