Profile of Angelika Amon, winner of the 2019 Vilcek Prize in Biomedical Science

In 2006, the New York City-based Vilcek Foundation launched a prize program to honor US-based biomedical scientists who immigrated to the United States and made extraordinary contributions to their fields (1). Established in 2000 by Jan and Marica Vilcek, the Vilcek Foundation has been supported by Jan Vilcek’s donation of royalties received from the New York University School of Medicine for his contribution to the development of the antiinflammatory drug infliximab. The Vilcek Foundation’s prize program was born out of the Vilceks’ desire to recognize the contributions of immigrants to science and arts in the United States. It is also a celebration and emblem of immigration’s role in securing the primacy of the United States in science and arts on the world stage. There is no other major prize that specifically recognizes immigrant contributions to science in the United States.

Angelika Amon. Image courtesy of Samara Vise (Koch Institute for Integrative Cancer Research, Cambridge, MA.

Since the establishment of the prize program in 2006, 15 scientists have received the Vilcek Prize in Biomedical Science. The Vilcek Foundation also recognizes outstanding young foreign-born scientists through the establishment of Prizes for Creative Promise in Biomedical Science; these prizes are open to candidates who are not more than 38 y old at the time of consideration. To date, 22 scientists have received Prizes for Creative Promise in Biomedical Science (in parallel, the Vilcek Foundation also awards an equal number of prizes in the arts to outstanding foreign-born artists active in the United States) (2).

The recipient of the 2019 Vilcek Prize in Biomedical Science is Angelika Amon, an Austrian-born molecular and cell biologist at the Massachusetts Institute of Technology.

Solving the Puzzle of Cell Division: Angelika Amon

Angelika Amon’s passion for biology began early, when a picture of dividing plant cells viewed through a microscope sparked an enduring fascination with life’s grand mysteries. Over the course of a career spanning nearly three decades, Amon, a professor of cancer research at Massachusetts Institute of Technology and winner of the 2019 Vilcek Prize in Biomedical Science, has brought to light principal players in the balletic process by which cells bequeath genetic material to offspring. Along the way, her work has revealed how missteps in the process result in outcomes such as cancer. For her crystalline insights into life’s elemental problems, the scientific community has heaped plaudits on Amon, including memberships in the National Academy of Sciences, the American Academy of Arts and Sciences, and the European Molecular Biology Organization; a Breakthrough Prize in life sciences; a National Academy of Sciences molecular biology award; and a Howard Hughes Medical Institute Investigator award.

Moving Picture

Amon was born and raised in Vienna, Austria. Her passion for cell biology was sparked in middle school, when a teacher showed the class time-lapse images of dividing plant cells. As she thrilled to the sight of the cells sharing chromosomes in a ritualized sequence, the riveting images seized her imagination and were seared into her memory. “They were amazing black-and-white movies from the sixties, long before fluorescence microscopy and the fancy techniques we use today. Plant cells have these large chromosomes, and I just loved seeing the cells divide,” she recalls.

Amon channeled her youthful fascination into undergraduate studies in biology at the University of Vienna. In 1989, she enrolled in a doctoral program at the Institute of Molecular Pathology, joining the laboratory of a new arrival at the institute, the Englishman Kim Nasmyth, who had earned an international reputation as a first-rate geneticist. Nasmyth was quick to spot his protege’s promise and armed her with practical skills in the genetics of yeast, a model organism favored by cell biologists.

Amon’s research in Nasmyth’s laboratory was no mere finger-exercise for the full-scale work on yeast genetics she later undertook. Besides sharpening her instincts, her doctoral studies led to major discoveries on the cell cycle. A byzantine process by which cells duplicate their contents and divide, the cell cycle progresses in well-defined stages: G1 (gap1), S (synthesis), G2 (gap2), and M (mitosis); the gaps allow cells time to grow and duplicate organelles before division.

The cell cycle is controlled by a staggering web of interlinked signals. Among these signals are the aptly named cyclins, proteins that accumulate within cells as they enter mitosis. Amon’s work revealed that cyclins must be broken down before cells make the passage from mitosis to G1. Cyclin breakdown, she found, continues throughout G1 and ceases as cells enter the next stage, the S phase, when DNA is duplicated. “What this work really established is the logic of the cell cycle, how one stage sets up the next,” she explains. Published in Cell, the findings marked an overture to a career rich in elegant reports on the elaborately orchestrated symphony of cell division (3).

Ascent to Success

Armed with a doctoral degree, Amon next braved a foray into fruit fly research during a brief postdoctoral stint with developmental biologist Ruth Lehmann at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts. In 1994, as she left the comforts of her native Austria for the chance to perform research in the United States, the move marked a departure in more than one sense. Amon had become adept at working with yeast, a model organism then deemed far easier to manipulate for molecular genetic studies than fruit flies, which proved a daunting prospect before the advent of such handy tools as CRISPR. “Ruth was an amazing role model and mentor, and I learned so much from her. But I soon found out that I didn’t like working with flies. Back then, once you had worked with yeast, you were spoiled; the only rate-limiting step in working with yeast was your brain,” she says.

When the opportunity to launch her own laboratory arose, thanks to a prestigious Whitehead fellowship for young scientists she received in 1996, Amon embraced it. As an independent fellow at the Whitehead Institute, she dove into the question of how yeast cells progress through the cell cycle and partition their chromosomes. Over time, those efforts ossified her standing among the world’s leading geneticists and landed her a faculty job at the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, where she has since stayed. From her perch at the institute, Amon has vastly expanded researchers’ understanding of aspects of cell division intricately tied to human disease.

Chief among those findings is the role of an enzyme called Cdc14 in inducing cells to exit from mitosis. The final stage in the cell cycle, exit from mitosis marks a period in the life of dividing cells when the cellular apparatus that partitions chromosomes between daughter cells is dismantled, the envelopes surrounding the daughter nuclei are rebuilt, and the contents of the daughter cells are pulled apart and packaged. Previously, Amon had demonstrated that cyclins must be degraded before cells can exit from mitosis. Building on that work, Amon found that cyclin breakdown is promoted by a pair of proteins, Cdc20 and Cdh1, that activate the cyclin-degrading machinery, dubbed the anaphase-promoting complex (4).

Peeling back the layers of a magnificently textured web of signals, she next showed that the enzyme Cdc14 triggers exit from mitosis (5). “It turns out that Cdc14 essentially resets cells for the next stage of the cell cycle by acting on Cdh1 and activating cyclin breakdown,” explains Amon. In turn, Cdc14, she found, is regulated by an assorted crew of proteins collectively called the mitotic exit network (6).

Having established the primacy of the mitotic exit signaling network in cell division, Amon sought to uncover signals at the heart of the network. One such signal turned out to be the physical position of the nucleus. A natural mechanism in dividing cells ensures that they postpone exit from mitosis until the nuclei are correctly partitioned between daughter cells; the alternative would result in cellular mayhem. “You would end up with a cell that has two nuclei and one that has none,” explains Amon. Amon found that the activation of Cdc14, as well as exit from mitosis, is stalled until a pair of interacting proteins called Tem1 and Lte1 assume their position in the nascent bud of budding yeast cells. The Tem1/Lte1 duo, it turns out, cohabit the bud only after the nucleus, freshly minted in the mother cell, has slipped through the slender bud neck into the bud. Together, this and other signals, asymmetrically arrayed between the mother cell and bud, ensure that cell division results in cells with the correct genetic complement. These acutely observed insights revealed how molecular asymmetry ironically underpins the wondrous symmetry of cell division (7).

Peril in Numbers

Because cell division is a life-sustaining process, Amon’s research has a direct bearing on a range of diseases. Perhaps nowhere is the link more evident than in her decades-long studies of aneuploidy, a term used to describe the off-kilter chromosomal complement that results when chromosome separation during cell division goes awry. Aneuploidy marks a range of conditions such as miscarriage, mental retardation, and cancer. Among the oft-cited examples is Down syndrome, which results when missteps in chromosome separation generate sperm or egg cells with an extra copy of human chromosome 21. Cells in the resulting embryo harbor three, instead of the normal two, copies of the chromosome.

To probe the effects of aneuploidy at the cellular level, Amon induced strains of yeast to spontaneously lose or gain preordained or random chromosomes. Analysis of these aneuploid yeast strains proved enlightening. Although some effects of aneuploidy are tied to incorrect dosages of genes on affected chromosomes, Amon’s work revealed that aneuploidy exerts sweeping detrimental effects on cell function. “Independent of which chromosome is gained or lost, we see that aneuploid cells have these widespread stresses,” says Amon. To wit, they harbor unstable genomes prone to mutations, consume more energy than normal cells for survival and proliferation, accumulate misfolded proteins, and suffer impaired cell division. Collectively, these adverse effects, which Amon has dubbed aneuploidy-associated stresses, give aneuploid yeast cells a crippling disadvantage during division (8).

Cancer Conundrum

Yet the vast majority of solid human cancers are marked by aneuploidy, paradoxically hinting that the condition might drive rather than deter cancer, a disease of runaway cell division. Amon has spent years developing mouse models to explain the incongruity, and her observations have led to a working theory awash in nuance. The theory posits that although aneuploidy hobbles cell division, it occasionally confers adaptive advantages on cancer cells, allowing them to weather stress, prodding them toward malignancy, and enabling them to resist chemotherapy and evolve rapidly (9–11). Because aneuploidy helps cancer cells adapt and evolve, the reasoning goes, targeting aneuploidy might yield therapeutic benefits.

Following that reasoning, Amon and coworkers (12) reported that an array of chemical compounds, including the antimalarial drug chloroquine, preferentially block the proliferation of aneuploid human cancer cells over cells with a correct chromosomal complement—both in laboratory dishes and in mice implanted with human tumors. The findings support the notion that targeting aneuploid cells might be a viable strategy to combat a broad range of human cancers. Yet, says Amon, the notion has not been greeted with a groundswell of interest from the biotechnology industry, partly because of the formidable risks of betting on a phenomenon with such far-reaching and subtle physiological effects and partly because of the overwhelming focus on genomic medicine and immunotherapy, approaches whose primary appeal is their precision.

Aneuploidy might be underappreciated as a direct target in cancer, but Amon has demonstrated that the condition triggers an innate immune response in mammalian cells, a finding with implications for cancer treatment (13). The immune attack, mounted by a group of cells called natural killer cells, selectively eliminates cells with an abnormal genetic makeup. Cancer cells have evolved ways to sidestep the immune defense, and Amon’s work suggests that reactivating natural killer cells might trigger an effective immune riposte against cancer.

Over the coming years, Amon hopes to expand her efforts into the clinical realm, exploring how her basic insights on cell division might be used to treat human disease. Equally, she intends to continue plumbing the mysterious depths of mammalian cells in pursuit of life’s primal truths.