C. THOMAS CASKEY, M.D.

1938-2022

C. Thomas “Tom” Caskey was born on the 22nd of September 1938, and died quietly in Houston, Texas, on Thursday, the 13th of January 2022. He was 83 years of age.

Tom was known for his enthusiasm for science, his brilliance, and his ability to identify internationally bright young scientists starting their careers. His laugh, quick wit, and optimism were iconic. The joy of ocean sailboat racing, his family, and his friends were constants in his remarkable life.

Dr. Caskey was born in the small southern town, Lancaster, South Carolina, the son of John Harper and Inez Bell Caskey. Following WWII years spent as a shipbuilder in Baltimore, his father returned with his family to South Carolina where he founded the Caskey-Rhyall company – and described himself as a “traveling salesman.” Inez a schoolteacher, proud to have earned a college degree during the depression emphasized to her sons the importance and genuine pleasure of education and learning. Caskey attended the University of South Carolina briefly before being accepted to Duke Medical School. At the University of South Carolina, he became fascinated by chemistry and in 1992 was awarded an Honorary Doctoral Degree in Chemistry.

His first biomedical research experience was as a medical student under the tutelage of the renowned

Dr. James B. Wyngaarden at Duke. He dedicated a year to working on gout and received the Borden Research Award. Caskey received his M.D. degree with AOA honors in 1962 as the youngest in his class.

In 1965, he was accepted to the National Institutes of Health as a Research Associate “Yellow Beret” during the Vietnam War joining the lab of Marshall Nirenberg, when Nirenberg was in the middle of his research elucidating the genetic code, which would lead to a Nobel Prize. Caskey conducted critical studies demonstrating the Universality of the Genetic Code (UGC) demonstrating that the code was the same in humans, amphibians, bacteria, and all life on earth. This Universality has led scientists to speculate, perhaps assuming transfer between planets, that any life discovered on Mars would use this same code. He identified the triplet stop sequences in the genetic code and characterized the proteins in bacteria, and later in mammals, which mediate the termination of protein translation.

In 1971, Caskey left NIH to initiate a program in genetics at Baylor College of Medicine in Houston, then a large city with a vacuum in Medical Genetics. This initiative evolved to become the Department of Molecular and Human Genetics, which is the largest and most distinguished genetics programs at any medical school in the world, with extensive NIH grant and other funding. The Department:

1)Fostered the initiation of a Human Genome Sequencing Center (HGSC),

2)Developed very large predoctoral Ph.D. and postdoctoral training programs for M.D., Ph.D. and combined degree trainees, and

3)Established programs for clinical and laboratory board certification under the auspices of the ABMGG.

In building genetics at Baylor, Caskey proved to be a great recruiter of internationally talented scientists. He envisioned a department, although at a freestanding medical school, which would bridge from bacteria to yeast, Drosophila, mouse, and human. He identified Allan Bradley who introduced mouse embryonic stem (ES) cell research creating a whole new thrust at the medical school. He recruited Hugo Bellen to lead Drosophila research. Caskey advocated for Richard Gibbs to lead the HGSC, which evolved to be one of only three federally funded centers to sequence the human genome. He led the M.D., Ph.D. (MSTP) training program at Baylor from 1982-1993. Caskey’s enthusiasm for his field, his personality, and his belief in young scientists infused the program with his contagious excitement. Caskey was particularly fond and proud of the MSTP program and donated generously over the years to support it.

In 1979-1980, Caskey was accepted by Sidney Brenner, Nobel Laureate, for a sabbatical faculty year in Cambridge UK. Caskey focused on disease gene cloning and cloned the first human disease gene, HPRT, that is mutated in Lesch-Nyhan syndrome, a childhood neurological disease linking back to gout. He published the cloning of the cDNA sequence for HPRT in 1982.

At Baylor, Caskey’s personal research focus was on the discovery of human disease genes with many firsts. His lab was the first to describe triplet and tetramer repeats in human DNA in 1991. His group collaborated to identify the causative gene and the novel causative expanding triplet repeat mechanism underlying fragile X syndrome. This explained anticipation, a mechanism whereby the severity of a disease in a family worsens over generations through serial expansions of the triple repeat. His group quickly identified a similar triplet repeat mechanism as the cause of myotonic dystrophy. Now an additional 47 disease genes are known to involve this disease mechanism.

In 1990-91, at a time when polymorphisms (individual variations) in repetitive DNA sequences were being recognized in the human genome, Caskey conceptualized and patented a strategy to use multiplex PCR and a few tetranucleotide repeats in the genome as unique, simple, and rapidly scored genetic markers to distinguish one human from another. Caskey wrote, “We resolved in one evening, in our laboratory, 32 casualties from that (Gulf ) war, identifying each individual. The military was incredibly impressed.” This use of short tandem repeats (STRs) became the basis of the FBI Combined DNA Index System (CODIS) for identification and exclusion of suspects in a crime. For this, he received a Courage in DNA Award from the US Department of Justice.

Caskey joined Merck Research Laboratories in 1994 as Senior Vice President, Human Genetics and Vaccines Discovery and as President of the Merck Genome Research Institute. There, he led Merck’s effort to incorporate modern genetics into drug and vaccine development. He was also responsible for drug discovery at the West Point, PA laboratory, and under his leadership, two breakthrough drugs for the treatment of HIV were discovered. Tom’s wife remembers so well the excitement at Merck over many developments at that time.

Tom Caskey was also a great friend of Canada. This was a friendship rooted in the 1898 historic cottage on 31-Mile Lake in Quebec that he and his wife Peggy restored with love and care, and expanded in his active role in Genome Canada, where he served for a decade as a Board member and from 2009-2012 as Chair, providing vigorous leadership to its research agenda. During his tenure, Genome Canada discovered the SARS virus and was first to establish the undiagnosed disease program for children. For his service to genomics research in Canada, he was made a Fellow of the Royal Society of Canada in 2010. He leaves many friends north of the border.

At the time of his death, Caskey was using genomics, metabolomics, and proteomics in combination to advance the field of precision medicine working with Human Longevity, a company founded by Craig Venter of human genome fame.

Caskey received many recognitions and awards. He was a member of the

USA National Academy of Sciences, National Academy of Medicine, and a Fellow of the Royal Society of Canada. He received the William G. Anlyan Duke Lifetime Achievement Award and the William Allan Award of the American Society of Human Genetics where he was also a past president. He received the Giovanni Lorenzini Foundation Prize for Basic Biomedical Research and many other awards. Despite these awards, Caskey was very humble, never arrogant, telling his wife that while he was incredibly honored, he was not deserving saying: “We still have not worked smart enough, hard enough, or long enough to solve all biomedical challenges.

Perhaps the most remarkable accomplishments in Caskey’s life were his impacts on many budding and often uninitiated scientists. At the NIH within the Nirenberg lab, he mentored Nobel Laureate Joseph Goldstein, Edward Scolnick, and Arthur Beaudet. At Baylor College of Medicine, he personally mentored over 90 scientists in training and nourished the careers of many others. Many reported that he had an enormous impact on their early careers, and he continued to follow their science.

Caskey is survived by his loving wife of 62 years, Peggy Pearce Caskey; his two children, Clifton Caskey and Caroline Goodner; three grandchildren, Sam Caskey, Sam Jackson Goodner and Catherine Goodner; his brother, John B. Caskey; and his nonrelated “son” Steve Marinier.

The family will gather for a private service at St. Paul United Methodist Church. A public memorial service and celebration of his life will be held at a later date. In the interim, you may opt to receive updated information by visiting his online memorial tribute at GeoHLewis.com and selecting the “Receive Notifications” icon.

In lieu of customary remembrances, the family requests with gratitude that memorial contributions in Tom’s name be directed to the M.D., PhD Training Program at Baylor College of Medicine www.bcm.edu; to The Davison Club (M.D. PhD training program scholarships at

Duke University Medical School) www.medschool. duke.edu; or to St. Paul’s United Methodist Church of Houston www.stpaulshouston.org.

Please visit Dr. Caskey’s online memorial tribute at GeoHLewis.com where memories and words of comfort and condolence may be shared electronically with his family.