High Risk, High Reward: By selecting Tsg101, a protein that sorts the trash, as our personal ESCRT, both HIV and I were able to bud

Abstract

Being asked to write this “Reflections”-type article is a special honor offered at the end of one’s career and I am grateful for the opportunity to think back over the more than 4-decade span of my career in the field of HIV/AIDS Retrovirology. Although at this point in time there is still no vaccine or curative therapy for HIV/AIDS, this invitation to reminiscence comes in the year of FDA approval of Lenacapavir, the first-in-class anti-HIV agent targeting the viral capsid. This triumph in the field is the culmination of efforts of many, including some in my own laboratory, who were among the first to produce recombinant capsid protein (CAp24) for structural and biochemical studies. A current drawback of this drug is its low genetic barrier to viral resistance. The research finding considered to be our most important contribution to the field of HIV research was framed by the challenge to suppress the emergence of resistant variants, and I describe the paths that drove me to risk exploration of the non-traditional for potential solutions. Finally, I share my views on what I consider to be an important open question for the future: how to achieve greater diversity and inclusion in Science.

Background

My laboratory has been utilizing a structure-based approach to the study of virus particle formation and transmission since we first entered the field of HIV/AIDS in the mid-1980’s. AIDS (acquired immunodeficiency disease syndrome) “hit the scene” in the early 1980s, with an increasing number of reports at scientific meetings and in published articles from clinicians describing cases in which young and otherwise healthy young men presented with diseases (i), previously typically only diagnosed in individuals with compromised immune systems and (ii), caused by a broad range of pathogens belonging to bacteria, viruses, protozoan and fungal groups. In a book entitled “And the Band Played On: Politics, People, and the AIDS Epidemic”, published in 1987, San Francisco Chronicle journalist Randy Shilts tells the stories of individuals in science, public health, politics and the gay community involved in the incredible debate that unfolded during the preceding years of the AIDS epidemic that contributed to the spread of the disease. I was not a part of the field of Retrovirology (initially known as RNA Tumor Viruses) in this initial challenging period. However, once the etiological agent was established to be the human immunodeficiency virus (HIV) [Gougeon 1983; Broder 1984] I, as a basic scientist, felt that obtaining a fundamental understanding of the agent was of utmost importance. Achieving a molecular understanding of any pathogen informs us about its origin and provides insights into cure of the diseases it causes. The infectious agents that have emerged since HIV reinforce this notion.

Looking back, I feel that serendipity, i.e., circumstances beyond my immediate control and encountering individuals who extended kindness and support just because it was “in their DNA” to do so played a tremendous role in my scientific journey. Early examples are the elementary school teacher I had for grades 4, 5 and 6, Robert Babcock, who gifted me outdated volumes of the library’s “Book of Knowledge” encyclopedia series for my “light” reading; my African-American high school Guidance Counselor, Hope Williams, who insisted that every minority student in the school apply to the City University; my work-study employer at CCNY, Professor Jim Organ, who insisted that I apply to Yale U for graduate studies.

Serendipity-1:

[Graduate School: Trusting my instincts] I entered the Department of Microbiology at Yale University with a class of 7 pre-doctoral students of which 6 were females. This was certainly unprecedented. Their similarity to this African-American girl from Harlem NY ended with gender: One was from the Ukraine via Canada; another, blond, blue-eyed and divorced, hailed from Mississippi; a 3^rd was a New Jersey girl; a 4^th was from the US mid-west and a 5^th boasted descendants on the Mayflower and described streets in New York City named after her Mayflower family. An additional member was a married Jewish mother of 2, 30 years older than the rest of us and matriculating for a Masters’ degree. Despite this broad diversity, the intensely challenging graduate school experience fostered an incredible bonding between those of us that survived to obtain the degree (3 dropped out), remaining friends in contact until 2 died. I quickly learned that being the 1^st graduate student of a brand new, young and exciting but untenured Assistant Professor with limited social skills and no cross-cultural sensitivity was a big mistake. She epitomized just about every racist descriptor I had managed to avoid throughout my schooling to that point. After passing the qualifying examination, I became the 1^st student in the history of the department to bolt, against the advice of the Departmental Chair and Graduate Program Director. This time, I selected a mentor significantly older: A well-established Full Professor, Francis Black, in the Department of Epidemiology & Public Health. This rerouting served me well: The study of animal viruses had just become feasible with the advent of methodology for maintaining HeLa cells in culture. Francis Black, a renowned expert in viral immunology, genetics and epidemiology with background training in biochemistry was anxious to add basic studies on animal virus replication to his mainly applied immunological and anthropological repertoire. Black played a major role in developing the measles vaccine during the early 1960s, and subsequently initiated innovative biomedical research in the Amazon, taking yearly trips to investigate the immunological and clinical responses of Indigenous populations exposed to the vaccine (Santos 2020). Together we published 4 papers: 3 that described aspects of measles virus replication in cell culture and 1 highlighting similarities between the structural polypeptides of measles virus and the subacute sclerosing panencephalitis agent (SSPE), an entity linked to devastating post-measles sequelae (Schluederberg 1972; Carter 1973a; 1973b; Schluederberg 1974). Wonderful female role models prevailed in his circle: Frank Black’s Research Technician, Dottie Davis, was one of the very, very few Black researchers at Yale; Dr. Ann Schluederberg, Frank Black’s Research Associate, also a virologist, was mother of 5 whose hobbies included ice skating and sailing; and Dr. Dorothy Horstmann, the 1^st woman to become a Professor at Yale (1961) and who later contributed my 1^st PNAS submission, were there as role models. Additional engaging African-American role models included the renowned child psychologist James Comer and parasitologist Professor Curtis Patton; both hosted graduate and medical students at their homes frequently. My relationship with my mentor was non-traditional: He regularly brought me with him to the scientific meetings sponsored by the NY Academy of Sciences and the American Society for Microbiology. There, he introduced me to his peers in virology, many whose names later appeared in textbooks I used for next generation instruction. I believe that his intrinsic inclusiveness and broad perspective that focused on the infectious agent, its impact on the host and the host response, prepared me well for the pivoting necessary in both interpersonal interactions, teaching and research that was required as the animal virus field evolved intellectually and technically.

Serendipity-2:

[The thesis defense] At Yale, the procedure for defense of the doctoral dissertation required obtaining a positive evaluation from a faculty member outside the university. Frank chose Harvard Professor Michael Bratt, who had published extensively on paramyxoviruses, the group to which measles virus belongs, to assess my measles virus studies. I was asked to travel to his office in Cambridge for the occasion solo, i.e., unaccompanied by my advisor. Following the event, which proceeded without drama, Michael introduced me to several Harvard and MIT Professors, among them David Baltimore, Jon King, and Sheldon Penman. I’ll never know Mike’s underlying intentions but, on that day, David Baltimore and his lab were celebrating David’s promotion to Professor with tenure at MIT and there was plenty of ice cream and cake! Subsequently, I wrote to David requesting an opportunity to pursue postdoctoral studies in his laboratory. He agreed and invited me to begin there in the following year. Ann Schluederberg hired me to work with her on SSPE for the interim period.

Serendipity-3:

[Encountering Aaron Shatkin, a compassionate human being and outstanding mentor] The Gordon Research Conferences (GRCs) are a prestigious international venue where frontier research in diverse subspecialities are discussed. Frank Black was a regular attendee. My experiences with both he and Jim Organ had taught me not to be intimidated of faculty. I learned that a GRC on “Animal Cells and Viruses” was scheduled for summer 1973, organized by Sheldon Penman, whom I had met on the day of my thesis defense in Cambridge. I wrote to him, reminded him that we had met, and asked to attend. To my delight, he kindly acquiesced. All year, I looked forward to attending this meeting. It started out with a misadventure that had far-reaching consequences: The airline delivered me but not my luggage to the Boston airport. This meant no toothbrush, no hair comb, no clothing: an inconvenience for anyone but particularly a penniless graduate student. Fortuitously, among the GRC attendees waiting in the Boston terminal for the chartered bus to the site, Dr Aaron Shatkin, a reovirus investigator who would discover the m⁷GpppN^(m) 5′-terminal cap structure on reovirus RNA and the majority of eukaryotic cellular and viral mRNAs [reviewed in Furuichi 2000], noticed my distress and chivalrously offered assistance and support that continued throughout the week of the conference. Several months later, after I had married and relocated to NY, that chance meeting facilitated my reaching out to him as a venue for postdoctoral training. Fortunately, he agreed. I was unaware then but looking back now, I realize that, like the first re-routing I undertook in graduate school, this 2^nd detour was another most impactful decision of my career.

Serendipity-4:

[Encountering Joe Kates, a visionary free spirit] Aaron’s lab at the Roche Institute for Molecular Biology (RIMB), the basic research division of the pharmaceutical giant Hoffmann-La Roche, was like Aaron himself: caring, collegiate and collaborative. Periodic joint lab meetings with other RIMB members in Aaron’s circle, specifically, Amiya Banerjee (vesicular stomatitis virus (VSV), Anna Marie Skalka (avian retrovirologist), and Gebhard Koch (poliovirus) permitted exposure to a diverse group of animal viruses. Physically, Aaron’s lab was adjacent to that of Brian McAuslan, a renowned vaccinia virus investigator who had mentored Joseph Kates. While in McAuslan’s laboratory, Kates had discovered that purified vaccinia virus particles contain a DNA-dependent RNA polymerase that is critical for replication (Kates & McAuslan 1967). This was the first demonstration that viruses can package enzymes required for their own replication and makes drugs targeting viral RNA polymerases one of the most successful anti-viral strategies in use today. Later, as an independent investigator, Joe discovered that vaccinia virus mRNAs and HeLa cell mRNAs have poly A tails, distinguishing this class of RNA from others and providing an unequivocal means to identify and isolate this form of RNA (Kates 1973). When Joe accepted an offer from Arthur Upton, then Dean of the School of Medicine at Stony Brook (later to become head of the National Cancer Institute) to create his own Department of Microbiology, he became their youngest chair (34 years old!). Joe reached out to his network, which included Brian, to help him identify potential faculty. One of the feats I had accomplished in Aaron’s lab was preparation of very high titer reovirus so that I could investigate the origin and function of the polyA found within its capsid. Employing a trick that had worked for measles virus, and much to Aaron’s delight, I was able to recapitulate this feat with reo. It involved modifying his laboratory’s protocol for virus purification by employing an anti-diarrheal agent, kaopectate, purchased from my corner drug store, to concentrate the particulate viral material prior to adding to the cells in tissue culture. At seminars he was invited to give, Aaron would open with the line, “one of my postdocs did a shitty experiment ……”. It always got a laugh. I learned later that Brian McAuslan told Joe that story and suggested that he interview me for a job.

As is evident from what is described above, my mentors and colleagues were mostly men. Hired at Stony Brook University (SBU) in 1975, I remained one of a very small number of tenured women holding doctoral degrees (and an even smaller number of tenured African-American women) for more than 3 decades. Sadly, in the 1970s, 1980s and early 1990’s, it was the practice of women in Science to shun other women in public places so as to avoid being identified as a member of that group. This made forming a supportive network of like-minded peers very challenging. Indeed, one unforgettable incident took place at a GRC where, during a break, graduate students and postdocs who had gathered in the women’s bathroom started sharing their personal experience of unacknowledged greetings, smiles or nods, prompted by the particularly egregious behavior of many of the senior women in attendance on that occasion. The discussion got very heated. I can still see the look of confusion and fear on the face of one senior woman as she entered the room at the peak of the hysteria. The awkward silence and resentful stares that ensued spoke volumes. Fortunately, this practice has taken a 180° turnabout with the new generation emerging in the past two decades.

Serendipity-5:

[Negotiating hard times] I had been fortunate to sustain myself sufficiently as an Assistant Professor to garner academic tenure having been awarded two R01 grants for reovirus research from the National Institutes of Health (NIH) and one from the American Cancer Society. I had carried in addition a full teaching load essentially from the day of arrival at SBU and had provided service to the university on just about every committee that I was asked to join (sadly, the practice of asking women and underrepresented faculty to “represent” on university committees can become a burden and must be balanced with the obvious need to be in the room vs priorities set by Appointment, Promotion, and Tenure Committees). I enjoyed outstanding mentoring from Full Professors Eckard Wimmer and Peter Tegtmeyer and benefited greatly from their dazzlingly different styles: Peter was extremely well-organized, was willing to share his wisdom on demand and always maintained a very “zen” demeanor. I learned that his grant applications invariably scored in the top percentile. Eckard, was just the opposite: very disorganized, he celebrated good results joyfully but could be equally deeply depressed by what he perceived as bad ones. He treated me more like a peer than a mentee from the day I arrived, showing me both his positive and negative manuscript reviews and grant critiques. I remain to this day very grateful for this sharing. This was especially the case beginning in 1983, when NIH and other funding sources for reovirus research became more and more difficult to identify and I struggled to maintain the lab. At a desperate low point, I bartered with my then chair, Dr Arnie Levine, and exchanged my spacious lab for a much smaller accommodation and some dollars to purchase supplies. The move relocated me to the wing occupied by Eckard Wimmer: This proved to be quite fortuitous, as we ended up talking “Science” casually much more. Just before I moved, I decided to take a sabbatical and re-tool. A hot topic in the field at the time was whether or not viruses were etiological agents of human cancers. That fact and its proximity prompted me to choose the laboratory of Carol Privies, a premier DNA tumor virologist at Columbia University whom I greatly admired both professionally and personally. This turned out to be a wonderful experience: I ended the year with new ideas for experimental strategies and approaches, loads of new techniques tucked under my belt and a fresh perspective on how to run a laboratory. My super-supportive spouse and I also delivered our son into this world during this sabbatical period. This made both home and lab life wonderful! At the end of the year, I returned to SBU with renewed enthusiasm. A comment about “work-life balance”: Both my husband and I worked long hours, and our son was part of that. My department faculty peers, my graduate students and my postdocs welcomed him into the community whenever I would return to the lab with him, surreptitiously demonstrating to him the latest computer game apps!

Key Discoveries

Serentipity-6:

[Best decision I ever made: Joining an emerging field] Looking back, it is clear that the global urgency brought on by the advent of the AIDS pandemic contributed incredibly to promoting interactions between otherwise silo-trending scientists. As I was gearing up to apply for funds to switch to the field of tumor virology, a NIH Program Officer and AIDS activist, Nava Sarver (later became chief of the NIH branch for AIDS research) encouraged me to switch to investigation of the then emerging human immunodeficiency virus (HIV). This turned out to be incredibly good advice: At that point, the field of tumor virology was quite mature and very crowded. In contrast, although initially highly controversial, HIV-1 had been established as the etiological agent of AIDS and identified as a member of the well-established RNA tumor virus (retrovirus) group. While HIV shared many replication features with the well-characterized avian and mouse RNA tumor viruses, such as expressing its structural and enzymatic functions initially in the form of a polyprotein, it also presented genetic, morphological and pathological properties that were distinct. Identifying others who wanted to understand how best to deal with this novel retrovirus became easy. It was clear that there were challenges to rapid vaccine development so pharmaceutical companies saw opportunities for development of novel antivirals. The fact that pharma already had extensive experience in production of highly successful inhibitors of acidic proteases, the class of enzyme involved in control of blood pressure in humans, made the link to targeting the structurally and functionally similar virally encoded acidic protease very compelling. I think the combination of having been a graduate student with Frank Black, whose lab had studied poliovirus and finding my post-sabbatical self serendipitously situated across the hallway from the laboratory of Eckard Wimmer, an eminent polio virologist, converged to make collaboration with Eckard to tackle HIV a natural next step. Together with an Infectious Disease clinician (Roy Steigbigel) and a Pharmacologist (Francis Johnson), Eckard and I submitted to NIH a program project grant proposing poliovirus as a model for HIV structural and enzymatic gene expression that could be exploited for both understanding HIV assembly and for production of viral proteins for diagnostics and anti-viral drug development. Our grant was awarded. Eckard used his connections to pharmaceutical companies to form collaborative interactions for translational development. I entered the world of HIV protease (PR) activation, PR substrate specificity, Gag proteolytic processing and capsid (CAp24) protein assembly. Talented graduate students (PR: Katherine Partin, Gabriele Zybarth; CA: Beth Agresta), outstanding postdoctoral fellows (CA: Lorna Ehrlich; PR: Fiona Fernandes, Hans-George Krausslich) and structural biology collaborators (HIV-1 CA: Michael Summers, Michael Rossman; EIAV MA: Nico Tjandra; EIAV, HTLV CA: Nico Tjandra) made this new direction hugely productive for us and enabled me to re-establish myself in a new field. Key discoveries during this period include identification of determinants of HIV-1 protease specificity and activation (Kräusslich 1988; 1989; Partin 1990; 1991; Zybarth 1994; 1995) and contributions to understanding of HIV-1 capsid protein structure and function (Ehrlich 1990; 1992; 1994; 2001; Momany 1996; Prongay 1990).

Serendipity-7:

[The challenge that drove our research efforts] Back in the 1990’s and subsequently, there were antivirals against the HIV enzymatic functions, i.e., reverse transcriptase, protease and eventually integrase. However, although many were highly effective, the virus quickly developed resistance, making constant surveillance, adjustment to new drug regimens, the self-discipline of the patient and tolerance to highly cytotoxic agents critical requirements for successful treatment. These challenges make managing the affliction daunting for both people living with HIV and their health care providers. NIH spokespersons repeatedly exhorted “You (scientists) need to think about ways that the virus won’t accrue resistance to drugs so quickly.” Like many other viruses, HIV “travels light”, i.e., it encodes in its genome relative few genes (9 in the case of HIV) and usurps functions encoded by the host. Relatively early on (~1990’s), we began efforts to identify cellular proteins that the virus uses (as opposed to viral proteins it encodes) in order to assess their feasibility as potential antiviral targets. Again, serendipitously, Stan Fields, a yeast geneticist, was at that time a member of our department at SBU. Stan, who was just beginning to develop the yeast two-hybrid assay for protein-protein interactions for which he would later become renown, was anxious for others to test out his system and so was delighted when a graduate student in my lab, Beth Agresta, volunteered to use it and his housekeeping cDNA library to search for potential binding partners of HIV-1 Gag among the cellular proteins. Among other gene products, Beth pulled out cyclophilin A and a gene product that was later identified in the literature as Tsg101 (Li & Cohen 1996). Concerned that the tsg101 sequence was not in the protein database, Beth chose to work on cyclophilin A. However, driven by curiosity, she and I periodically checked for its appearance. It appeared there several months later, submitted by Stan Cohen, a cancer geneticist at Stanford University. I called him and learned that he had discovered that anti-sense knock-out (k/o) of the tsg101 gene in mice resulted in tumor development (hence the name “tumor suppressor gene”). The status of Tsg101 as a bonafide tumor suppressor is still controversial today. However, that fortuitous telephone conversation in which he revealed that k/o promoted tumor formation, reinforced my belief that HIV’s interaction with the cellular protein was very different from that of the cell: Firstly, HIV was not (and is not) known to cause cancer directly; secondly, the orthologue of Tsg101 in yeast, Vps23, was known to function in sorting of ubiquitinated proteins to degradative compartments. We knew at that point that, in contrast to the manner in which the cell employed the protein, i.e., to deliver cellular “trash” to the garbage pail, HIV exploited Tsg101 to escape from infected cells. Interference with the Tsg101 steady-state impaired HIV production: An undergraduate student in our lab, Tracy La Grassa, working with graduate student Lynn VerPlank and postdoctoral fellow Fadila Bouamr had learned that the C-terminal p6 domain of Gag recognized the Tsg101 protein both in vitro and in cells and that the region of interaction within p6 was a Pro-Thr-Ala-Pro motif that had been designated as the “late” (L) domain by earlier investigators because it is required for release of mature virus particles from the cell periphery (Ver Plank 2001). Using constructs and reagents provided by Stan Cohen, graduate student Arthur (Jay) Goff and Research Associate Lorna Ehrlich demonstrated experimentally that both tsg101 depletion and over-expression were deleterious to HIV-1 production in the absence of impact on cell growth (Goff 2003). Independent studies were conducted in the laboratories of Wesley Sunquist (U Utah) and Paul Bieniasz (Rockefeller U), essentially simultaneously. Insights founded on studies conducted by yeast geneticist Scott Emr (who coined the acronym “ESCRT”) and cell biologists converged to establish a model positing that HIV Gag, modified by ubiquitination, recruits Tsg101, a component of ESCRT (endosomal sorting complexes required for transport) machinery to assembly sites at the cell periphery to facilitate membrane evagination events that are the topological opposite of the membrane invagination events occurring at sorting endosomes in the cell interior. Occurring at the cell periphery, this membrane remodeling fosters budding of assembled viral particles into the extracellular environment rather than into the lumen of the endosome where, upon acidification, cargo is degraded. Many laboratories, including those of Heinrich Gottlinger, John Wills, Eric Freed, Eric Hunter, Jon Leis, Steve Goff, Ron Montelero, David Derse, Louis Mansky and Ron Harty, subsequently identified cellular partners of L domains, establishing the broad applicability of this model to many virus families. Collectively, these findings provided the first evidence of a host–pathogen interaction that enabled the virus to evade the fate of cellular cargo and opened new avenues for development of antiviral therapeutics. Identification of a potential first-generation therapeutic based on the Tsg101 interaction with Gag and ubiquitin signaling was published by our laboratory in 2017 (Strickland 2017). It provides “proof-of-principle” that targeting host proteins is a feasible antiviral strategy that can be made to work with limited cytotoxicity. Subsequent studies demonstrate the broad yet selective applicability to other virus groups (Watanabe 2020; Leis 2021; Mannemuddha 2021; Nyenhuis 2024). Perhaps the broad dependence of diverse virus groups on ESCRT machinery reflects highly niched mechanisms for its recruitment that inherently limit the cytotoxicity otherwise anticipated to accompany host protein targeting.

Overview and future directions

My election to the National Academy of Sciences was timely, as it came just as I was planning to retire from active research, feeling that we had vindicated Tsg101 as a viable target. However, there is still much to learn about the Tsg101 protein: While it is well established that the protein functions as an early-acting component of ESCRT machinery, our most recent studies have revealed its ability to interact with and regulate a broad array of ubiquitin (E3) ligases (Watanabe 2024; Nyenhuis 2023; 2025). Control of ligase expression and activity might underlie and explain Tsg101’s participation in cellular functions outside the realm of ESCRT. Moreover, the challenge that drove our research efforts over the years still exists: Is countering viral resistance achievable? In the virus-host “arms race” each side continuously improves its weapons. As noted in the Abstract to this Reflections article, the mature HIV capsid protein (CAp24) has emerged as a tractable target for antiretroviral therapy, with the FDA approval just this year of a 1^st in-class drug that incapacitates the viral coat. As our lab was among the first to demonstrate that a recombinant form of the protein could be expressed in E. coli, purified and encouraged to self-assemble in vitro, we believe we can claim a small share of this achievement. Others optimized and refined biochemical conditions that led to solving the structure of the N- and C-terminal domains of the protein at high resolution, characterizing its biophysical properties, and imaging the structure using cryoelectron tomography and microscopy. Fast forwarding to today, Lenacapavir, developed by Gilead Sciences, is the first drug able to target the assembled capsid (composed of hexameric and pentameric assemblages of CAp24 proteins) approved for medical use. Lenacapavir’s potent antiviral activity is predominantly due to a hyper stabilization of the capsid lattice induced by binding that prevents the capsid from entering the nucleus, initiating/completing reverse transcription and integrating the proviral (DNA) genome into that of the host. Interestingly, however, despite its high potency and favorable deliverability properties, a significant drawback of Lenacapavir is its low barrier to viral resistance (Briganti 2024). A mutation in the HIV-1 capsid, M66I, confers > 80,000-fold resistance and was found to emerge in both cultured cells and in HIV-1-infected individuals treated with the drug. In the absence of Lenacapavir, this mutation causes a substantial defect in viral fitness (<5% infectivity relative to WT). This raises an urgent question: Given the high mutation rate of HIV-1, it is anticipated that emergence of the mutation in patients will occur in association with additional changes to compensate for the loss of fitness. How will this affect the course of infection and the drug’s ultimate efficacy? Countering the emergence of resistant variants may continue to be challenging when viral-encoded genes are the target.

Finally, an issue that is even more pressing both in academia and outside pertains to the fact that women and individuals under-represented in any given area who seek to enter the space are often greeted with apprehension rather than welcomed. I’ve always wondered why. The message I hope to convey here is that offering opportunity only broadens inclusion; fate decides whether or not they succeed. In an academic career spanning over 50 years, I believe I have directly mentored more females and underrepresented minority (URM) doctoral students than many men significantly more established than me (females: 88%; URM, 41%; n = 17; including high school and college students would increase the numbers significantly). Based on statistics from the National Center for Science and Engineering, 54% of doctoral recipients in the biological and biomedical sciences in 2020 were women. Even though this statistic focuses on disciplines where the numbers are traditionally higher, (i.e., excludes physics, mathematics and engineering) only 32% of tenure-track faculty in the Biological Sciences were women at 4-year degree granting institutions and this number declined to 18% at the rank of Full Professors, highlighting a significant gender gap at the highest academic rank within the field. The percentage of URM with doctoral degrees in the Biological Sciences is dismal, estimated to be around 3% or less. Although many refute the notion, it has been argued that diversity and inclusion have positive impacts on problem solving. Given the challenging problems faced in all facets of life today, I would suggest that the concept of “all hands on deck” should be universally embraced as a potential means of improving the quality of life for all.

Research Highlights for the Perspectives article.

• Graduate School: Trusting my instincts

• Negotiating hard times

• Best decision I ever made: Joining an emerging field

• The challenge that drove our research efforts

• The research finding considered our most important contribution to the field

• An important open question for the future

Abbreviations

HIV

Human Immunodeficiency Virus

AIDS

Acquired Immunodeficiency Disease Syndrome

Tsg101

Tumor Suppressor Gene 101

ESCRT

Endosomal Sorting Complexes Required for Transport

CA(p24)

Capsid Protein

SBU

Stony Brook University

k/o

(gene) knock-out

Biography

I graduated from the City College of the City of New York (CCNY) in 1967. At that time, CCNY was touted as one of the greatest sources of graduates who would go on to obtain PhDs in the country. It was among the country’s earliest liberal colleges, founded in 1847 as the Free Academy whose mission was to deliver free public higher education (Albert Einstein delivered lectures there in the early 1900s) and serve as “an Ellis Island of education and driver of upward mobility for New Yorkers of all backgrounds” (words of current Chancellor Félix V. Matos Rodríguez), whose criteria for admission was based on GPA and SAT score alone and irrespective of sex (open to women in 1946), race, family income, or religious preference. At graduation, I was one of only 2 of ~300 biology majors headed to graduate school (the rest targeted medical school). My parents had emigrated to the US from the Caribbean to find work at the end of World War I. Neither had been educated past grade 6. As an ethnic and gender minority in the biology/chemistry sciences, the school’s motto, “ERUDITIO POPULI LIBERI SPES GENTIUM” (The education of free people is the hope of humanity), resonated throughout my family then and still does now: My siblings and my spouse are CUNY alums.