Beth Levine (physician)

[1]Beth Cindy Levine (April 7, 1960 - June 15, 2020) was an investigator at the Howard Hughes Medical Institute (HHMI), Professor of Internal Medicine and Microbiology, Director of the Center for Autophagy Research and Charles Cameron Sprague Distinguished Chair in Biomedical Sciences at the University of Texas Southwestern Medical Center.[1] She specialized in the field of autophagy; more specifically in its regulation and its role in diverse diseases, including cancer and infectious diseases.[2] She is a pioneer in the field of modern mammalian autophagy [3]

Dr. Beth Levine
Beth Levine, MD
Born(1960-04-07)April 7, 1960
Newark, New Jersey
DiedJune 15, 2020(2020-06-15) (aged 60)
Alma mater
Known forIdentified the mammalian autophagy gene BECN1/beclin 1
Spouse(s)Dr. Milton Packer
ChildrenRachel and Ben
AwardsThe American Cancer Society Junior Faculty Research Award (1994); election into the American Society of Clinical Investigation (2000); the Ellison Medical Foundation Senior Scholars Award in Global Infectious Diseases (2004); elected member, American Association of Physicians (2005); appointment as a Howard Hughes Medical Institute Investigator (2008); Edith and Peter O’Donnell Award in Medicine (2008); elected fellow, American Association for the Advancement of Science (2012); election into the National Academy of Sciences (2013); election into the Academy of Medicine, Engineering and Science of Texas (2013); the ASCI Stanley J. Korsmeyer Award (2014); Phyllis T. Bodel Women in Medicine Award, Yale University School of Medicine (2018); recipient, Barcroft Medal, Queen’s University Belfast (2018).
Scientific career
Institutions

Education

In 1981, Dr. Beth Levine majored in French studies at Brown University (magna cum laude) and completed her M.D. at Cornell University Medical College, New York. She completed her internship and residency in Internal Medicine at Mount Sinai Hospital in New York City and her fellowship in "infectious diseases and the pathogenesis of neurotropic viruses"[2] at Johns Hopkins University, Baltimore. She served as Director of Virology Research at Columbia University from 1994 to 2004, and Director of the Division of Infectious Diseases at the University of Texas Southwestern Medical Center from 2004-2011.

[3]At the time of her death, Beth was professor of internal medicine and microbiology, director of the Center for Autophagy Research, Charles Cameron Sprague Distinguished Chair in Biomedical Science at the University of Texas Southwestern Medical Center, and a member of the Howard Hughes Medical Institute. She was a leading light in linking autophagy to pathology and a strong advocate for integrating clinical and scientific training toward a holistic understanding of organ systems and afflictions. As part of her mission to bring together scientists from diverse countries and disciplines to link fundamental biology to human health, in 2003 Beth created and organized the Gordon Conference on Autophagy in Stress, Development, and Disease, which continues to this day. Early clues hinted at a bright career ahead in science: as a trainee at Mount Sinai Hospital, Beth published an impressive study examining a potential mechanism of chronic heart failure (Levine et al., N. Engl. J. Med. 323, 236–241) and, 30 years later, showed that cardiac glycosides block autophagy-dependent cell death (Fernández et al., JCI Insight 5, 1). With a keen, unwavering focus on fundamental biological concepts, Beth’s contributions influenced many biomedical disciplines and informed the understanding of numerous clinical conditions. She made an indelible impact on her colleagues and the scientific community at large.

Work

Beth was well published and received many deserved honors, but the caliber and type of discoveries she made were extraordinary. Beth was given to bouts of remarkable scientific intuition and insight about biology. She was eclectic in thought with an eidetic memory, drawing connections that others did not see: Beth lived in a galaxy of possibility, while others inhabit the atmosphere of a single planet. Her scientific achievements were frequently characterized by the alignment of divergent areas of biology. She had the singular capacity to weave disparate facts into a tapestry of truth, somehow managing to understand the whole cell and organism in a way that allowed her to cross boundaries, create new fields, and thereby see and document associations that others simply had not imagined. Beth frequently formed productive cross-disciplinary collaborations to create integrative experiments that opened new areas for investigation. Furthermore, she utilized a wide range of experimental systems, including yeast, plant, nematode, mouse, and human, to publish observations spanning from complex physiology to structural studies of molecular mechanisms, often in the same study. This capacity to bring together both fields and the people in them is a notable legacy that cannot be underestimated and one that we deeply admired and respected in Beth. Reviewing her achievements upon her passing, we remain surprised by the exceptional brilliance of her insights. Though we aim to honor the importance and breadth of Beth’s work as a scientist herein, the totality of her accomplishments is near limitless.[3]

With her discovery of the first mammalian autophagy gene Beclin 1 (Liang et al., Nature 402, 672–676), Beth established an entire field with ever-increasing and wide-ranging influence on human physiology and longevity, innate immunity, cellular and organismal metabolism, and cancer. In a series of landmark papers, Beth and her group connected autophagy and cell survival pathways, identifying the direct association of Beclin 1 with the anti-apoptotic protein Bcl-2, an association that resulted in inhibition of Beclin 1-dependent autophagy (Liang et al., J. Virol. 72, 8586–8596.). These pivotal findings revealed an unexpected function for Bcl-2 as an anti-autophagic protein that modulates levels of autophagy to promote cell survival (Pattingre et al., Cell 122, 927–939). Expanding on this study, the Levine lab generated a mouse model harboring a mutation in Beclin 1 that disrupts its interaction with Bcl-2. They discovered that this mutation, which increases basal autophagy by eliminating effective inhibition by Bcl-2, remarkably, prolongs lifespan, promotes healthy aging, and decreases the incidence of spontaneous cancers (Fernández et al., Nature 558, 136–140). Work from Beth’s group previously demonstrated the requirement for autophagy in lifespan extension in C. elegans (Jia et al., Proc. Natl. Acad. Sci. U. S. A. 106, 14564–14569; Meléndez et al., Science 301, 1387–1391), but improving mammalian longevity was a tremendous accomplishment with profound implications for human health. Further examining the physiological impact of autophagy modulation on health, the Levine lab showed that exercise induces autophagy and generated a mouse model with a mutation in the Bcl2 gene that prevented such exercise-induced autophagy in skeletal and cardiac muscle, decreased endurance, and showed significant systemic metabolic effects via impaired regulation of glucose metabolism (He et al., Nature 481, 511–515). Through their meticulous dissection of pathways controlling exercise-induced autophagy, the Levine lab also discovered a link between inflammation and metabolism (Liu et al., Nature 578, 605–609) and described mechanisms potentially underlying the benefits of exercise in human health. This latter work involved linking three disparate fields—innate immunity, autophagy, and organismal physiology—providing an example of the remarkable span of conceptual and experimental work often observed in papers published by Beth and her colleagues.[4]

[3]The Levine lab made numerous critical discoveries surrounding viral disease and later extended that expertise into the field of virophagy, one form of selective autophagy. In a seminal paper published during her postdoctoral work, Beth showed that Bcl-2 expression converted lytic viral infection to persistent infection through effects of Bcl-2 on apoptosis, thereby linking the inhibition of cell death to viral persistence (Levine et al., Nature 361, 739–742). As a newly independent investigator, Beth pursued the mechanism underlying these effects, making the seminal discovery that Beclin 1 confers resistance to Sindbis virus infection by inhibiting viral replication and antigen expression through neuron-intrinsic effects (Liang et al., J. Virol. 72, 8586–8596). In an example of how Beth spanned experimental systems to answer fundamental questions, she turned to plant genetics to confirm that autophagy induction occurred in response to infection in an evolutionarily conserved manner and that the plant response to viral infection, which is mechanistically distinct from the mammalian response, depends on multiple autophagy genes (Liu et al., Cell 121, 567–577).

[3]Beth and her group first demonstrated that viruses, such as herpes simplex virus type 1 (HSV-1), are targeted by selective autophagy for lysosomal degradation (Tallóczy et al., Autophagy 2, 24–29). They showed that this mechanism of host defense was inhibited by the HSV-1 virulence protein ICP34.5 via direct effects on Beclin 1 and alterations in the antiviral protein kinase R (PKR) pathway (Tallóczy et al., Proc. Natl. Acad. Sci. U. S. A. 99, 190–195). An important observation was that, absent this viral virulence protein, HSV-1 virions appeared within autophagosomes, demonstrating that ICP34.5 inhibits HSV-1 degradation during PKR-induced autophagy. These studies revealed a novel antiviral innate immune response and, importantly, new mechanisms by which a virus subverts the host autophagy machinery for its own benefit (Tallóczy et al., Autophagy 2, 24–29). Beth’s lab proceeded further to describe the mechanism by which ICP34.5 inhibits virophagy through direct binding to Beclin 1 and demonstrate the importance of this mechanism in vivo (Orvedahl et al., Cell Host Microbe 1, 23–35). To directly interrogate the role of essential autophagy genes in mammalian antiviral responses, Beth’s group demonstrated that autophagy components in addition to Beclin 1, including Atg7, Atg5, and p62, mediate viral protein clearance and cell survival in the context of Sindbis virus infection (Orvedahl et al., Cell Host Microbe 7, 115–127). They also identified Beclin 2, an autophagy gene involved in endolysosomal trafficking and metabolism (He et al., Cell 154, 1085–1099), and demonstrated that it protects against viral oncogenesis by interacting with a viral oncoprotein to induce its degradation (Dong et al., Proc. Natl. Acad. Sci. U. S. A. 113, 2994–2999). In all, Beth’s work on viral disease provided the first evidence of virophagy as well as a mechanism for virus-directed inhibition of innate immunity.

[3]Beyond her significant contributions to the field of virophagy, Beth’s discoveries advanced the understanding of additional forms of selective autophagy, including xenophagy and mitophagy. In fact, Beth coined the term xenophagy to distinguish selective autophagy targeting intracellular pathogens from classical non-selective autophagy (Levine, Cell 120, 159–162). Her early work connecting autophagy to lifespan in C. elegans additionally showed that autophagy disruption impairs resistance to Salmonella infection (Jia et al., Proc. Natl. Acad. Sci. U. S. A. 106, 14564–14569). The Levine lab developed systematic approaches to identify novel genes required for selective autophagy, including a genome-wide small interfering RNA (siRNA) screen that implicated hundreds of genes in recruitment of core autophagy machinery to the Sindbis virus (Orvedahl et al., Nature 480, 113–117) as well as in parkin-mediated mitophagy. Of these gene candidates, the E3 ubiquitin ligase SMURF1 was further characterized as a selective autophagy factor that targets viruses to the autophagosome and clears damaged mitochondria. Beth’s group later demonstrated that SMURF1 ubiquitin ligase activity is required for antibacterial targeting to autophagosomes and dissected its role in host defense against Mycobacterium tuberculosis infection in vivo (Franco et al., Cell Host Microbe 21, 59–72). Analyses of additional genes identified in the siRNA screen revealed novel roles for each in virophagy and mitophagy. For example, multiple Fanconi anemia (FA) pathway genes, previously known to be essential for DNA damage repair, were found to have distinct cytoplasmic roles in selective autophagy (Sumpter and Levine, J. Cell Sci. 130, 2657–2662; Sumpter and Levine, Oncotarget 7, 50820–50821; Sumpter et al., Cell 165, 867–881). Peroxisomal proteins PEX3 and PEX13 were also implicated in virophagy and mitophagy, and Beth’s subsequent work suggested that these functions contribute to the pathogenesis of fatal peroxisome biogenesis disorders (Lee et al., EMBO Rep. 18, 48–60). The Levine lab also identified prohibitin 2, a mitochondrial inner membrane protein, as a mitophagy receptor that mediates mitochondrial degradation (Wei et al., Cell 168, 224–238). This latter observation provided data supporting a role for the inner mitochondrial membrane in mitophagy, a process that had previously been primarily thought to focus only on the outer mitochondrial membrane. Altogether, Beth’s work produced foundational contributions to the understanding of multiple selective autophagy pathways and their role in diseases including neurodegeneration, inflammatory disorders, and cancer (Jia et al., Autophagy 3, 21–25; Levine and Kroemer, Cell 176, 11–42).

[3]Beth was one of the first investigators to recognize the significance of monoallelic deletion of Beclin 1, occurring in 40%–75% of sporadic breast, ovarian, and prostate cancers (Liang et al., Nature 402, 672–676; Qu et al., J. Clin. Invest. 112, 1809–1820), at a time when the consequence of loss of heterozygosity of tumor suppressor genes was not widely appreciated. This work provided the first functional validation of the involvement of a mammalian autophagy gene in cancer. Her lab provided compelling evidence that complementation of Beclin 1 in haploinsufficient human breast carcinoma cells restores autophagy and reduces proliferation (Liang et al., Nature 402, 672–676). To conclusively demonstrate the function of Beclin 1 as a tumor suppressor, Beth’s group generated a mouse model in which loss of a single Beclin 1 allele was sufficient to increase the frequency of spontaneous malignancies and accelerate the development of premalignant lesions induced by the hepatitis B virus (Qu et al., J. Clin. Invest. 112, 1809–1820). These data were confirmed in an independent report, thereby firmly establishing the role of this gene as a haploinsufficient tumor suppressor (Yue et al., Proc. Natl. Acad. Sci. U. S. A. 100, 15077–15082). Subsequently, Beth systematically uncovered multiple mechanisms by which oncogenic signaling pathways suppress autophagy through direct regulation of Beclin 1. The Levine lab also found that HER2-enriched, mainly triple-negative, breast cancers tend to express lower levels of Beclin 1 mRNA than other subtypes (Tang et al., EBioMedicine 2, 255–263). They further demonstrated interaction between HER2 and Beclin 1 and identified a requirement for the tyrosine kinase activity of HER2 in autophagy inhibition (Vega-Rubín-de-Celis et al., Proc. Natl. Acad. Sci. U. S. A. 115, 4176–4181). Notably, the Beclin 1 mutant mice, in which Bcl-2 does not effectively inhibit basal autophagy and which showed enhanced autophagy and increased longevity (Fernández et al., Nature 558, 136–140), exhibit reduced tumorigenesis in the HER2 MMTV transgenic model of breast cancer. Work from Beth’s lab continued to identify oncogenic pathways converging on autophagy at the level of Beclin 1. For instance, they showed that phosphorylation of Beclin 1 by EGFR inhibits autophagy and contributes to tumor progression and chemoresistance (Wei et al., Cell 154, 1269–1284). Akt and Jnk2 were also identified as having opposing effect on autophagy, with Akt-mediated phosphorylation of Beclin 1 inhibiting autophagy (Wang et al., Science 338, 956–959), whereas Jnk1-mediated phosphorylation of Bcl-2 leads to dissociation from Beclin 1 and induction of autophagy (Wei et al., Mol. Cell 30, 678–688). Moreover, stimulus-induced autophagy improved the efficacy of chemotherapy and enhanced an anticancer immune response, introducing potential cancer prevention and therapeutic strategies.

[4]These key findings demonstrating the tumor suppressive role of Beclin 1 in vivo and the regulation of Beclin 1 and autophagy by oncogenic pathways raise the challenging question of how autophagy influences cell growth control, which Beth and her lab addressed head-on. Clarifying several long-standing debates in the field, they characterized a mechanism of autophagy-dependent programmed cell death termed autosis. They performed genetic studies and screened an annotated library of small bioactive molecules, demonstrating the requirement of Na+,K+-ATPase for autotic cell death (Liu et al., Proc. Natl. Acad. Sci. U. S. A. 110, 20364–20371). Subsequent studies observed the induction of autosis by excessive autophagy in cardiomyocytes within the context of tissue injury (Nah et al., J. Clin. Invest. 130, 2978–2991). The Levine lab also demonstrated that autophagy controls energy-dependent engulfment signals required for clearance of cellular corpses (Qu et al., Cell 128, 931–946). This body of Beth’s work established autophagy as a central regulator of tumorigenesis and cell growth control, while introducing autosis as a new area for exploration among cell death programs.

[4]An overarching goal of Beth’s career was to improve human health by understanding fundamental biological processes, and she therefore sought to develop new therapeutics for neurodegeneration, infectious diseases, and cancer. Leveraging insights from anti-autophagy mechanisms used by HIV and its viral protein Nef, the Levine lab developed an autophagy-inducing peptide, Tat-Beclin, that ameliorated clinical outcomes for neonatal mice challenged with chikungunya and West Nile virus infections (Shoji-Kawata et al., Nature 494, 201–206). This drug-like compound has been used by many additional groups to explore the potential physiologic consequences of autophagy induction. Recent structural and biochemical work has revealed that this peptide activates autophagy by regulating the membrane targeting activity of class III PI3 kinase, which includes Beclin 1 as a subunit (Chang et al., Molecular Cell 73, 339–353). The Levine lab also screened small molecule collections for novel inhibitors of Beclin 1-Bcl-2 interaction, identifying three candidates that induce autophagy in vitro (Chiang et al., ACS Chem Biol. 13, 2247–2260). Together with the Tat-Beclin peptide, these molecules represent only a small fraction of therapeutic starting points for the treatment of a range of human diseases that are based on Beth’s innovative and extensive basic science research. We experienced firsthand Beth’s dedication to autophagy-based therapeutics through our shared roles in a Center for Excellence in Translational Research grant from the NIH; despite her prognosis, Beth worked to ensure the continuation of the Center and, more importantly, the research.

For the above discoveries and many other contributions throughout her career, Beth was recognized by dozens of awards and honors: American Cancer Society Junior Faculty Research Award in 1994; induction into the American Society of Clinical Investigation (ASCI) in 2000; Harvey lecture in 2004 (Levine, Harvey Lect. 99, 47–76); Ellison Medical Foundation Senior Scholars Award in Global Infectious Diseases in 2004; membership in the American Association of Physicians in 2006; Howard Hughes Medical Institute Investigator appointment in 2008; Edith and Peter O’Donnell Award in Medicine in 2008; fellowship in the American Association for the Advancement of Science in 2012; induction into the National Academy of Sciences in 2013; membership in the Academy of Medicine, Engineering and Science of Texas in 2013; ASCI Stanley J. Korsmeyer Award in 2014 (Levine and Jackson, J. Clin. Invest. 124, 1423–1424); Phyllis T. Bodel Women in Medicine Award from Yale University School of Medicine in 2018; Barcroft Medal from Queen’s University Belfast in 2018; and many more.

Beth’s scientific achievements were inextricably linked to the person she was, the combination of which is rare indeed. Constant, unswerving integrity formed the core of all of Beth’s actions. She maintained high standards without arrogance, respecting and treating everyone as an equal. She made many close friends in the autophagy field. Beth was determined: she organized many autophagy meetings, attending every one, and spent hours in the microscopy room capturing images on her birthday. Beth was a strong mentor who advocated for her trainees, an exemplary role model for women in science and medicine, and a caring physician with a lifelong dedication to easing human suffering. She proudly bragged about her children, was joyful, and loved to laugh. Brave in the face of her illness, Beth was admirable to the end working to minimize the effect that her passing would have on her trainees. She was our close friend for decades, and we will miss her. It is evident from the outpouring of remembrance and commentary from colleagues since her untimely death that she will be missed by many others, as well. As we mourn her loss, we celebrate Beth’s legacy—one that will undoubtedly continue through the many foundational observations she laid, the scientific colleagues she influenced, the new biological connections that she contributed, and the trainees of whom she was so proud. [4]

Accomplishments
Awards
Year(s) Award Awarded By
1987 Diplomate National Board of Medical Examiners
1989 Diplomate American Board of Internal Medicine
1992 Board Certified Infectious Diseases
1993 - 1994 Silberberg Assistant Professor of Medicine Columbia University
1993 - 1995 Lederle Biologicals Young Investigator Award in Vaccine Development
1994 - 1996 Junior Faculty Research Award The American Cancer Society
1994 - 1996 Pfizer Scholars Program for New Faculty Award
1994 - 1996 NIH Clinical Investigator Award
1994 - 1996 James A. McDonnell Foundation Award
1996 - 2001 Irma T. Hirschl Trust Award
1996 - 2001 NIH R29 First Award
1999 - 2002 31st Mallinckrodt Scholar Award
2000 Elected American Society of Clinical Investigation
2000 Doctor Harold & Golden Lamport Award for Excellence in Clinical Research Columbia University College of Physicians & Surgeons
2003 TIAA-CREF/American Cancer Society Award for Outstanding Achievement and Contributions to Cancer Research The American Cancer Society
2004 Harvey Society Lecturer (Autophagy in Development, Tumor Suppression, and Innate Immunity)
2004 - 2008 Ellison Medical Foundation Senior Scholars Award in Global Infectious Diseases
2005 Elected American Association of Physicians
2007 Appointed as Investigator Howard Hughes Medical Institute
2008 Edith and Peter O'Donnell Award in Medicine The Academy of Medicine, Engineering, & Science of Texas (TAMEST)
2012 Elected fellow American Association for the Advancement of Science
2012 Elected Member Henry Kunkel Society
2013 Elected National Academy of Sciences
2014 Received the Stanley J. Korsmeyer Award The American Society for Clinical Investigation
2014 Thomson Reuters 2014 List of the World’s Most Influential Scientific Minds (Molecular Biology & Genetics)
2015 Distinguished Scientist Award Thomas Jefferson University
2015 Thomson Reuters 2015 List of the World’s Most Influential Scientific Minds (Molecular Biology & Genetics)
2016 Thomson Reuters 2015 List of the World’s Most Influential Scientific Minds (Molecular Biology & Genetics)
2017 Thomson Reuters 2015 List of the World’s Most Influential Scientific Minds (Molecular Biology & Genetics)
2018 Phyllis T. Bodel Women in Medicine Award Yale University School of Medicine
2018 Barcroft Medal Queen’s University Belfast
2019 The William J. Larsen Distinguished Lecture University of Cincinnati College of Medicine, Cincinnati, Ohio
2019 Thomson Reuters 2019 List of the World’s Most Influential Scientific Minds (Molecular Biology & Genetics)
PROFESSIONAL ORGANIZATIONS AND SOCIETIES
Year(s) Organizations/ Societies
1991 - 1996 Associate Member, American Society for Virology
1992 - 1998 Associate Member, Infectious Diseases Society of America
1994 - Member, American Society for Microbiology
1997 - Member, American Society for Virology
1998 - Member, Infectious Diseases Society of America
1999 - Founding Member, International Society for Neurovirology
2000 - Member, American Society for Clinical Investigation
2006 - Member, American Association of Physicians
2009 - International Founding Member, European Research Institute for Integrated Cellular Pathology (ERI-CP)
2012 - Fellow, American Association for the Advancement of Science
2012 - Elected Member, Henry Kunkel Society
2013 - Elected Member, National Academy of Sciences
2013 - The Academy of Medicine, Engineering and Science of Texas (TAMEST)
2016 - Honorary Member, European Academy of Tumor Immunology (EATI)
2019 - 2024 Institutional Representative, American Society for Clinical Investigation (ASCI)
gollark: This is very ethical.
gollark: You can fix climate change by deploying self-replicating nanomachines to dissemble atmospheric carbon dioxide into solid carbon and oxygen.
gollark: Birds are NOT real.
gollark: There are entirely too many weird interacting trends going on right now which make it hard to predict much, not that that was ever very easy.
gollark: The best estimate I'm aware of is that humanity has a 1/6 chance of ceasing to exist within a century, although this says nothing about societal collapse which doesn't wipe out everyone.

References
  1. "Beth Levine, M.D. - Faculty Profile - UT Southwestern". www.utsouthwestern.edu.
  2. "Beth Levine, MD - HHMI.org". hhmi.org.
  3. https://www.cell.com/cell/fulltext/S0092-8674(20)30867-9?rss=yes. Missing or empty |title= (help)
  4. https://www.cell.com/cell/fulltext/S0092-8674(20)30867-9?rss=yes. Missing or empty |title= (help)
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