Wednesday, 20 July 2016

What is death?

What is Life? The physical aspect of the living cell was published by Cambridge University Press in 1944. It is a short book in seven chapters based on a series of lectures given by physicist Erwin Schrödinger at Trinity College Dublin in 1943 while he was working at the Dublin Institute for Advanced Studies. That was ten years before Crick and Watson worked out the structure and function of DNA and started the field of molecular biology.  It was written for intelligent adults not scientists but had an disproportionate impact on the thinking of the key early players, including both Crick and Watson independently, in the process of finding out what genes are and how they tick.  That's 72 years ago and we now know a helluva lot more about these matters.

One of the many residual problems stems from over-specialisation and a failure to integrate information discovered at different levels of detail. Ecologists work in the Serengeti and write up in Departments of Ecology and know the difference between a hartebeest Alcelaphus buselaphus and a wildebeest Connochaetes gnou from the dung they leave behind. Geneticists by contrast only go to the Serengeti on honeymoon and spend their lives in the lab wrestling with DNA. They never go to seminars in the Ecology Department because they are too busy flipping open eppendorfs and running the contents through gel rigs. Physiologists and immunologists fill in some of the gap but they are no better at recognising birds or bees than their teenage children, and really don't integrate evolution in their daily practice.

Thus on one level we know how we die [bloboprev]: small black children die from malaria and infectious diarrhoea, gay white males no longer die of AIDS, straight white males and their wives die of atherosclerosis, hypertension, adult-onset diabetes, obesity, dementia, cancer, and decreased resistance to infection but until recently nobody bothered to look at what happened to genes after death.  Why bother? There's nothing we can do now, no further interventions are possible. Wrong! It turns out the behaviour of genes in dying tissues is wild and wonderful and offers us clues to better medical practice on/for the living.

This has all surfaced from a couple of recent papers tracking post-mortem gene activity at various time-points after death in mice Mus musculus and zebra fish Danio rerio. Those species were chosen because they are standard 'genetic' organisms and we know how rather a lot about their physiology, development and genetics. We also have the hubris to believe that we can terminate the lives of such creatures at will in the cause of science. One of the great technological break-throughs of the last 25 years has been the techniques of Next Generation Sequencing NGS [bloborecent] and microarrays which allows us to look at the 'expression' [switch on, switch off, ramp up, slow down] of thousands of genes in one high-throughput experiment. We're not afraid of Big Data any more because the whole schmeer can be loaded into mighty computer and the sense sifted out of it.

Far from being a slow general decay of function as the oxygen runs out, there is a complex pattern of genetic activity. Some genes start up, even days after death. At the least exciting, the reproducible sequence of genes metaphorically turning red and green can be used to accurately calculate the time of death; so forensic scientists will no longer need to turn the corpse over to see how much blood is pooling under the down-facing skin.

Another more intriguing finding is that a number of developmental genes get switched on for the first time since they were used to sculpt the fetus before birth. What's all that about? At the moment, the best [but not very good] explanation for that is mechanistic: some aspect of the biochemical conditions are similar in these two, before & after, states.  That's intriguing and may let the hounds off to find out what are those aspects.  Maybe there's a clue that can be used as a medical intervention to prevent failures of correct in utero development: polydactyly, spina bifida, maybe even microcephaly [whoop whoop Zika alert].

Another observation that has the ring of truth is that a number of 'cancer genes' are switched on after death. That may help explain the peculiar finding that recipients of transplants experience a blip-up in their likelihood of developing cancer. We can imagine doing something about that. All you need to do [this will be 20 person years of work and $3million] is drill down in to the peculiar zombie state of the "dead" people who contribute their organs for transplant - because their liver-and-lights can't be dead if they're going to be useful to the recipient. There are ethical issues attendant on that: would anyone dream of suggesting that doctors' fingers are quicker to the switch on the life-support system if there's a young chap on the ward with no kidneys?

I know all about this because it was the topic for discussion at last night's Science Café at Wexford. The SciCaff is wholly unpredictable; in June we were just three, last night a full coven of thirteen turned out . . . appropriately enough for a zombie night out.  I was particularly delighted because four students from The Institute appeared! I'd heard in class at the end of last academic year that a handful of them had a mighty 60km commute from Wexford each day and I put them on the SciCaffWex mailing list.  This was the first time they'd freed up their calendar sufficiently. We all, young and old, had an interesting discussion about What is Life and how the post-mortem papers illuminated what we knew about this, the fundamental philosophical problem for thinking reeds.

Being the polymaths we are, the other paper up for discussion was an amazing essay by the Czech poet/immunologist, Miroslav Holub, one of the few people in the last century who successfully had a foot in the two cultures. He is not to be confused with Václav Havel Czecho's poet/president, let alone with Michael D. Higgins our own ditto. Holub was known internationally to immunologists for his discovery/development of the nude mouse, which, in addition to having no hair has no thymus! No thymus, no T-cells and a severely compromised immune system.  As a poet, he was a pal of our own Seamus Heaney who invited him to Dublin in 1992.  Just about half a century after Schrödinger, TCD scooped another really interesting central European.  Read the essay, it reflects on the nature of death and the essence of life as the T-cells leak out from a muskrat Ondatra zibethica that has recently become dead in swimming pool.

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