Gregg Semenza, the 2019 winner of the Nobel Prize in Medicine or Physiology, recalls several early experiences that put him on a path to becoming a pediatrician and a physician scientist. There was his 3rd grade teacher, who chose not to embarrass him after he presented his first book report on a book he clearly had not read. That transformed Semenza into a voracious

reader. Then there was his biology teacher who elegantly conveyed, and inspired in him, the beauty and thrill of scientific discovery. He was hooked. With her help he was able to enroll in a National Science Foundation summer program at the Boyce Thompson Institute, his first exposure to research and experiments. That led to a vision in his junior year at college to pursue a Ph.D. and a career in genetics. Then a friend’s family had a child born with Down syndrome, at a time when he was in a lab focusing on human gene mapping and, in particular, chromosome 21. Children born with Down syndrome, he learned, have a third copy of that chromosome, called trisomy 21. Semenza then remapped his own path and added medical school, and later pediatrics, to his doctoral studies.

“I decided to go for the M.D./Ph.D. at the University of Pennsylvania so I could also get clinical training to take care of patients with genetic disorders,” he says. “Because many genetic diseases are manifest at birth,” he adds, “the next logical course was pediatrics.”

That training Semenza found in Duke’s pediatric residency program. His next stop was Johns Hopkins and a fellowship in pediatric genetics. Already he had gleaned insights into the influence of pediatric training and practice on genetic research. What other connections would he discover? Would his prize have alluded him had he not followed a pediatric path early on? Why not internal medicine? What is the relationship between pediatrics and scientific discovery — between treating patients and finding answers for them through basic science research in the lab? Is there one? Through the lens of Semenza’s seasoned colleagues, there are many connections.

For Dave Valle, a faculty member when Semenza arrived at Hopkins — and who points to his junior high school biology teacher as a major factor in his career — a significant pediatrician/basic scientist connection is the continuum of development. Valle, now director of the Department of Genetic Medicine, concedes that environment and the social and family context of the child affects a child’s development, but its primary influence is biology and genetics. That means the opportunities to understand biology, human biology, genetics and pediatric health and disease are completely obvious in a young patient. In the simplest terms, Valle says, “A child is biology looking at you in the face.”

That face may include one of more than 7,000 Mendelian disorders, almost all quite rare and caused by some abnormality in one particular gene, 90 percent of which present in the pediatric age range. That raises questions about the variants and the gene involved in the patient’s particular problem.

“But the answer is right there in front of you, sitting in your office or exam room or on a mother’s knee, saying ‘c’mon doc, figure me out and help me out,’” says Valle.

Pediatric pulmonologist Sharon McGrath-Morrow, who began treating children with ataxia telangiectasia early in her career, agrees. “By being a clinician, I’m able to look at the patient and ask the question: What kind of therapies can we do to extend life, increase quality of life, slow disease progression? Can we borrow from other chronic lung diseases and start instituting interventions in this genetic disease, which we did and increased survival by about 8 years.”

McGrath-Morrow explains that she and her colleagues were able to show high levels of pro-inflammatory cytokines in ataxia telangiectasia, from which they were able to obtain molecular signatures as potential biomarkers of the disease.

“Then we can prognosticate and think about possible interventions mechanistically based on these biological signatures in the blood,” says McGrath-Morrow.

Semenza concurs: “I always say the human body is the most sensitive assay we have. There are subtle effects over long periods of time that will manifest themselves, particularly during development. You may not have an assay sensitive enough to see what this small change does to the protein — you change one amino acid in a protein with 800 amino acids — it may be difficult to demonstrate that effect in any kind of lab assay. But you have the patient staring you in the face.”

That interaction, Valle says, lends to the focus required of physician scientists, to ask thoughtful and clear questions so they can reasonably expect their experiments will lead to meaningful answers. The problem the pediatrician sees, he adds, tends to be more distinct than the problem the internist sees.

“In a child there may be associated complications but the particular problem is occurring in an individual who is otherwise healthy,” says Valle. “Whereas an adult patient has hypertension, diabetes, all this wear and tear, and it’s just not as clean and sharp of a situation.”

Also, adds geneticist Garry Cutting, the pediatrician can take advantage of the child’s plasticity to alter the disease path.

“An adult, I’m afraid to say, only has a certain ability to recover from certain insults,” says Cutting, “whereas with a child there’re things you can do, therapies you can consider for a child that can change lives.”

In medical school, he adds, his mentors were pediatric geneticists who also formed his thinking. Then a hematologist gave him an opportunity to work in his lab, which sharpened his vision.

“I just liked the idea of being able to profile children with these diseases with new tools that really gave us an opportunity to change direction and make a difference for the child and the family,” says Cutting. “It made me feel that’s where I had the greatest opportunity to make a difference.”

Creating a Collegial Environment

In ways, the canvas has been set for the Semenzas of the world, suggests Valle, awaiting the brush strokes that will render a motivated and talented trainee’s pursuits. That’s where mentors come in, Valle adds, creating and sustaining a collegial and collaborative environment seasoned with some serendipity. In Semenza’s case, it was what Valle calls “a powerful happenstance.”

During the course of his Ph.D. work at Penn, Semenza became interested in thalassemia, an inherited blood disorder in which the body makes an inadequate amount of hemoglobin, the protein in red blood cells that carries oxygen. Indeed, it would become the subject of his thesis. He accepted a position as a genetics fellow at Hopkins because of the opportunity to work in the lab of pioneering geneticist Haig Kazazian, who was then at the cutting edge of understanding the molecular basis of thalassemia, and Stylianos Antonarakis, an associate professor of pediatrics.

“It was another case where Gregg’s career, through his own choices and some degree of serendipity, put him in the perfect place for what was really turning him on,” says Valle.

Then, something surprising happened. Their work on red blood cells prompted Semenza to ask a more fundamental question: What is hemoglobin trying to do? It’s trying to carry oxygen. So, then, how does the cell translate that information? At that moment he scientifically intuitively asked the question that would lead to decades of groundbreaking research on how cells sense oxygen and a Nobel Prize, but not one tied to the specific grant work of the lab at the time. Nonetheless, Kazazian and Antonarakis gave Semenza their blessing to pursue the answer.

“They did something that really good mentors do at a place that allowed it to happen,” says Valle. “What often happens, the trainee comes into a lab and the PI says here’s what we’re working on and I want you to work on this. They did not do that. They said here’s the general area we’re interested in, why don’t you think about this and come up with a question you think you would like to investigate. When you do it that way, the trainee is more inspired and more invested in the work.”

In that environment, Semenza found the freedom to pursue answers to other questions that provoked him. Some of the questions were stimulated by morning rounds with Saul Brusilow in the Pediatric Clinical Research Unit (PCRU), where one third of the patients were afflicted with genetic disorders of metabolism. Inherited abnormalities of the urea cycle, which were nearly always fatal, was the focus of Brusilow’s work.

“It was this classic physician-scientist mix of taking care of these patients, some of whom were very sick, and at the same time learning from these experiments of nature in a compassionate way,” says Valle.

The questions and answers surfaced through the extremely collegial and collaborative environment Semenza found at Johns Hopkins, especially in pediatric genetics. How did that happen among physician scientists? In large part, through pediatrician Barton Childs.

After graduating from Johns Hopkins University School of Medicine in 1942, Childs quickly built a reputation as a superb pediatrician, who many faculty members had asked to care for their children. His interest in birth defects stimulated an interest in genetics, a science new to medicine and one characterized as “professional death” for those who pursued it. So, in 1952-53, Childs pursued genetics training at the University College London and returned to begin his life’s work of advocating for the role of genetics in all of medicine and not just pediatrics. In so doing, Child’s model of a physician scientist — whose clinical insights and first-hand look at disease symptoms and human variation prompted important biological questions in the lab — had a magnetic effect.

“What came out of that were people strongly attracted to Hopkins, people who understood the importance of the physician perspective in basic science and the importance of training,” says George Dover, former director of Johns Hopkins Children’s Center. “All of this was occurring in pediatrics at a time when there was no genetics department, when medical genetics didn’t exist. The science behind this was in its very nascent phase, so no one really understood it very well. Barton’s energy influenced everything — then it became a very exciting place.”

Indeed, Child’s vision aligned with budding physician scientists, including Barbara Migeon, his first fellow who would start a medical training program for Ph.D.’s in genetics and go on to make significant contributions to the field, particularly in understanding X-chromosome linked diseases such as hemophilia. Another arrival was Kazazian, who would start a fellowship training program in genetics for physician scientists, and whose lab later on would be one of the first to use the polymerase chain reaction (PCR) to identify human disease mutations. Next up, Antonarakis, who with Kazazian published several important papers on the molecular bases of classical hemophilia due to the deficiency of clotting factor VIII. Other genetics minded fellows and future luminaries included Cutting, whose lifelong focus has been on understanding cystic fibrosis. His lab followed a large group of CF patients, nearly all who had the same genotype of the disease gene locus but varied widely in their clinical severity. This work allowed for the prediction of differences in the course of disease and response to therapy for individual patients. Then came Hal Dietz, whose groundbreaking studies on the molecular pathology of Marfan syndrome (MFS) led to the repurposing of an existing cancer drug to treat MFS. And, of course, Gregg Semenza and the seminal discovery of hypoxia-inducible factor 1, or HIF-1, and how its expression is important in many areas of biology and medicine, including cancer.

Led by Child’s influence, the Division of Pediatric Genetics emerged in the mid-1960s, merged with the Division of Medical Genetics under Kazazian in 1989, and morphed into the McKusick-Nathans Institute of Genetic Medicine (IGM) in 1999. Valle took over as director of the IGM in 2007; Ada Hamosh is clinical director of the Department of Genetic Medicine, of which two thirds of the patients are in the pediatric age range. Among other accomplishments, she is scientific director of Online Mendelian Inherited in Man, or OMIM®, a catalog of human genes and genetic disorders and traits created by Victor McKusick. Citing her experience and those of her colleagues, the Hopkins trait she cites first for physicianscientist success is a collegial and collaborative nature, which she sees as a natural for pediatricians.

“In pediatrics, it’s about working as a team. Everyone is invested in fixing the child,” says Hamosh. “When you’re a pediatrician, you’re aligned with parents to care for the child. It’s a very, very different world than adult medicine.” So, she finds that same collegiality in the lab world at Johns Hopkins?

“You can talk to anyone about anything anytime,” answers Hamosh. “If you have a piece of equipment and want to test it out in somebody’s lab, they will say, ‘Sure, c’mon over.’ If you don’t have a piece of equipment and cannot afford it, someone will collaborate with you to get this done. You want to talk to someone who is an expert in a certain disease, they’ll say ‘Let’s grab some coffee.’ You come and stay here because it’s an unbelievably bidirectional collegial environment.”

Pediatric pulmonologist McGrath-Morrow cited similar experiences with Dover, who along with Johns Hopkins’ Samuel Charache discovered that the cancer drug hydroxyureacan boost fetal hemoglobin and decrease the excruciating painful sickling crises for patients with sickle cell disease. Early in McGrath-Morrow’s lab studies of cystic fibrosis and neonatal lung disease as a junior faculty attending, she was developing mouse models to look at pathways dysregulated by different injuries. Dover asked her how the studies were going, noting that it’s really important to find a clinical correlate to her work. Her answer was chronic lung disease of prematurity, which prompted him to suggest she start a clinic for those patients. She did, which led to a registry of 1,000 patients and outcomes she has been following longitudinally since the year 2000. Her most recent paper explored a possible link between bronchial pulmonary dysplasia and early adult onset chronic obstructive pulmonary disease.

“When he said that to me, it made absolute sense but I had never put it together,” says McGrath-Morrow. “George was always my go-to person in having vision, being able to look at your work and get an idea what direction to go.” These invaluable go-to people tend not to go away, either, says Semenza, explaining in part the systemic nature of mentoring at Hopkins.

“When I came here there was a whole bunch of faculty who helped me and made a major contribution to my success, and now I feel a great need to repay that debt,” says Semenza. “The way I pay it is by mentoring the junior people now. It’s a positively reinforcing culture, that’s the way things are here, it’s always been this way.”

What makes a physician scientist?

A collegial and collaborative environment, wise and supportive mentors, smart young trainees — doesn’t that sound like a formula for producing successful physician scientists? What else is needed? One quality is the ability to focus, which Valle and others saw in Semenza early on.

“He was very focused, very sharp, and he asked very pungent questions,” says Valle. “I tell our scientists in training, many of us can come up with questions that would be useful to know the answer. But there are few questions that, if you know the answer, will really move the field and move you to a new level of understanding. Gregg was able to do that.”

“If in real estate it’s location, location, location, in science it’s focus, focus, focus,” adds Cutting, who shared a lab with Semenza early on. “If you want to be successful, if you want to add to the knowledge base, you put out decent manuscripts, get funded for the work you’re doing, and keep your eye on the prize. Gregg exemplifies that laser-like focus.”

What makes a physician scientist successful? Curiosity and persistence, says pediatric cardiologist Anne Murphy, citing Semenza’s perseverance in searching for HIF through labor intensive protein purification when traditional approaches failed. “I would have given up,” she laughs.

An observant clinical eye, helps too, she adds, noting that a patient’s deteriorating condition in the OR following bypass heart surgery prompted her research into the molecular basis of myocardial stunning, which may lead to sudden heart failure after open heart surgery. The work of her research team was named one of the top 10 research achievements for 1999 by the American Heart Association.

“There are clues all around us, we just need to look,” says Murphy. “As Yogi Berra used to say, you can see a lot just by looking.”

Being extraordinarily industrious, or producing the hard work, of course, is essential. Semenza says the goal is to be efficiently industrious, “not spending as many hours as possible at work, but getting as much done possible during that time at work. You do that is by learning to be efficient.”

That reinforces the lab team to be more productive. Rather than having your staff stressed out over making their deadline because things were left to the last minute, they are ahead of the game. “Which is why a lot of the staff like working with me because I’m never breathing down their neck at one minute to midnight,” says Semenza.

That in turn supports the work life balance, which physician scientists acknowledge is a necessary ingredient for success in science as well. As is spending some time at the end of each day to “think hard” about what you learned that day, says Valle. Allowing yourself to fail helps, too.

“Not every experiment works and you need time to figure out why it didn’t work,” says Dover.

Last but not least, passion and a vision.

“To be successful, you have to really want it, because it’s hard,” says McGrath-Morrow. “You can be a super smart person, but if you don’t really want it, you’re not going to do it. But you can’t do it unless you have the environment and people who can help you — you can’t do it on drive alone.”

In that regard, concludes Cutting, “Gregg has been a nice exemplar. There are many of us who have had our own great successes and we’re happy to pursue these paths.”

Adds Dover, “Gregg Semenza, in my mind, has inherited and reached the epitome of what we all have felt since Barton Childs, what we as physician scientists wanted to accomplish — we wanted to make a difference. We wanted to straddle the clinic and the patient with the laboratory — we wanted to change medicine.”

This feature originally appeared the spring 2020 issue of Hopkins Children's magazine.