Summary
This article is based on the address given by the author at the meeting of the American Society of Human Genetics (ASHG) held virtually October 18–22, 2021. The video of the original address can be found at the ASHG website.
Main text
It is events like this which lead you to reflect on your past discoveries and the people who made it possible. I would like to tell a few stories, in the Southern tradition—let no good story be spoiled by the truth! So, there may be some slight modifications you would want to make on these comments.
Mentors
We have advances in science related to the fact that we’ve had good mentors, and we make our new discoveries with our colleagues. Let me review that for you, about me. My first mentor was Eugene Stead. He taught me medicine; he taught in the Oslerian school. That is, take the plethora of abnormalities that you see in a patient and look for a single cause. He would have made a good geneticist.
Jim Wyngaarden took this chemist (me), at that time, into the field of biochemistry. I’ve always marveled at the power of enzymology, as a chemist, and would ever be grateful for his teaching me how to use enzymology in the discovery and exploration process. We studied gout.
Marshall Nirenberg was incredible to work with. He took the strategy of using biochemistry to evolve the genetic code and did it very successfully with very novel assays, the first of which used what we refer to in the lab as the “uni-sucker,” a device that enabled us to decipher the triplet code (Figure 1). We were able to determine the universality of the genetic code, and there was a big celebration that was held approximately 50 years after the discovery by the New York Academy of Sciences. In that audience were not only zealots of our early discovery but also zealots of NASA. And so the universality of genetic transmission of information will carry on as our space program advances.
Figure 1.
The “uni-sucker”—A device used for deciphering the genetic code
I made my first original discovery in Marshall's lab. I had failed at an experiment but came up with a new idea. Marshal said, “Well, it might work, Tom. Why don’t you try it?” Well, we tried it and we successfully identified the two proteins that were able to recognize the triplet terminators and to work out the biochemical mechanisms that engage the ribosome to be able to release the finished peptide, by peptidyl-transferase of protein synthesis.
My last mentor, who was great fun, was Sydney Brenner, at the MRC in Cambridge England. I took my time to be able to study under him to do molecular cloning, and it was a successful venture.
A new department in Houston
The Institute for Molecular Genetics—later the Department of Molecular and Human Genetics—here at Baylor College of Medicine (BCM) was started by Arthur Beaudet and myself as we came down from the National Heart and Lung Institute. Art and I were never really collaborators a great deal in science as we pursued our independent research careers, but we were really “joined at the hip” in developing this department.
We were supported by Michael DeBakey, whose museum is here on the ground floor of the DeBakey building, at BCM. Michael had operated on too many families with aneurysms and too many families with vascular disease and wanted to fully understand how genetics formed the basis of many of the disorders that he operated on.
It was essential for us to expand in skills and also talents to emerging technologies that were coming through in genetics.
Richard Gibbs was one of the major factors. Richard brought automated DNA sequencing for the Department and trained many PhDs and mid-career scientists. He also developed individual whole-genome sequencing and also exome capture and discovered, of course, a number of disease genes along the way.
Alan Bradley was transformative for the entire Texas Medical Center, with regard to mouse genetics.
And then Juan Botas and Hugo Bellen brought in Drosophila.
We had, in addition to that, the skills of biochemical diagnostics, which was becoming a necessity as the department discovered more and more disease genes. In that role, we had Bill O'Brien, while Ray Fenwick successfully established our first molecular diagnostic laboratory.
Ed McCabe was in control of the development of the clinical genetics program. Ed did a beautiful job, then went on to establish the rules and regulations for the American College of Medical Genetics.
Our second production was really the generation of young scientists that made their way “under their sun,” and we were very blessed by having a lot of talent that came into the department. Huda Zoghbi, for example, worked on Rett syndrome and ataxia molecular genetics. I could go down the list of the many BCM-trained scientists who founded companies and now lead the industrial side of medical genetics.
Every lab also has someone who makes the trains run, and they deserve recognition. I start with David Konecki. David Konecki went on to get his PhD, and his son, just recently, this past week, earned his PhD in genetics and informatics at BCM.
Donna Muzny, an outstanding collaborator with Richard Gibbs, is now professor within the Genome Center. Holly Hammond—I recruited her to work in the area of forensic science—we'll talk about her in just a moment.
Training
We recognized the need for training programs and did this in three different sectors. One was the so-called SMART program, which we got Rebecca Remmel with the Pew Charitable Trust to fund. Gail Slaughter led this effort and did such a good job that she received a Presidential Award for the system, which trained college students, getting them interested in the area of science. The program has been replicated at many universities. I was just back for the 25th anniversary of that program and was pleased to see how high performance has been.
The MD-PhD program in medicine now is headed by Jim Versalovic and Sharon Plon. This program has been incredibly productive, training many high-performance researchers who now combine medicine and science in their careers.
And then we needed a PhD program. Gretchen Darlington and Craig Chinault initiated and led that program, with help from others, including David Ledbetter in Cytogenetics. So, overall, three scientific areas were emphasized for training.
Postdoctoral fellows
My postdoctoral fellows were critical for the scientific success of the laboratory. In September 2020 Pragna Patel organized a massive Zoom meeting with all of them. I was roasted severely, and I’m glad that these individuals were not on the Allan Award committee! I’d have never made it. It was fun telling the tales. It was wonderful. I have a story for each of these postdoctoral fellows, but I want to tell one that was special to me.
I invited Marshall Nirenberg to give the Texas Medical Center lecture, and as we planned it, he asked me to arrange an appointment with my MD-PhD student, Bill Craigen. Bill had cloned and sequenced the two protein release factors, following their isolation by expression cloning, and he discovered frame-shift translation regulation. This was later discovered also in SV40 by Harold Varmus. Furthermore, he found that R1 terminated R2, and vice versa—R2 terminated R1. It was a perfect scientific loop. Marshall trained me, and my student trained Marshall. It was the best of times.
Pharmaceutical industry
My experience in the pharmaceutical industry was the equivalent to a medical center residency in drug development. Drug development is the ultimate team initiative. Ed Skolnick was head of the Merck Research Laboratories and brought me on board as enior ice resident to look over the West Point or Pennsylvania site. This enabled me to bring genetic drug targets into Merck, developing gene expression chips for our drug programs for both specificity and safety. Additionally, I was able to introduce the gutted adenoviral vectors for vaccine development.
Joel Huff was head of Medicinal Chemistry and Emilio Emini, head of HIV and vaccine research. These were the movers and shakers of our successes. We developed drugs for cardiovascular disease, HIV, prostate cancer, osteoporosis and pain—all out of the Merck West Point site. The vaccines that were approved were pneumococcal, hepatitis B, rotavirus, and herpes simplex. It was an exciting and productive time.
The 2020 success of the RNA and adeno-based vaccines is remarkable. These technological developments made a big difference in the success achieved by the Warp SpeedInitiative. The U.S.-government-backed production of these vaccines, not knowing whether they would work or be safe, was a gamble by government and pharma. We mitigated the global devastation that occurred in the 1918 flu epidemic by sourcing government facilities and pharmaceutical facilities. Hopefully, we will do more initiatives of this type for future urgent health needs.
Six transitions
It is said in the business community that a businessman will undergo six transitions in their career. Those of us in genetics are undergoing more rapid transitions than that. I’ve given you my transitions. The first areas we’ve already covered: the areas of discovery and disease genes. The most important and exciting project that I worked with, I think, was working with Steve Warren, who died this past year, on the discovery of the Fragile X gene.
There was a second act that occurred from that. Ying-Hui Fu, who was in my laboratory, took the wild gamble of saying “Aha, since we understand anticipation, the likelihood is high that myotonic dystrophy uses the same mechanism.” And within a 6-week period of time, betting on that mechanism, she was able to identify the sequences, indeed, a GC-rich repeat, that accounted for the repeat expansion in myotonic dystrophy. That was a courageous step on her part because we had so much that we could do with Fragile X, and yet she took the initiative to make this second discovery. There are now at least 40 diseases known to be caused by repeat expansions.
Forensics
That discovery transitioned me into the world of forensic science; this was quite an exciting time period. We recognized that short tandem repeats (STRs) could be variable and steady, not unstable like the disease gene loci. And so therefore, if one were to multiplex a number of these variable STRs, you could end up with a very powerful identification tool for individuals.
So, we did just that. We developed a series of STR markers that were very powerful in personal identification. The very first application that we put it to use was on, unfortunately, the Gulf war casualties. We resolved in one evening, in our laboratory, 32 casualties from that war, identifying each individual. The military was incredibly impressed. This went on of course into the application in forensic science. I had the pleasure working with an FBI lawyer on cases in all the Federal districts. His name was “Dead Man.” He kept saying. “Tom it’s ‘Deadman.’” I said, “No, it’s ‘Dead Man.’ You're my assistant in taking these cases to court”. And so we did: we released the innocent and found the ones guilty of crime to be guilty.
The Home Office and FBI have taken this work to a higher level. They created databases because this was something you could test with PCR. You could test it in a multiplex format. You could digitize it and be able to search it very easily. So now we have today forensic science that is STR-based, with an incredible ability to identify the “bad guys.”
Precision medicine
The last area I want to discuss with you is the precision medicine area, which really is kind of the culmination of many things that I have done. It was made possible for me to explore this area by the Young Presidents Organization and by working with the corporation Human Longevity, which was founded by Craig Venter. The premise is that you can use these new tools to identify the risk of disease before the onset of the pathology and then have the opportunity to be able to intervene on that risk. I think this will lead to the transformation of medicine. It will be in addition to medicine. It's not the way medicine will be always practiced, but it's going to be an addition to improve longevity and health. So, I praise the opportunity to have been involved in the early phases.
Peggy Caskey
My wife contributed significantly. I married the girl next door. Peggy is always fun. She was enthusiastic about supporting the career, and she always made it fun for the postdocs and students who were in the laboratory at the time, in the department. She swears that we had 32 events at our house in a single spike year. I never questioned that. But I give praise to Peggy, who was able to see through some of the rough spots and enjoy the pleasures of the development of the department. Thank you, Peggy.
And thank you very much for this award.