Here’s the first in a series of science essays from NC’s resident scientist (also painter, author, musician, mountain woman), Simon Fraser University gene biologist Lynne Quarmby, who promises to lead us into that fierce nexus of mystery, art, literature, beauty and science. Lynne has already contributed aphorisms, a “What it’s like living here” piece and paintings to the pages of NC. It seems only fitting that she now extend our reach into the laboratory, into the cell and atom. Lynne wrote her own short intro to the series. DG could do no better.

dg

It’s amazing all

this motion going

on and

water can lie still

in glasses and the gas

can in the

garage doesn’t rattle. —AR Ammons Have you ever watched a sunset and reminded yourself that you are standing on a ball that is spinning and that you are flying backwards away from the sun? It totally changes the experience. Try flying into a “sunrise”-– that’s really wild. On the evolutionary timescale, it has been the blink of an eye since Copernicus realized — and Galileo observed — that we have day and night because we live on a spinning world that orbits the Sun. We’re still trying to get used to the idea. Our direct sensory experience of the world evolved with us; in our hearts the world is what our sensory organs tell us it is. Our senses are superbly effective for helping us function in the everyday world—that’s why we’re still here—so it’s understandable that when science reveals something counter-intuitive or paradoxical, we have difficulty integrating the new ideas into our worldview. But if we can recognize and acknowledge that our direct biological senses, as wonderful as they are, give us only a tightly pinched and cloudy view of the world, then we open ourselves to unimagined beauty. From where I view the spinning world—as a cell biologist—I see our experience of the world expanding so much that what it means to be human is changing as profoundly as it did when Copernicus and Galileo bumped Earth out of the centre of the Universe. Our intellectual peripheral vision has picked up on the shift, but as usual, our spirits and souls are lagging behind, as though they fear that there isn’t a place for them. —LQ

Stem Cells and the Fountain of Youth

By Lynne Quarmby





I hope I die before I get old

—Pete Townshend (from “My Generation”)

In some societies the aged are venerated, in none are they envied. The inevitable decay of our bodies and minds is something we prefer not to contemplate. There is nothing appealing about decreased mobility, loss of muscle and bone mass, reduced immune function, decreasing liver, kidney and brain function, decline in ability to respond to stress and an increasing susceptibility to stroke, heart attack, diabetes and neurodegenerative disorders. A dollop of increased wisdom seems meager compensation.

Everyday we are witness to the inevitability of decay; our buildings and roads crumble, landscapes erode and holes appear in our socks. It is something we know more deeply as we grow older: if we manage to dodge the proverbial bus, our bodies will decay until one day we die. The idea of reversing this decay goes entirely against our experiential knowledge of the world. Yet time and again the tools of science reveal that the world is not as it seems. We are learning that ageing is not simply the inevitable decay we’ve assumed it to be.

Our bodies are not static structures. The cells lining our intestine turn over approximately every five days. Similarly, our skin cells last on average two weeks, our blood cells a few months and the cells in our liver turn over approximately once/year. The average age of our muscles is estimated at 15 years. Cells of the heart are longer lived, but they too turn over. There is a large variation in the lifetime of our brain cells: Olfactory neurons are short-lived, but the neurons of our visual and cerebral cortices may be the ones we were born with. The average age of the cells in an adult has been estimated to be something like 10 years.

Old cells die and new ones are born. The dying cells are those that have done specialized service (filtering urine, absorbing glucose, detoxifying drugs, secreting milk, engulfing bacteria, detecting odors, and so on). At the end of their life span cells undergo a process known as apoptosis, or programmed cell death, and housekeeping cells clear the debris away. New cells go through a program of specialization (known as differentiation) and assume the duties of the old cells.

The new cells are born from adult stem cells that reside in special niches in every tissue. Stem cells can divide indefinitely and with each division one of the daughters replaces the stem cell and the other becomes a progenitor for the differentiated cells of the tissue. Embryonic stem cells have the potential to produce any cell in the body – that is how we develop from sacs of cells – but so far as we know, adult stem cells are restricted in the variety of cells they can produce.

About five years ago scientists discovered that adding extra copies of a specific set of genes could convert differentiated adult cells (from your skin, for example) back into pluripotent stem cells – called iPSCs for induced Pluripotent Stem Cells. These cells earned the name “pluri potent” because their daughters can be enticed (by various combinations of hormones) to become any of a wide variety of differentiated cell types. iPSCs were big news medically because they suggested the possibility of grow-your-own replacements for diseased or damaged tissues. The original iPSCs caused cancer (in mice) and while it isn’t clear yet whether we will be able to overcome all of the problems that are hindering the use of iPSCs in tissue regeneration, these cells have already become hugely valuable for research. Ageing is one of the research areas that is benefitting from iPSCs.

Scientists trying to understand ageing have taken two general approaches. The first involves identifying why some people live longer than most – was it Aunt Judy’s daily cigar that got her to 104? Intriguingly, longevity studies with a small nematode worm provided the first demonstration that ageing is more interesting than simply decay by wear and tear. Genetic mutations change the way their products function and this virtually always causes defects, but a mutant worm was discovered that lived much longer than it’s compatriots. Worms with this mutation lived a very long and vigorous life. Subsequent work revealed that the effect of this and similar mutations was to restrict metabolism, a finding that fit well with earlier work showing longevity in response to calorie restriction for a wide range of animals from worms to mice and dogs. Ongoing research suggests the likelihood of a much smaller effect for humans than the worms enjoy. It seems that for us it would take decades of misery to gain an extra year or two of life. Longevity researchers have other hypotheses up their sleeves – we haven’t heard the last from them.

Another approach to the study of ageing is to understand why some people (and animals) age prematurely. These studies have also provided strong support for the idea that some aspects of ageing can be delayed or accelerated, turned on or turned off. An acceleration of some aspects of ageing is apparent in one of the most severe diseases of premature ageing, Progeria. Ashley Hegi was fourteen years old when this video was made.





Ashley died when she was seventeen – most children with Progeria do not survive past thirteen. Ashley lives on in videos and documentaries that compel us to embrace our own lives more fully. But the Progeria children have bequeathed us a gift beyond inspiration. They have given us a window into a deeper understanding of life itself.

We know that a small mutation in a gene known as lamin A can cause Progeria. It is a change that affects the structure of cellular nuclei and the genetic programs they activate. In young Ashley’s cells a program associated with ageing was turned on much too early. The cells of children with Progeria have many of the same molecular markers of ageing that are found in the cells of octogenarians, and this is where things start to get interesting.

Last month it was reported that iPSCs can be made from the skin cells of Progeria patients*. Progeria iPSCs lost the molecular marks of age, in fact, by a large number of measures they became indistinguishable from iPSCs made from a healthy individual – the cells were rejuvenated. The iPSCs were then treated with hormones to coax them into becoming smooth muscle cells. Differentiated cells age, and the Progeria-derived smooth muscle cells aged at an accelerated rate – premature ageing was re-activated coincident with the activation of differentiation. These experiments demonstrate something remarkable: it is possible to switch a program for some aspects of ageing off and then on again in a system that is considerably more experimentally amenable than Aunt Judy.

This study deepens our understanding of how cells work. The idea that ageing might not be inevitable is revolutionary. It necessitates addressing the question of the Fountain of Youth.

Immortality is overpriced and overrated. For $200,000 you can arrange to have your “legally dead” (but still fresh) body frozen in the hopes that we’ll learn how to thaw you, revive you and fix whatever it was that made you legally dead in the first place. The drive for eternal life seems closely coupled to our concept of self. When it was easier to believe in a life after death, a reincarnation, a heaven or a hades, what happened to our bodies was of less import. But as we slowly come to understand that our individual selves, our memories, our personalities, our hearts and souls are manifestations of our physical being, we begin to feel the weight of a finite existence.

Death is not a necessary feature of life. It has been about 4 billion years since a cell was built de novo. All of the cells that are alive today came from preexisting cells – all the way back 4 billion years, with some changes along the way. For single celled organisms, cells beget cells beget cells and no one ever dies unless they are eaten or meet with some misfortune of unfavorable environment. They simply split in two and make more cells. The situation is similar for our germ cells, our eggs and sperm – the successful ones make an embryo that makes new germ cells and so on. In contrast, the rest of our bodies (our soma), including our cherished brains have evolved to do their best to keep the germ line going. Evolutionarily speaking, that’s the sole job of the soma. After that, it doesn’t matter whether we write the great Canadian novel or not; natural selection doesn’t care – but we do.

The knee jerk response of our soma is to desire life and more life, yet art, literature and philosophy are replete with depictions of the downsides of immortality. Jorge Luis Borges, for example, has much to say on eternal life: several short stories, essays and lectures. The stories are wonderful and the meditations insightful, but to pull out one key thread: forever is just too long. “The Immortal” is a complex and fascinating literary tale of a people who live beside the river of immortality. Because of their immortality they have become tolerant of and indifferent to almost everything – everything eventually happens to everyone and it all, good and evil, balances out. Everyone eventually takes on every identity and they come to believe that no one is anyone, inactivity abounds. Death, it turns out, defines us as individuals.

The reason we die is that our bodies evolved to last just long enough to take care of our germ cells (get them through college). Fortunately, philosophers, theologians and writers all agree that we are better off with death than without it. This is a good thing because immortality remains firmly in the realm of science fiction. Because some of our parts do not turn over and therefore cannot readily be renewed, they remain subject to wear and tear decay. In some instances, such as the cartilage that forms the structure of our trachea and our nose, the non-renewing structures make fine targets for cyborg-style replacement parts. Another non-renewing part is substantially more challenging: most of the neurons in our brain do not turnover.

No one really knows how many neurons are in our skulls, but the number is something like 100 billion. The accompanying images are of Purkinje neurons stained green, in situ in a mouse brain; the axon isn’t visible, but the dentritic arbor is the portion of the neuron that integrates signals of different strengths and durations of connections between this one neuron and about 200,000 other neurons. These contacts are the synapses. Cellular neuroscience is a world of wonders, with stunning stories to tell. We know a great deal about how senses work and we are learning how memories are stored, yet understanding the phenomenally complex and dynamic interconnections between neurons which translates into our experience of being alive is not even on the horizon. In contrast, understanding ageing, including the neurodegenerative diseases, may be within our reach.

*

Youth is wasted on the young

—George Bernard Shaw

A Canadian woman can expect to live to 82.7 years of age; I have about 10,767 days to go. Given the fun I am having and the things I want to do, it doesn’t seem like enough time, especially when I contemplate the early signs of senescence. Imagine an extra 20 high quality vital years of climbing mountains, reading books and thinking clearly! The discovery that the premature ageing of cells from children like Ashley Hegi can be reversed and then turned on again is astonishing. Simply knowing that ageing is not an inevitable accompaniment to growing old, nor a necessary long prelude to death changes how we think about ourselves.

As for immortality, there is another variety that is absolutely my cup of tea. I leave you with Jorge Luis Borges:

To conclude, I would say that I believe in immortality, not in the personal but in the cosmic sense. We will keep on being immortal; beyond our physical death our memory will remain, and beyond our memory will remain our actions, our circumstances, our attitudes, all that marvelous part of universal history, although we won’t know, and it is better that we won’t know it. — Lecture on Immortality, 1978

—Lynne Quarmby

*Liu et al. Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature. Feb 23, 2011 [epub ahead of print]