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Sunday, 23 July 2017

Nothing in Medicine Makes Sense Except in the Light of Evolution

The title of this post is a direct allusion to Theodosius Dobzhansky's famous 1973 article Nothing in Biology Makes Sense Except in the Light of Evolution [1] in which he outlined facts from areas such as ecology and molecular biology, and stated that "all these remarkable findings make sense in the light of evolution: they are nonsense otherwise." In a similar manner, aspects of human anatomy, developmental biology, physiology, and genetics which look bizarre, poorly designed, and otherwise defy rational description (not to mention difficult to memorise and store for quick recall) become perfectly understandable when understood in the light of an evolutionary origin for the human species. Examples include extra nipples along the milk line [2], the inverted retina [3], the multiple  pseudogenes, retrotransposons, and endogenous retroviral elements we share with primates [4], not to mention the presence of non-coding intronic DNA, which leads to mutations at intron-exon borders that "often disrupt premRNA splicing in ways that alter gene products and lead to countless genetic disabilities, including various cancers and other metabolic defects." [5]

I am not the first to allude to Dobzhansky in reflecting on the increasing importance evolution has for both understanding the basic clinical sciences on which medicine is based, and for the practice of medicine itself. Ajit Varki, Distinguished Professor of Medicine and Cellular & Molecular Medicine at the University of California,  San Diego wrote in 2012 a paper with the same title as this post where he states that the 'scientific aspects of medicine are rooted in understanding the biology of our species and those of other organisms that interact with us in health and disease. Thus, it is reasonable to paraphrase Dobzhansky, stating that, 'nothing in the biological aspects of medicine makes sense except in the light of evolution'" and proceeds to outline his experience in teaching evolution to medical students. [6] Given that there are more than 4.7 million hits in Google Scholar when searching for evolution and medicine, Varki's desire (and that of many other physician and scientists) to integrate evolutionary biology in the teaching of medicine is eminently sensible.

The utility of evolution to understand the vagaries of human anatomy and genetics would, I would imagine for those readers who have read my previous posts on evolution and medicine, not to mention my frequent posts on the genomic evidence for evolution. This is beyond dispute. At the coalface of medicine, while evolution is not as immediately apparent (I don't routinely worry about Hardy-Weinberg equilibrium in my everyday job), in areas such as infectious disease and medical oncology, ignoring evolution in the day to day aspect of that job is simply not an option. As science writer Cassandra Willyard noted in a 2016 Nature news article:
About six years ago, Alberto Bardelli fell into a scientific slump. A cancer biologist at the University of Turin in Italy, he had been studying targeted therapies — drugs tailored to the mutations that drive the growth of a tumour. The strategy seemed promising, and some patients started to make dazzling recoveries. But then, inevitably, their tumours became resistant to the drugs. Time and time again, Bardelli would see them relapse. “I stumbled into a wall,” he says. The problem wasn't the specific mutations, Bardelli realized: it was evolution itself. “Unfortunately, we are facing one of the most powerful forces on this planet,” he says. [7]
Ignoring evolution when treating cancer (or infectious diseases) is simply not an option. Of course, grasping this at an intuitive level is one thing, but formally establishing this, and then using an evolutionary understanding of cancer to create more effective treatments:
That is beginning to change. Thanks to advances in sequencing technology and the development of massive collections of samples and clinical data, scientists are piecing together a more precise picture of how cancer evolves, revealing the roots of resistance and, in some cases, finding out how it might be overcome. With a growing arsenal of treatments, biologists are trying to capitalize on these insights.

“Cancer is continuously adapting, therefore we have to do so as well,” Bardelli says. In that spirit, last year he shifted the focus of his lab to studying the evolution of cancer. His team has modelled how colorectal cancers respond to targeted therapies that are given in combinations, potentially revealing ways to prevent the tumour cells from becoming resistant. “We have very exciting data now on the possibility to track and treat evolution,” he says. [8]
A succinct description of evolution is descent with modification, with mutations in the common ancestral population resulting in new populations that branch, diverge, and create new species. Cancer likewise can be modelled this way, with an ancestral cancer cell growing, multiplying, and as mutations arise, diverging. By taking samples of cancer cells from a patient with cancer, analysing their genomes, plotting these cells on an evolutionary tree and taking note of particular mutations, it is possible to see which mutations are early, common to all descendant tumour cells, and use those to target cancer therapies that are likely to wipe out more of the cancer than therapies that target mutations common only to cancer cells at the tips of the evolutionary tree.


Of course, things are far more complicated than simply sequencing as many tumour cells as possible to create an individual phylogenetic tree for a patient's cancer, and tailoring a chemotherapeutic regimen that targets mutations common to all the descendant cells, partly because of the lack of appropriate chemotherapeutic for many mutations, and partly because any drug that kills cancer cells can also kill non-cancerous cells, which is why there is growing emphasis on getting the body's immune system to recognise particular elements on tumour cells and destroy them. Willyard notes that researchers:
...found that people with lung cancer who had lots of trunk antigens — and a high proportion of trunk antigens to branch antigens — survived longer than those who had either few trunk antigens or a higher proportion of branch antigens. What's more, people with many trunk antigens seemed to respond better to immune therapies. That makes sense, Swanton says, because if the immune system targets trunk antigens, it's hitting most of the cancer cells, rather than “nipping off little branches”. [9]
It's still early days, but the results are promising, and show that evolutionary biology is increasingly important in understanding cancer dynamics, and creating targeted approaches to fighting it. Research into an evolutionary approach to fighting cancer is hardly standing still, with the April 2017 special edition of BBA -  Reviews on Cancer.  Radiation oncologist Robert A. Gatenby, department chair in Radiology and co-director of the Cancer Biology and Evolution Program at the Moffitt Cancer Center who edited the special edition concluded his introductory paper with these remarks:
This edition includes articles challenging the conventional gene-centric, mutation-centric view of cancer evolution. Wooten and Quaranta point out that Darwinian dynamics select phenotypes (not genotypes) and emphasize the role of epigenetic changes in up or down regulating normal genes as the source of the “heritable phenotypic variations” necessary for Darwinian evolution. Scott and Marusyk point out that the gene-centric models lack a critical component of Darwinian dynamics – environmental selection forces – which can vary over time and space within a tumor. As a more accurate conceptual model than a mutation-centric driver gene paradigm, they invite us to see the selection forces acting on the populations of neoplastic cells as the driving force of somatic clonal evolution. Similarly, Liggett and DeGregori et al. focus on how aging and the accumulation of tissue insults change the selection forces within human tissues leading to the increasing incidence of cancer with age. Gatenby and Brown also focus on levels of selection whereby the tissue and genomic changes allow for the transition from normal somatic cells governed by tissue controls to ones with a “self-defined fitness function.”

In total, this edition demonstrates the lively debates as well as the growing intellectual depth and diversity of evolutionary models in cancer biology and therapy. It is particularly impressive and heartening to observe the highly multidisciplinary paradigm in this avenue of research as investigators combine evolutionary first principles and sophisticated mathematical methods to both plan and analyze experimental observations. Adoption of this physical sciences research strategy is likely necessary to fully understand the complex often non-linear dynamics that govern the evolutionary arc of malignant disease from carcinogenesis through treatment. [10]
Evolution, far from being "science falsely so-called" is not only a fact of nature, but of critical importance to understanding and practicing medicine. It is definitely why it is impossible for me to take seriously any claims from fundamentalists that evolution is false. The reality of it is written in our body from gross anatomy to genomic sequence, and increasingly important in understanding how and why we fall ill, and how to better create a cure for what ails us.

References

1. Dobzhansky, Theodosius, "Nothing in Biology Makes Sense Except in the Light of Evolution", American Biology Teacher (1973) 35 (3): 125–1
2. Lewis I Held Jr.,  Quirks of Human Anatomy: An Evo-Devo Look at the Human Body  (2009: Cambridge University Press) 101 
3. Novella A "Suboptimal Optics: Vision Problems as Scars of Evolutionary History" Evo Edu Outreach (2008) 1:493–497
4. Finlay G Human Evolution: Genes, Genealogies and Phylogenies (2013: Cambridge University Press)
5. John C. Avise Footprints of nonsentient design inside the human genome Proc Natl Acad Sci (2010) 107 no. Supplement 2 8969-8976
6. Varki A "Nothing in medicine makes sense, except in the light of evolution" J Mol Med. 2012 90:481-94.
7.  Willyard C., "Cancer therapy: an evolved approach" Nature (2016) 532: 166–168
8. ibid.
9. ibid.
10. Gatenby R.A."Cancer Biology and Mr Darwin" Biochimica et Biophysica Acta (BBA) - Reviews on Cancer (2017) 1867:(2)67-68