Angelika Amon is annoyed about aging. Not because it happens— that’s unavoidable—but because we still can’t describe what aging even is. “I hate this imprecise language of cells in the body getting ‘worn out.’ Everybody says this, but what does it mean?” she asks. “You are ‘worn out’ if you run a marathon. But comparing cells to a human person is just completely unhelpful. It’s just improvised language that means gobbledygook.”
“I have to say,” she adds, “a lot of times I start working on something because I’m annoyed that it makes no sense.”
Other things annoy Amon for the same reason. Cancer. Down syndrome. Her research on these conditions has earned Amon a succession of eminent titles—she is the associate director of the Paul F. Glenn Center for Biology of Aging Research at MIT (which was founded in 2015 with a $2 million grant from the Glenn Foundation for Medical Research), co-director of the Alana Down Syndrome Center, and the Kathleen and Curtis Marble Professor in Cancer Research in the MIT Department of Biology. But, the Vienna-born biologist, who is also a member of the Koch Institute for Integrative Cancer Research at MIT, insists she is just trying to answer “simple questions” about how cells work.
“I call it the ‘grandma principle,’” Amon says. “Something is worth studying if you can explain it in a simple way to your relatives who aren’t scientists—for instance, your grandma— and then she goes ‘Ooh, that’s interesting.’”
Amon’s grandma-friendly questions are all about chromosomes, the tightly wound coils of DNA that reside within the nucleus of every animal and plant cell. All healthy human cells (except sperm and eggs) contain 46 chromosomes; Amon investigates what happens to cells when that number deviates from the norm, a condition called aneuploidy. For example, Down syndrome is caused by an extra copy of the 21st chromosome, and 90% of solid tumors are made of aneuploid cells.
“Having extra chromosomes is pretty bad,” Amon says. “The reason is because when you change the number of copies of an entire chromosome, you change the expression of all the genes that are on that chromosome. That really affects the composition of the cell and causes stress in all its internal processes,” including protein folding and metabolism.
Amon hypothesizes that this cascade of negative effects within cells is responsible for some of the health problems associated with Down syndrome, such as acute lymphoblastic leukemia, which is 20 times more prevalent in children with the disorder. “Everybody looks for the one specific gene on chromosome 21 where having an extra copy causes all these problems in Down syndrome,” Amon says. “But if the generic stresses caused by aneuploidy also contribute to some of the traits observed in Down syndrome, we can begin to think about targeting these general effects to improve some of the difficulties that individuals with Down syndrome experience.”
Amon finds the connection between aneuploidy and tumor cells, which divide uncontrollably, similarly intriguing. “We have a paradox here,” Amon says. “Aneuploidy makes cells really sick, so why on earth would it also be a key characteristic of a disease—cancer—that’s defined by unrestricted cell proliferation?” Amon suspects that aneuploidy must confer some genetic advantage on tumor cells that outweighs the negative effects of having an entire extra chromosome. “The condition must bring something to the cancer, otherwise it wouldn’t persist,” she explains.
For example, while aneuploidy causes a tumor cell’s genome to become unstable—“Bad!” as Amon says tersely—this instability also lets the cell “roll the dice more often” to generate potentially useful genetic alterations, such as the ability to metastasize to other tissues or resist chemotherapy. Amon and her collaborators are investigating whether aneuploid tumor cells have the same weaknesses seen in noncancerous aneuploid cells; if so, she says, the next step would be to develop a drug targeting this “vulnerability of the aneuploid state.”
“If we had a drug that miraculously only killed aneuploidy cells, it would be incredible,” Amon says. Such a drug wouldn’t be appropriate for people with Down syndrome or other chromosomal disorders, because every cell in their bodies is aneuploid. But for people without these disorders, “it would work on basically all solid tumors, but at the same time it wouldn’t touch normal cells,” she explains, noting that such a drug remains in the distant future. “We don’t have it yet, but we’re working on it.”
Amon is also searching for a straightforward mechanism to explain cellular aging, or “cellular senescence”— a phenomenon that scientists believe contributes to the overall aging of organisms. Biologists have known since 1961 that normal human cells will only divide 40 to 60 times before ceasing to replicate—a constraint known as the Hayflick limit. Amon’s latest research (published in Cell in February 2019) shows that this limit may be defined by a cell’s physical size. “When Leonard Hayflick first described this senescence phenomenon, he pointed out that these senescent cells were actually huge,” Amon says. She showed that when cells below the Hayflick limit are induced to grow larger than they should be, “they have all the characteristics of senescent cells.”
But why do cells get so large, and why should that increased size cause a cell to senesce and ultimately stop dividing? The explanation, Amon says, lies in how cells repair damage to the DNA coiled in their chromosomes. Natural DNA damage occurs constantly, and cells must periodically pause their natural dividing process (called the cell cycle) to fix it. However, other processes inside the cell—such as building proteins and other biomolecules—don’t pause during DNA repair. As a result, every time the cell cycle stops, the cell gets a little larger. If a cell becomes too large, its own genes can’t direct the production of enough protein to sustain the cell’s function—and cellular functions decline and the cell becomes senescent.
One clue supporting this connection between size and senescence, Amon explains, is that doubling the number of genes inside the cell—which doubles the amount of proteins it builds to sustain itself—reverses the aging process. “The cell resurrects when we induce genome doubling in extremely large cells,” Amon says. Furthermore, when Amon uses a drug called rapamycin to inhibit cells’ ability to manufacture proteins (and get larger) while pausing to repair DNA damage, “the cells stay small and stay young—they don’t lose their replicative potential,” she says. “We’ve known for a very long time that DNA damage causes senescence, but nobody could explain it. I think we’ve come up with a proposal for why this is happening—cells get larger during the time they arrest in the cell cycle to repair the damage, and when they are large they lose their functionality—this appears to be universally true from yeast to humans.”
Amon insists that her work on aging and aneuploidy—which earned her a 2019 Breakthrough Prize in Life Science—is less about discovering clinical applications, and more about answering the “grandma questions” that initially excite her curiosity (and occasionally annoy her). “I’m a concept person,” she says. “I’m very interested in how it all works together in the big picture. By studying very fundamental questions in biology, you actually end up learning important things about human health. But at heart, I am just a very basic scientist who studies cells.”
One significant example of NON-senescence is in the Monarch Butterfly. The “typical” Monarch lives 5 to 7 weeks. But the “overwintering” generation that must fly south to Mexico lives there for 4 months before returning north to lay eggs and die.
For 8 months, the life cycle is 5 to 7 weeks.
For 4 months, for the same species, the life cycle is 4 months.
WHAT is happening to make a 4 month life possible?
Perhaps this phenomenon could shed additional light on current research efforts!