Remembering Physician-Scientist and Mentor Arthur Nienhuis

Arthur Nienhuis, physician-scientist, past director and CEO of St. Jude Children's Research Hospital, a founder of the American Society of Gene and Cell Therapy (ASGCT) and past president of ASGCT, died February 3, 2021. Over the course of his remarkable career, Art received numerous professional honors, including induction into the National Academy of Medicine. Art’s career began with the molecular revolution in understanding genetic diseases and continued through novel approaches to treat those diseases. He was an early proponent of gene therapy as a discipline, and he was an extraordinary mentor to generations of researchers.

Art was born in Michigan and attended Cornell College before moving to Los Angeles to receive his M.D. from the University of California, Los Angeles. He completed clinical training in internal medicine before moving to the National Institutes of Health in 1970 just in time to perform pioneering work on the analysis of globin gene expression. From there, Art completed training in pediatric hematology at Boston Children's Hospital and returned to the NIH in 1973. Over the next two decades Art established an extraordinarily productive bench-to-bedside research program, leading a series of clinical trials demonstrating that fetal hemoglobin expression could be reactivated pharmacologically, first with 5-azacytidine, and later with hydroxyurea, laying the groundwork for FDA approval of the first drug to treat sickle cell disease. Through these efforts Art developed his life-long friendship and collaboration with George Stamatoyannopoulos, the founder of ASGCT.

In the late 1980s, Art foresaw the gene therapy revolution and began to develop gene-based approaches to the treatment of blood diseases. Anticipating the need for preclinical data to support clinical trials, Art set up a non-human primate model to optimize hematopoietic stem cell transduction that not only was critical to support the early clinical trials but also undercovered critical problems Art spent the rest of his career striving to overcome. In 1993, Art left the NIH to become the director and chief executive officer of St. Jude Children's Research Hospital in Memphis, Tennessee. He was a visionary leader of this leading pediatric cancer and genetic disease hospital and research institution, while continuing his active research program. Art directed an enormous expansion of the facilities and research at St. Jude, including the Children’s GMP facility. His St. Jude colleague Malcolm Brenner, 2002 ASCGT president and past editor of Molecular Therapy, recalled “Art was a rare combination of visionary administrator and superb scientist. He enthusiastically developed a specialized manufacturing facility for cell and gene therapy at St. Jude at a time when no other centers in the USA would seriously consider such an investment.”

In his laboratory at St. Jude, Art expanded into gene therapy of hemophilia B. Working with Andrew Davidoff and Amit Nathwani, Art’s mentees and colleagues at St. Jude, Art’s group developed a novel factor IX (FIX) AAV vector and began the process to get approval for a clinical trial. Andy Davidoff recalled Art’s guidance regarding a switch to AAV8 from AAV2 during their hemophilia clinical trial submission process, saying “the switch in serotypes was critical to the early success of the trial, and much of the credit goes to this help and direction provided by Art.” Kathy High, 2005 ASGCT president and long-time collaborator, stated that “Art, Andy, Amit and Ted Tuddenham were smart enough to hedge their bets and to make a provision for a short course of steroids if they indeed encountered transaminase elevation [which was a side effect noted in earlier hemophilia B trials], kudos to them for achieving the first evidence of long-term expression of FIX from an AAV vector introduced into the liver.” This groundbreaking clinical trial was published in the New England Journal of Medicine in 2011.

Art believed strongly in the mission of the ASGCT  to advance knowledge, awareness, and education leading to the discovery and clinical application of genetic and cellular therapies to alleviate human disease.  Art joined with George Stamatoyannopoulos and other gene therapy pioneers to found ASGCT in 1997. Art was a strong and thoughtful leader during the initial growth of ASGCT and its journal Molecular Therapy. He served as ASGCT president in 2008. Ted Friedman, 2007 ASGCT president, recalled that time as a difficult one for gene therapy, but “Art recognized that the field of gene therapy was on the verge of making advances and that such a leap would require more effective federal funding. Toward that goal, in 2009 he played an instrumental role in organizing a proposal from ASGCT to the NIH for enhanced clinical training funding that continue to serve the field of gene therapy so effectively to this day. On a personal level, it always struck me that Art was the kind of clinician-scientist that I and many in the field of gene therapy have tried to emulate – someone who not only developed innovative tools of molecular genetics but who also applied those tools in the clinical service of the sick and who applied his administrative talents and energy to make that transition happen.”

An equally significant accomplishment was Art's outstanding legacy of mentorship. His laboratory was always a mixture of clinicians with little scientific background, basic researchers and even patients. His list of trainees is absolutely extraordinary, including two presidents of ASGCT, directors of at least four major research institutions or hospitals and more than 13 cancer center directors or department chairs, the director of NIDDK, and many other leaders worldwide. Amit Nathwani, a mentee and later collaborator said: “what is remarkable about Art Nienhuis is that I am just one among hundreds who he has helped in the same manner throughout his career. His impact, therefore, extends way beyond the NIH and St. Jude in the U.S. to many other parts of the world. I am devastated to hear of his passing, as I feel that I have lost my scientific father.”

The authors of this obituary can attest that Art willingness to “sponsor” trainees, making them visible to the scientific community. To his trainees, Art provided unwavering, career-long advice and support and he provided the same to colleagues outside his laboratory. Francis Collins, NIH director said “He inspired many scientists who were just starting out. Forty years ago, I was one of them.” 

Finally, Art was a wonderful colleague and friend. Many of his colleagues stressed how rare Art’s loyalty and basic “niceness” were given his accomplishments and prestige. Don Kohn, 2004 ASGCT president, stated that “As a trainee and junior faculty I was totally intimidated by him for his scope of knowledge and accomplishments. Over time, I got to know him personally and appreciate his warmth, wit, scientific insight and vision.” Art is survived by his wife, Corinne; his children, Carol, Craig, Kevin, and Heather, multiple grandchildren; and siblings Marilyn, Wilma, Robert, and Jan. He was predeceased by his wife Sheryl and his sister Dorothy. Speaking for Art’s trainees, collaborators, and colleagues, Art Nienhuis will be deeply missed. 

This tribute will be published in the April issue of Molecular Therapy.