In Memoriam, Beth Levine

We mourn the loss of Prof. Beth Levine. Beth was a pioneer and a visionary who launched the obscure but burgeoning field of autophagy into stardom. Few had heard the word autophagy before Beth’s brilliant work made autophagy a medically relevant field of study and a tractable field of basic science. She was a precious colleague and an inspiration. Her contributions allowed us to appreciate the importance of this evolutionarily conserved phenomenon. Beth was crucial to the establishment of autophagy as a major research field of biology and medicine.

Beth Levine studied French in college at Brown and earned an M.D. from Cornell in 1986. Following her internship and residency at Mount Sinai, she was an infectious disease fellow at Johns Hopkins before starting her own research lab at Columbia, where she married cardiologist Milton Packer. They relocated to UT Southwestern and raised two children. Beth passed away on June 15^th at age 60 of breast cancer.

Being a specialist of infectious diseases, Beth’s interest in neurotropic viruses led her to the field of autophagy. During the study of a Sindbis virus model of encephalitis, she discovered Beclin 1 (BECN1) as an interactor of BCL2 and as the mammalian orthologue of the yeast autophagy protein ATG6/VPS30. Further studies in a seminal paper (Nature 1999*) by Beth revealed that Beclin 1 was indeed a key activator of autophagy in mammals. This identification of a mammalian autophagy gene sent shock waves; the obscure word autophagy became almost a household word, and a new field with its own meeting venues was born. The protein Beclin 1 has been demonstrated to be involved in the regulation of the lipid kinase VPS34, and it helps determine the sites of autophagosome formation through regulation of phosphoinositol phosphorylation. Additional roles for Beclin 1 in later stages of autophagosome maturation and endosome regulation were also described.

The role of autophagy in cell death was a long debated issue. Although an increase in autophagic activity was clearly observed in non-apoptotic cell death scenarios, and ultrastructural observations by Lockshin et al. date back to late 60’s, molecular mechanisms of autophagy-related cell death were unknown. Beth and colleagues discovered that unleashing of Beclin1 from an inhibitory interaction with BCL2 family of proteins could activate autophagy and cell death. Indeed, a short fragment of Beclin1 fused to HIV Tat peptide (facilitating cellular entry), led to the activation of a caspase-independent type of cell death. Beth and colleagues named this novel type of programmed cell death as “autosis”. Morphologically, autosis was characterized by increased cell adherence to substrate, swelling and fragmentation of the ER, followed by disappearance of the organelle, nuclear membrane changes and local swelling of the perinuclear space. Further studies showed the importance of autosis in ishemic cell death of various tissues, including neurons.

Beth was also an excellent mentor who touched the lives of many young scientists. She had an unwavering commitment to always find the positives in other people, seeking to be a peacemaker. Beth devoted countless tireless hours to pour over colleagues’ grant proposals and manuscripts. Scientists and friends who knew her best have pointed out in various ways that Beth recognized her genius starting at an early age, but never felt the need for you to know this. Her scientific intuition was remarkable, built on a galaxy of  knowledge. Still, family was first to Beth. In addition to her excellent publications that helped guide the field, Beth was an inspiration and a role model for all of us.

This final paragraph is a reflection on Beth Levine based on yearly encounters at autophagy conferences, where she touched the life of one of us (DG) more than once. demonstrating her lovely and gentle character as well as her scientific perspicacity.

“The most memorable encounter was in an EMBO Meeting in Ascona, Switzerland: Following completion of my graduate studies in some of the finest scientific institutions in the World, I decided to continue my independent career in my native country, Turkey. Many said “A very risky but bold move”. Indeed, pursuit of an international career in a peripheral country is a big challenge. In addition to physical shortcomings, lack of facilities, material import problems and a serious brain drain of the most motivated and talented students, peer-pressure against scientific excellence and academic “Byzantine politics” (maybe traditional in Istanbul(!)) rapidly leads to the exhaustion of most noble (and “Nobel”) ambitions. I was in Ascona to present the results of the very first scientific story that was shaping up in my independent lab in Turkey. I presented our results in front of some of the most prominent scientists in the field. Beth was there and she asked me several very interesting and mind-opening questions. I was very nervous and not sure how good were my answers. She sensed that and came next to me during the coffee break. In her always elegant and gentle style, she whispered, ” A very interesting work and you made an excellent presentation. Well done.” And then we talked. It meant the world to me to hear these encouraging words from Beth’s mouth. It was a memorable moment and a milestone in my career. She gave me the courage to dare and not give up, no matter what. Her kindness and generosity continued in all of our encounters, communications and collaborations. Rest in peace, we will always remember you.”

Thank you for the memories, Beth Levine. We will remember you.

 

Contributed to our web page by two board members, J. Marie Hardwick and Devrim Gozuacik, with editing by Richard A. Lockshin.

*Liang, X., Jackson, S., Seaman, M. Brown K, Kempkes B, Hibshoosh H, and Levine B. Induction of autophagy and inhibition of tumorigenesis by beclin 1 . Nature 402, 672–676 (1999). https://doi.org/10.1038/45257