Gregg L. Semenza

Biographical

Gregg L. Semenza

Childhood

I was born on July 12, 1956 in Flushing, which is a neighborhood in the Borough of Queens, in New York City. My mother’s family was of German-English-Irish descent and lived in Queens, whereas my father’s family was of Italian descent and lived in the Bronx. I was the first born of five children, followed by Laurie, Beth, Matt and Paul. Our family lived in Old Bridge, New Jersey for five years, not far from Bruce Springsteen’s childhood home. When I was nine years old, we moved to the village of Tarrytown in New York. Tarrytown is basically one long uphill climb, extending from the Hudson River to Main Street and Broadway (the center of town) and further up the hill to the aptly named Altamont Avenue, where my family resided.

I attended Sleepy Hollow High School, so named because Washington Irving had set his famous story The Legend of Sleepy Hollow in Tarrytown. In the story, a Headless Horseman chases a superstitious schoolmaster named Ichabod Crane, who is never seen again. The mascot of the high school’s sports teams was the Headless Horseman and the players were referred to as the Horsemen. My freshman biology teacher, Rose S. Nelson (Figure 1), was the inspiration for my career in biomedical research. Dr. Nelson had earned a Ph.D. in Endocrinology and then worked as a postdoc at Woods Hole. Because of her research training, she did not recite facts but instead described discoveries in vivid detail and told us about the scientists who had made those discoveries. She transmitted to us the thrill of performing biomedical research. I also took Advanced Placement (AP) Biology with Dr. Nelson in my junior year and she recommended that I apply to attend a National Science Foundation-sponsored summer program at the Boyce-Thompson Institute for Plant Research in Yonkers, New York. I was accepted into the program, which was my first hands-on laboratory research experience and, despite the fact that my pipetting was clumsy, I loved it. During Dr. Nelson’s AP Biology course, I became particularly intrigued by genetics.

Mentors and collaborators

Figure 1. Mentors and collaborators.

College life

In the fall of 1973, I made a road trip with my mother to visit Cornell University in Ithaca, New York. I had recently visited Harvard, where a former Sleepy Hollow High student who had graduated the previous year was enrolled. I had purchased a Harvard t-shirt as a souvenir of my visit and was wearing it when we stopped in Albany for the night. My mother’s cousin looked at me and said with disdain: “Why are you wearing that shirt? You will never get in there.”

My first year at Harvard, I lived in Wigglesworth Hall, which had several unique attributes that made it a memorable college residence. We occupied the first-floor suite, under which was located the terminus of the Red Line. When the subway train rumbled into Harvard Square station, the floor of my bedroom rumbled with it. Fortunately, the last train came into the station around midnight during the week and around 1 a.m. on the weekends. Wigglesworth also served as a sound barrier between the noise of Harvard Square and the tranquility of Harvard Yard. Public transit buses queued outside my bedroom window and the hustle and bustle of the Square was just a few feet away. On Saturday mornings in the fall, when the football team was playing at home, I would wake up to the sound of the Harvard Band marching up Massachusetts Avenue performing the fight song “Ten Thousand Men of Harvard Want Victory Today.”

The first two years as a Harvard undergraduate were challenging and at times unpleasant for me, as they were filled with math and chemistry courses about which I possessed neither interest nor ability, which I attributed, at least in part, to my prior experiences. I took chemistry as a high school sophomore. The class met right after lunch and the teacher often had a strong odor of liquor on her breath. She did not inspire me. I took AP Calculus in my senior year of high school and had great difficulty with it. I decided that I would need to take Calculus over again in college, so there was no reason to take the AP exam. My teacher was quite displeased to learn about my plans. He informed me that if I did not take the AP exam, I would have to take his exam. I told him that because I was a senior with an 85 grade-average in the class, I was exempt from final exams. He replied that I did not have an 85 average, because he was giving me a 65 for the final quarter. My guidance counselor, Bill Burnette, who was a man of infinite wisdom and patience, brokered a compromise, in which I received a grade of 65 for the final quarter but did not have to take either exam. My indifferent attendance also led to a 65 in physical education, so my high school career ended not with a bang, but a Bronx cheer.

Starting in the spring of my junior year at Harvard, I worked in the laboratory of Dr. Park Gerald on the Genetics Unit of Children’s Hospital in Boston. My introduction to the lab involved helping to prepare karyotypes from blood samples. Karyotypes identify chromosome abnormalities, such as the extra copy of chromosome 21 that is present in the cells of children with Down syndrome. After several months spent “paying my dues” in the karyotype lab, I was invited to move down the hall to the research lab. The goal was to map a human gene encoding glutathione peroxidase (GPX) using somatic cell hybrids. Increased GPX enzyme activity had been reported in cells from patients with Down syndrome, which suggested that a gene coding for GPX might be located on chromosome 21. We now know that there are eight genes encoding GPX in the human genome. Sadly, none of them are located on chromosome 21. Nevertheless, as I was working out the conditions for assaying GPX activity, which took several months of trial and error, Dr. Gerald provided me with valuable advice regarding the nature of the scientific enterprise. He told me: “Search and re-search.”

Penn, CHOP, and MSTP

Although I had planned to go to graduate school to study genetics, the human gene-mapping project increased my interest in medical genetics, and I decided to apply to MD-PhD programs with the intention of pursuing both a clinical and a research career in human genetics. I was accepted into the Medical Scientist Training Program (MSTP) at the University of Pennsylvania School of Medicine. The National Institutes of Health had funded the MSTP at two-dozen medical schools in order to encourage training of clinician investigators. The MSTP covered my medical and graduate school tuition and provided a small monthly stipend, all of which I would be required to repay only if I chose a career other than biomedical research. During my first semester at Penn, I spent pretty much all of my savings on Gray’s Anatomy and other expensive medical school textbooks. I had a meal plan that covered Monday through Saturday. On Sundays, when the dining hall was closed, I would venture to a greasy spoon called Troy’s, which featured a 99-cent breakfast that would tide me over until Monday morning.

My initial efforts to earn a PhD in genetics did not go well. I started my thesis research in a lab as a junior faculty member’s first graduate student. After a year attempting two projects, neither of which was generating any encouraging data, I sought advice from the graduate program director and then, with his blessing, met with Elias Schwartz, who was the director of the hematology division at Children’s Hospital of Philadelphia (CHOP), and Saul Surrey, who was in charge of Eli’s research laboratory. They generously provided me with the opportunity to join their lab team.

The goal of my thesis project at CHOP was to perform a molecular analysis of the β-globin gene in a family with a variant form of β-thalassemia known as the silent carrier. β-thalassemia is a caused by defects in the expression of the β-globin polypeptide, which associates with the α-globin polypeptide and a heme ring to form hemoglobin, the protein in red blood cells that carries O2. In patients with β-thalassemia, β-globin production is defective, leading to the precipitation of α-globin and subsequent destruction of red blood cells, causing anemia. Affected individuals carry two mutant copies of the β-globin gene, one inherited from the mother and one inherited from the father. Because the parents have one mutated and one wild-type copy of the β-globin gene, they do not develop the severe anemia associated with β-thalassemia, but they usually have smaller red blood cells that contain less hemoglobin than normal and can thus be identified as carriers of a mutant β-globin gene.

In the family that I studied, the son and daughter had β-thalassemia, indicating that both parents were carriers. The mother’s red blood cells showed typical findings of a carrier, whereas the father’s red cells appeared completely normal and thus he was described as a ‘silent’ carrier. My goal was to determine whether the silent carrier allele, like all other β-thalassemia alleles that had been studied so far, contained a mutation in the β-globin gene. We hoped that the mutation would have some unique feature at the molecular level that was responsible for its unique clinical presentation.

I drew blood samples from the parents and children, isolated genomic DNA, constructed a library of DNA fragments in a bacteriophage vector, and then isolated and sequenced a 4.4-kilobase DNA fragment containing the β-globin gene that the affected daughter had inherited from her father. At that time, obtaining the sequence of 4 kilobases of DNA on both strands of the double helix was a manual process that took about a year to complete. To my horror, after a year’s work, I identified the same mutation that had been previously discovered by someone else in the lab studying an unrelated patient. Further analysis indicated that the mutation was not present in the daughter’s DNA but was apparently the result of contamination with another DNA sample somewhere along the process of the gene cloning and sequencing. The source of the contamination will forever remain a mystery.

At this point, I was quite depressed and went to see a psychiatrist, who happened to be the father of two of my medical school classmates. I told him my tale of woe regarding the prospect of starting my thesis research over yet again. He looked at me and said “Gregg, it certainly seems that you have good reason to be depressed!” After that validation, I felt much better and went back to the lab with renewed enthusiasm. I found that the β-thalassemia allele that the daughter had inherited from her mother contained a mutation in the β-globin gene at the junction between exon 1 and intron 1 that prevented proper processing of β-globin mRNA, leading to a failure to translate the β-globin mRNA into protein. In contrast, the β-globin gene that the daughter had inherited from her father had a completely normal DNA sequence. Moreover, the analysis of DNA polymorphisms spanning the entire β-globin gene cluster, which includes the genes for embryonic and fetal as well as adult β-globin, revealed that the two affected children did not even inherit the same β-globin gene cluster from their father, indicating that the silent carrier allele was due to a mutation somewhere else in the genome, a truly novel finding.

After my thesis presentation, I sat in the hallway for an hour while my committee members debated whether the bar was lower for MD-PhD students, who needed to apply for internship and residency well in advance of their thesis defense, thus exerting “pressure” on thesis committees to approve the student’s work in time for graduation and commencement of clinical training. The implication was that the work I had done was in some way not up to the lofty standards associated with a PhD from Penn. Fortunately, the editors of the Journal of Biological Chemistry and Cell did not have such misgivings when they accepted for publication the manuscripts I had written reporting the results of my thesis research.

Duke

Following graduation from Penn, I spent two years as a pediatrics intern and resident at Duke University Medical Center. When I drove a rented U-Haul truck into Durham, North Carolina in June of 1984, I was greeted by the pungent aroma of tobacco, which was still being made into cigarettes in a downtown factory. Mr. Duke had made his fortune in the tobacco trade and cigarettes were still offered for sale from a vending machine in the hospital cafeteria. My residency training there preceded the major national reforms that placed limits on the amount of time that house officers were permitted to spend on the wards, both in terms of consecutive hours and hours per week. Our schedule involved working more than a hundred hours per week, and being “on call” every third night, which meant that all or part of that night would be spent awake taking care of acutely ill children (except for a month on the Pediatric Surgery service, when the call was every other night).

The most difficult rotation was the neonatal intensive care unit (the “NICU”), where extremely premature infants with severely immature lungs were kept alive on ventilators. Two residents would split the night’s work when possible, thereby allowing each to have a few hours of sleep, provided that no emergencies arose that required the simultaneous efforts of both physicians. During my first rotation as an intern in the NICU, I had managed a brief sleep and then reported for duty; the senior resident observed my half-awake state and said “Gregg, go back and splash some water on your face.” Working a full day, then a full night, then a full day again before finally going home was a grueling experience, especially when repeated over many weeks.

Another feature of the Duke pediatrics residency at the time was that the delivery room was located in the old South hospital, whereas the NICU and pediatric wards were in the new North hospital. There was an electric tram that ferried patients, staff, and visitors at a leisurely pace between the two buildings. However, when a newborn baby required resuscitation at night, the on call resident literally had to sprint from North to South and hope to arrive in time to save the neonate’s life.

When I reminisce about my time at Duke, I usually mention that by some miracle, I only fell asleep at the wheel driving from the hospital to my apartment once. Fortunately, the car did not drift across the centerline, but rather towards the side of the road, which was covered with gravel, and the noise of the tires on the rough surface woke me before an accident occurred.

The fast track to Baltimore

Sue Church, who was one of the senior pediatric residents at Duke, noticed that I did not appear to be particularly happy in my position as a house officer. She suggested that I forego my final year of residency and fast track to a medical genetics fellowship. The pediatric genetics unit at Johns Hopkins was well known to me because Haig Kazazian and Stylianos Antonarakis (Figure 1), in collaboration with Stuart Orkin at Harvard, had led the effort to identify and characterize the functional consequences of mutations in the β-globin gene that caused β-thalassemia. I had read their papers with the intensity and devotion reserved by others for the Bible. In addition to the fantastic research environment, the Johns Hopkins fellowship provided the opportunity to learn Medical Genetics at the foot of the master, Victor McKusick (Figure 1). I interviewed at several genetics programs and when Haig Kazazian offered me a position at Hopkins, I immediately accepted. In order to fulfill the requirements for board certification in Pediatrics, I worked in the pediatric emergency department at Johns Hopkins Hospital on those evenings when I was not already on call as a Medical Genetics fellow.

During this first year in Baltimore, I also contemplated the possibilities for a research project. I was interested in studying the regulation of gene expression in vivo using transgenic mice. The Kazazian and Antonarakis labs had moved on from identifying mutations in the β-globin gene that cause β-thalassemia to identification of mutations in the gene encoding factor VIII that cause hemophilia A. I contacted Chuck Shoemaker at Genetics Institute, who had isolated the factor VIII gene, to ask whether he could provide me with cloned genomic DNA. After I told him what I had in mind, he said that he could provide factor VIII gene sequences, but that there was this other gene that I might want to consider studying called EPO, which he had cloned before starting work on factor VIII.

My education about EPO was facilitated by the happy coincidence that one of the world’s experts on the role of EPO in erythropoiesis was Jerry Spivak (Figure 1), a Hopkins hematologist, whose office was just down the hall from mine in Johns Hopkins Hospital. Based on Chuck’s suggestion and Jerry’s encouragement, I decided to focus on EPO gene regulation and was fortunate that John Gearhart (Figure 1), who was a faculty member in the physiology department at Hopkins, agreed to collaborate with me to generate EPO transgenic mice. Stylianos Antonarakis served as my mentor on a daily basis in the lab and Haig Kazazian provided advice about the direction of the project and funding opportunities.

At this point I should emphasize how uncommon – if not inappropriate – it was for me, as a starting postdoc, to: (a) enter the Kazazian-Antonarakis lab, in which the investigators were establishing a paradigm for molecular dissection of human genetic disease, which subsequently served as the template for hundreds of investigators studying dozens of inherited disorders, and blithely assume that I would initiate a completely unrelated (and unfunded) research project; and (b) enlist the participation of a senior faculty member in another department as well. Such was the incredible generosity of my mentors.

My good fortune grew larger when John Gearhart called me up one day and asked me if I had seen the RFA on EPO. I replied, “What’s an RFA?” John told me that the National Institutes of Health (NIH) had released a Request for Proposals (a.k.a. RFA) to study the molecular mechanisms of EPO gene regulation. It seemed to be a tailor-made source of funding for my project. The only catch was that the RFA funded R01 grants, which are awarded to faculty members, not postdoctoral trainees. Stylianos agreed to serve as the principal investigator, with John as a co-investigator. I composed the application on a Macintosh SE computer in my apartment during a midwinter blizzard. The application scored in the fifth percentile and was funded for three years.

Around the same time, Haig Kazazian was on a flight back to Baltimore from California with Tom Pollard, a faculty colleague in Cell Biology who was an expert on the workings of actin and myosin in driving cell motility. Tom told Haig about his involvement with the Lucille P. Markey Charitable Trust, which was at that moment soliciting applications to fund research programs for young investigators as a bridge from postdoctoral to faculty positions. Mrs. Markey had been married to, and outlived, two wealthy men, including the owner of Calumet Farms in Lexington, Kentucky, a famous stable that had produced eight Kentucky Derby champions. She had several very enlightened advisors, who suggested that she use her considerable wealth to establish a trust to foster biomedical research. At its peak, the annual funding expenditures by the Markey Charitable Trust exceeded those of the Howard Hughes Medical Institute.

Although this grant application seemed like a great opportunity, there was a catch: the application was due the following week. I worked nonstop that weekend to prepare the application, secured letters of recommendation from Haig and Victor McKusick, and sent the application off to the Trust headquarters in Lexington. Incredibly, the application was funded for six years (one extra year as a postdoc and five years as an assistant professor). Although Tom Pollard was on the selection committee, he was no doubt recused when my application was considered, which was probably a good thing: several years later, when a faculty member in Tom’s department told him that she had discovered the Drosophila gene responsible for a developmental mutant, and that it encoded a transcription factor, he said to her, “Oh, I’m so sorry!”

The studies of EPO gene regulation in transgenic mice, and later in human cells, that were funded by these two grants led directly to the discovery of hypoxia-inducible factor 1 (HIF-1), as described in my Nobel Lecture. One of the great benefits of receiving funding from the Lucille P.

Markey Charitable Trust was that the grantees met annually to present their research progress to the members of the selection committee, which was a Who’s Who of Science that included Mike Brown, Joe Goldstein, George Palade, and Torsten Wiesel. At the annual meeting in 1993 or 1994, Joe Goldstein, who was one of my personal scientific heroes, gave an after dinner speech that made a deep impression on me. He spoke of what he called “technical courage,” by which he meant a determination to follow the science wherever it led, rather than being limited by the particular experimental techniques that one was most comfortable using.

This advice was soon put to the test. We had attempted to identify cDNA sequences encoding HIF-1 using a bacteriophage expression library cloning approach without any success. In mulling over my options, I came up with three choices: (1) We could continue to use the same screening approach and hope that our luck would somehow change after screening millions of bacteriophages; this seemed very close to Einstein’s definition of insanity. (2) We could give up and wait for someone else to do the job; that wasn’t an appealing option. (3) We could take an entirely different experimental approach, which was to perform a biochemical purification of the protein. This seemed improbable, given that I was trained in molecular biology and we did not even possess a fraction collector at the time. Fortunately, Tom Kelly (Figure 1), who was then the director of the department of molecular biology and genetics at Hopkins, was one of the pioneers of DNA affinity chromatography. Tom’s lab provided advice and assistance that was essential to our eventual success in purifying HIF-1 and isolating DNA sequences encoding the HIF-1α and HIF-1β subunits. This work was reported in papers published in 1995 in the Journal of Biological Chemistry and the Proceedings of the National Academy of Sciences. The latter manuscript, which was communicated by Victor McKusick, was submitted to and returned without review by the editors of Cell, Science, and Nature. This PNAS paper has now been cited over 6,000 times.

It is satisfying that the first translation of our discovery of hypoxia-inducible factors to the clinic has been the development of drugs that increase HIF activity as a means of stimulating red blood cell production in patients with chronic kidney disease. Unlike recombinant human EPO, which must be injected, these new HIF stabilizers are small molecules that can be taken by mouth. Four different drugs are currently in phase III clinical trials that have enrolled over 20,000 subjects and it seems likely that one or more of these will be approved by the FDA sometime in 2020, exactly 25 years after the publication of our papers reporting the purification, cloning and sequencing of HIF-1 of the HIF-1α and HIF-1β subunits.

Friends, collaborators, and trainees

By now, the reader is fully aware that our discovery of HIF-1 could not have been achieved without the mentoring that I received from Haig Kazazian, Stylianos Antonarakis, Victor McKusick, Jerry Spivak, John Gearhart, and Tom Kelly at Johns Hopkins. I have also been extremely fortunate to have an abundance of wonderful collaborators at Johns Hopkins and at other universities with whom I have investigated the role of HIF-1 in development, physiology, medicine, and evolution as described in my Nobel Lecture. Among the longest and most valued friendships, forged over decades of collaboration, have been those with Nanduri Prabhakar (University of Chicago) and Joe Prchal (University of Utah), and my Hopkins colleagues Chi Dang, Larissa Shimoda and Akrit Sodhi (Figure 1). I am honored to serve as the C. Michael Armstrong Professor at Johns Hopkins University. Mike Armstrong (Figure 1) has been a tremendous supporter of our work and with Mike’s help we hope to one day reach our goal of developing drugs that block HIF activity for the treatment of cancer.

I have had the distinct pleasure of training an extremely talented and hardworking group of 55 postdoctoral fellows, 30 graduate students, and 40 undergraduates. Since 1996, when I decided that I would not be able to adequately mentor the members of my lab unless I gave up my spot at the bench, all of our experimental data has been produced by these trainees and collaborators. Some, but by no means all of them, are mentioned in my Nobel Lecture.

Among my fondest memories of the whirlwind that occurred between the Nobel Prize announcement on October 10 and the Nobel Lectures on December 10, 2019, two stand out. The first of these was a lab reunion at our home in November, which was attended by over fifty present and former lab members from as far away as Hong Kong. The second was a private dinner, which Laura and I hosted for thirty of our closest family members and friends at the Gondolen restaurant, that lasted late into a snowy December night in Stockholm.

Saving the best for last

My fulfilling scientific career has been made possible by the love, understanding, and support of my wife Laura and my children Allie, Evan, and Gabe (Figure 2). They have transformed my pedestrian life into a fantastic journey and give meaning to every breath I take.

Family

Figure 2. Family.

From The Nobel Prizes 2019. Published on behalf of The Nobel Foundation by Science History Publications/USA, division Watson Publishing International LLC, Sagamore Beach, 2020

This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/ Nobel Lectures/The Nobel Prizes. The information is sometimes updated with an addendum submitted by the Laureate.

Copyright © The Nobel Foundation 2019

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