Comments on a cultural reality between past and future.

This blog describes Metatime in the Posthuman experience, drawn from Sir Isaac Newton's secret work on the future end of times, a tract in which he described Histories of Things to Come. His hidden papers on the occult were auctioned to two private buyers in 1936 at Sotheby's, but were not available for public research until the 1990s.

Saturday, August 2, 2014

Entropy and Immortality: An Interview with Miguel Coelho

Dr. Coelho at the Murray Lab, Harvard University. Image Source.

Today, Histories of Things to Come is very pleased to interview biochemist Dr. Miguel Costa Coelho, a Postdoctoral researcher at Harvard University, who has done ground-breaking research in the field of ageing. He is based at the Lab of Professor Andrew W. Murray and the FAS Center for Systems Biology at Harvard; and he is also affiliated with the Human Frontier Science Program.

Coelho's doctoral research at the Max Planck Institute in Germany traced the way a type of yeast actually gets younger as it ages. He found that when a stressed mother cell divided, it passed on all cellular junk associated with accumulated damage (the process we know as ageing) to one daughter cell, which died shortly thereafter. This left the other daughter cell pristine. Normally, both daughter cells would inherit cellular junk, allowing damage to accumulate in both over time. Coelho likened the outcome in this study to "the eternally young and beautiful Dorian Gray, and his corrupt and damaged portrait in the attic" (public access here; the full article is here).

There we have it, published 17 June 2014: under certain conditions, these yeast cells can grow toward immortality via compartmentalization, segregation and consequent elimination of progressive cellular damage as they divide over time. This finding was widely reported in the international press.

ToB: How are anti-ageing processes already present in nature?

Miguel Coelho: Ageing does not need to be universal. Biological organisms are "open", in the sense that they can harvest energy from the environment and use this energy to repair themselves (going back to the general principle that entropy increases with time, and this is why machines erode and stop working - the wear and tear theory - part of this entropy can be counteracted by repair mechanisms that maintain the system in a steady state). Therefore, certain organisms such as fission yeast, prefer to repair their damage, or maintain it at low levels by splitting it between both cells at birth, while others actively segregate damage asymmetrically, like the budding yeast, or establish a complete separation of germline (immortal) and soma (mortal).

Simple organisms, like single cell yeast or bacteria, which take a long time to replicate themselves in nature and are not directly competing with other organisms for resources, have time to perform this efficient repair. Besides the fission yeast, examples of other organisms with extreme longevity and repair are the bacteria Deinococcus radiodurans, the hydra, the jellyfish Turritopsisnutricula and the naked mole rat.
One complication that arises is when during evolution, the immortal germline separated from the soma - meaning that in most animals, the cells of the reproductive system are immortal, while the functional part exists only to "serve" this reproductive purpose, and can perish once reproduction is achieved. An extreme example of this is the salmon, which dies a few days after reproducing.

ToB: Are mortal creatures partly immortal for purely evolutionary purposes? Or is there more to this than millions of years of genetic reproduction? Anti-entropic biologic processes sound radical!

Miguel Coelho: I think mortal creatures act as a vessel for the “immortal” germline. The final purpose of life is reproduction, and by having enough time to reproduce, an organism perpetuates its genetic information, so it is indeed a successful evolutionary strategy to separate the germline from the soma, since in this way the soma can evolve more elaborate functional adaptations that will allow the organism to harvest energy and reproduce more efficiently. There are examples of experiments where the expression of germline genes in the soma increases the lifespan of the organism (yeast and worm), showing that this process can be slowed down. I am not so sure that anti-entropic life processes are so radical, just think of how organized and complex is the cellular architecture: you have miniature machines copying molecules, inside very organized lipid membranes, and all this depends on energy: the magical ATP molecule that drives most enzymatic reactions in the cell.

* * *

After his PhD, Coelho moved to Harvard, where he has started Postdoctoral work to explore further the cellular and genetic bases of immortality. In fact, he strives now to answer a question posed in my last blog post about his work, namely, why cancer cells do not age: "Is the way cancer works - or the way other non-ageing cells work - the grim key to immortality?" More from that post:
Researcher Paul Davies - author of The Goldilocks Enigma - wrote a 2012 report for The Guardian to ask if cancer is actually a way that a multi-cellular organism can regress to the single-celled organism model, where cells do not seem to age. Thus, he postulates, cancer essentially reverses the normal course of evolution from single cell to multicellular organism, even as the disease reverses the clock on cell death processes. But the question remains: why does cancer do this? What purpose is an evolutionary reversal trying to serve? Davies and an Australian physicist, Charles Lineweaver, maintain that cancer de-evolves a sufferer of the disease at the cellular level. The disease serves to activate increasingly archaic genes in a body as it spreads. Lineweaver claims that cancer is a "default cellular safe mode."
From The Guardian report: "In the frantic search for an elusive "cure", few researchers stand back and ask a very basic question: why does cancer exist? What is its place in the grand story of life? ... Charles Lineweaver, of the Australian National University, and I have proposed a theory of cancer based on its ancient evolutionary roots. We think that as cancer progresses in the body it reverses, in a speeded-up manner, the arrow of evolutionary time. Increasing deregulation prompts cancer cells to revert to ever earlier genetic pathways that recapitulate successively earlier ancestral life styles. We predict that the various hallmarks of cancer progression will systematically correlate with the activation of progressively older ancestral genes. The most advanced and malignant cancers recreate aspects of life on Earth before a billion years ago.
ToB: What do you make of that hypothesis from Lineweaver and Davies? Does cancer de-evolve a cancer sufferer to activate ancient genes? And if so, why? What purpose would that serve?

Miguel Coelho: I think cancer is a consequence of very small probability events that our “soma” was engineered to avoid – all the DNA repair mechanisms and cell division control mechanisms that check and repair these errors, or ultimately kill the cells that accumulate them, have a failure rate. Time in biological organisms is correlated with the total number of DNA replication and cell division events, the more occurrences, the higher the likelihood that one such low probability event will go undetected and cause cancer.

Nonetheless, in most cases, cancer is more prevalent in older individuals, individuals that already had the chance to reproduce. Therefore, it is hard for selection to act against cancer, since it occurs after the peak of reproductive fitness – this is why cancer in non-genetically predisposed children is rare. It would be interesting to test the hypothesis that shifting the reproductive age of an organism would also shift the age at which cancer manifests. I agree with Lineweaver and Davies, in the sense that for instance in teratomas you reach an undifferentiated state that can originate cell types from multiple tissues, but I would think more in the sense of “reverse development” that “reverse evolution”.

Evolution is a continuous process that is built upon the present landscape of genetic diversity, and as such, does not have a “reversible” component. You can move organisms back and forth between different environments, but you will not erase the complete mutational signature of adaptation events every time they cycle, they will most likely accumulate. I think cancer is a consequence of an accumulation of errors that makes one cell type proliferate faster than normal cell types, and it is selected for that giving rise to tumours. It is better understood as a “selfish” cell-cell competition inside our bodies, where the faster growing cell wins – which is generally also the cell that can better mutate around targeted therapies, unfortunately.

ToB: An earlier post on this blog described how Harvard researchers found they could stop ageing, but to do so, they had to turn off the mechanism in the body that prevents cancer. Can you elaborate on the current theory that relates cancer, ageing and evolution?

Miguel Coelho: There are complex players in ageing. I think ageing is an integrated process and that there is not a “single hit” magical cure that can completely reverse or stop ageing. Delaying ageing is possible, but like peeling an onion, once we slowdown one process of ageing, the next one takes over and becomes the new age limiting process. Cancer is a consequence of a small probability event, and the likelihood that a cancer causing mutation will occur increases with the total number of times that a cell divides, which correlates with the age of the organism, if we do not consider other stressors, like smoking or drinking habits. I think evolution has perfected living replicating machines, and that once replication is achieved, there is no real selective advantage of long-living, especially in the context of competing with your own progeny. Some very simple organisms though, like S. pombe, seem to have evolved a different strategy, where there is no distinction between mother and daughter, and therefore, all individuals compete to replicate, since their “age” is reset after each division.

ToB: Other reports comment that ageing in normal cells can be halted through protection of telomeres, the caps on the ends of chromosomes. This is done through supply of the enzyme telomerase. By contrast, with cancer, researchers need to be able to turn telomerase off, because cancer cells use the enzyme to stop ageing, even though they are dividing aggressively and exponentially creating cellular damage. According to a report from the University of Utah, this control of telomerase would force cancer cells to age and die:
"As a cell begins to become cancerous, it divides more often, and its telomeres become very short. If its telomeres get too short, the cell may die. Often times, these cells escape death by making more telomerase enzyme, which prevents the telomeres from getting even shorter.

Many cancers have shortened telomeres, including pancreatic, bone, prostate, bladder, lung, kidney, and head and neck.

Measuring telomerase may be a way to detect cancer. And if scientists can learn how to stop telomerase, they might be able to fight cancer by making cancer cells age and die. In one experiment, researchers blocked telomerase activity in human breast and prostate cancer cells growing in the laboratory, prompting the tumor cells to die. But there are risks. Blocking telomerase could impair fertility, wound healing, and production of blood cells and immune system cells."
Does this mean that understanding how cancer cells manipulate telomerase could paradoxically provide the key to everlasting life for normal cells? If so, how would you prevent telomerase-bathed normal cells from turning cancerous?

Miguel Coelho: Again, it is a matter of integrating the knowledge we have. I think telomerase regulation is one of the keys to maintain a healthy and proliferating cell population, however, lack of telomerase is a cancer protective feature. Cells that are differentiated and more directly in contact with environmental insults, like our skin or lung cells, accumulate mutations more rapidly due to UV radiation or smoke (chemicals). This is probably what is keeping us from developing cancer more frequently, as this cells are more likely to accumulate mutations than other cells (like stem cells). Other mechanisms of DNA protection are also important, such as error-free DNA repair. To prevent telomerase-bathed cells from turning cancerous we would have to find the ideal minimal telomerase activity that would maintain the genome stable, and possibly tumor-supressor mutations that would lower the frequency of cancer under these new conditions. You just gave me an excellent idea for an experimental evolution project!

If we consider other cell types that do not divide so frequently, like neuronal cells, which suffer from Alzheimer’s and Parkinson due to the accumulation of aggregated proteins, then other mechanisms such as protein aggregate degradation might be more important to delay ageing. It depends on the cell type, physiological context, etc. Complex puzzle to solve!

ToB: These processes in normal and cancerous cells seem to be mirror images of each other. Can you comment on that symmetry?

Miguel Coelho: Depends on what you define as normal. Differentiated cells, which lose their potential to divide indefinitely, perform extremely important functions (think neurons and skin). They do not “need” telomerase, either because they do not divide that frequently, like neurons, or because they are constantly renewed. The stem-cells, for instance, which divide and originate differentiated cells, express high levels of telomerase and are stable! So in this sense, it is possible to have “immortal” cells, such as the germline of human males, which function properly and do not originate cancer. It would be interesting to understand in a large context, if cancer is originated primarily in differentiated cells or stem-cells, while the former are more exposed to the environment and accumulate more mutations, the later already have active telomerase. In cancerous cells, there is another event that occurs that shatters the balance: a mutation that creates genetic instability and drives good behaving cells to the other side of the mirror.

ToB: Your Postdoctoral research at Harvard focuses on the role genes play in this picture of cancer cells:
Project: Experimental evolution of genetic instability during a yeast model of cancer. Life depends on the faithful transmission of genetic information. During cancer progression, the selection for successive mutations favors the evolution of genetic instability. However, how genetic instability arises remains an unsolved question. Instead of testing a catalog of mutants, I propose to evolve genetic instability in Saccharomyces cerevisiae (a species of yeast) by placing cells under selective pressure to, as in tumor suppression, inactivate growth suppression and identify genes that mutate early to cause instability. This model will allow us to later understand genetic instability during cancer in humans.
Can you elaborate on how this planned research might relate to anti-ageing research?

Miguel Coelho: That is an excellent question. I think it is related in the sense of understanding how time works together with natural selection to shape certain properties in living organisms. As a young researcher at the Gulbenkian in Portugal, I studied how cilia (similar to sperm flagella) grow, in a time of tens of minutes. Then in the Max-Planck in Germany, I studied how cells age, in the time frame of hours to days. Now, at Harvard, in the US, I am interested in more long-lasting changes and I study experimental evolution of genetic instability, in a time course of weeks to months, in an attempt to capture and study how genomes and environment shape each other. This new research project might identify genes that cause genetic instability, which might be similar to cancer causing genes in mammals. Again, ageing and cancer go hand-in-hand and one of the reasons why cancer is more prevalent nowadays is due to the extended lifespan in humans, so maybe cancer is one of the barriers we have to overcome if we want to increase our healthy lifespan.

ToB: What brought you to this research?

Miguel Coelho: I was curious about ageing and the inevitability of death since I was a child, both due to my religious and scientific education. But I would say it was a chance event, from all the possible Ph.D. projects that were offered to me, that I ended up trying to solve this simple question: If a cell divides symmetrically, which half is going to be the old cell, and which half is the young cell? Turns out both are young, at least for the case of fission yeast, since the damage is split equally during favorable growth conditions. When I introduced "stress" in the system, I could see that this behaviour changes, one cell inheriting most of the damage and ageing, while the other was born rejuvenated.

It was also important for me to perform this study in a research group where the main interest was focused on biophysics of the cell, and how the internal components of the cell move to arrange its internal architecture. Fantastic collaborators from Physics, Mathematics, Computational Biology and Biochemistry resulted in a productive and colourful work, where we could integrate knowledge and techniques from different fields to understand the phenomena.

ToB: Can you give some examples of how researchers from other fields are approaching the same questions you are asking from different angles?

Miguel Coelho: There is a common thing in all good ageing studies: a gain-of-function phenotype. For me the good research is the one that takes ageing as an integrated physiological process, and is able to prolong lifespan with minimal and very acute perturbations that are mechanistically and biochemically well understood. This contributes not only to test how plastic and amenable to manipulation these mechanisms are, but to better define ageing. We still lack a good, conserved and generally applied definition of ageing, as the phenotype and properties vary from organism to organism. What I do not believe to be so useful are studies of the type “we break a system, we see the organism ages faster or dies, therefore this component that we manipulated must be important for ageing”. A classical case is the Werner-Syndrome, where, to my knowledge, the mutation causes accelerated ageing due to DNA replication and repair defects, but no one has showed that activation actually increases the lifespan. There is lots of confusing literature in the field and I think we are lacking a good definition and an integrated view of ageing, maybe through fostering of collaborations between labs from different fields or using different model organisms, such as the Dan Gottschling lab or the Thomas Nystrom, Brian Kennedy or Andrew Dillin labs.

ToB: People reading will certainly be interested in your work, but they like to understand why anti-ageing research is being pursued, and what it means for them, or what it implies about the changing world around them. How would you contextualize your research with reference to other medical advances?

Miguel Coelho: Anti-ageing research is not the 'Dorian Gray' quest for immortality, but it is the 'Dorian Gray' expansion of youth. By delaying the early symptoms of ageing, and the life quality of an individual can permit him to increase his productivity in society and also its happiness and independence until later in life. Ideally, we should die young at the age of 90. At least, for me, it is about living healthier for as long as possible, as opposed to living 300 years without being able to move or recognizing our loved ones.

I think one of the central problems of ageing research is defining what is ageing in the first place, and later, distinguishing what correlates with ageing, from what is causative of ageing. The causative agents can be targeted for prevention or delay. I believe that one of the most important and conserved players in ageing, extremely important also in Alzheimer's or Parkinson's disease, are protein aggregates. It was shown that lowering the levels of these aggregates increases lifespan, in many different species. Other spectacular advances in the ageing field have showed us that by eliminating senescent cells, which were thought until now as a by-product of ageing, we can actually increase healthy lifespan in mice. Also, in the zebrafish, re-activating the expression of telomerase, an enzyme that promotes genetic stability and cell division, increases the lifespan. Also, the impact of muscle or adipose tissue, previously thought of as effector tissues, in general health and lifespan retardation is immense, and these can be easily manipulated through a balanced diet and physical exercise. Simple steps.

So the next important steps: First define ageing - my favorite is the mathematical definition of a decrease of organismal fitness with time that correlates with an increase in death probability - in biochemical terms, and second, understand that ageing is an integrative process, and that a broad approach to several targets in consort is necessary to prevent the "domino effect" visible later in life, where several systems fail in a short time period and lead to a poor quality of life in our last years.

ToB: You had a Roman Catholic upbringing in Portugal. I wondered if your religious background had any impact, or no impact, on your research. Even in today's most secular circles, religion provides a spiritual and cultural background to the way we think about some of life's more profound questions. What do you make of the fact that whole moral and ethical systems of belief revolve around precisely the knowledge you are seeking?

Miguel Coelho: My religious education taught me to be introspective and thoughtful, and to be sensible to the problems of others. Still today I constantly ask myself if the scientific and philosophical questions that I pursue in my everyday life are the most important ones, for me, and for our society. I try to advise younger students, by listening to them and learning from that experience as well. My friends often joke around with my willingness to “lecture” them or to offer advice, by calling me a priest. I cannot stress the importance of learning through the problems and problem solving techniques of others, as this is how we scientists communicate: a paper is nothing more than a story comprised of a problem, a specific question, a key experiment or model, and meaningful controlled experiments that sthrengthen our confidence to have found a solution. Often more questions arise, than the answers given, and the process iterates itself.

ToB: To be more precise, religions often guard the secret of death. You focus on biological mechanisms which enforce immortal lines of continuity. But a large part of that continuity involves the failure of the organism! Are entropy, imperfection and death essential for the continuation of life? Do you sense from your research that we cannot live without these fatal elements, and to thwart them is forbidden? In many cultures, knowledge of immortality is taboo.

Miguel Coelho: Any immortal life without evolution that might occur mainly through reproduction, would render a species very susceptible to extinction. That might be the very reason why the more complex living organisms show ageing. The dynamic equilibria that occurs and causes imperfections is essential for continuous adaptation. I sense that research like mine can in principle increase the healthy lifespan of individuals for a better quality of life, but that escaping death is an utopia, as the small probability event of getting killed by predation or an accident will happen sooner or later.

ToB: Is this a simply a case of expanding awareness because science is reaching the boundaries of known existence? Are we ready to redefine those boundaries?

Miguel Coelho: We live in a beautiful time of the history of mankind, where people that live from discovering exoplanets using fancy telescopes, or hunting for birds using slingshots, co-exist. We have to consider all manners of existing and integrate the knowledge from all possibly sources. Being a skeptic is the first line of defense for a scientist, and an important one to make sure our data and conclusions add up, but sometimes we have to let ourselves be surprised by our findings. I spent a lot of time looking at cells dividing, trying to find ageing, where there was none. This was a big shock, but at the same time taught me that when you idealize something, and you think you have all the facts right, nature pulls your leg, most of the times. As scientists and humans, we have to wonder and questions our beliefs with a regular frequency.

ToB: In another post, I covered some generational fads around anti-ageing research. I asked: if scientists eliminate the biological mechanism of ageing, will nature generate something deadly to reassert the balance?

Miguel Coelho: Back to the onion idea, if you peel out the most common sources of ageing (telomerase, protein aggregates, accumulation of toxic intermediates of metabolism like ROS), I think others will arise. This is an important exercise, and I am sure that cancer still represents the most challenging one due to its complexity and adaptability to therapies. Even if we would eliminate all of the mechanisms of ageing, we would still be in an ecological environment, where provided we could escape predation and disease, natural accidents or changes in geology and atmosphere of the planet would most likely terminate our existence.

If we could shelter our immortal cellular legacy from all external damages, all things that lead to death, would that be a life worth living, when all the stars in the universe would fade and we would drift away in the nothingness? I prefer the idea of understanding ageing to control its adverse effects to allow us to share time with our grand our great-grandparents, increase their quality of life and the active role of the elder in society. Stories, experience and advice should be protected and cherished. For me, ageing research is about a healthy-lifespan, not the quest for immortality.

I would like to thank Miguel very much for speaking to Histories of Things to Come. His main Website is here. You can follow his work at Harvard at the Murray Lab.

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