style="font-size:15px;"> The work Mortimer and Johnston did—and, in particular, a seminal paper in 1959 that demonstrated that mother and daughter yeast cells can have vastly different lifespans—would set the stage for a world-shattering change in the way we view the limits of life. And by the time of Mortimer’s death in 2007, there were some 10,000 researchers studying yeast around the globe.
Yes, humans are separated from yeast by a billion years of evolution, but we still have a lot in common. S. cerevisiae shares some 70 percent of our genes. And what it does with those genes isn’t so different from what we do with them. Like a whole lot of humans, yeast cells are almost always trying to do one of two things: either they’re trying to eat, or they’re trying to reproduce. They’re hungry or they’re horny. As they age, much like humans, they slow down and grow larger, rounder, and less fertile. But whereas humans go through this process over the course of many decades, yeast cells experience it in a week. That makes them a pretty good place to start in the quest to understand aging.
Indeed, the potential for a humble yeast to tell us so much about ourselves—and do so quite quickly relative to other research organisms—was a big part of the reason I decided to begin my career by studying S. cerevisiae. They also smell like fresh bread.
I met Mortimer in Vienna in 1992, when I was in my early 20s and attending the International Yeast Conference—yes, there is such a thing—with my two PhD supervisors, Professor Ian Dawes, a rule-avoiding Australian from the University of New South Wales,6 and Professor Richard Dickinson, a rule-abiding Briton from the University of Cardiff, Wales.
Mortimer was in Vienna to discuss a momentous scientific endeavor: the sequencing of the yeast genome. I was there to be inspired. And I was.7 If I’d harbored any doubts about my decision to dedicate the opening years of my scientific career to a single-celled fungus, they all went away when I came face to face with people who were building great knowledge in a field that had hardly existed a few decades before.
It was shortly after that conference that one of the world’s top scientists in the yeast field, Leonard Guarente of the Massachusetts Institute of Technology, came to Sydney on holiday to visit Ian Dawes. Guarente and I ended up at a dinner together, and I made sure I was sitting opposite him.
I was then a graduate student using yeast to understand an inherited condition called maple syrup urine disease. As you might imagine from its name, the disease is not something most polite people discuss over dinner. Guarente, though, engaged me in a scientific discussion with a curiosity and enthusiasm that was nothing short of enchanting. The conversation soon turned to his latest project—he had begun studying aging in yeast the past few months—work that had its roots in the workable genetic map that Mortimer had completed in the mid-1970s.
That was it. I had a passion for understanding aging, and I knew something about wrangling a yeast cell with a microscope and micromanipulator. Those were essential skills needed to figure out why yeast age. That night, Guarente and I agreed on one thing: if we couldn’t solve the problem of aging in yeast, we had no chance in humans.
I didn’t just want to work with him. I had to work with him.
Dawes wrote him to tell him that I was keen to join his lab and I was “skilled at the bench.”
“It would be a pleasure to work with David,” he replied a few weeks later, the same way he probably did to so many other enthusiastic applicants. “But he’s got to come with his own funding.” Later I learned he had been excited only because he’d thought I was the other student he’d met at dinner.
I had a foot in the door, but my chances were slim. At the time, foreigners weren’t considered for prestigious postdoctoral awards in the United States, but I insisted I be interviewed and paid for a flight to Boston myself. I was interviewed by a giant in the stem cell field, Douglas Melton, for a Helen Hay Whitney Foundation Fellowship, which has been providing research support to postdoctoral biomedical students since 1947. After waiting in line outside his office with the other four candidates, I had my chance. This was my moment. I don’t remember being nervous. I figured I probably wouldn’t get the award anyway. So I went for it.
I told Melton about my lifelong quest to understand aging and find “life-giving genes,” then sketched out on his whiteboard how the genes work and what I’d be doing for the next three years if I got the money. To show my gratitude, I gave him a bottle of red wine that I’d brought from Australia.
Afterward, two things became clear. One, don’t bring wine to an interview because it can be seen as a bribe. And two, Melton must have liked what I said and how I said it, because I flew home, got the fellowship, and then got onto a plane back to Boston. It was, without a doubt, the most life-changing meeting of my life.8
At the time of my arrival, in 1995, I had expected to build our understanding of aging by studying Werner syndrome, a terrible disease that occurs in less than 1 in 100,000 live births, with symptoms that include a loss of body strength, wrinkles, gray hair, hair loss, cataracts, osteoporosis, heart problems, and many other telltale signs of aging—not among folks in their 70s and 80s but rather among people in their 30s and 40s. Life expectancy for someone with Werner is 46 years.
Within two weeks of my arrival in the United States, though, a research team at the University of Washington, headed by the wise and supportive grandfather of aging research, George Martin, announced that they had found the gene that, when mutated, causes Werner syndrome.9 It was deflating at the time to have been “scooped,” but the discovery allowed me to take a bigger first step toward my ultimate objective. Indeed, it became the key to formulating the Information Theory of Aging.
Now that the Werner gene, known as WRN, had been identified in humans, the next step was to test if the similar gene in yeast had the same function. If so, we could use yeast to more rapidly determine the cause of Werner syndrome and perhaps help us better understand aging in general. I marched into Guarente’s office to tell him I was now studying Werner’s syndrome in yeast and that’s how we would solve aging.
In yeast, the equivalent of the WRN gene is Slow Growth Suppressor 1, or SGS1. The gene was already suspected to code for a type of enzyme called a DNA helicase that untangles tangled strands of DNA before they break. Helicases are especially important in repetitive DNA sequences that are inherently prone to tangling and breaking. Functionality of proteins, such as the ones coded for by the Werner gene, is therefore vital, since more than half of our genome is, in fact, repetitive.
Through a gene-swapping process in which cells are tricked into picking up extra pieces of DNA, we swapped out the functional SGS1 gene with a mutant version. In effect, we were testing to see if it was possible to give the yeast Werner syndrome.
After the swap, the yeast cells’ lifespan was cut in half. Ordinarily, this would not have been news. Many events unrelated to aging—such as being eaten by a mite, drying out on a grape, or being placed in an oven—can and do shorten the lifespan of yeast cells. And here we’d messed with their DNA, which could have short-circuited the cells in a thousand different ways to cause early death.
But those cells weren’t just dying. They were dying after a precipitous decline in health and function. As the SGS1 mutants became older, they slowed down in their cell cycle. They grew larger. Both male and female “mating-type” genes (descendants of gene A) were switched on at the same time, so they were sterile and couldn’t mate. These were all known hallmarks of aging in yeast. And it was happening more quickly in the mutants we’d made. It certainly looked like a yeast version of Werner’s.
Using specialized stains, we colored the DNA blue and used red for the nucleolus, which sits inside the nucleus of all eukaryotic
