One day in the mid 2010s, Ann Gauger and I received a message that a scientist was in town and wanted to meet us. This scientist turned out to be Karl Krueger, who at the time was a high-level manager of cancer research at the NIH’s National Cancer Institute. Karl received his PhD in biochemistry from Vanderbilt University, and had a long career both conducting and managing research. At that meeting, Karl explained to us that he is very supportive of intelligent design (ID), but at the time could not be public about it due to potential harm to his career. There are a lot of folks like Karl – highly credible scientists who support ID, but whom you probably have not heard of for the same kinds of reasons.
Well, after Karl retired a couple of years ago, he discussed the idea that he’d like to publicly announce his support for ID. Karl did that recently on an ID the Future episode — give it a listen to learn more about Karl and his personal story!
Since his retirement, Karl also began working on a couple of papers within his field of expertise — cancer. Karl had read Michael Behe’s 2019 book Darwin Devolves, which argued that when Darwinian evolution operates at the molecular level, it tends to break features at a much faster rate than it builds them. This thesis resonated with Karl’s experience with the mechanisms that cause cancer. And so he has now published two ID-inspired papers in the journals Molecular Cancer Research and Journal of Molecular Evolution. In fact, I cited one of Karl’s papers in the recent conversation I had with Denis Noble and Perry Marshall (see here). I’d like to share a little bit more about his papers and how they insightfully apply ID-thinking to the study of cancer.
Fundamentally a Darwinian Process
The basic premise of Karl’s papers is that cancer progression is fundamentally a Darwinian process: cells are competing to survive and reproduce within a host. But what cancer reveals about the Darwinian process is that it breaks features far more frequently than it produces new ones.
Most of the time our cells have built-in mechanisms that prevent cells from replicating out of control. But if these failsafe mechanisms break, cancer can “evolve.” This is how Krueger sees the “Darwin Devolves” thesis applying to cancer. The cells that are most common in tumors are those that have demonstrated mechanisms to proliferate to the greatest extents, dividing autonomously through asexual reproduction, much like bacteria. Essentially, these cells have broken free of the normal regulatory mechanisms required in multicellular organisms where cells fulfill their designated roles to benefit the organism. Thus, in a very real sense, tumor cells have become selfish without regard for the well-being of the host.
In 2023, Krueger published his first paper in the journal Molecular Cancer Research titled “Neo-Darwinian Principles Exemplified in Cancer Genomics.” He explains his basic thesis in the paper’s abstract:
This article covers the insights gained through these extensive studies where neo-Darwinian principles can be inferred to play roles throughout neoplastic transformation. The cells promoted during cancer development exhibit cancer hallmarks combined with the related enabling characteristics as outlined by Hanahan and Weinberg, analogous to natural selection and survival of the fittest. Selection of driver mutations that inactivate proteins encoded by tumor suppressor genes differs in profound ways from mutations that activate tumor promoter proteins. In most cases, the later stages of cancer development are characterized by sudden, extensive damage to chromosomes in a process that is not Darwinian in nature. Nevertheless, cells that survive these cataclysmic events remain subject to Darwinian selection promoting clones exhibiting the greatest rates of progression. Duplications of chromosomal segments containing oncogenes, deletions of segments harboring tumor suppressor genes, or distinctive chromosomal rearrangements are often found in cells progressing into later stages of cancer. In summary, the technological developments in genome sequencing since the start of the century have given us clear insights into genomic alterations promoting tumor progression where neo- Darwinian mechanisms of clonal selection can be inferred to play a primary role.
All About “Cellular Proliferation”
Krueger then explains that while Darwinian evolution rewards “survival and reproduction” of individuals within a species, in cancer the situation is a little different. With cancer, it’s all about “cellular proliferation” — i.e., out-of-control growth. Here’s how he puts it:
Darwin’s theory of evolution was based on a process he called natural selection where those individuals of a species best fit to survive in their environment reproduce and thereby propagate phenotypes better suited for survival and continuation of the species. This paradigm is altered with cancer. Instead, for a tumor to manifest itself will require substantial and continued cellular proliferation. Those cells which proliferate at faster rates and maintain this growth process at their site of origin, or beyond in the case of metastasis, supersede the role of natural selection. In this game, it is not survival of the fittest but rather the fastest proliferating cells that present themselves most prominently in tumors (excluding accessory cells of the tumor microenvironment recruited to serve the needs of the tumor)…. The mutational pathways that different cancers follow are variable but undoubtedly are governed by explicit neo-Darwinian selection for each cell type.
Krueger further notes that the idea that cancer progression is an evolutionary process is widely accepted:
Most cancer researchers today agree that the emergence and progression of cancer is governed by principles akin to evolutionary processes. Within the lifetime of an individual, it is now possible to study the genomic changes occurring in tumors providing clues for evolutionary mechanisms driving this pathologic process. Cancer progression is driven primarily through selection of cell clones that autonomously proliferate, harnessing their tissue environment for their own expansion.
Krueger has even told me that he did not believe in Darwinian evolution until he observed what was being discovered in the area of cancer genomics. Cancer is the prime example of Darwinian evolution, with one caveat: cellular systems have lost their integrity, pushing to advance themselves rather than promote survival of the host. In his view, this is the opposite of what one would expect for evolution of species.
But what exactly are the kinds of mutations that allow cells to begin to replicate out of control? These mutations have certain common effects:
Each core process can account for multiple hallmarks, for example, cell survival can encompass proliferative signaling, evading growth suppression, resisting cell death, enabling replicative immortality, deregulating cellular metabolism, avoiding immune destruction, and achieving access to vasculature. It should be apparent that all cancers hold much in common despite their many biological differences posing great challenges to cure all cases of such a wide range of diseases. The common thread shared by all tumors has been the neo-Darwinian process of selecting those cells harboring mutations and other genetic impairments that confer a growth/survival advantage while at the same time shutting down normal cellular control mechanisms that should eliminate such damaged or dysregulated cells.
Two Kinds of Driver Mutations
He gives specific examples of two kinds of driver mutations, the mutations that promote the growth and survival of cells in the context of cancer. Mutations can affect either tumor promoter proteins or tumor suppressor proteins. With tumor promoters the action of the mutation, with few exceptions, serves to persistently activate the protein, driving up the rate of cell division. Tumor suppressors have the opposite role, acting as negative regulators of cell growth. He notes: “Because the actions of tumor suppressors are to retard cellular processes that uphold cancer advancement, these driver mutations promoting cancer need merely to inactivate or diminish the activity of tumor suppressor genes.”
In the case of tumor promoter mutations, this often involves the breakage of mechanisms that would keep the protein deactivated at the right times. In one example, he notes that a gene, Kras, is frequently associated with cancer where “KRAS mutations are found in nearly 20% of all cancers with the highest prevalence being found in 95% of pancreatic cancers, 20% of colon cancers, and 15% of lung cancers.” Yet Krueger finds that many common cancer mutations in Kras result in impairment of normal activity at the molecular level:
Functional studies on these mutated codons reveal that binding of GAPs to Kras is impaired allowing Kras to retain its bound GTP and persist in an activated state. In the case of Q61 missense mutations, Kras exhibits diminished GTPase activity upon binding a GAP enabling Kras to remain activated. These mutations are typically referred to as “gain-of-function” by virtue of the fact that these are “activating” mutations. Ras proteins inherently have a slow catalytic rate of GTP hydrolysis and its interaction with GAPs increases this rate of hydrolysis by several orders of magnitude. Mutation of Q61 deters GAP-induced hydrolysis of GTP. Likewise, the mutations at G12 and G13 result in substituting amino acids with sidechains, to sterically impede an effective interaction of Kras with GAPs. Consequently, contrary to the portrayal of a gain in function, persistent activation of Kras is mediated by interfering with GTP hydrolysis stimulated by GAPs.
An Activated State
With Kras as just one example, he finds that cancer often involves the breaking of switches that turns these genes off, leading them to exist in an activated state that eventually leads to cancer:
A common principle apparent for oncogenes is that their native state is conformationally inactive but interactions with other signaling factors activate each protein kinase [oncogene]. The “gain-of-function” mutations listed here simply reflect what was described in parallel fashion for KRAS. Kinase [oncogene] downregulation to an off-state is a critical switch in cellular regulation of these key enzymes, but their constitutive activation has been [positively] selected leading to increased proliferation of the host cells.
As he puts it, “These activating mutations, as for the other oncogenes just described, transform the EGFR from inactive to a persistently active state promoting cell growth.” He concludes:
In cancer, we see mutations and other genomic alterations that cause cells to deviate significantly from their “natural” state to a highly dysregulated entity where many finely-tuned cell regulatory mechanisms have been abolished and neo-Darwinian principles have encouraged the emergence of a new class of cells distant from the roles they play in their tissues of origin. In this scenario it would be legitimate, in every sense of the word, to refer to this outcome of tumor evolution as a monstrosity.
The “Darwin Devolves” Thesis
In a second paper titled “Survey for Activating Oncogenic Mutation Variants in Metazoan Germline Genes,” published in Journal of Molecular Evolution, Krueger further explores how cancer fits within a “Darwin Devolves” thesis. Krueger examines driver mutations in tumor promoter genes, noting that “There are few ways to hyperactivate a tumor promoter where in most cases constitutive activation is observed to occur upsetting tightly-controlled cellular homeostasis.” He looked at the mutational profiles in six widely studied tumor promoter genes, BRAF, KRAS, JAK2, PIK3CA, EGFR, and IDH1/2:
- Regarding BRAF, he found that one common mutation breaks the normal activation pathway, “replacing the requirement for phosphorylation activation” and “accounting for why this mutated oncogene is constitutively activated in cancer.” This mutation is normally selected against when it occurs in the germline, because a “likely lethal outcome places a rigid evolutionary constraint against this mutation.”
- Next, Krueger further investigates KRAS, which he also explored in his previous paper, and similar Ras proteins. He notes that “Mutation of either glycine 12 or 13 to any other amino acid would sterically prohibit GAPs from approaching the GTP binding pocket of Ras in an effective orientation. Mutation of Ras Q61 eliminates a crucial functional group of the GTPase catalytic domain.” These mutations inhibit the normal function, leaving Ras “constitutively activated, since GAPs are not able deactivate the GTP-bound state.”
- Regarding JAK2, he finds that a common cancer-related mutation in this gene “appears to disrupt the JH1–JH2 interaction at their interface thereby negating the inhibitory activity of JH2” which has the effect to “reduce ionic character likely sustaining the JH1–JH2 autoinhibitory interaction,” leading to JAK2 to be “constitutively activated promoting cell proliferation and altering cell differentiation.”
- As for PIK3CA, Krueger finds that a common mutation breaks its normal function, causing a “lock” in the active site “in an open configuration allowing access by substrates.” Other mutations “have the same general affect to change the surface charge from anionic to cationic destabilizing interactions with the regulatory subunit impeding its autoinhibitory effects.” Again, the normal auto-inhibitory regulation of this protein is broken.
- EGFR is a gene often involved in lung cancer. Krueger finds that a common type of mutation leads to “receptor alterations” which “promote receptor dimerization independent of ligand binding to constitutively activate the receptor.” In other words, a regulatory mechanism is broken, leading this gene to be turned on when it shouldn’t be.
- Lastly, Krueger looks at the genes IDH1 and IDH2. Three primary mutations associated with cancer essentially cause these genes to carry out a different reaction “at the expense of oxidizing NADPH back to NADP+.” The normal pathway it participates in is broken, as the change “comes at a significant cost, since the enzymatic activity is reduced over 20-fold from the wild-type enzyme and oxidation of the provisional NADPH cofactor is required to reduce the intermediate α-ketoglutarate substrate to the final hydroxydicarboxylic acid.” This unnatural oncometabolite actually exerts it major oncogenic effects by competing for binding of the normal metabolic product to different proteins that play roles in epigenetic regulation of the genome. In this case normal gene regulation is thwarted by this competing metabolite again leading to de-differentiation and enhanced cellular growth. The one difference with IDH mutations is they are genuine gain-of-function mutations, however, the new metabolite formed upsets normal cell regulatory schemes. So the ultimate effect is breakage.
Krueger summarizes his results, finding that in the first five of the genes he studied, mutations “all result in constitutive activation of their cognate signaling protein, thereby resulting in unceasing promotion of cancer hallmarks in the incipient cells such as sustaining cell proliferation, dedifferentiation, inhibiting growth suppression, enabling replicative immortality, etc.” Crucially, however, he finds that these involve loss of function at the molecular level:
detailed molecular modeling studies have revealed that these mutations technically result in loss of functions inherent in each protein, namely inhibitory mechanisms to deactivate each enzyme have been thwarted.
A key finding of his paper is that these cancer-related mutations, therefore, are normally deleterious to the organism and are typically selected out of the germline:
In conclusion, survival of metazoans requires cooperation of many cell types. Alterations that disrupt this finely controlled biological balance threaten the life of the host and expectedly should undergo negative selection in species germlines. It is these contrasting scenarios that demarcate foundational differences how mutations are selected when comparing tumor evolution with that of genetic changes in species.
Krueger’s two papers are highly consistent with Michael Behe’s “Darwin Devolves” thesis: mutations tend to break features at the molecular level. In cancer, this often involves breaking mechanisms that are designed to inhibit the activity of key genes, and when those mechanisms are broken, out-of-control cell growth results. Yes, cancer is a Darwinian process – but what reveals is that at the molecular level, the Darwinian mechanism typically works by breaking features, not by creating new ones.