April 13, 2024

Why We Die: Lessons in Genes from a Humble Worm

Extracted from WHY WE DIE: The New Science of Aging and the Quest for Immortality by Venki Ramakrishnan with permission from William Morrow, an imprint of HarperCollins. Copyright © 2024 by Venki Ramakrishnan.


Lessons from a humble worm

We all know families of long-lived individuals. But exactly to what extent do genes influence longevity? A study of 2,700 Danish twins suggested that the heritability of human longevity – a quantitative measure of the extent to which differences in genes are responsible for differences in their ages at death – was only about 25 percent. Furthermore, these genetic factors were thought to be due to the sum of small effects from a large number of genes and therefore difficult to identify at the level of an individual gene. When the Danish study was carried out in 1996, a humble worm was already helping to debunk that idea.

This humble worm was the soil nematode Caenorhabditis elegans, introduced into modern biology by Sydney Brenner, a giant in the field known for his caustic wit. Born and initially educated in South Africa, he spent much of his productive life in Cambridge, England, before establishing laboratories across the world, from California to Singapore, leading some of us to observe that the sun never set on the Brenner Empire . He became famous for the discovery of mRNA. More generally, he worked closely with Francis Crick on the nature of the genetic code and how it was read to produce proteins. Once he and Crick decided they had solved the fundamental problem of using genetic information to make proteins, Brenner turned his attention to investigating how a complex animal develops from a single cell and how the brain and its brain function. nervous system.

Brenner identified C. elegans as an ideal organism to study because it could be cultured easily, had a relatively short generation time, and was transparent, so it was possible to see the cells that made up the worm. He trained numerous scientists at the MRC Molecular Biology Laboratory in Cambridge and spawned an entire worldwide community of researchers studying C. elegans for everything from development to behavior. Among his colleagues was the biologist John Sulston, whom you met in chapter 5. One of Sulston’s most notable projects was to painstakingly trace the lineage of each of the mature worm’s approximately nine hundred cells, back to the single original cell, which led to an unexpected discovery: certain cells are programmed to die at precise stages of development. Scientists began to identify the genes that led these cells to suicide at the right time for the organism’s development.

For an animal with just nine hundred cells, these worms are incredibly complex. They have some of the same organs as larger animals, but in a simpler form: mouth, intestine, muscles, brain, and nervous system. They do not have a circulatory or respiratory system. Although tiny – only about a millimeter long – nematodes can easily be seen squirming under a microscope. Being hermaphrodites, they produce sperm and eggs, but C. elegans It can also reproduce asexually under some conditions. They are normally social, but scientists have discovered mutations that make them antisocial. Worms feed on bacteria and, like bacteria, they are grown in Petri dishes in the laboratory. They can be frozen indefinitely in small vials of liquid nitrogen and simply thawed and revived when needed.

The worms typically live for a few weeks. However, when faced with hunger, they can enter a state of dormancy called dauer (related to the German word for endurance), in which they can survive for up to two months before resurfacing when nutrients are again abundant. In relation to the lifespan of humans, this would be equivalent to three hundred years. Somehow, these worms managed to suspend the normal aging process. However, there is a caveat: only juvenile worms can enter the dauer state. Once animals go through puberty and become adults, they no longer have that option.

David Hirsh became interested in C. elegans while he was a Brenner researcher at Cambridge, he continued working on worms when he joined the faculty at the University of Colorado. There he did a postdoc named Michael Klass, who wanted to focus on aging.

This occurred at a time when aging was simply considered a normal and inevitable process of wear and tear, and mainstream biologists viewed aging research with some disdain. However, things were starting to change, in part because the US government was concerned about the aging population. As Hirsh recalled, the National Institutes of Health had just created the National Institute on Aging, and at least part of his and Klass’s motivation for working in the field was that they knew they had a good chance of receiving federal funding.

Image: William Morrow Group, an imprint of HarperCollins Publishers

Hirsh and Klass showed for the first time that, by many criteria, worms age little or not at all in the dauer state. Next, Klass wanted to see if he could isolate worm mutants that would live longer but not necessarily go into dormancy. This would help him identify genes that affected lifespan. To quickly produce mutants that he could screen for longevity, he treated the nematodes with mutagenic chemicals. He ended up with thousands of plates of worms, which he continued studying after opening his own laboratory in Texas. In 1983, Klass published a paper on some long-lived mutant nematodes, but eventually closed his laboratory and joined Abbott Laboratories near Chicago. Before doing so, however, he sent a frozen batch of his mutant worms to a former Colorado colleague, Tom Johnson, who was at the University of California, Irvine at the time.

By inbreeding some of the mutant worms, Johnson discovered that their average life expectancy varied between ten and thirty-one days, from which he deduced that, at least in worms, life expectancy involved a substantial genetic component. It was not yet clear how many genes affected lifespan, but in 1988 Johnson, working with an enthusiastic graduate student named David Friedman, came to a surprising conclusion that went completely against the conventional wisdom that many genes, each making small contributions , influenced longevity. Instead, a mutation in a single gene, which the two called age-1, was found to confer a longer life expectancy. Johnson went on to show that worms with the 1-year mutation had lower mortality at all ages, while their maximum life expectancy more than doubled that of normal worms. Maximum life expectancy, defined as the life expectancy of the richest 10% of the population, is considered a better measure of the effects of aging because average life expectancy can be affected by all sorts of other factors that don’t necessarily have the same effect. to do with aging. such as environmental risks and disease resistance.

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