PROFILE

Profile of , winner of the 2019 Vilcek Prize in Biomedical Science PROFILE Jan Vilceka and Prashant Nairb,1

In 2006, the New York City-based launched a prize program to honor US-based bio- medical 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 Univer- sity School of Medicine for his contribution to the devel- opment of the antiinflammatory drug infliximab. The Vilcek Foundation’s prize program was born out of the Vilceks’ desire to recognize the contributions of immi- grants to science and arts in the United States. It is also a celebration and emblem of immigration’s role in secur- ing 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. Since the establishment of the prize program in 2006, Angelika Amon. Image courtesy of Samara Vise (Koch Institute for Integrative Cancer 15 scientists have received the Vilcek Prize in Biomedical Research, Cambridge, MA). Science. The Vilcek Foundation also recognizes outstand- ing young foreign-born scientists through the establish- has brought to light principal players in the balletic ment of Prizes for Creative Promise in Biomedical Science; process by which cells bequeath genetic material to these prizes are open to candidates who are not more than offspring. Along the way, her work has revealed how 38 y old at the time of consideration. To date, 22 scientists missteps in the process result in outcomes such as have received Prizes for Creative Promise in Biomedical cancer. For her crystalline insights into life’s elemental Science (in parallel, the Vilcek Foundation also awards an equal number of prizes in the arts to outstanding problems, the scientific community has heaped plaudits foreign-born artists active in the United States) (2). on Amon, including memberships in the National Acad- The recipient of the 2019 Vilcek Prize in Biomedical emy of Sciences, the American Academy of Arts and Science is Angelika Amon, an Austrian-born molecular and Sciences, and the European Molecular Organi- cell biologist at the Massachusetts Institute of Technology. zation; a in life sciences; a National Academy of Sciences award; and a Solving the Puzzle of Cell Division: Angelika Howard Hughes Medical Institute Investigator award. Amon Angelika Amon’s passion for biology began early, Moving Picture when a picture of dividing plant cells viewed through a Amon was born and raised in , . Her passion microscope sparked an enduring fascination with life’s for was sparked in middle school, when a grand mysteries. Over the course of a career spanning teacher showed the class time-lapse images of di- nearly three decades, Amon, a professor of cancer viding plant cells. As she thrilled to the sight of the research at Massachusetts Institute of Technology and cells sharing chromosomes in a ritualized sequence, winner of the 2019 Vilcek Prize in Biomedical Science, the riveting images seized her imagination and

aDepartment of Microbiology, New York University School of Medicine, NYU Langone Medical Center, New York, NY 10016; and bProceedings of the National Academy of Sciences USA, Washington, DC 20418 Author contributions: J.V. and P.N. wrote the paper. Conflict of interest statement: J.V. is the president and cofounder of the Vilcek Foundation, whose mission is to raise awareness of immigrant contributions to the United States. P.N. has received remuneration for promotional work for the Vilcek Foundation. Published under the PNAS license. 1To whom correspondence should be addressed. Email: [email protected]. Published online March 18, 2019.

www.pnas.org/cgi/doi/10.1073/pnas.1903221116 PNAS | April 9, 2019 | vol. 116 | no. 15 | 7157–7159 Downloaded by guest on September 29, 2021 were seared into her memory. “They were amazing cells progress through the and partition their black-and-white movies from the sixties, long before chromosomes. Over time, those efforts ossified her fluorescence microscopy and the fancy techniques we standing among the world’s leading geneticists and use today. Plant cells have these large chromosomes, landed her a faculty job at the Koch Institute for In- and I just loved seeing the cells divide,” she recalls. tegrative Cancer Research at the Massachusetts Institute Amon channeled her youthful fascination into un- of Technology, where she has since stayed. From her dergraduate studies in biology at the University of perch at the institute, Amon has vastly expanded re- Vienna. In 1989, she enrolled in a doctoral program at searchers’ understanding of aspects of cell division the Institute of Molecular Pathology, joining the lab- intricately tied to human disease. oratory of a new arrival at the institute, the Englishman Chief among those findings is the role of an en- , who had earned an international repu- zyme called Cdc14 in inducing cells to exit from mi- tation as a first-rate geneticist. Nasmyth was quick to tosis. The final stage in the cell cycle, exit from spot his protege’s promise and armed her with practical marks a period in the life of dividing cells when the skills in the genetics of , a model organism favored cellular apparatus that partitions chromosomes be- by cell biologists. tween daughter cells is dismantled, the envelopes Amon’s research in Nasmyth’s laboratory was no surrounding the daughter nuclei are rebuilt, and the mere finger-exercise for the full-scale work on yeast contents of the daughter cells are pulled apart and genetics she later undertook. Besides sharpening her packaged. Previously, Amon had demonstrated that instincts, her doctoral studies led to major discoveries must be degraded before cells can exit from on the cell cycle. A byzantine process by which cells mitosis. Building on that work, Amon found that duplicate their contents and divide, the cell cycle breakdown is promoted by a pair of proteins, Cdc20 progresses in well-defined stages: G1 (gap1), S (syn- and Cdh1, that activate the cyclin-degrading machin- thesis), G2 (gap2), and M (mitosis); the gaps allow cells ery, dubbed the -promoting complex (4). time to grow and duplicate organelles before division. Peeling back the layers of a magnificently textured The cell cycle is controlled by a staggering web of web of signals, she next showed that the enzyme interlinked signals. Among these signals are the aptly Cdc14 triggers exit from mitosis (5). “It turns out that named cyclins, proteins that accumulate within cells as Cdc14 essentially resets cells for the next stage of they enter mitosis. Amon’s work revealed that cyclins the cell cycle by acting on Cdh1 and activating cyclin must be broken down before cells make the passage breakdown,” explains Amon. In turn, Cdc14, she found, from mitosis to G1. Cyclin breakdown, she found, is regulated by an assorted crew of proteins collectively continues throughout G1 and ceases as cells enter the called the mitotic exit network (6). next stage, the S phase, when DNA is duplicated. Having established the primacy of the mitotic exit “What this work really established is the logic of the signaling network in cell division, Amon sought to cell cycle, how one stage sets up the next,” she explains. uncover signals at the heart of the network. One such Published in Cell, the findings marked an overture to signal turned out to be the physical position of the a career rich in elegant reports on the elaborately or- nucleus. A natural mechanism in dividing cells ensures chestrated symphony of cell division (3). that they postpone exit from mitosis until the nuclei are correctly partitioned between daughter cells; the Ascent to Success alternative would result in cellular mayhem. “You Armed with a doctoral degree, Amon next braved a would end up with a cell that has two nuclei and one foray into fruit fly research during a brief postdoctoral that has none,” explains Amon. Amon found that the stint with developmental biologist at activation of Cdc14, as well as exit from mitosis, is the for Biomedical Research in stalled until a pair of interacting proteins called Tem1 Cambridge, Massachusetts. In 1994, as she left the and Lte1 assume their position in the nascent bud of comforts of her native Austria for the chance to per- budding yeast cells. The Tem1/Lte1 duo, it turns out, form research in the United States, the move marked a cohabit the bud only after the nucleus, freshly minted departure in more than one sense. Amon had become in the mother cell, has slipped through the slender adept at working with yeast, a model organism then bud neck into the bud. Together, this and other sig- deemed far easier to manipulate for molecular genetic nals, asymmetrically arrayed between the mother cell studies than fruit flies, which proved a daunting and bud, ensure that cell division results in cells with prospect before the advent of such handy tools as the correct genetic complement. These acutely observed CRISPR. “Ruth was an amazing role model and men- insights revealed how molecular asymmetry ironically tor, and I learned so much from her. But I soon found underpins the wondrous symmetry of cell division (7). out that I didn’t like working with flies. Back then, once you had worked with yeast, you were spoiled; the only Peril in Numbers rate-limiting step in working with yeast was your Because cell division is a life-sustaining process, Amon’s brain,” she says. research has a direct bearing on a range of diseases. When the opportunity to launch her own labora- Perhaps nowhere is the link more evident than in her tory arose, thanks to a prestigious Whitehead fellow- decades-long studies of , a term used to ship for young scientists she received in 1996, Amon describe the off-kilter chromosomal complement that embraced it. As an independent fellow at the White- results when chromosome separation during cell division head Institute, she dove into the question of how yeast goes awry. Aneuploidy marks a range of conditions such

7158 | www.pnas.org/cgi/doi/10.1073/pnas.1903221116 Vilcek and Nair Downloaded by guest on September 29, 2021 as miscarriage, mental retardation, and cancer. Among and evolve rapidly (9–11). Because aneuploidy helps the oft-cited examples is Down syndrome, which results cancer cells adapt and evolve, the reasoning goes, when missteps in chromosome separation generate targeting aneuploidy might yield therapeutic benefits. sperm or egg cells with an extra copy of human chro- Following that reasoning, Amon and coworkers mosome 21. Cells in the resulting embryo harbor three, (12) reported that an array of chemical compounds, instead of the normal two, copies of the chromosome. including the antimalarial drug chloroquine, prefer- To probe the effects of aneuploidy at the cellular entially block the proliferation of aneuploid human level, Amon induced strains of yeast to spontaneously cancer cells over cells with a correct chromosomal lose or gain preordained or random chromosomes. complement—both in laboratory dishes and in mice Analysis of these aneuploid yeast strains proved en- implanted with human tumors. The findings support lightening. Although some effects of aneuploidy are the notion that targeting aneuploid cells might be a tied to incorrect dosages of genes on affected chro- viable strategy to combat a broad range of human mosomes, Amon’s work revealed that aneuploidy ex- cancers. Yet, says Amon, the notion has not been erts sweeping detrimental effects on cell function. greeted with a groundswell of interest from the bio- “Independent of which chromosome is gained or lost, technology industry, partly because of the formidable we see that aneuploid cells have these widespread risks of betting on a phenomenon with such far- stresses,” says Amon. To wit, they harbor unstable reaching and subtle physiological effects and partly genomes prone to mutations, consume more energy because of the overwhelming focus on genomic medicine than normal cells for survival and proliferation, accumu- and immunotherapy, approaches whose primary ap- late misfolded proteins, and suffer impaired cell division. peal is their precision. Collectively, these adverse effects, which Amon has Aneuploidy might be underappreciated as a direct dubbed aneuploidy-associated stresses, give aneu- target in cancer, but Amon has demonstrated that the ploid yeast cells a crippling disadvantage during condition triggers an innate immune response in division (8). mammalian cells, a finding with implications for cancer treatment (13). The immune attack, mounted by a Cancer Conundrum group of cells called natural killer cells, selectively Yet the vast majority of solid human cancers are eliminates cells with an abnormal genetic makeup. marked by aneuploidy, paradoxically hinting that the Cancer cells have evolved ways to sidestep the im- condition might drive rather than deter cancer, a mune defense, and Amon’s work suggests that reac- disease of runaway cell division. Amon has spent years tivating natural killer cells might trigger an effective developing mouse models to explain the incongruity, immune riposte against cancer. and her observations have led to a working theory Over the coming years, Amon hopes to expand her awash in nuance. The theory posits that although efforts into the clinical realm, exploring how her basic aneuploidy hobbles cell division, it occasionally insights on cell division might be used to treat human confers adaptive advantages on cancer cells, allow- disease. Equally, she intends to continue plumbing ing them to weather stress, prodding them toward the mysterious depths of mammalian cells in pursuit of malignancy, and enabling them to resist chemotherapy life’s primal truths.

1 Vilcek J, Cronstein BN (2006) A prize for the foreign-born. FASEB J 20:1281–1283. 2 Vilcek Foundation (2019) The Vilcek Prizes. Available at https://www.vilcek.org/prizes/the-vilcek-prize.html. Accessed March 5, 2019. 3 Amon A, Irniger S, Nasmyth K (1994) Closing the cell cycle circle in yeast: G2 cyclin proteolysis initiated at mitosis persists until the activation of G1 cyclins in the next cycle. Cell 77:1037–1050. 4 Visintin R, Prinz S, Amon A (1997) CDC20 and CDH1: A family of substrate-specific activators of APC-dependent proteolysis. Science 278:460–463. 5 Visintin R, et al. (1998) The phosphatase Cdc14 triggers mitotic exit by reversal of Cdk-dependent phosphorylation. Mol Cell 2:709–718. 6 Bardin AJ, Amon A (2001) Men and sin: What’s the difference? Nat Rev Mol Cell Biol 2:815–826. 7 Bardin AJ, Visintin R, Amon A (2000) A mechanism for coupling exit from mitosis to partitioning of the nucleus. Cell 102:21–31. 8 Torres EM, et al. (2007) Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 317:916–924. 9 Williams BR, et al. (2008) Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science 322:703–709. 10 Williams BR, Amon A (2009) Aneuploidy: Cancer’s fatal flaw? Cancer Res 69:5289–5291. 11 Sheltzer JM, et al. (2011) Aneuploidy drives genomic instability in yeast. Science 333:1026–1030. 12 Tang YC, Williams BR, Siegel JJ, Amon A (2011) Identification of aneuploidy-selective antiproliferation compounds. Cell 144:499–512. 13 Santaguida S, et al. (2017) Chromosome mis-segregation generates cell-cycle-arrested cells with complex karyotypes that are eliminated by the immune system. Dev Cell 41:638–651.e5.

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