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Commentary Completing the Great Unfinished Symphony of Cancer Together: The Importance of Immigrants in Cancer Research

Pat J. Morin,1,* Denis Wirtz,2,3,* and Ashani T. Weeraratna3,4,* 1Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19106, USA 2Department of Chemical and Biomolecular Engineering and Institute for NanoBiotechnology, Johns Hopkins University, Whiting School of Engineering, Baltimore, MD 21218, USA 3The Sidney Kimmel Cancer Center, Johns Hopkins School of , Baltimore, MD 21231, USA 4Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA *Correspondence: [email protected] (P.J.M.), [email protected] (D.W.), [email protected] (A.T.W.) https://doi.org/10.1016/j.ccell.2020.08.017

Recent changes in U.S. immigration policy are adversely affecting biomedical science, at a time when biomedical research is most sorely needed on multiple fronts. Here we discuss the immense contributions of immigrants to cancer research and the adverse impact that current administration policies will have on successful cancer research.

‘‘America, you great unfinished but in recent years, an anti-immigrant grees than multi-generational native- symphony, you sent for me sentiment has rapidly burgeoned. This is born peers, and increasingly contribute You let me make a difference manifesting itself not only in crackdowns to the U.S. economy overall. Nearly 50% A place where even orphan on illegal immigration, but also in the of all Fortune 500 companies were immigrants thwarting of legal immigration, and the founded by immigrants and their children Can leave their fingerprints and sciences are particularly vulnerable to (Fearnow, 2019), and since 2000 nearly rise up .’’ this. In this commentary, we address the 40% of U.S.-based winners of the Nobel —Leslie Odom, Jr. and Lin-Man- issues this anti-immigrant sentiment Prizes in Physics, Chemistry, and Medi- uel Miranda, Hamilton poses, specifically for cancer research. cine have been immigrants (Ander- son, 2018). Introduction Immigrants and the Economy America has always had a complex and Immigrants are strong contributors to the Immigrants in Cancer Research: checkered history of immigration. From U.S. economy. Data show that immi- Current Status the first colonists who set foot on its grants make up a high percentage of the The contribution of immigrants to the shores to the waves of immigrants that essential workforce and are employed at biomedical, and specifically cancer came after—some involuntarily, like Afri- far higher rates than their native-born research, workforce cannot be over- can slaves so cruelly torn away from their counterparts (Sherman et al., 2019). Partly stated. A recent study looked at some of homes, others seeking to voluntarily this may be due to the lack of ‘‘roots’’ in the top cancer research centers in the escape theirs, like Irish immigrants who one particular geographical area, which country, including MD Anderson, Johns fled the potato famine to come here; Ital- allows immigrants to go where the work Hopkins, and others, and found that the ians who immigrated to Ellis Island to is, and this in itself contributes to the number of foreign-born cancer re- escape the unstable 1920s government economy. In figures from 2009, the searchers at these institutions ranged of Italy; European Jews who flocked average foreign-born adult with an from 40% to more than 70% (Neill and steadily here over the years, especially advanced degree was shown to pay Avasthi, 2020). It is not clear if these fig- during the pogroms (1880–1914) and over $22,500 in taxes, including federal, ures include those working in internet then again during the heinous reign of state, FICA, Social Security, and Medi- technology, artificial intelligence, and Nazi Germany; and more recently, refu- care, while receiving about a tenth of bioengineering, all critical fields for the im- gees from Central and South America. that back in government-sponsored ben- plementation of cancer research through Indeed, with the exception of the slaves efits (such as unemployment, Medicare, the technologies they provide. Many of brought here against their will, immigrants etc.) (Zavodny, 2011). Compare that to these immigrant workers are here on visas came to America to seek the American American taxpayers who reap two to for highly skilled individuals (H1B), schol- Dream and the solace offered by our three times more than they pay into the arly visas with a requirement to return Lady Liberty: ‘‘Give me your tired, your system in Medicare, Social Security, and home and provide service to their own poor, your huddled masses yearning to other benefits. Further, data show that countries (J-1), or student visas (F-1). In breathe free.’’ America was the beacon children born to immigrant families the past few weeks, we have seen two for innovators, scientists, and pioneers, are upwardly mobile, getting higher de- of these groups of visa holders suddenly

Cancer Cell 38, September 14, 2020 ª 2020 Published by Elsevier Inc. 301 ll Commentary subjected to increased and draconian re- latter couple were both born in Prague, many in March 1945. After the war, her strictions with paltry explanations pro- but because of scientific limitations and family emigrated to Canada. After obtain- vided. While the executive order restrict- anti-Semitism came to the Roswell Park ing her Bachelor’s degree from the Uni- ing F visas was stopped through Cancer Institute in 1922 to pursue their versity of Toronto and her PhD from the lawsuits brought by an array of public studies on carbohydrate metabolism. Rockefeller University, Dr. Werb moved and private universities, processing of While not focused specifically on cancer to the University of California, San Fran- these visas at U.S. embassies abroad research, the Coris published an early pa- cisco, where she initiated her classic has slowed to a crawl. Further, re- per on tumor metabolism in 1925, which studies on the tumor microenvironment, searchers from specific countries— together with the body of their work focusing on the extracellular matrix (Ege- China, Iran, and others—are banned (including the Cori cycle, discovered in blad et al., 2020). The tradition of from entering the U.S. These restrictions, 1929) paved the way for the important outstanding immigrant scientists in the coupled with the abysmal failure of the research area known as cancer meta- field of tumor microenvironment con- U.S. response to COVID-19, will likely bolism. In 1931, the Coris moved to tinues to this day with researchers such serve to drive away talented international Washington University, where they as Kornelia Polyak (Hungary), Rakesh researchers in droves, who might prefer continued their groundbreaking work Jain (India), Mikala Egeblad (Denmark), to take their talents where they are and won the in 1947. At Yibin Kang (China), and many others. In welcomed and appreciated, and where WashU, they built a leading department addition, immigrant scientists have made healthcare systems provide affordable of biochemistry which included seven huge contributions to cancer research care, especially during a pandemic. This future Nobel laureates (Rubin, 2019), an fields such as epigenetics, e.g., Danny is particularly true now that the gap in sci- immense contribution to cancer research Reinberg (Argentina), Peter Jones entific funding and excellence has been and biomedical science. (Zimbabwe), Jean-Pierre Issa (Lebanon); decreasing between the U.S. and other Another area of groundbreaking genomics and cancer genetics, e.g., advanced and developing economies. research encompassing the outstanding Alan Ashworth (UK), work of multiple outstanding immigrant (Australia), (Italy), Edison Immigrants in Cancer Research: scientists is the crucial role of the micro- Liu (Hong Kong); , e.g., An- Major Contributions environment in cancer progression. This toni Ribas (Spain), Lieping Chen (China), The contribution of foreign-born physi- field became widely accepted due largely Anjana Rao (India), Olivera Finn (Serbia), cists to American physics is well docu- to the efforts of Mina Bissell, who was Francesco Marincola (Italy); and count- mented, with luminaries such as Albert born in Tehran, Iran, and came to the less others. Einstein, Enrico Fermi, Leo Szilard, Hans U.S. in 1959 for college and later received The development of chemotherapy in Bethe, and many others helping America her PhD from Harvard in 1969. Dr. Bissell cancer treatment certainly represents a to become a leader in technology and, then moved to Lawrence Berkeley Na- watershed moment in cancer research. incidentally, playing a major part in the tional Laboratory, where she has been Before the 1950s the treatment of cancer U.S. winning the space race via the suc- ever since. Her paradigm-shifting work was limited to surgery and radiation ther- cessful 1969 moon landing. A similar has been crucial in demonstrating the apy, but a series of experiments at NCI in argument can be made that immigrant role of the microenvironment in tumor the 1950s and 1960s led to the develop- scientists have played a major role in progression, a role that had been contro- ment of modern chemotherapy. A crucial U.S. cancer research, working in labora- versial before her studies. In 1982, Bissell member of the team involved in the devel- tories across the nation and helping to un- proposed the theory of dynamic reci- opment of this new approach was Min ravel the basic mechanisms of oncogen- procity, which altered our view of how Chiu Li, an immigrant from Shenyang, esis and develop new innovative tools cancer cells affect their environment and China, who had come to the University for cancer therapies. In fact, through the vice versa (Bissell and Aggeler, 1987). of Southern California in 1947 to pursue help of immigrant scientists, the U.S. has Similarly, Isaiah Fidler, born in Israel in postgraduate education following his MD become one of the world leaders in can- 1936, came to the U.S. to study veterinary in China. Dr. Li was part of the NCI team cer drug development, stimulated by the medicine. In time he would play a major that first successfully treated a solid tu- combination of strong basic academic role in revisiting and proving the seed mor with chemotherapy. In addition, while laboratories and a large number of and soil hypothesis, demonstrating the treating choriocarcinoma with metho- pharmaceutical and biotech companies. crucial interactions between tumor cells trexate, Dr. Li used serum hCG levels to Table 1 lists immigrant cancer scientists (the seed) and the microenvironment of assess treatment efficacy, continuing who have received Nobel Prizes or Lasker the metastatic sites (the soil). His work treatment even after clinical remission, Awards. It is impossible to describe all the has paved the way for the development an important insight which represents notable contributions of foreign-born sci- of novel approaches for therapy aimed the first use of a molecular biomarker to entists to the U.S. cancer research enter- at modulating the microenvironment assess therapy response. Dr. Li later prise, which range from those of Salvador (such as anti-angiogenesis therapy) (Fi- moved to Memorial Sloan Kettering Can- Luria (Italy) and Max Delbruck€ (Germany), dler, 2003). Another important contributor cer Center and shared the Lasker Award who showed that mutations can be in- to understanding of the roles of the micro- in 1972 for his enormous contributions to herited from cell to daughter cell, to the environment in disease progression was the field of cancer chemotherapy (Freir- birth of the tumor metabolism field, Zena Werb. Dr. Werb was born in the Ber- eich, 2002). In fact, in oncology, basic described by Carl and . This gen-Belsen concentration camp in Ger- and translational science are a critical

302 Cancer Cell 38, September 14, 2020 ll Commentary

Table 1. Immigrant Lasker and Nobel Prize Winners in the Name Country of Birth Year of Prize U.S. Institution Research Area Sidney Altman Montreal, QC, Canada Nobel, 1989 Yale University, Catalytic properties of RNA Baruj Benacerraf , Nobel, 1980 , Columbia Genetic basis of immunology University, National Institutes of Health, , Dana-Farber Cancer Institute Elizabeth Blackburn Hobart, Tasmania, Lasker, 2004; University of California, Berkeley; Co-discovered telomerase Australia Nobel, 2009 University of California, San Francisco; Yale University; Salk Institute Gunter€ Blobel Niegos1awice, Poland Lasker, 1993; Rockefeller University Protein transport and Nobel, 1999 localization in the cell Mario Capecchi Verona, Italy Lasker, 2001; Harvard School of Medicine, Gene targeting in mouse Nobel, 2007 University of Utah embryo-derived stem cells Brussels, Belgium Nobel, 1974 Rockefeller University Electron microscopy in biology Gerty Cori Prague, Austro- Nobel, 1947 Roswell Park Cancer Institute, Cell metabolism Hungarian Empire Washington University in St. Louis Carl Cori Prague, Austro- Lasker, 1946; Roswell Park Cancer Institute, Cell metabolism Hungarian Empire Nobel, 1947 Washington University in St. Louis Max Delbruck€ Berlin, German Empire Nobel, 1969 Vanderbilt University, California DNA replication/genetic Institute of Technology structure of viruses Catanzaro, Italy Lasker, 1964; Indiana University Bloomington, Found that certain animal Nobel, 1975 California Institute of Technology, cancer viruses can insert Salk Institute for Biological Studies themselves into a cell’s DNA Hidesaburo Hanafusa Osaka Prefecture Lasker, 1982 The Rockefeller University Genetics of RNA tumor viruses Charles Brenton Halifax, Nova Scotia Lasker, 1963; University of Michigan, University Use of hormones in cancer Huggins Nobel, 1966 of Chicago therapy Raipur, Multan, Lasker, 1968; University of Wisconsin-Madison, Deciphering the genetic code Punjab Province, Nobel, 1968 Institute of British India (present- Technology day Punjab, Pakistan) Rita Levi-Montalcini Turin, Italy Lasker, 1986; Washington University in St. Louis Discovery of nerve growth Nobel, 1986 factor (NGF) Min Chiu Li Mukden, China Lasker, 1972 National Cancer Institute, Memorial- Solid tumor chemotherapy Sloan Kettering Cancer Center, Nassau Hospital Fritz Lipmann Ko¨ nigsberg, Germany Nobel, 1953 Massachusetts General Hospital, Bioenergetics Harvard Medical School, The Rockefeller University Turin, Italy Nobel, 1969 , Indiana Genetic structure of viruses University, University of Illinois at Urbana-Champaign, Massachusetts Institute of Technology Norwich, Norfolk, UK Lasker, 1998; The Rockefeller University Cell cycle Nobel, 2001 Luarca, Asturias, Spain Nobel, 1959 New York University School of RNA polymerase discovery Medicine, Washington University School of Medicine in St. Louis Iasi, Romania Lasker, 1966; New York University; The Electron microscopy and Nobel, 1974 Rockefeller University; Yale cell fractionation University; University of California, San Diego Georgios Papanikolaou Kymi, Euboea, Greece Lasker, 1950 Cornell University, New Early cancer detection; York-Presbyterian/Weill developer of the Pap smear Cornell Medical Center

Cancer Cell 38, September 14, 2020 303 ll Commentary

Table 1. Continued Name Country of Birth Year of Prize U.S. Institution Research Area (Continued on next page) West Yorkshire, UK Lasker, 2001; University of Wisconsin- Gene targeting in mouse Nobel, 2007 Madison, University of North embryo-derived stem cells Carolina at Chapel Hill Ralph Steinman Montreal, QC, Canada Lasker, 2007; The Rockefeller University Dendritic cells Nobel, 2011 Jack Szostak London, UK Lasker, 2006; Harvard Medical School Telomeres and the Nobel, 2009 enzyme telomerase Nagoya, Aichi, Japan Nobel, 1987 Massachusetts Institute Genetic mechanisms of Technology of antibody production

intermarriage, and a number of immigrant of the trainee workforce, and while some color increases representation among physician scientists have had a critical of their names may go unnoticed, their ef- the ranks of scientists, which hopefully in- impact on bringing new treatments forts speak volumes. It is clear that creases the recruitment and retention of to the clinic. Waun Ki Hong (Korea), without their contributions our country minority scientists. Importantly, this com- Carlos Arteaga (Ecuador), Olufunmilayo would not occupy its unique position in mentary is not meant to devalue the Olopade (Nigeria), Gabriel N. Hortobagyi the world in terms of innovation and the incredible contributions of American can- (Hungary), Irene Ghobrial (Egypt), Chi development of new cancer therapies. cer researchers, which are legion, but it is Van Dang (Vietnam), Lieping Chen imperative to highlight the fact that there (China), Baruj Benacerraf (Venezuela), are more jobs than available U.S. workers Dispelling Myths Regarding Azra Raza (Pakistan), Kristiina Vuori in STEM. In a 2012 report by the Presi- Immigrants (Finland), and many, many others have dent’s Council of Advisors on Science Finally, we feel it is incumbent upon us to all contributed enormously to translational and Technology, it was projected that dispel a couple of myths surrounding and clinical cancer research. Of the 71 over the next decade the United States immigrant scientists. One of the most NCI-designated cancer centers in the will need approximately 1 million more common complaints we hear is that immi- U.S., at least 10 are led by foreign-born STEM professionals than it will produce grant scientists are ‘‘cheap labor.’’ In fact, directors. at the current rate (PCAST, 2012), mean- the National Institutes of Health sets the Given the history of contributions of ing that the immigration of highly skilled same pay guidelines for all trainees, and foreign-born researchers in the United professionals is critical for the continued nationality does not factor into pay rates. States to the understanding of cancer success of U.S. science. Another overriding concern is that immi- mechanisms, including five Nobel Prizes grant workers ‘‘take American jobs’’ and directly in cancer research, and to seminal that this could also potentially cause un- Conclusions discoveries that have led to improve- derrepresented minority U.S. scientists In conclusion, the data overwhelmingly ments in cancer care, immigrants, to to get ‘‘pushed out’’ by international support the importance of immigrants for paraphrase Lin-Manuel Miranda in Hamil- trainees, reducing their chances for posi- biomedical sciences and, in particular, ton, are getting the job done. With so far tions in academia. In fact, a comprehen- cancer research. It is worth noting that yet to go, however, depleting this critical sive study of the U.S. labor market from all three authors of this commentary are resource of immigrant scientists is a 2000 to 2007 showed that an increase in immigrant scientists, cancer researchers, dangerous path for U.S. science and immigrant workers actually boosts Amer- and, now, naturalized Americans. To beat medicine. The critical contributions of im- ican jobs, where for every 100 immigrant a disease this deadly, we need the bright- migrants to cancer research, and the par- workers there is an increase of 262 jobs est minds, no matter from where they hail. allels between the increase in immigrant for American workers (Zavodny, 2011). If We strongly propose that a diverse set of cancer researchers and physicians and we look specifically at H1B visa holders, approaches, views, and backgrounds will ever-improving survival rates in cancer each 100 H1B visa holders result in 183 work best to unravel the mysteries of can- patients, are beautifully and comprehen- additional jobs among U.S. natives. It is cer and point to important new avenues sively outlined in a 2013 report by the only fair to assume that this increase in for therapy. Let us bring a diverse array National Foundation for American Policy jobs is equally reflective of increased of instruments to the floor so we can com- (Anderson, 2013). While the examples jobs for minority scientists as well. Given plete this great unfinished symphony. above provide an idea of the breadth of also that grants and fellowships targeted the impact foreign-born scientists have toward underrepresented populations by ACKNOWLEDGMENTS made on the U.S., it is impossible to fully and large exclude foreign-born scientists, acknowledge the contributions of immi- it is unlikely that it is truly the case that im- We dedicate this review to the thousands of immi- grants to cancer research. Even in labora- migrants, rather than systemic failures, grant trainees who have come to the U.S. to pursue tories run by American-born scientists, cancer research, to the hundreds of well-recog- adversely affect minority scientists. And immigrants make up a large proportion nized immigrant researchers we did not have finally, having foreign-born scientists of room to mention, and to the U.S.-born cancer

304 Cancer Cell 38, September 14, 2020 ll Commentary research colleagues at every level who train (and direct gene expression? Prog. Clin. Biol. Res. 249, and mathematics. In Report from the President’s train with) immigrants, who collaborate with immi- 251–262. Council of Advisors on Science and Technology, grants, and who create safe spaces for immigrants February 2012 https://obamawhitehouse.archives. to flourish. While this commentary has been U.S. Egeblad, M., Coussens, L., and Weaver, V. (2020). gov/sites/default/files/microsites/ostp/pcast-engage- focused, given the immigration policies that Zena Werb 1945–2020. Nat. Cancer 1, 753–754. to-excel-final_2-25-12.pdf. adversely affect research in this country, we also Fearnow, B. (2019). Nearly half of All Fortune 500 commemorate the native and immigrant re- companies were founded by immigrants or their Rubin, R.P. (2019). Carl and Gerty Cori: A collabo- searchers all over the world whose contributions children, study finds. Newsweek, July 22, 2019 ration that changed the face of biochemistry. to cancer research are invaluable. Together, we https://www.newsweek.com/immigrant-founded- J. Med. Biogr. 967772019866954. https://doi. can make a difference in the race to cure cancer, fortune-500-companies-us-gdp-1450498. org/10.1177/0967772019866954. and it will take a global effort. Fidler, I.J. (2003). The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revis- Sherman, A., Trisi, D., Stone, C., Gonzales, S., and REFERENCES ited. Nat. Rev. Cancer 3, 453–458. Parrott, S. (2019). Immigrants contribute greatly to U.S. economy, despite administration’s Anderson, S. (2013). The Contributions of Freireich, E.J. (2002). Min Chiu Li: a perspective in ‘‘public charge’’ rule rationale. In Report from Immigrants to Cancer Research in America cancer therapy. Clin. Cancer Res. 8, 2764–2765. the Center on Budget and Policy Priorities, (National Foundation for American Policy Brief). August 15, 2019 https://www.cbpp.org/research/ Neill, U.S., and Avasthi, P.A. (2020). The anti-immi- poverty-and-inequality/immigrants-contribute- Anderson, S. (2018). Immigrant Nobel Prize grant Trump administration is hurting American sci- greatlyto-us-economy-despite-administrations. winners keep leading the way for America. ence. Medium, June 4, 2020 https://medium.com/@ Forbes, October 14, 2018 https://www.forbes.com/ ushmaneill/the-anti-immigrant-trump-administration- sites/stuartanderson/2019/10/14/immigrant-nobel- is-hurting-american-science-a52fd26f4337. Zavodny, M. (2011). Immigration and American jobs. prize-winners-keep-leading-the-way-for-america/ In Report from the American Enterprise Institute for #5b6f8cb04d4b. President’s Council of Advisors on Science and Public Policy Research and the Partnership for A Technology (PCAST) (2012). Engage to excel: pro- New American Economy, December 2011 https:// Bissell, M.J., and Aggeler, J. (1987). Dynamic reci- ducing one million additional college graduates www.newamericaneconomy.org/sites/all/themes/ procity: how do extracellular matrix and hormones with degrees in science, technology, engineering, pnae/img/NAE_Im-AmerJobs.pdf.

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