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A Race Against Time
In DepthMore In Depth Articles
A Race Against Time
November 2014—Yeast—the single-celled organism that makes life’s most delicious beers and breads—doesn’t really “grow old” like humans do, but it is helping us unlock the secrets of aging. It may even provide the key to stopping the premature aging of children with the ultrarare disease Hutchinson-Gilford progeria syndrome. What’s curious is that these insights are coming from studies of a yeast mating pheromone.
Yeast: Our Teacher
Susan Michaelis came to the school of medicine in 1988 to study yeast—not exactly what we think of as a close relative of ours. But Michaelis, now a professor of cell biology, knew that answers that come from more complex organisms like humans are themselves more complex. Simple organisms like yeast can provide very clear insights—in this case, into some basic cellular mechanisms common to most cells.
The yeast that Michaelis studies (Saccharomyces cerevisiae) can contain a single or double set of genes. Those with one set come in two types and can merge with each other, or “mate.” To attract a mate, the cells release one of two signaling molecules, called pheromones, into the environment. The production and processing of one pheromone was already understood, but the processing of the other, a-factor, was not, so that’s what Michaelis focused on.
Around the same time, a young woman named Leslie Gordon was at Brown University, beginning the long process of earning an M.D./Ph.D. and becoming a clinical researcher. Like Michaelis, Gordon didn’t have progeria on her radar at all, and neither woman could have predicted how their paths would cross a few years later.
A-factor in Time
Back in the lab, protein by protein and gene by gene, Michaelis and her team began to piece together the path taken through the cell by the immature version of a-factor. By 1991, they knew that one piece of the puzzle involves adding a small fat molecule, a “farnesyl group,” to one end of the immature a-factor protein. The enzyme that makes the addition is appropriately called a farnesyltransferase, and its genetic identity was determined by Michaelis.
Another puzzle piece was that immature a-factor gets trimmed down, but it has to be farnesylated before it can be trimmed. The group still doesn’t know why cells start with a protein that needs to be shortened, but Michaelis has a theory. “Space shuttles don’t need boosters to orbit Earth, but they need that fuel blast to get above the atmosphere,” she says. “I think the extra length of protein guides a-factor to where it needs to be.”
In 1997, they found another part of the jigsaw—the enzyme responsible for the trimming, which they named Sterile 24 (Ste24). As one often does when a new protein has been discovered, Michaelis compared its sequence against known human proteins to look for matches. There was one: an enzyme now known as ZmpSte24. To see how similar the two enzymes were, Michaelis swapped out the Ste24 gene in yeast and replaced it with the human ZmpSte24 gene. A-factor was produced as though nothing had changed.
The Plot Thickens
The next year, Gordon’s 22-month-old son, Sam Berns, was diagnosed with progeria. Since it is such a rare disease, affecting fewer than 250 kids worldwide, not much research had been done on it. All Sam’s parents knew was that children with progeria age rapidly and die of heart disease at an average age of 13. Gordon transformed herself from a new pediatric ophthalmology resident into a progeria researcher and, together with her husband, Scott Berns, and her sister, Audrey Gordon, she founded The Progeria Research Foundation (PRF) in the hopes of finding a remedy for her son and all those affected by the devastating disease.
In the meantime, Michaelis was wondering what ZmpSte24 was doing in human and mammalian cells, since humans don’t make a-factor. To find out, she teamed up with Steve Young, now a professor of medicine at the University of California, Los Angeles, to create mice missing Zmpste24. They found that ZmpSte24 doesn’t clip phermones like a-factor in mice but instead clips immature versions of Lamin A, a protein that shapes a cell’s nucleus by forming lattice support structures below its membrane. As might be expected, the nuclei of mice without ZmpSte24 were warped and wrinkly, but the mice themselves were “wrinkly,” too, with weak muscles, thin skin and frequently broken bones.
“The physical characteristics of the mice were interesting in their own right,” says Michaelis. “But we didn’t yet realize how similar they were to progeria.”
That was in 2002. Only a year later, and just three years since the founding of PRF began to provide a network for kids with progeria, a collaboration of researchers, including Gordon and Francis Collins, now the director of the National Institutes of Health, started connecting the dots. They found that all kids with progeria have wrinkly nuclei and a single mutation in the Lamin A gene.
Michaelis had a hunch that the mutation was leaving Lamin A unprocessed, since immature Lamin A is farnesylated and then trimmed just like the yeast phermone a-factor. Over the next two years, her laboratory followed this hunch with studies that showed that preventing Zmpste24’s trimming of Lamin A caused wrinkly nuclei just like mutations in Lamin A did.
“It was sobering to realize that a phenomenon I had been studying for so long could have such profound consequences for kids with progeria,” says Michaelis. “Simultaneously, it was exciting to think that our work could lead to therapies for those kids.”
There were even hints that her findings could answer broader questions about healthy aging. Other researchers’ studies suggest that everyone’s cells harbor some untrimmed Lamin A, now called progerin. Since the amount of progerin buildup seems to correlate with symptoms of aging, it could very well be a molecular metronome of human life.
Slowing the Metronome
In 2004, Michaelis and her team tested several drugs on human cells bearing the progeria mutation. The drugs had already been extensively tested, since they were originally created years before to prevent the farnesylation of a cancer-associated protein. The drugs successfully normalized the cells’ wrinkly nuclei.
Three years later, Michaelis’ work was brought to humans. Gordon and PRF recruited 28 children from around the world to receive lonafarnib, a farnesyltransferase inhibitor very similar to the one that Michaelis had tested. Though it was a small trial, it strongly suggested that preventing farnesylation is a good strategy, since some symptoms improved.
Sam passed away early this year at the age of 17, but his “can-do” attitude lives on. Now, thanks to the PRF community and its funders, lonafarnib trial has been extended, with up to 80 kids from more than 25 countries, so longer-term lonafarnib use can be explored.
So far, all of the evidence suggests that progerin does mark the passage of time. How it does so is not clear, but Michaelis and her team just might come up with an answer.
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