INSIGHTS | PERSPECTIVESPHOTO: BAYLOR COLLEGE OF MEDICINEscience.org SCIENCER
enowned molecular and human ge-
neticist C. Thomas Caskey died on
13 January. He was 83 years old. Tom
transformed biomedical research in
both academic medical centers and
the pharmaceutical industry, effort-
lessly moving between the two worlds and
catalyzing new ideas and applications. His
discovery of trinucleotide repeats and their
role in dynamic mutations helped overturn a
century’s worth of assumptions about genetic
inheritance. A visionary physician-scientist,
he also had a gift for nurturing talent and
building programs that would themselves re-
draw the boundaries of scientific possibility.
Born in Lancaster, South Carolina, on 22
September 1938, Tom never lost his relaxed
southern charm. He studied chemistry at
the University of South Carolina for 2 years
before transferring into the Duke University
School of Medicine. There, he spent a year re-
searching purine biosynthesis and the genet-
ics of gout under the mentorship of physician
James B. Wyngaarden before receiving an
MD in 1963. In 1965, after completing a resi-
dency in internal medicine, he joined geneti-
cist Marshall Nirenberg’s lab at the National
Institutes of Health. Tom’s experiments dem-
onstrated the universality of the genetic code
from bacteria through mammals and identi-
fied the proteins that terminate translation of
mRNA. During this time, he mentored Arthur
L. Beaudet, Edward Scolnick, and Joseph
Goldstein, physicians who later became pio-
neers in their own right. In 1971, Caskey left
for Baylor College of Medicine in Houston,
Texas, where he started the division of genet-
ics that eventually became the Department of
Molecular and Human Genetics.
Although Tom was a physician, he did not
overprioritize human genetics—instead, he
recruited scientists working in diverse spe-
cies, so that yeast, fly, mouse, and human
genetics researchers were constantly rubbing
shoulders in the hallways, at seminars, and
at journal clubs. Cross-species collaborations
became the norm at Baylor. Tom also had akeen sense for which new technologies would
be most important in advancing genetic re-
search. For example, he brought in viral gene
therapy and sequencing technologies and
persuaded Allan Bradley to come all the way
from England, bringing embryonic stem cell
technology with him. All this helped the de-
partment become renowned as a cradle for
discoveries. When we joined the faculty in the
late 1980s, we benefited tremendously from
this intellectual and technological vibrancy.
Tom’s early work in enzymology bore fruit
in 1982 when he cloned the gene that en-
codes hypoxanthine-guanine phosphoribo-
syltransferase, the enzyme whose loss causes
gout and Lesch-Nyhan syndrome. His great-est scientific contribution, however, was the
discovery of tri- and tetranucleotide repeats
in the genome. These repeats form tracts of
variable length in healthy individuals but
over a certain threshold can become subject
to further expansions. In 1991, three teams
(one of which included Tom) showed that
fragile X syndrome was caused by an unsta-
ble CGG repeat tract that expands on germ-
line transmission. This “dynamic mutation”
explained how a disease could become more
severe with each generation. We now know
of 60 distinct disorders caused by dynamic
mutations, including myotonic dystrophy,
the mutation for which was discovered by
Ying-Hui Fu, then a postdoc in Tom’s lab.
Tom also recognized that short tandem re-
peats could have a socially beneficial use:
Because the length of these repeat tracts
varies between healthy individuals, theyprovide a shortcut for identifying genetic
material. He used this approach to iden-
tify 32 Gulf War casualties, and the method
forms the basis of the Federal Bureau
of Investigation’s Combined DNA Index
System for identifying suspects in crimes.
The Caskey lab contributed to the discov-
ery of more than two dozen human disease
genes, but Tom had wider ambitions. He
rallied his faculty to each contribute their
own skills and interests to mapping dis-
crete regions of the genome. This call to ac-
tion spurred Richard Gibbs to establish the
Baylor College of Medicine Human Genome
Sequencing Center, one of the five sites that
collaborated to assemble the human genome
reference sequence.
In 1994, Tom relinquished the position he’d
held since 1976 as a Howard Hughes Medical
Institute investigator to join Merck Research
Laboratories as senior vice president of re-
search, where he incorporated human genet-
ics into drug development. In 2006, he re-
turned to Houston and founded the Institute
of Molecular Medicine at the University of
Texas Health Science Center, and in 2011 he
returned to Baylor and launched one of the
first programs in precision medicine. He per-
formed whole-genome sequencing on 1190
volunteers, identifying risk variants that he
used to guide interventions to forestall the
development of disease.
Tom served as president of the American
Society of Human Genetics, and in 2021 the
society honored him with the William Allan
Award. He was also elected to the National
Academy of Sciences and the National
Academy of Medicine. Despite his stature in
the field, his interactions with faculty and
the more than 90 postdocs and graduate stu-
dents he trained at Baylor were characterized
by warmth and humor. He could be tough,
but he also took pains to give encouragement.
We mostly remember the twinkle in his eyes
when he asked an unexpected question and
walked off, leaving you to ponder what you
were missing. Whether or not you figured out
what he intended, he always made you think.
Tom had a zeal for life. He was an avid
sailor and often took his family and friends
out on the water. He and Peggy, his wife of 62
years, frequently opened their home for lab
and faculty gatherings and invited trainees to
celebrate holidays with them. His memorable
lab parties usually involved people swim-
ming in his pool and Tom sporting a cowboy
hat. Those of us lucky enough to know Tom
learned to be more ambitious about improv-
ing human health and serving society but,
above all, to cherish the people around us. He
will be remembered as an innovative scien-
tist, a dedicated mentor, and an enthusiastic
man who loved life in all its forms. j
10.1126/science.abo3949(^1) Telethon Institute of Genetics and Medicine, Pozzuoli,
Italy.^2 Department of Translational Medicine, University of
Naples Federico II, Naples, Italy.^3 Neurological Research
Institute, Texas Children’s Hospital, Houston, TX, USA.
(^4) Department of Molecular and Human Genetics, Baylor
College of Medicine, Houston, TX, USA.^5 Howard Hughes
Medical Institute, Baylor College of Medicine, Houston, TX,
USA. Email: [email protected]; [email protected]
RETROSPECTIVE
C. Thomas Caskey (1938–2022)
A visionary architect of genomic medicine
By Andrea Ballabio1,2,3,4 and Huda Zoghbi3,4,5
824 25 FEBRUARY 2022 • VOL 375 ISSUE 6583