C. Thomas Caskey 1938–2022: Genetics pioneer and a cherished friend

On January 13, 2022, C. Thomas Caskey passed away after a hemorrhagic stroke. My relationship with Tom goes back to July 1967, when I joined Marshall Nirenberg’s laboratory in the National Heart Institute. I had just finished my internship and assistant residency in Internal Medicine at the Massachusetts General Hospital and had been accepted to serve my 2 years in the Public Health Service at the NIH. As many other physician scientists at the time, I was a “Yellow Beret,” serving my 2 years of selective service at the NIH instead of the Armed services. I was always interested in medical research as a student and intern but had only modest success.

C. Thomas Caskey. Image credit: Bayer College of Medicine/Huda Zoghbi.

My intention was to serve my 2 years and return to medicine in some specialty training program. When I arrived at the Nirenberg laboratory, Marshall told me I had two choices: 1) I could work directly with him on neurobiology in worms, or 2) I could work with Tom Caskey on the problem of how termination of protein translation worked. I was disappointed about my choices (who was this Tom Caskey?) but chose to work with Tom. That was the best decision I have ever made in my research life. Tom was cordial, kind, and brilliant as a mentor.

We began the project to solve how protein termination worked in bacteria. The presumptive codons were UAA, UGA, and UAG. But no assay existed to prove this unambiguously. Dr. Mario Capecchi at Harvard Medical School had published a paper (1) using two major components: a viral protein on polyribosomes not yet terminated and a complex source of factors from the S100 from an ultracentrifuge clarification step of a bacterial extract. Capecchi’s assay and results showed there was a “factor” in the S100 that led to the release of the nascent chains from the polyribosomes. But the assay was too cumbersome to delve into any further. One day after a few months of stumbling in the project, Tom had a brilliant idea. He reasoned that a simple two-component assay might work, building on the idea of the use of triplets that Dr. Phil Leder had pioneered in deciphering the genetic code.

Tom prepared Formyl Methione bound to ribosome containing the F met codon AUG. In theory, the substrate could be released from the bound form if one added a terminator codon to the bound F met and a source of S100. One could measure the free F met by a simple two-phase extraction solution. The first assay attempt worked but the counts released were very small. The assay was perfected and the search for the S100 factor began (2). We set about to purify from the S100, the factor that led to the chain termination event.

In late May of 1968, just before Memorial Day, Tom went on vacation leaving myself, Dick Tompkins, and Theresa Caryk to carry on. We fractionated the S100 on a Deae ion exchange column, assaying for all the known factors involved in protein synthesis and using the Caskey termination assay. The huge experiment began early on a Friday morning and by late Friday afternoon we found a peak of activity eluting from the column. Tompkins had gone home, and Theresa and I were running the remaining studies. The peak of activity had not yet come back to baseline, and I asked Theresa to keep assaying subsequent elutions for another 40 to 50 fractions to be sure we had captured the whole peak. We were using UAA as the release codon. When she returned with the data about an hour later, I was stunned. There were two separate peaks eluting from the column that had release factor activity using the codon UAA. I begged her to take the peak tube from each eluted activity and test it against all three codons. When she returned an hour later, we were more than stunned. One peak recognized UAA and UAG and the second one UAA and UGA. All at once, we knew we had the problem in sight. We carefully froze the activities and finished around 9:30 PM. I called Marshall at home to tell him and he was ecstatic. As usual for Marshall, he immediately asked what controls were used in the experiment. Tom returned Monday and the laboratory was clean with no notebooks in sight. After teasing him for a few minutes, we brought out the data and Tom was also ecstatic. He forgave me for teasing him and we published the work in PNAS (3).

My research career had launched. Tom had taught me how to do pristine research in the best Nirenberg way. He transformed my life and my life goals. I can state with certainty that if I had not been exposed to the Nirenberg laboratory and Tom Caskey, my research career would not have happened. Tom was a brilliant scientist, creative and meticulous. He was a warm and friendly human being, always handing out encouragement. I am forever in his debt for his mentorship.

From the NIH, Tom went to Baylor College of Medicine in 1971, where he started a division of genetics, which evolved into the Department of Molecular and Human Genetics and to this day is considered one of the best in the world. Tom had the insight to recruit the best candidates from diverse fields in genetics, ranging from yeast, through fruit flies, to mammals. He nurtured and inspired the young trainees he mentored and the faculty he recruited. He cared deeply about their success and was the proudest when they shone. While at Baylor, he discovered trinucleotide repeat sequences in the human genome, an observation that later on led to his discovery (with the late Steve Warren) that fragile X syndrome is caused by CGG expansion and that CTG expansion causes myotonic dystrophy. Tom’s discovery of trinucleotide repeats facilitated the discovery of dozens of disease genes and remains one of the most exciting and transformative discoveries in human genetics. Beyond his human genetic studies, Tom embraced new technologies and encouraged his laboratory and his faculty to contribute to the mapping and sequencing of the human genome. This resulted in Baylor being a leader in genomics research and home to a Human Genome Sequencing Center that continues to contribute and innovate to this day.

In 1994, when I was President of Merck, Tom wanted to join us to teach us how to use human genetics to choose targets for drug discovery. I was delighted and he was hired to oversee the Merck site in West Point, Pennsylvania. He did that successfully for a few years before returning to Baylor, which helped Merck into the field of human genetics as the genome was being sequenced and allowed us to renew our deep friendship. Over the years, we corresponded by email with an occasional phone conversation. Our friendship remained strong with high degrees of mutual respect. When I learned from Arthur Beaudet of Tom’s stroke, I was stunned and deeply saddened. Shortly after, Tom passed away.

Tom Caskey was a giant in Genetics research. He solved the protein termination problem in bacteria and later in mammalian cells. He built a powerhouse genetic department at Baylor and helped transform Baylor into a research powerhouse. All the while, he was a warm, humorous mentor and human being. I never met a person who did not both admire and like him. I will miss him deeply and am still saddened by his death. It will take a long time for my sadness to lift because he played such an important role in my life. I think every person he touched in his 83 years feels the same way.