Stephen T. Warren, Ph.D. (1953–2021): A remembrance

Introduction

Our field of human genetics lost one of its most significant contributors on June 6, 2021. Stephen T. Warren had enormous impact through his discoveries, his service to our field, and especially his mentorship to both colleagues and trainees. Steve’s clever use of somatic cell hybrid methods was key for discovering the mutation in fragile X syndrome, providing a mechanistic answer for the long-standing question of genetic anticipation in humans. He established and led the Department of Human Genetics at Emory University, building a vibrant community, training generations of geneticists and setting an example for us all. His involvement with the American Society of Human Genetics (ASHG) was profound; his membership dated to his undergraduate days in the early 1970s and he had high regard for the Society and its efforts. He served as Editor of The American Journal of Human Genetics, which is the Society’s journal, a member of the Board of Directors, and President. Steve’s accomplishments were recognized with the William Allan Award in 1999 (Figure 1). We write in fond remembrance of our dear colleague; he is missed immensely. Hopefully we can convey the depth of his loss to readers of his beloved journal.

Figure 1.

Stephen T. Warren, Ph.D.

Photo courtesy of Emory University.

Early years

Steve was born in Detroit, Michigan, in November of 1953. He liked to point out that his birth was only shortly after publication of the discovery of the structure of DNA. He was an only child. His father was a dentist. Like many, he had an early fascination with the natural world and decided to major in zoology as an undergraduate at Michigan State University (MSU) in East Lansing. Inspired by an older roommate to work in a research lab as an undergraduate, he was taken in by geneticist James Higgins, who was always in need of volunteers to assemble karyotypes and do other basic work. Well in advance of IRB, CLIA, and HIPAA regulations, lab members routinely swapped blood samples for karyotyping purposes, and Steve became known as the elite phlebotomist of the group. He met several lifelong friends and colleagues in the Higgins lab, including Terry Hassold, Tom Glover, Roger Schultz, Pat Hunt, Helga Toriello, Larry Wiesniewski, and Ajovi Scott-Emuakpor. He also met Karen Pierce (Warren), whom he later married in 1978. Steve often said that it was quite remarkable that such a small program turned out so many future human geneticists!

Steve’s career in human genetics began early—he became a member of ASHG and attended his first conference in 1975 as an undergraduate, beginning a four-decade unbroken string of meetings. He and his lab bench mate, Tom Glover, drove to Baltimore in Tom’s Ford Pinto, where they met a number of leading human geneticists in the hotel lobby even before checking into their room and establishing an enduring friendship and a long tradition of rooming together at the annual meeting.

Sometimes at the expense of his undergraduate coursework, Steve devoted himself to human genetics early in his training and began attending genetics clinic, learning diagnostics, and counseling, leading the way for other students to follow. From early on, Steve became dedicated to helping patients and their families. He understood how receiving a diagnosis often gave relief to families, who could stop wondering “Why did this happen to my child, and will this happen again?” He acquired his lifelong compassion and respect for patients and families with genetic disorders and worked diligently to help them understand and cope.

Steve spent summers at Henry Ford Hospital in Detroit with Lester Weiss and Gene Jackson. He also spent time one summer with Charles Scriver in Montreal to learn about Tay-Sachs disease carrier screening, a program he would help establish in Michigan. By the time he graduated in 1976, Steve had taken all the graduate-level genetics courses, making the choice to stay at MSU for graduate studies an easy one. Steve’s Ph.D. work with James Trosko characterized the high rate of mutation in cells derived from patients with Bloom syndrome. He published a dozen papers as a graduate student. Meanwhile, Karen entered medical school at Wayne State University.

An intriguing puzzle in genetics found in human families

Steve joined the lab of Richard Davidson as a postdoctoral fellow at the University of Illinois in Chicago in 1981 while Karen was a resident in internal medicine. Davidson’s group was carrying out leading-edge genetic mapping, using somatic cell genetics, a method for isolating chromosomes in heterologous (mouse or hamster) cells to link genes, especially those encoding enzymes, to human chromosomes. This was accomplished by fusion of human and mutant rodent cells and selecting for retention of human chromosomes capable of complementing the rodent mutation. Occasional breaks and translocations allowed mapping to regions smaller than whole chromosome length and the ability to characterize enzymatic activity allowed mapping of genes in addition to those under selection. These studies provided crude maps of human chromosomes as well as reagents for developing chromosome and region-specific clone libraries. Numerous laboratories were engaged in similar efforts, and many of the cell lines created were used for dedicated regional human genome mapping projects. Steve’s work overlapped with David Nelson, then a student with David Housman at Massachusetts Institute of Technology. Although they did not meet, they, along with Harry Orr and many prominent human and molecular geneticists, attended the seminal Somatic Cell Genetics conferences organized by the Federation of American Societies for Experimental Biology (FASEB) in the early 1980s, where progress in these and other methods of gene analysis and transfer was presented. When Nelson and Warren finally met, their parallel experimental directions provided a strong foundation for a life-long friendship and multiple collaborative efforts.

Steve’s interest in fragile X was kindled by conversations with fellow MSU students Tom Glover, Terry Hassold, and Patricia Hunt, who had joined Patricia Jacobs’ lab at the University of Hawaii in Honolulu to work on the early cytogenetics of fragile X syndrome and chromosome errors in miscarriage. Jacobs and her husband, Newton Morton, were also joined by Stephanie Sherman whose postdoctoral project was to study Jacobs’ large international collection of families with fragile X syndrome. It was this analysis that led to the “Sherman Paradox,” Stephanie’s quantification of the increasing likelihood of fragile X syndrome in subsequent generations of pedigrees segregating the disorder, a variant of the anticipation described (and intensely debated) in myotonic muscular dystrophy. Steve and Karen’s visits to see their MSU friends in Hawaii were meant for rest and relaxation, as Karen was in the middle of her residency. However, Steve’s scientific interests were not easily quelled. Stephanie recalls Steve finding her in her lab to have a quick look at a pedigree on which he was conducting a linkage analysis for fragile X syndrome and the factor IX gene. After a short discussion, the group (Steve and Karen with Pat Hunt, Terry Hassold, and Stephanie Sherman) was off to the Big Island, staying in cabins in Volcanoes National Park. They were shocked to unexpectedly witness the sudden 1984 eruption of Mauna Loa, a volcano that had been quiet for 9 years. Steve’s first instinct was to find a pilot to fly the group over the eruption—he did and all were in awe of the fountains of lava. Steve was delighted and cherished the photos he took from the airplane.

Tales of the peculiarities of fragile X syndrome chromosomes and the disorder’s unusual genetics from Tom Glover, Pat Jacobs, and Stephanie Sherman led Steve to develop an approach to identifying the site of fragility in Xq27.3. He created hybrid cell lines that retained the X chromosome from individuals with fragile X syndrome. The fragility of the chromosome was commonly elicited by growth in conditions of low folic acid, and Steve reasoned that breakage might also occur in the hybrid background. Using HPRT to select for or against the distal part of the X below the breakpoint, and G6PD to characterize the presence or absence of Xq28, Steve developed a panel of hybrid cell lines with breakpoints at the fragile X site at the resolution of light microscopy. This work merited a cover article in Science in 1987.¹ Steve’s panels of hybrid cells retaining the broken X chromosomes fused to rodent chromosomes became crucial reagents for mapping DNA fragments near the fragile site and ultimately for confirming the locations of clones containing the region. Attempting to use the hybrids to isolate the junction directly, Steve traveled to the lab of Annemarie Poustka and Hans Lehrach in Heidelberg, Germany, in 1984. There he developed cosmid libraries from the hybrid cells. Unfortunately, no clones carrying the translocation junction fragment (assessed as containing both human and rodent DNA) could be found. In hindsight, the instability of the expanded CGG repeats in E. coli cloning vectors may have significantly reduced the likelihood of this experiment’s success and cloning of the site was only achieved by screening libraries from non-fragile X sources.

In 1985, Steve and Karen moved to Atlanta, where Steve had accepted a faculty position in the Departments of Biochemistry and Pediatrics and Karen joined a primary care practice. Hassold and Sherman joined the Emory faculty in the Division of Medical Genetics in the Department of Pediatrics in 1988, after being heavily recruited by Steve. Steve’s vision was to build the foundation for a Department of Human Genetics that would combine clinical care, diagnostics, and basic science. His vision was most likely the outcome of his early training at MSU where he saw the important questions emerging from such collaborative experiences. From his earliest years, he continually pushed the Emory administration to make this happen. As Steve built his lab, he continued to be highly collaborative. He emphasized the need to broaden expertise and collect additional resources to accelerate research. He was an early proponent of the Human Genome Initiative, recognizing the enormous potential for human genetic disease research. To stimulate discussion among his lab members, Steve frequently took the group to lunch at local restaurants. One nearby Thai restaurant kept track of customers’ ability to consume highly spiced dishes, and members of the Warren lab were high on the list. Steve firmly believed that many research discoveries began with discussions over a shared meal.

Finding the fragile X mutation and characterizing FMR1

David Nelson first met Steve in spring of 1988 at the first Genome Mapping and Sequencing meeting at Cold Spring Harbor. In many ways it was a chance meeting. Steve had elected to attend the meeting despite having planned a Florida vacation with Karen and their son Tom, then 18 months old. Karen and Tom drove from Atlanta to Port St Lucie and Steve joined them later, after the meeting. Nelson attended in place of his postdoc mentor, C. Thomas Caskey, who had a conflict. Warren and Nelson each spoke in a session devoted to investigating the gene-rich region of human Xq28. Nelson described creating libraries from hybrid cell lines (including Steve’s) in yeast artificial chromosomes (YACs), aiming to develop region-specific resources for gene isolation. Nelson’s focus was on the X chromosome because of Caskey’s long term interest in X-linked disorders. Nelson had joined Caskey at Baylor College of Medicine in late 1985 and was developing libraries and collecting reagents with the help of David and Susan Ledbetter for mapping fragments to regions of the X chromosome. Steve was inspired to see whether YAC cloning might yield junction fragments. Nelson and Warren agreed to begin working together to identify the fragile X chromosome breakpoints. Again, no junction fragment could be found (largely confounded by the high rate of two or more unlinked DNA fragments present in YAC clones). However, human YAC clones that were quite close to the breakpoints were identified, and these were used to find overlapping clones closer to the site in additional libraries. Nelson and Warren engaged Ben Oostra at Erasmus Medical Center in Rotterdam in the pursuit after meeting Ben at subsequent Cold Spring Harbor conferences. Together, the three groups were able to identify cloned DNA fragments crossing the breakpoints in Steve’s hybrids, refine the interval, demonstrate intergenerational instability of DNA in the region, sequence the repeats at the junction, and characterize cDNA clones encoding FMR1, the gene affected in fragile X syndrome. The combined effort from Atlanta, Houston, and Rotterdam was published in Cell on May 31, 1991.² In back-to-back papers published a week earlier in Science,^3,4 the groups of Jean-Louis Mandel and Grant Sutherland/Robert Richards also defined the unstable nature of the sequences at the site in families with fragile X syndrome (Figure 2). All groups made use of Steve’s hybrid cell lines for mapping, and Steve was also granted authorship on discovery papers from the Australian group;^4,5 he was very generous with his cell lines.

Figure 2.

Warren with co-discoverers of the fragile X mutation at a conference in the Netherlands in Spring 2001

From left to right: Rob Richards, Ben Oostra, Jean-Louis Mandel, Warren, David Nelson. Photo courtesy of Harry Orr.

The fragile X discovery was quickly followed by descriptions of repeat expansions in spinobulbar muscular atrophy, myotonic muscular dystrophy, Huntington disease, and spinocerebellar ataxia. Thus, at the dawn of the human genome project, before methods for extensive genome sequencing were available, several examples of human Mendelian genetic disorders known to deviate from expectations of penetrance and expression were identified via positional cloning. The apparent “anticipation” found in myotonic muscular dystrophy had been a vigorously debated topic in human genetics, and prominent geneticists had claimed for many years that no mechanism was known that could explain the increasing severity of this autosomal dominant allele as it passed from generation to generation. These phenomena in spinocerebellar ataxia, Huntington disease, and fragile X syndrome similarly defied explanation. As with the Sherman Paradox, intergenerational instability of repeats resolved the peculiar genetic features of these disorders and provided a mechanistic answer for anticipation.

Thus, the 1991 discovery of an unstable triplet repeat that expanded to cause loss of function in fragile X syndrome proved to be a ground-breaking observation. Steve discovered and characterized this mechanism by developing reagents and collaborating with several groups. His deep knowledge of human genetics and his clever insights into somatic cell genetic approaches to isolate the cytogenetically detected site of chromosome instability allowed identification of FMR1 and its CGG repeat expansion. Warren and his consortium of investigators collaborated in an exhilarating race to understand how repeat length predicted likelihood of expansion of premutation alleles to full mutations that caused loss of FMR1 function in families exhibiting with this most common inherited form of intellectual disability and autism. Today, some 60 loci are known to contain unstable repeats that lead to pathology.⁶ Collectively, these disorders affect many millions of individuals. It is likely that many more repeat loci contribute to both disease susceptibility and normal variation.

The FMR1 repeat and gene discovery were just the beginning of a long and very productive series of studies in Steve’s group to characterize the genetics of the disorder and the function of FMR1. His lab’s location in a biochemistry department and his natural aptitude for collaboration led to numerous high-profile studies led by his trainees who have gone on to prominent careers. In just a few years, Catherine Kunst demonstrated the importance of AGG interruptions for limiting instability of the CGG repeat,⁷ James Sutcliffe characterized the mechanism of FMR1 downregulation by the full mutation,⁸ Claude Ashley demonstrated that FMR1 encodes a selective RNA-binding protein,⁹ and Yue Feng showed that repeat-bearing FMR1 mRNA is not well translated.¹⁰ Steve was invited to join the Howard Hughes Medical Institute (1991) as an investigator and rapidly promoted to professor (1993). In 1999, he was awarded ASHG’s prestigious Allan Award.

But Steve was not one to rest on his laurels. With the recognition that FMR1 premutation length expansions can lead to pathology (fragile X-associated tremor ataxia syndrome [FXTAS] and fragile X-associated primary ovarian insufficiency [FXPOI]), Steve’s lab turned to model organism approaches to characterize incomplete penetrance in these conditions, collaborating with Kevin Moses. Peng Jin joined the group and initiated a highly impactful series of studies of FXTAS modifiers by using a fruit fly model that he developed with Daniela Zarnescu.¹¹ This model and its derivatives have had high impact on understanding mechanisms by which expanded CGG repeats in mRNA can result in pathology and had implications for numerous other human loci with similar repeat elements. Studying flies lacking the FMR1 homolog also led to potential therapies for fragile X syndrome aimed at enhancing neuronal inhibition through the GABA receptor.¹² This work led to clinical trials that continue to show therapeutic potential.

Steve played a key role in enticing neuroscientists to engage in research into FMR1 and fragile X syndrome. William Greenough, studying translation of mRNAs in dendrites, found that FMR1 is locally translated and became intensely interested. The founders of the FRAXA Foundation, Kathryn Clapp and Michael Tranfaglia, whose son was diagnosed with fragile X syndrome shortly after the mutation was identified, have been wonderful champions for raising both awareness and research funding. Along with Greenough, Tranfaglia, and Clapp, Steve was a key contributor to the development of a decade-long series of small conferences at Cold Spring Harbor Laboratory’s Banbury Center, aimed at understanding FMR1 and consequences of its absence. These meetings elevated visibility of the disorder tremendously and were key to orienting academic scientists and those in pharmaceutical companies toward clinical application of research on FMR1. Steve’s efforts to spread understanding of fragile X syndrome also led to studies by Mark Bear and Kim Huber that pointed to an important role for defective metabotropic glutamate receptor (mGluR) signaling to protein translation in dendrites. Their 2004 development of the mGluR theory of fragile X syndrome stimulated significant efforts aimed at developing therapeutic strategies.¹³ Steve’s open, welcoming, and collaborative approach to new entries to the field had a strong impact on furthering research but also set a tone for subsequent investigators to follow.

Service to the field

Steve became editor-in-chief of the flagship journal of ASHG, The American Journal of Human Genetics (AJHG), in 2000. He inherited the reigns from Peter Byers and passed them on to Cynthia Morton in 2006. Steve hired Cathy Alden and Carissa Gilman as managing editors and Kate Garber as deputy editor, who together moved The Journal into the electronic era. Among his many initiatives were rapid review and communication of high-impact studies, the report format for brief papers, and the development of the Cotterman award for trainees who published first author papers in The Journal. Steve relished talking about science, and his daily visits to The Journal office often led to excited chatter about the recent submissions. He reveled in discussions of the latest tools and techniques and was honored to have a hand in shaping the field as editor-in-chief. Steve raised the impact factor of The Journal and saw significant increases in submissions. He also initiated open access for papers one year after publication. This effort was well ahead of later requirements by funding agencies. Of course, this was controversial for the Society and publisher. In his farewell piece for AJHG, he wrote about his pride in taking The Journal into the electronic age and working with University of Chicago Press to eliminate the enormous amounts of paper sent by overnight delivery among editors, reviewers, and authors. He also expressed his excitement about the education required to serve as editor, broadening his appreciation of the field.

Steve served ASHG in numerous additional roles; he was elected to the Board of Directors and served as president in 2006. His presidency coincided with the Society’s annual meeting planned for New Orleans in the aftermath of Hurricane Katrina. Steve argued strongly for holding the meeting in the still-recovering city that desperately needed the infusion of money and confidence that a large conference could provide. Other societies had elected to move their meetings. Steve’s leadership was key to the successful return to New Orleans. His Presidential Address to ASHG¹⁴ discussed the importance of outreach in allaying concerns about human genetics research and establishing trust with the general public, themes that resonate even more today, 15 years later. He spoke of his enthusiastic love for our field and Society:

I am [more] proud to be a human geneticist. It is without a doubt in my mind, the best job in the world. Being a scientist is great, being a human geneticist is better. We are part of a most remarkable field. Human genetics research is one of the broadest areas of science I can imagine….The American Society of Human Genetics brings us all together (Figure 3).

Figure 3.

Steve Warren, ASHG president, at his Presidential reception with former fellow students from Michigan State University during ASHG’s October 2006 meeting in New Orleans

From left to right: Terry Hassold, Patricia Hunt, Karen Warren, Roger Shultz, Warren, Tom Glover, Helga Toriello. Photo courtesy of Karen Warren.

Steve achieved his dream of founding the Department of Human Genetics at Emory in 2001. He strongly believed that human genetics deserved its own department in the medical school, and he was quite insistent that the name include “Human.” It provided focus that was consistent with Steve’s entire career and training. The name recognized the maturity of the research and clinical topics, noting the remarkable improvements in genome analyses and incipient therapeutics. Housed in this department were basic researchers, the Emory Genetics Laboratory (EGL), and the Division of Medical Genetics, bringing together people with different points of view and expertise in order to foster collaboration and inspire better science. The department grew from five faculty members in the early days to over 50 when he stepped down as chair in 2020. As one marker of Steve’s success, the department currently receives more annual extramural funding than any other basic science department at Emory. He recruited and mentored many junior investigators who developed very successful research programs. With these recruitments, the department established major strengths in neurogenetics, metabolic diseases, computational and quantitative genetics, and translational research. He recruited David Ledbetter, making Emory a hub of cytogenetics activity during the introduction of chromosome microarray to clinical testing. Under Steve’s leadership, EGL became a prominent provider in testing rare genetic disorders. EGL was one of the first academic laboratories to bring next-generation sequencing (NGS) technologies to the genetic testing markets, which later led to a joint venture between Emory and Eurofins Scientific. He also recruited Michael Gambello to lead the Division of Medical Genetics that has developed a vibrant clinical program and is conducting a large number of clinical trials for patients with rare genetic disorders. This unique combination of a full-fledged basic research faculty along with the comprehensive clinical genetics division places the department at the forefront of contemporary translational research and predictive, precision health, which is what Steve envisioned many years earlier (Figure 4).

Figure 4.

Steve Warren with members of the Fragile X Research Center team in 2004

The Center has been named in his honor: The Stephen T. Warren Fragile X Center at Emory University. Photo courtesy of Emory University.

In addition to his service to and recognition by ASHG, the society he called home, Steve was honored by the American Association for the Advancement of Science as a fellow and elected to membership in the American Academy of Arts and Sciences, the National Academy of Medicine, and the National Academy of Science. He received the March of Dimes Colonel Harland Sanders Award for lifetime achievement and was an Inaugural Inductee into the Hall of Honor of the NIH National Institute of Child Health and Human Development for his “identification of triplet repeat expansion … as an entirely new inheritance mechanism of genetic disease.”

Steve had a strong desire to communicate his knowledge in reviews and perspectives.^15,16 He was a very frequently requested lecturer, widely known for his lucid and informative presentations. He also gave back to the public and communities such as the fragile X family groups. He participated in family conferences and worked tirelessly to answer questions as an organizer of email listservs and later implementations of electronic communications for informing and educating families about genetic conditions. He was often called upon by science writers and reporters to discuss human genetics advances. With Cable News Network (CNN) located in Atlanta, Steve became a frequent interview subject for commentary on genetics. Along with Huda Zoghbi, Eric Kandel, and others, Steve discussed genetics and the human brain in a series of interviews with Charlie Rose as part of The Brain series on the U.S. Public Broadcasting Service. Steve’s explanation of the role of genes in autism spectrum disorders was clear and accessible and well received by those who watched the show. Steve firmly believed in helping journalists convey the rapid advancements in knowledge of human genetics and did his best to assist.

Steve was a frequent participant in review of grant applications for the NIH, March of Dimes, and numerous other agencies. He chaired and served on the storied Mammalian Genetics Study Section in the early 1990s during a very fertile time in development of genetic analyses in humans and other mammals. He reviewed papers for many journals and served as an associate editor for Proceedings of the National Academies of Science (PNAS) until his passing.

Interests outside of the lab

Steve had many interests outside of genetics. He was always happiest on holidays; Thanksgiving, Christmas, and Easter were good excuses for big meals with family. Steve was an excellent cook and enjoyed planning elaborate meals. To his family, Steve was more well known for his cooking than for his esoteric research. Steve enjoyed boating, often recalling his days sailing his uncle’s boat on Lake Michigan during his postdoc in Chicago. In Atlanta, he kept a boat on Lake Lanier. He and Karen also maintained a lake cabin for many years. He enjoyed hosting friends and colleagues there, and departmental retreats at Lake Lanier offered additional opportunities. At conferences, he was often drawn to the marinas to inspect the docked vessels. Slow strolls through the marina allowed continued scientific discussions in more scenic environs.

At the 1993 International Fragile X and X-linked Intellectual Disabilities meeting outside Cairns, Australia, Steve and Ben Oostra enjoyed a boat trip to snorkel the Great Barrier Reef. David Nelson arrived at the meeting too late to join, but Steve was eager to later accompany him on a post-meeting trip to snorkel the reef by seaplane. They were left on a pile of sand out of sight of the mainland with a lunch box and snorkeling gear. They recalled hoping that the pilot could find his way back. He did, but landing the plane in Cairns harbor required Nelson to exit the cabin of the moving plane to stand on the float, allowing the pilot to jump out of his seat and grab the dock in order to tie up the plane. Steve delighted in retelling the story, quoting the pilot, “It’s perfectly safe, mate—just stay away from the propeller!” David and Steve enjoyed many similar adventures around meetings, from Broadway musicals in advance of Cold Spring Harbor meetings to an open-cockpit biplane ride over the Columbia River valley north of Portland, Oregon. Steve was always keen to find a unique adventure to mark meetings. Some were more hair-raising than others. He and Tom Glover rented a car in Italy, driving from Rome to Troina, Sicily, for an International Workshop on Fragile X in 1987. Along the way, they found themselves fleeing from highway bandits through narrow twisting mountain roads and villages. Steve and Harry Orr also had a memorable snowmobiling adventure near Taos. Steve reveled in recounting these and many other stories.

A challenging diagnosis

In the winter of 2002, Steve slipped on ice while visiting his boat and broke his lower leg. His recovery was slow despite extensive physical therapy. Travel became increasingly difficult, but he kept attending conferences, accepting lecture invitations, and serving on advisory and review committees through 2013. In 2015, Steve learned that he had inherited an expanded repeat that was responsible for his slow recovery, diminishing his leg strength and providing the reason for his earlier cataracts. Steve was diagnosed with myotonic muscular dystrophy type 2 (DM2), resulting from a tetranucleotide repeat expansion. While the diagnosis was a shock, it helped explain his increasing disability. Of course, he noted the irony of having discovered the repeat expansion in fragile X syndrome while having inherited the DM2 expansion. He accepted the limitations with grace. He attended the ASHG meeting in Boston in 2015, but it was to be his last in-person meeting. He was very pleased to be able to attend the 2020 virtual ASHG meeting.

Steve met this new challenge with courage and with the full support of Karen, who helped him continue his work in his new context. He turned his attention to more local matters of building his department and ensuring the success of his faculty. Steve loved advances in technology, often competing, especially with Nelson, to have the latest computers, cell phones, and other gadgets, including electric vehicles. Steve approached his DM2 diagnosis with similar curiosity, turning to the latest devices to assist with his mobility. In combination with Karen’s dedication, these allowed him to carry on and participate in life. He closed his lab but continued his work as an associate editor for PNAS and contributed to grant applications, including two recently successful Fragile X Center awards.

Steve’s intellectual contributions as well as his unparalleled leadership after his diagnosis speak to his resilience and his ability to focus on what is positive in life and on what he can control and make better. Steve has truly been a role model not only for his trainees but for all his friends and colleagues. His decency, dedication, resilience, and deep care have inspired us and will continue to inspire all those touched by him.

Missing seeing Steve at conferences, his friends, colleagues, and former trainees scheduled more frequent visits to Atlanta. A symposium was held at Emory in the Fall of 2016 to mark the 25^th anniversary of the identification of FMR1. It was organized by Peng Jin with the help of Janelle Clark, who joined Steve in 1991 and worked with him for almost 30 years, most recently as financial analyst with the department. The conference included presentations from numerous colleagues, and many of Steve’s trainees returned to celebrate the anniversary. Some out of town colleagues continued a tradition of visiting with Steve at least annually until the COVID-19 pandemic intervened (Figure 5). Even then, Clark organized a virtual birthday celebration for Steve over Zoom in November 2020 that was attended by some of his closest friends and colleagues (Jin, Clark, Nelson, Orr, Sherman, and Glover).

Figure 5.

Steve Warren in his office with friends celebrating his 65^th birthday, December 2018

From left to right: David Nelson, Huda Zoghbi, Warren, Harry Orr, Janelle Clark, Peng Jin. Photo courtesy of Janelle Clark.

Steve formally stepped down as chair but continued to be an important advisor for Peng Jin this past year. Steve participated actively in a virtual meeting of the NIH Fragile X Centers just 2 weeks before he became ill. News of his death came as an enormous surprise. On November 30, 2021, Steve’s many friends and colleagues gathered to celebrate Steve’s life with a memorial service at Emory University’s Cannon Chapel on what would have been his 68^th birthday.

A lasting legacy

Losing Steve Warren leaves our field greatly diminished. His many friends, collaborators, trainees, and family mourn his loss. He touched numerous lives directly through his research and his efforts to enhance training and education. Many more were influenced by the strong example he set as a researcher and mentor who took rigorous approaches to tough problems. Those fortunate to be department faculty under his leadership recount his advocacy and his insight and strong support both when things were going well and when they stumbled. Many have commented on Steve’s wise and gracious nature. He was a brilliant researcher who had an impressive ability to have insights that surprised and delighted his colleagues. He was so often right, usually suggesting an experiment that was perfectly able to demonstrate the point. He cared deeply for the field and its traditions, manuscripts, journals, societies, and in-person meetings and the opportunities they provided for trainees and others to develop skills, networks and collaborations. Steve was a champion for human genetics, and along with the field and our Society, we will miss him deeply.