An interview with Dr Charles Lineweaver published in Science & Vie

“Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors” – authors Paul Davies and Charles Lineweaver.

An interview with Dr Charles Lineweaver about the theory described in the above paper by reporter Marine Corniou from the French magazine, Science&Vie.

Marine Corniou: What gave you the idea of this theory? Is it that cancer is ubiquitous, so it might be a result of a well conserved evolutionary process? Did astrobiology help?
Charles Lineweaver: Yes, astrobiology did help. Both Paul and I were trained as astrophysicists. About 10 years ago we both became interested in astrobiology and the question “Are we alone?” Astrobiologists study the big picture view of the evolution of life on Earth – that is macro-evolution on time scales of billions of years. The origin of multicellularity in terrestrial life is one of the important things we need to know about if we want to make guesstimates about multicellular life forms on other planets. The ideas in our paper had their origin in a cancer workshop that Paul hosted about a year ago. As astrobiologists we had studied the evolution of the cellular differentiation that leads to the different organs in a multicellular body. As new students of cancer, we were taught that cancer cells de-differentiate….it seemed natural to us that to reverse the pathways of differentiation as cancer does, it had to be informed by the genes that evolved to differentiate cells.

Marine Corniou: Could you describe what the first multicellular simple organisms looked like? Do such organisms still exist nowadays?

Charles Lineweaver: It is much easier to deal with the first multicellular animals and our paper focuses on these. The connections we make with the first multicellular organisms (probably the common ancestor of all multicellular eukaryotes, animals, plants and fungi) is more speculative. Our best guesses at the first multicellular eukaryotes would come from looking at the phylogenetic trees of animals, plants and fungi and comparing the most basal life forms from these three trees. The first metazoan multicellular simple organisms are discussed on page 5 of our paper. Deeply rooted, but extant (still existing) metazoans are Trichoplax and Amphimedon.
Marine Corniou: What are the strongest arguments that support your theory?
Charles Lineweaver: The evidence in support of our theory includes:
1) cancer has many abilities that cannot be explained by only a few decades of trial and error evolution inside an aging body. These abilities have to have evolved.

2) To accurately de-differentiate and still remain viable, as cancer cells do, requires a degree of navigation through an adaptive landscape that has to be regulated by genes that have to have already been in place.
3) There are simpler proto-colonial and colonial metazoans with a small number of cell types. These have some similarities with neoplasms.

4) Cancer is a genetic disease of cells of our own body. Therefore, we need to look at the sources of the genetic information in our own cells to understand cancer.

Marine Corniou: Why was this ancient “toolkit” conserved in modern animals if it is not useful anymore? Is it unlocked during embryo development?

Charles Lineweaver: I would say that this more ancient toolkit is very active (unlocked) during the earliest stages of embryo development and then gets locked by regulatory genes that have evolved more recently. For example, as embryos we had tails and gills and webbing between our fingers. There are fairly old genes that regulate the formation of these structures. Those old genes are probably ~ 400 million years old. However, more recently evolved genes are activated in the later stages of embryo development and these new genes shut down the development of tails and gills and webbing and prevent them from being useful in the adult animal. If something goes wrong with these new genes during embryogenesis, then occasionally a child is born with gills or a tail or webbing between toes or fingers. These are morphological atavisms. Our hypothesis is that cancer is a physiological atavism at a cellular level. There is an important difference between morphological atavisms and physiological atavisms. We think that physiological development is more reversible than morphological development – once webbing is destroyed it won’t come back. Cancer is the de-differentiation of cells.

Marine Corniou: And what triggers the “reawakening” of this ancient regulation system?

Charles Lineweaver: There are many and varied proximal triggers for cancer. Oncologists spend their careers tracking down proximal oncogenic factors. The ultimate “trigger” is old age. After reproduction there is not much Darwinian advantage to keeping somatic cells alive and their genes in order – so they age and atrophy – and the more recently evolved genes seem to atrophy first. There seems to be a last-in-first-out principle, which could probably be restated as most-highly-entrenched-most-difficult-to-mutate-with-impunity principle.

Marine Corniou: The past few years have unveiled the amazing genetic complexity of cancerous cells: thousands of mutations, genetic chaos, hundreds of genes that can cause cancer. Your theory claims that cancer is not that complicated. How can it explain what we observe? Why are there so many mutations in a cancer cell if the cancer is driven by a limited toolkit of genes?

Charles Lineweaver: You’re right about the amazing genetic complexity of cancerous cells. It takes a lot of complex genetic machinery to differentiate cells with the same DNA into liver cells, skin cells and brain cells. We are not claiming that cancer is not complicated. We are claiming that the complexity of cancer has a pretty well defined limit. We don’t seem to have reached that limit yet, but our prediction is that we will very soon. Despite the genetic complexity of cancer progression, recognizable patterns of oncogene expression are starting to emerge.

Marine Corniou: And how can cancer escape different treatments? If the number of defense mechanisms is limited, how come cancer is always evolving resistance?

Charles Lineweaver: We don’t think that cancer is always evolving resistance. We know it seems that way but we think that is not really what is going on. Those resistances and protective adaptations probably evolved more than a billion years ago. For example, about a billion years ago or earlier cells had to evolve mechanisms to pump toxins out of themselves. When anticancer chemical therapy is developed that targets special proteins or tries to block the progression of cancer, the cancer cells can, with relative ease, mutate to upregulate the ancient genes that are responsible for pumping poisons of any kind out of the cell. In our metaphor, when the genome is challenged, it pulls old poems out of a trunk, it doesn’t write new ones by trial and error.

Marine Corniou: Cancer is usually described as an accumulation of mutations that lead to an aberrant behavior. Do you think that, on the contrary, this behavior is totally controlled? Is it good news for therapy?

Charles Lineweaver: No, not totally controlled. I would call it highly directed. We don’t think that mutations are completely random. Think of a oil painting canvas that has been painted on over and over again with multiple scenes in the different layers. When turpentine is splashed on it, removing regions of the top painting, you don’t get random scenes, you get glimpses of the underlying scenes that were painted years earlier. Those underlying scenes are what we call the ancient toolkit…and those scenes do not contain the genes to regulate cell proliferation, so cells can proliferate without knowing where they are in the body….thus cancer emerges.

Marine Corniou: Do we know how “big” the basic toolkit could be (in order to block it)?

Charles Lineweaver: The size of the “basic toolkit” is set by the number of genes responsible for the complex adaptations of cancer. This is a smaller number than the entire genome which also contains the more recently evolved genes, specifically
the genes of cooperation that had to regulate cellular proliferation and convert cells to a no-child-policy.

Marine Corniou: Thank you Dr. Lineweaver.

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One Response to “An interview with Dr Charles Lineweaver published in Science & Vie”

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