Vilcek Prize in Biomedical Science
“Exemplary” is a word that befits Angelika Amon’s scientific career. As a young woman, Amon left the comforts of her home and country to pursue her dream in the United States, charting a path to scientific success at a time when few women occupied the upper echelons of science. Today, as a geneticist at Massachusetts Institute of Technology, Amon is considered among the world’s leading experts on cell division, the biological process by which life begets itself. Using innovative approaches, Amon has revealed how mistakes that arise during cell division can result in a condition called aneuploidy. Along the way, her work has offered researchers a new vocabulary with which to address aneuploidy’s effects on cell function and its role in life-threatening ailments like cancer.
Amon’s journey from her native Vienna, Austria, to Cambridge, Massachusetts, is marked by milestones that attest to her ambition. Driven by an early desire to learn, Amon nursed a bottomless curiosity about the natural world. At high school in Vienna, she became smitten with cell biology when a teacher showed the class movies of plant cells parceling out chromosomes during division. Enthralled by the movies, she studied biology at the University of Vienna.
Upon graduation, she resolved to pursue her passion by enrolling for a doctorate. She mustered the courage to approach the English geneticist Kim Nasmyth, who had recently arrived to launch his own lab at Vienna’s renowned Institute of Molecular Pathology. Nasmyth, who is among the world’s foremost authorities on the genetics of cell division, took Amon under his wing. Before long, Amon became adept at using yeast as a model organism to probe the molecular basis of cell division.
Amon’s doctoral studies produced major insights into the logic that drives the cell cycle, the perfectly timed succession of steps through which living cells cycle as they replicate genetic material, split contents, and divide. Her efforts revealed that the timely breakdown of proteins called cyclins helps ensure the cycle’s orderly progression. “This work really showed how one stage of the cell cycle sets up the next,” says Amon. More to the point, the experience gave Amon the sturdy technical foundation that has supported a sterling scientific career.
Doctoral degree in hand, Amon set her cap for the United States, arriving in 1994 at the Whitehead Institute for Biomedical Research in Cambridge to pursue a postdoctoral stint with developmental biologist Ruth Lehmann. Lehmann’s support and mentorship proved invaluable to Amon, whose instincts and work ethic earned the notice of her peers as well as a prestigious Whitehead fellowship for young scientists.
As a Whitehead fellow, Amon struck out on her own, using genetic techniques to unravel the complex web of signals that orchestrate cell division in yeast. In a slew of highly cited articles that fortified her influence in the field, Amon described the roles played by these signals. Notable among the factors that control cell division is the enzyme Cdc14, which induces dividing cells to exit a stage of the cell cycle known as mitosis. In turn, Cdc14 is controlled by an assortment of proteins collectively termed the mitotic exit network.
Singular insights into the spatial dynamics of cell division soon followed. Amon reported that in yeast cells, which divide by budding, exit-from-mitosis is suspended until the freshly formed nucleus, birthed in the mother cell, moves into the bud. “You really want to move the nucleus into the bud before you exit mitosis. Otherwise, cell division is in vain, and you end up with a cell with two nuclei and one with none,” explains Amon. Thus, she established that nuclear position serves a crucial signal in ensuring that cell division results in daughter cells with the correct complement of chromosomes, the carriers of genetic material.
Errors in the separation of chromosomes during cell division can lead to a condition called aneuploidy—a word whose Greek roots evoke multiplication mistakes. Aneuploid cells harbor nonmultiple numbers of cells’ normal chromosomal complement. The condition can lead to debilitating illnesses like Down syndrome, in which cells carry an extra copy of human chromosome 21. Amon is best known for her work on how aneuploidy throws vital cell functions into disarray, and much of this work took shape at MIT’s Koch Institute for Integrative Cancer Research, where she was appointed a faculty member in 1999.
At MIT, where she briskly scaled the ranks to a full professorship, Amon developed a collection of aneuploid yeast strains in which preordained or random chromosomes were induced to become aneuploid. Analysis of these strains confirmed the notion that some of aneuploidy’s effects on cell function are tied to the surfeit or insufficiency of specific genes—products of the numerical anomaly in the chromosomes that harbor those genes. More generally, though, Amon found, aneuploidy subjects cells to wide-ranging stresses, overwhelming cells’ protein recycling machinery, sending cells into a feeding frenzy, and, most notably, hampering normal cell division. Together, these effects constitute what Amon has dubbed aneuploidy-associated stresses. Probing this phenomenon in detail has led Amon to broaden her arena into a major human scourge caused by unchecked cell division: cancer.
When it comes to cancer, aneuploidy presents a paradox. Though the vast majority of human solid tumors are aneuploid, tumor cells divide unimpeded. This apparent dissonance has long fueled animated debates among biologists on aneuploidy’s import to cancer. Amon’s studies of yeast and mammalian cells have lent a measure of clarity; they suggest that despite exerting sweeping stress and hobbling cell division, aneuploidy can confer adaptive advantages on cancer cells, forcing them to evolve mutations to survive such stresses. Identifying such mutations, Amon reasons, might render cancer cells vulnerable to controlled attacks. Following that reflection, Amon’s team reported that certain chemical compounds can preferentially kill aneuploid cells over normal cells in lab dishes as well as in mice implanted with human tumors. Those findings raise the hope that aneuploidy might be a viable therapeutic target in cancer.
More recently, Amon and her colleagues found that aneuploid human cells trigger an innate immune response, activating a type of immune sentinel called natural killer cell, which helps curb runaway cell division. Cancer cells have evolved strategies to circumvent natural killer cells, and reactivating the immune sentinels might help selectively target cancer cells, hinting at another potential therapeutic approach for cancer.
In the coming years, Amon hopes to apply the insights gleaned over a remarkable career to the treatment of human disease, particularly cancer. She attributes the scientific success she has enjoyed to the support she received as a young immigrant scientist in the United States. “What I love about the United States is that what counts is what you accomplish,” she says. “This prize has a lot of power to highlight the accomplishments of immigrants, and I’m extremely grateful for this recognition.”
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