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There is nothing quite like the excitement of discovery in science—of finding something no one else knew and seeing a story unfold. One has to be part of an emerging picture to feel the elation. These moments in a lifetime are few and far between, but they fuel enthusiasm and keep one going. They are embedded in struggles and joys of everyday life, years of establishing what Louis Pasteur called “the prepared mind,” working with mentors, trainees, and colleagues, failures and successes. This article recalls 1) how I got to be a biochemist; 2) my contributions as an educator and researcher, especially regarding meprin metalloproteases; and 3) my participation in communities of science. Perhaps my reflections will help an aspiring scientist see how fulfilling a career in science can be.
I was born in New York City and grew up in Brooklyn, New York, home of the Brooklyn Dodgers (in the 1940s and 1950s), the mixing pot of cultures, second- and third-generation American families, with a great delicatessen, bakery, and movie theater in every neighborhood. The public schools were excellent, and education was a high priority of most families. My grandparents were Jewish immigrants from Austria and Russia. They came to the USA in the early 1900s, lived in the Bronx and Brooklyn, and worked diligently to integrate into “the land of the free and the brave” and achieve middle-class comforts (rental apartments in buildings of six stories; summer vacations in the Catskill Mountains). Somewhere in my background there was a tailor, as my family surname was Schneider. My mom was born Natalie Perkins in 1911. Her life was not easy in that her father died while she was in college, and she became the main breadwinner for her mom and younger brother. The Great Depression of 1928 also interrupted her education. She persisted and received a bachelor's degree from Hunter College in 1938. She worked most of her life as a secretary, either in nonprofit organizations or at Brooklyn College. She loved biology, music, and art, and she instilled an appreciation of the arts and sciences in my sister and me (Fig. 1). We took piano lessons and dance lessons, were great fans of Rogers and Hammerstein musicals as well as Gilbert and Sullivan operettas, and were encouraged to learn about science and mathematics. My dad had a high school education with some college courses and became an insurance broker. He was a loving and devoted husband and father and worked hard to allow me and my sister to follow our dreams and succeed in whatever paths we envisioned. Some of the valuable lessons he imparted to me and my sister came from his love of sports. He taught me how to play tennis and about the “team sports mentality”—practice, practice, practice; learn how to win and lose; find your position in a team; and aim to excel. In addition to contributing to staying physically fit, these lessons served me well in academia!
The New York City public schools were strong in mathematics and the sciences. I attended Public School 199 and particularly remember one elementary school teacher who encouraged me to work diligently and made me feel I could achieve excellence in school. Many of my female colleagues concur that some words of encouragement from a teacher or mentor during the elementary school years were important in gaining confidence in oneself and succeeding in academic pursuits. I became part of an accelerated program in Hudde Junior High School and completed grades 6, 7, and 8 in 2 years. I then went on to Midwood High School, in Brooklyn's Flatbush, a strong school in the sciences that today maintains that strength and draws students from all parts of Brooklyn. I learned to love the rigor and logic of chemistry there and to avoid history (because of a frightening teacher). The distribution of men and women in science and math courses became obvious in high school. In my senior year, my friend Maria and I were the only girls in a calculus class of about 25, and after the first two sessions we yearned to drop the class because we felt intimidated. Our teacher, however, strongly encouraged us to remain in the course, and he helped us with special after-school tutoring. We stayed and completed the course, but with a feeling of imposter syndrome (Do I belong in the sciences?). Again, teachers (a male math teacher and a female chemistry teacher) were important to our success as they counteracted our hesitancy and built our confidence. Having a female classmate in the course was also important, as we consoled and strengthened each other. We learned too the importance of persistence and that we could master the concepts. Another encouraging high school experience was winning a Westinghouse honorable mention for a project having to do with hibernating frogs. I do not remember the question I was trying to answer, but I enjoyed working on the project and the feeling of accomplishment. I do remember how my mother and grandmother encouraged me to complete the project even though they were not happy about keeping the frogs in our refrigerator! My high school class had 1,000 students; the school had 5,000. There were advantages to being in a school of this size, as there were many options for classes and activities. I became involved in a volleyball club and the student government (secretary of my senior class). I belonged to Arista (an honor society) and was a cheerleader for athletic teams.
When it came time to choose a college, smaller institutions were more attractive. I chose a women's college, Bennington College in Bennington, Vermont. This was a college of 350 women at the time I attended. It was mainly known for English/literature and the arts (dance, theater, and fine arts) and had a small but excellent science faculty. The school's philosophy of education was based on the ideas of John Dewey: “Learn by doing.” Rather than studying the history or characteristics of a subject (e.g. art appreciation), one participated in the subject (by painting, sculpting, dancing). This philosophy was well-suited for science, as laboratory classes were excellent examples of “learn by doing.” I majored in science, which meant I took biology, chemistry, physics, and math. Qualitative analysis was my favorite subject, especially the problem-solving aspects. There were no highly technical advanced science courses such as those that existed at larger colleges and universities, but there were tutorials in which students could delve into a subject if a faculty member would agree to work with them. The faculty encouraged individual projects. It was through individual projects that students could explore questions of interest, read the literature, test hypotheses experimentally, or find answers through the literature. It was through such projects that I affirmed that I liked research and attempting to answer scientific questions. Bennington also had a nonresident term (each January through March) during which students would leave the campus and find a position in a field they might be interested in pursuing after college. I chose laboratory jobs in hospitals or research laboratories (e.g. drawing blood for a hematology laboratory in a NYC hospital and working in a biomedical research laboratory at Yale University). These experiences were critical in confirming my feeling that I would like a career in research, and particularly someplace at the interface of chemistry and biology.
Bennington College also provided the opportunity to explore the humanities and arts. There were no required courses, but one was encouraged by counselors to explore a variety of fields. I avoided history and political science (unfortunately, as I might have learned more about government and our current political situation). I did take advantage of fine arts, music, dance, and literature courses. These courses had long-range benefits and opened my eyes to the commonalities of art and science, artists and scientists. My most intriguing course was called “Myth, Ritual, and Literature,” taught by Stanley Edgar Hyman. We explored commonalities of civilizations (from primitive to modern), the importance of dance and rituals, and celebrations of transitions in life. This course forever changed my view of human behavior. I am an advocate for a liberal arts education in college, as it opened my eyes to a wide variety of subjects and provided unique opportunities to explore areas I did not plan to pursue as a career.
When it came time to leave the idyllic life of a small college in Vermont, I applied to graduate schools in large universities in the Northeast. I enrolled as a graduate student in the Department of Biochemistry and Physiology at Rutgers, The State University of New Jersey, in New Brunswick, NJ, in 1961. My first-year classes were large (20–30 students), and one could hide in the back of the class, in contrast with the small, intimate Bennington classes of 1–5 students, in which you had to be present and participate at all times. I soon became fascinated with the biomedical sciences and particularly biochemistry, enzymology, and cell biology. I earned a Master of Science degree and then went on to candidacy in the Ph.D. program. There I learned rigor of science experimentation. John Bird, a physiologist, was my thesis advisor, and my project was related to muscular dystrophy, lysosomes, and proteases (Fig. 2A). The guinea pig developed muscle wasting and weakness on a vitamin E–deficient diet. The hypothesis was that lysosomes (containing several proteases) were destabilized by vitamin E deficiency and were responsible for the breakdown of cellular proteins. The options were that lysosomes initiated degradation of proteins or that they were secondary players reacting to the presence of denatured or partially degraded proteins. The data were consistent with the hypothesis that vitamin E deficiency resulted in unstable or denatured proteins that were consequently degraded by the lysosomes. The project taught me how to work with animal models, the importance of designing protocols that could lead to statistically significant results, and how difficult it was to come to definitive conclusions when there were so many variables. I received my Ph.D. in 1966. After graduation, I questioned whether I had the talent (imposter syndrome again) and stamina for a research career that involved long hours with little reward. By this time, I was married to a fellow graduate student, Guy Bond, and he accepted a postdoctoral position at Vanderbilt University Medical School in Nashville, Tennessee. I accompanied him to Nashville and decided to look for a teaching position. However, I could not find a teaching position at any level of education. I wasn't qualified to teach! I had not taken any education courses and had no credential or experience for any level of formal teaching.
My husband was in the Physiology Department at Vanderbilt, an exciting place in the 1960s. Earl Sutherland, a future Nobel laureate, was there, and he and his associates had discovered that cAMP was a central player in the mechanism of action of many hormones. This was a controversial idea in that it was difficult to envision how one molecule could be the mediator for so many different hormones that had different physiological responses. Sutherland and the chair of the department, Rollo Park, had recruited a number of bright, enthusiastic workers to the department, and there was an air of excitement about research. At a social meeting for faculty and trainees, I met Dr. Jane Park, a biochemist in that department (Fig. 2B). She suggested I consider doing postdoctoral work with her, and that was the beginning of the rest of my life in research. I worked with Janie on the mechanism of action of glyceraldehye-3-phosphate dehydrogenase. In Janie's laboratory I learned how to delve into enzymology. My project involved identifying critical amino acid residues at the active site of the enzyme. I found the detailed, analytical approach of enzymology fascinating. The work was published in the Journal of Biological Chemistry (JBC), my first experience with this journal that represents the best of biochemistry in my mind (
). Through these postdoctoral years, I became enamored with research and basic biochemistry.
A laboratory of my own: Beginning of a career as an independent woman scientist/faculty member
My first faculty position was as an instructor in the Department of Biochemistry at the Medical College of Virginia of Virginia Commonwealth University (MCV/VCU) in Richmond, Virginia, in 1968. It was a time when there was an expansion of faculty at research universities, and it was not difficult for couples to find independent positions at the same institution. I was promoted to assistant professor about a year after arrival at MCV/VCU. The first few of years as a faculty member were busy and exciting. These years included setting up a laboratory with new equipment, hiring a technician, attracting a graduate student or two, writing and presenting lectures, thinking about the main thrust of my research, working at the bench to get preliminary data, writing papers and grant applications, and finding my role as a faculty member in a basic science department. I enjoyed lecturing about basic biochemistry, especially to first-year medical and dental students in their first few weeks, who were interested in everything at that stage. Teaching awards reinforced my enjoyment of teaching. By the beginning of the 1970s as I approached 30 years old, I felt the pressure of the biological clock. I knew there is no good time in a career to start a family, but I knew too that I wanted to have a career and a child. My son, Kevin, was born in May of 1971. An infant son, of course, brought a whole new perspective to my life. I, and many of my female colleagues, can assure young female scientists that you can have a career and children, especially with the help of a supportive spouse or significant other.
I had never felt discrimination as a woman trainee, but as a woman faculty member this changed. I was originally assigned to teach nursing and dental hygiene students, because I was a woman, as were those students. When I had assignments in the dental school, I found the “faculty rooms” for that school were actually men's bathrooms. I complained about that! A year or so later that changed. In reflection, I believe many male faculty members saw me as a young woman rather than a young scientist, and this tainted interactions. There were some uncomfortable situations, but I never felt taken advantage of or threatened. With time, as I began to publish and present data at meetings, collegial attitudes dominated. There were attitudes and behaviors, however, that put women at a disadvantage to advance in academia (aggressive behaviors, egos, big brothers or buddies, golf and social interactions, assumptions about women and their place). I never dwelled on inappropriate or offensive comments and actions, and this served me well.
As a young faculty member, I read the book Games Mother Never Taught You by Betty Harragan (
). It focused on how businesses operate with the mentality of a sports team, and this applies to academia as well. There is a boss (coach, department chair) or bosses (coaches, senior faculty members) and players, and everyone has to learn the rules of the game, find their role in the team, and learn how to compete, win, and lose. Women who do not understand this mentality are at a disadvantage in the working world. In my generation, women sat on the sidelines and cheered for the team but did not participate in the contest. This has changed with time, thankfully, and has made it easier for more women to participate fully in businesses and academia. I attribute my comfort in the world of academia to my father's lessons, good mentors, and Betty Harragan's book.
Focusing on protein degradation and proteases
When setting up my own laboratory, I made the decision to focus on intracellular protein degradation. In the 1960s, there was an outpouring of new information about protein synthesis, but much less was known about protein degradation in cells; it was the road less traveled. We knew from the classic work of Rudolf Schoenheimer (
) and others that there was a “dynamic state” of proteins in cells and that protein turnover (synthesis and degradation) was critical for homeostasis, growth, and development in eukaryotic cells. However, little was known about degradative mechanisms or the proteases responsible for the turnover. Robert Schimke and colleagues (
) had published convincing data showing that there were short- and long-lived cytosolic enzymes in vivo, and the short-lived ones were subject to rapid fluctuation in response to hormones or other signals. These observations were intriguing and suggested that there were properties that distinguished the short- and long-lived proteins (such as susceptibility to proteases or denaturation). For prokaryotic cells, there was a belief that there was little endogenous protein degradation. Bacteria were generally studied under conditions of exponential growth, and it was thought that defective, denatured, or unneeded proteins would be diluted out with time; thus, there was no need to degrade protein. Against this background, I started working on protein degradation in eukaryotic and prokaryotic cells, primarily asking “What factors drive stability of cytosolic proteins in vivo and in vitro?”
We found that there are a number of physical and chemical properties of enzymes that correlate with in vivo stability. Cytosolic enzymes with long half-lives in vivo tend to be small, basic proteins that are less vulnerable to heat and acid denaturation and more resistant to inactivation by several proteases in vitro compared with short-half-lived proteins (
). My first federal grant was from the National Science Foundation (1971–1974) on the “Relative Stability of Enzymes in Vitro and in Vivo” and led to a long-term interest in factors that contribute to protein stability and vulnerability to cathepsins (e.g. see Refs.
). Bill Duncan and Kenny Offermann, M.D./Ph.D. students, and Malcolm McKay, a postdoctoral fellow, actively contributed to these studies. We also isolated several novel proteases. For example, Jerry Saklatvala and I isolated and characterized a serine protease from rat liver (
At the same time that I was searching for my niche as an independent scientist, I had several collaborative projects with colleagues on a variety of topics. One project was on protein degradation in Nocardia erythropolis, funded by a grant from NIAID, National Institutes of Health (1972–1975), showing that there was substantial protein degradation in this prokaryote. Another was on the toxicity of the antitumor drugs concanavalin A or pactamycin in combination with endotoxin (
). These projects addressed interesting questions, resulted in publications, and were funded by small grants from NIAID or private foundations. They were important too for establishing scholarly productivity and obtaining tenure, which I was granted in 1974. The pressures of obtaining tenure in the first five years of starting my laboratory were real and motivating.
By 1975, I had divorced and remarried. My second husband, Gaylen Bradley, had been a collaborator, a mentor, and a great supporter of my career (Fig. 2C). He helped me prepare for the tenure process, encouraged me to aim for national recognition and participate in international meetings, and cope with the strains of bringing up a child in the beginning stages of a research career. He also encouraged me to start thinking about a sabbatical year, which was allowed after seven years as a faculty member. It took a few years to plan a sabbatical for myself, my husband, and son. In the meantime, work continued, and I wrote multiple grants, most of which were not funded. However, just before we left for the sabbatical, I got word that my first major NIH R01 grant, entitled “Intracellular Protein Catabolism in Diabetes Mellitus,” from the National Institute of Arthritis and Metabolic Diseases, which later became the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), would be funded (1977–1983). In addition, I received an NIH Research Career Development Award (1978–1983). Fortunately, I was able to get permission to start receiving funds from these grants after I returned from sabbatical leave at the end of 1978.
For my sabbatical leave, the calendar year of 1978, I went to work with Dr. Alan Barrett at Strangeways Research Laboratory in Cambridge, UK. Strangeways was a private research institute associated with the University of Cambridge. Alan was an internationally recognized authority on proteolytic enzymes (Fig. 2D). In Alan's laboratory, I studied the effect of cathepsin B on fructose bisphosphate aldolase and found that inactivation of aldolase was due to an exopeptidase activity of the protease; only two amino acids were cleaved from the C terminus, which was sufficient to inactivate the enzyme (
). This was an unexpected finding because cathepsin B was considered an endopeptidase. The year was clearly a refreshing and scientifically important experience for me. In addition, my husband, son, and I had a wonderful time in England. We lived in a thatched-roof cottage built in 1641 and traveled to different areas of England when my son had vacations from the “infant school” (he developed a distinct British accent). My husband and I met new colleagues and learned about England and the British people—and different ways of working in the UK and USA. Strangeways provided a culture shock to me, as I found American and British work cultures to be very different. As an American, I would tend to be in the laboratory six or seven days a week, mostly from 8 a.m. to evening hours, and anxiously trying multiple approaches to a problem. The British at Strangeways were much more thoughtful and strategic in approaching problems. They would arrive at work sometime after 9 a.m., break for coffee at 10:30 a.m., have a lunch around noon to 1 p.m., break for tea ritually around 3:30 p.m., and then leave the laboratory around 5 p.m. It was rare to see a Brit in the laboratory on the weekends, and in fact the laboratories were locked to all on Sundays and holidays. I never did figure out how to complete experiments with the British schedule or how they got so much work done! I had the impression that they felt we (Americans) must be mindless to work so hard. I learned to put much more thought into experiments and how much communication occurred between colleagues at these rather formal coffee and tea times (quite uncomfortable for Americans). Most importantly, the sabbatical strengthened my conviction to focus on intracellular proteolysis and introduced me to the international community in this field.
On return from Cambridge, I began to investigate intracellular protein degradation in diabetes mellitus, funded by my new NIH grants. There was literature indicating that the rate of degradation of proteins in liver and muscle increased in diabetic animals, resulting in protein loss. Our studies, however, failed to find an increase in the rate of degradation of cytosolic liver proteins in streptozotocin-induced or alloxan-induced diabetes in mice (
). In fact, there was a decrease in the rate of protein degradation as measured by radioisotopic methods, as well as a decrease in the rate of synthesis of the liver proteins. Our results pointed to a loss of protein due to an altered balance between protein synthesis and protein degradation, where the rate of protein synthesis was decreased more than the rate of degradation. These results were not consistent with our hypothesis that there was enhanced degradation in diabetes.
Discovery of meprins: Unraveling the structure and function of unique metalloproteinases
During my sabbatical in England, I met Dr. Robert Beynon, a young faculty member at the University of Liverpool who was also interested in intracellular proteolysis (Fig. 2A). He came to my laboratory as a visiting professor in the summer of 1979 and brought an azocasein assay with him. Digestion of azocasein is measured at basic pH values (9.5) by the release of azo-dye peptides from the protein that are soluble in TCA. We asked whether there were changes in proteolytic activity at several pH values in various tissues in diabetic animals. We found no change in proteolysis in several tissues; however, we observed that mouse kidney had a very high specific activity with azocasein as substrate. We could not identify the proteinase that was responsible for this from the literature. There were known acid hydrolases and several peptidases (proteases that hydrolyze peptides but not proteins) in kidney tissue, but no enzyme had been identified to degrade proteins at basic pH values (pH 9.5). We decided to find out what protease(s) was responsible for this activity. This led to a long-term collaboration and friendship between Rob and me—and the discovery of meprins.
With the able assistance of John Shannon, a postdoctoral fellow from Australia, we purified and characterized a zinc metalloproteinase from the kidneys of BALB/c mice (
). This was not a simple matter, as the enzyme was membrane-bound, large (subunit molecular weight ∼85,000), and complex (oligomeric, disulfide-linked subunits, and a glycoprotein). We chose the name meprin as an acronym for metallo-endopeptidase from renal tissue, with an ending of “in,” which was commonly used for proteolytic enzymes (e.g. trypsin, thermolysin). We now know that there are several forms of meprins, as they are composed of two types of evolutionarily related subunits, and we now know that meprins can exist as homooligomers and heterooligomers and as dimers, tetramers, and higher-order oligomers (Fig. 3). Much of the research on meprins has been reviewed (e.g. see Refs.
). It took a number of years and insightful, devoted trainees and collaborators to decipher the complexity of the meprins, and I have fond memories of saying to many students (Fig. 4), “Someday we will understand what is going on with this protease.”
Discovery of a meprin “deficiency” in mice and the Mep-1a and Mep-1b genes
Meprin was originally characterized from BALB/c mice, and because this mouse strain was used extensively by other scientists at MCV/VCU (especially for immunology experiments), we could obtain a large number of kidneys for protein isolation. During the summer of 1981, there was a shortage of BALB/c mice in the animal facility, but other strains were available. A summer student, Jim Crute, obtained kidneys from C3H/HeJ mice. Unexpectedly, there was very little renal meprin activity in this strain. Of course, when this first occurred, we were sure that it was either the fault of the student or of reagents that had gone bad. However, after others in the laboratory checked everything out, it was clear there was very little meprin activity in the kidneys of C3H/HeJ mice. We could find no evidence for an inhibitor of meprin activity in this strain, nor an activator in the BALB/c mice, and no trivial explanation for the marked differences in activity. At this point, we started ordering many different mouse strains from Jackson Laboratory (Fig. 4A). There were indeed marked differences in the specific activity of meprin in homogenates or membrane preparations in various strains of mice. We described the findings as a heritable deficiency (
). The deficiency appeared to arise as an early event in the development of the C stock mice in Jackson Laboratory. Crosses between “meprin-sufficient” and “meprin-deficient” mice indicated that the trait for deficiency was recessive. This appeared to be the first demonstration of a heritable deficiency of an integral cellular proteolytic activity.
Upon publication of the “deficiency” of meprin in certain mouse strains, an immunogeneticist, Chella David, from the Mayo Clinic College of Medicine in Rochester, Minnesota, contacted us. He pointed out that the deficiency appeared to be restricted to the Strong Stock C mice established from a cross between a D Stock mouse and an A mouse in 1922! Many of the inbred strains at Jackson Laboratory were developed to study rejection of tissue transplants, and the “meprin-deficient” mice were all of the k haplotype, indicating that there may be a relationship between the major histocompatibility complex region and the regulation of expression of meprin. This was a most exciting time for us, as it opened up a whole new area of exploration relating to the genes regulating meprin. The sequence of events illustrates the importance of having scientists from different disciplines communicating and collaborating. The analysis of different inbred strains, as well as recombinant and congenic strains, conducted mainly by graduate student Jane Reckelhoff, led to the localization of the gene for meprin α, responsible for regulating meprin activity—the Mep-1 gene. Mep-1 is located on mouse chromosome 17 (human chromosome 6) at the telomeric end of the H-2 complex (
). Over time, it became clear that the structures of meprins have many attributes of major histocompatibility complex proteins. In addition, the enzymes are active in immune system cells and function in the immune system.
The discovery of the meprin β subunit came about when we found there was a protein in the “deficient” kidneys that cross-reacted with meprin polyclonal antibodies (
). This led to the purification of a latent metalloendopeptidase from the “deficient” mouse strains by postdoctoral fellow Elaine Butler and graduate student Maria Kounnas, that we called meprin-β or meprin B (
). Meprin α and β had similar amino acid compositions (∼50% identical), subunit molecular masses (∼85,000 Da), and degrees of glycosylation. Carlos Gorbea, Petra Marchand, and Weiping Jiang (Fig. 4B) and collaborators found that the mouse and human meprin β genes are both located in chromosome 18 (
). The α and β subunits provide an example of divergent evolution; clearly, there was a common ancestor that duplicated and evolved differently over time. The form of meprin that we originally discovered and isolated from BALB/c mouse kidney was a tetramer containing both the α and β subunits, and α was activated due to cleavage of the pro-sequence. The form of meprin isolated from C3H mice, the “deficient” or low-meprin mice, contained only β subunits, and this subunit maintains the pro-sequence at the kidney brush border membrane and thus is inactive. If we had used C3H mice rather than BALB/c mice in our original studies of diabetic mice, we would not have discovered meprins—an example of serendipity.
A new phase of rapid advances and discovery began in the late 1980s and early 1990s, when the techniques of molecular biology became readily available and Weiping Jiang came to work in my laboratory as a postdoctoral fellow (Fig. 4B). Weiping set out to clone and sequence the meprin subunits (
). Cloning and sequencing of the protease domains of mouse kidney and human intestine proteins showed that these enzymes were 90% identical in amino acid sequence, confirming that they are orthologues. Furthermore, comparative analyses using the data banks revealed that the mouse and human sequences are 30% identical with that of the crayfish Astacus astacus protease and the human bone morphogenetic protein 1 (bmp1 is a protease involved in bone formation). These data strongly indicate that these proteins are members of an evolutionary family. The crayfish protease was the simplest of the group (containing only a pro-sequence and protease domain) and the first of the group to be sequenced. Thus, the family was dubbed “the astacin family” (
). The mouse and human genomes have only six astacin family genes (one each for meprin α and β, three BMP/tolloid genes, and one ovastacin). By contrast, there are 18 astacin family genes in Drosophila melanogaster and 40 astacins in Caenorhabditis elegans! The functions of most of these astacins are unknown, but those that have been characterized are secreted or cell-surface proteins.
Molecular cloning and sequencing of the entire mouse meprin α and β subunits revealed that meprins are unique proteinases (Fig. 3) (
). The signal sequence directs the protein into the rough endoplasmic reticulum during biosynthesis. The pro-sequence must be removed by proteolysis for the enzyme to be active against peptides and protein substrates. For the α subunit, Jie Tang found that activation occurs after the subunit passes through the Golgi apparatus and near or at the plasma membrane (
). For the intestine, it is likely that trypsin in the lumen of the gut activates the β subunit. The protease domain of meprins, and all astacins, contains about 200 amino acids. The crayfish astacin was crystallized in 1992 by Wolfram Bode and his colleagues in Germany; this group solved the X-ray crystal structures of several metalloproteinases and defined a superfamily of metalloproteinases that they called “metzincins” because of a critical methionine residue near the active site that contains zinc. The metzincins (part of Clan MA(M) of the MEROPS classification) include several evolutionarily related families, such as matrix metalloproteinases and ADAMs (
). Interestingly, whereas the amino acid sequences of the different metzincin protease domains show very little sequence homology, the three-dimensional structures of their protease domains are very similar, having been conserved through evolution.
The oligomeric structures of meprins were primarily deciphered by graduate students Petra Marchand, Carlos Gorbea, Jie Tang, Greg Bertenshaw, Jeremy Hengst, and Faoud Ishmael (Fig. 4, B and C) (
). Meprins exist as homo- or heterodimers, and the two subunits are covalently associated via disulfide bonds (Fig. 3). However, their oligomeric structures are quite complex, depending on the expression of the subunits. If the meprin β subunit is expressed alone, it becomes a dimer at the membrane or when it is released from the membrane. If meprin α is expressed alone, it dimerizes, is released from the membrane in the endoplasmic reticulum, and forms higher-order (noncovalent-associated) oligomers upon secretion. If meprin α and β are expressed together, the α/β heterodimer is first assembled, and then it dimerizes to form a tetramer. Visualization of the oligomers by EM was made possible by collaboration with Mona Norcum (now Trempe), who was a faculty member at the University of Mississippi (Fig. 5) (
). This collaboration began with a poster presentation at an Experimental Biology meeting, where Mona and Faoud happened to be assigned to poster boards near each other. This demonstrates the importance of presenting your work at national meetings. The homomeric meprin A oligomers tend to form rings of 10–12 meprin α subunits, but higher oligomers have also been observed and estimated to have molecular masses of up to 6 MDa! We proposed that the ability to form large oligomers concentrates secreted meprin activity extracellularly, particularly in the lumen of the intestine, in kidney tubules, or at inflammatory sites. Meprins are also concentrated at the cell surface if they contain a β subunit (Fig. 6). The concentration of both secreted and membrane-bound forms is likely important for their physiologic functions.
The meprin subunits are highly glycosylated; about 25% of the total mass of the subunits is carbohydrate. Tomoko Kadawaki and Takayuki Tsukuba, postdoctoral fellows, showed that the N-linked oligosaccharides are required for the secretion of meprin α and for the enzymatic activity of meprin A (
). We proposed that the high level of glycosylation is important for stability of the meprins in the harsh environment of the intestine and urinary tract lumens, at sites of inflammation, infection, and tumor environment.
The roles of all of the meprin domains for structure, activity, and membrane association or secretion were determined by mutational analyses by graduate students and postdoctoral fellows in the laboratory. For example, Takayuki showed that the MAM, MATH, and TRAF domains are necessary for correct folding and transport through the secretory pathway and activity of the mature enzyme and identified chaperone interactions (
Functional aspects of meprins: Substrate specificity, tissue localization
The search for physiologically relevant substrates and small synthetic substrates (for ease of assay) occurred over a 30-year period. Early studies indicated that meprin A is a relatively nonspecific protease with a preference for hydrophobic or small neutral amino acids flanking the scissile bond; this was confirmed over time (
). Bradykinin (a bioactive peptide RPPGFSPFR), cleaved at the Phe–Ser bond, was found to be an excellent substrate for meprin A; Russ Wolz, a postdoctoral fellow, designed a chromogenic assay using phe5(4-nitro)-bradykinin that was useful for kinetic studies (
). Studies of the active sites of the α and β subunits by Greg Bertenshaw and Jim Villa provided insights into why the two evolutionarily related subunits have marked differences in substrate and peptide bond specificities, as they identified critical amino acids as substrate-specific determinants (Fig. 8).
A number of mediators of inflammation, mobility of leukocytes, and tissue injury are substrates of meprins. For example, cytokines and chemokines are good substrates for meprins. Osteopontin, RANTES, and MCP-1 are degraded by meprin α (
). Janet Kumar, a postdoctoral fellow, studied the embryonic expression of meprins and found that both subunits are expressed in the high- and low-meprin kidney strains of mice, but after weaning, the expression of meprin α in kidney decreases to very low levels, resulting in “activity-deficient” meprin B mice (
). Fewer (50%) null mice were born than was predicted by Mendelian distribution; however, those born developed normally and were fertile. There were some changes in the renal gene expression profiles in the null mice, and no meprin α was detected at cell surfaces because of the lack of meprin β to anchor it to the cell surface. However, there were no obvious gross abnormalities or pathologies. This was also true for meprin α knockout mice, generated by Sanjita Banerjee (
). I remember discussing this with Oliver Smithies, a Nobel laureate. I was disappointed that there was no obvious phenotype after going to such trouble to generate these mice. He reassured me that this result was quite common as there are compensatory processes for most enzymes (under homeostasis conditions); however, it was likely some abnormalities would appear as we further examined the mice and stressed the knockout mice in some manner. He was absolutely correct. The knockout mice were critical in determining how the meprins contribute to renal damage, enhanced monocyte migration, and cytokine processing in vivo (e.g. see Refs.
Many of our studies implicated meprins in renal, intestinal, and inflammatory diseases. Collaborations with Howard Trachtman, then at the Schneider Children's Hospital, using rodent experimental models suggested that meprins contribute to pathogenesis of acute renal injury and chronic diabetic nephropathy (
). More specifically, meprin α mRNA and protein are produced in invasive colorectal carcinoma cell lines; a novel form of meprin β mRNA is present in human breast cancer cell lines; and adenocarcinoma and osteosarcoma cell lines from a variety of tissues express a unique isoform of meprin β mRNA (
). Rene (Dusheck) Yura showed that women suffering from acute urinary tract infections have high levels of meprin α in urine, in contrast with healthy women, very likely due to leukocyte infiltration in response to inflammation (
Christoph Becker-Pauly and colleagues at the University of Kiel in Germany have found that meprins process amyloid precursor protein, which might have significance for understanding the etiology of Alzheimer's disease (
Meprin A is a biomarker for Kawasaki syndrome, now implicated in children infected with COVID-19. Specifically, elevated levels of meprin A and filamin C were found in the urine and blood of children with Kawasaki syndrome (a systemic inflammatory condition) and proposed as diagnostic markers of this syndrome (
). This has important implications for several reasons, but one is that the protein on the virus that attaches to ACE2 must be cleaved for efficient entry into cells, making meprins possible enablers of viral attachment and possible drug targets.
I would be remiss not to acknowledge how important the contributions of all the students, postdoctoral fellows and colleagues have been to the work cited in these “Reflections.” It would be impossible to recognize all 26 graduate students and 19 postdoctoral trainees, technicians, and collaborators for all the contributions they have made to advancing the science. They also provided great ideas (sometimes by asking “dumb questions”), tears, laughter, and joy.
Out of the laboratory into the scientific community: Giving back
When you are a new faculty member, it is essential to establish yourself as a scientist and educator and not become distracted by too many committee meetings and service activities. This means anchoring yourself in the laboratory with your research group, finding your role in formal teaching, and writing grant applications. But there comes a time when you will realize that getting out of the laboratory, meeting colleagues, collaborating, and presenting data at scientific meetings and outside institutions is essential. Participating in service activities (editorial work, scientific review committees, professional societies) is important for advancing your science and very satisfying as well. The expansion of your activities usually comes after achieving tenure at an academic institution—a significant step in an academic career. After I was granted tenure (1974), I became more active in editorial work as well as in activities of the international proteolysis community.
Editorial activities are one of first signs of being recognized by professional colleagues—and are important as they help maintain the high quality of published science. In initial stages, I remember getting requests for reviewing from editors of different journals. I advise young faculty that after an editor sends repeated requests for ad hoc manuscript reviews, it is time to suggest he/she nominate you for the editorial board of the journal (this gives you more recognition for your efforts). It worked for me! My first editorial board experiences were with the Journal of Bacteriology (1974–1977) and American Journal of Physiology (1983–1984), and I graduated to being an associate editor of AJP: Cell Physiology (1984–1990). I was also an editorial advisor for Biochemical Journal (1987–1999) and an executive editor for Archives of Biochemistry and Biophysics (1984–1996). For all of these journals, I was responsible for articles on proteases and protein degradation/turnover.
In 1997, I joined the editorial board of the JBC and became an associate editor in 1999. JBC editorship became a major activity lasting 14 years and was one of the most satisfying aspects of my career. The JBC maintained a high standard for publication under the leadership of Herb Tabor and the associate editors. It was a pleasure to see and enable publication of new/wonderful science in my field. There were many innovations instituted during my tenure with the journal. For example, the JBC was the first biochemical journal to go online. There was a close collegial relationship between the associate editors, fostered by Herb. Although I knew it was better for the journal to have turnover in the associate editors, when I had to give up the editorship, I was sad to go.
During the 1980s and 1990s, a group of European scientists, headed by John Kay at University College in Cardiff, began a newsletter under the banner of the European Committee on Proteolysis (ECOP) to foster communication among scientists interested in proteolysis. I thought this was a great idea and started an American (ACOP) newsletter. I solicited short review articles by leaders in the field and listed upcoming conferences and publications of interest to the community. A Japanese group, headed by Takashi Murachi at Kyoto University and Nobuhiko Katunuma at Tokushima University, then organized a JCOP newsletter. These newsletters resulted from all volunteer activities, were great fun, and elicited interest from scientists all over the world. Eventually, the groups merged into the International Committee of Proteolysis (ICOP), and the newsletter flourished from 1985 to 1998. International meetings, rotating among Europe, America, and Asia, also emerged from these committees. I believe the newsletter strengthened the sense of collegiality of scientists interested in proteases and protein turnover. ICOP evolved in 1999 into the International Proteolysis Society, which is thriving today.
Organizing professional meetings is one of the ways to establish leadership in your field. For large meetings, this comes after you have participated and presented data at many meetings, are able to attract leaders in the field to participate, and are able to obtain financial support for the meeting. For trainees and early-career faculty members, it serves you well to develop organizational skills at institutional meetings, local society meetings, and state and national meetings (e.g. Virginia Academy of Science, Experimental Biology).
My first experience organizing a large, international meeting (more than 100 participants) was an ACOP meeting, the International Symposium on Intracellular Protein Catabolism, held at the Airlie Center in Airlie, Virginia, in 1984. I had important secretarial support for this from my department, funding for the travel and accommodation of speakers from NIH, and help from students and staff in my laboratory. Tremendous effort goes into the organization of a national/international meeting, but it is worthwhile if you can manage it.
Reviewing grant applications is another activity important to career development and a professional responsibility that can be rewarding (to you and the recipients!). One of the best ways to learn how to review applications is from your graduate and/or postdoctoral mentors. In my case, the learning process occurred as a faculty member while reviewing institutional grant applications and from the reviews I received on my own applications. The standards for a good review are variable and change with time, funding organization, and type/level of the request. You have to limit the number of grants you agree to review and the agencies you agree to work with—especially true for women, as you might well be asked to do too much (resist the flattery of being asked). I found that establishing a relationship with one or two agencies as a reviewer has several advantages. My first major NIH grants were from the NIDDK, and those grants initiated a special relationship with the Institute. I served on many site visit teams and ad hoc panels for the Institute starting in 1983 and increasing after I received a MERIT Award from the institute (1989–1997). My feeling is that after a funding agency starts investing in a scientist, it becomes vested in that person's career growth. This pays off, for instance, when your grant application is at the border line for funding. If the staff of the agency knows you and your work, they can on occasion be an advocate for you and support the funding of your applications. I witnessed this firsthand when I served on the NIDDK Advisory Council (1996–2000). I believe that scientists who receive grants have an obligation to serve as reviewers. Reviewing takes a significant amount of time and energy, but you also learn a great deal about grant writing in the process, and it is an important way of giving back to the profession.
I served on the NIH Biochemistry Study Section as member and chair from 1987 to 1991. Those were the days when the review group convened in a windowless room for 2–3 days (10-plus hours per day), and the group reviewed about 100 applications. Each scientist was primary or secondary reviewer for 10–20 applications. The process was exhausting, and there were considerable disagreements and justifications for the reviewers' opinions. Ultimately, great camaraderie developed among the reviewers. One learned how important writing the abstract and specific aims of the application was so that the reviewer would not have to work hard to comprehend what was being proposed and the significance. One also learned that one has to write an excellent or outstanding grant, not just a good application, to be competitive and funded. It was a great learning experience and rewarding, especially in the days when 20–25% of the applications were funded. The process was frustrating when the funding level dropped down to the single-digit percentiles because so many excellent applications would not be supported.
Participating in professional societies
There are many benefits that result from joining a professional society. In the early years of a career, participating in local society activities (Virginia Academy of Science; local chapters of the American Chemical Society) allows you to meet faculty and students in your geographical area and provides a forum for your students to present their work. Sometimes these meetings lead to recruitment of graduate students from local colleges. Joining national societies provides opportunities to meet active researchers in your field from around the world, hear about the most current research advances and state-of-the-art technologies, serve on committees for society publications, engage in career development, and contribute to public affairs. As my work was interdisciplinary, I joined several societies (∼10) as a young faculty member and maintained membership in half of those over ∼40 years.
My most enduring allegiance to a society has been to the American Society for Biochemistry and Molecular Biology (ASBMB). I became involved with ASBMB by volunteering to join a committee (Equal Opportunities for Women) in 1988. Through committee meetings, I met colleagues with common interests, and this led to me being elected as a Council member (1996–1999 and 2002–2003), president-elect (2003–2004), and president (2004–2006).
Being president of the ASBMB was one of the most honorific and enjoyable experiences of my career. First of all, acting as spokesperson for the society of 12,000 members was an honor. There was a devoted, supportive staff, including Barbara Gordon and Chuck Hancock, and we tackled many issues, such as revising our magazine (ASBMB Today), strengthening our public affairs activities, and attracting young scientists to the society. Second, I was president during the centennial year of the society and the JBC, which were celebrated together at the annual meeting in San Francisco in 2006 (Fig. 9). Bettie Sue Masters, the previous president, had initiated plans for the celebration, and we saw them through together. Bettie Sue and I became great friends over these interactions and remain so today. There were several special events at the centennial celebration, including a recital by the San Francisco Symphony. The society president who succeeded me was Heidi Hamm, resulting in three woman presidents in a row! This was another thing to celebrate, as the society was primarily led by male scientists over the 100 years (there were just six previous female presidents), and three females in a row signaled a new era. Bettie Sue, Heidi, and I also got to sing a song, “Three Little Presidents are We,” at the centennial celebration. This came about through interactions with John Exton, a JBC associate editor, who wrote a skit based on Gilbert and Sullivan's The Mikado, entitled Publish or Perish. The story centered on a young author who struggled to publish in the JBC. Bob Simoni, then deputy editor of JBC, helped us find a producer from San Francisco, Rita Taylor, who assembled a group of singers from the San Francisco Savoyards and a pianist, who were essential to carrying out this endeavor. I never knew how hard it was to sing G&S songs before this experience, but with the help of Rita and her professional singers, we pulled off this production of Publish or Perish at the centennial celebration with great gusto!
As a consequence of being an active member of ASBMB, I also became involved in the Federation of American Societies for Experimental Biology (FASEB). FASEB, an organization formed in 1912, originally consisted of three biomedical societies—the American Physiological Society, the American Society of Biological Chemists (now ASBMB), and the American Society for Pharmacology and Experimental Therapeutics—and it was joined almost immediately by the American Society of Experimental Pathology (ASEP). The main purpose of the federation originally was to hold joint meetings. The federation has a fascinating 100-plus-year history, and I had the privilege of coauthoring a book on this history last year with Howard Garrison and Ralph Bradshaw (
). Over the years, other societies joined the federation (there were 30 societies in 2019), and the size of the meetings grew, peaking with about 21,000 participants in the 1960s. I remember going to the federation meetings in Atlantic City as a graduate student, postdoc, and young faculty member to present data, meet colleagues, and hear lectures from luminaries in various fields. Many scientists have told me that they presented their first national talk at a FASEB meeting and how important these meetings were to their careers. FASEB continued to foster communication among scientists through meetings (large and small) and publications, but its main strength has been to advocate for biomedical scientists, especially to policymakers. The federation has addressed issues such as the use of animals in research, employment of early-career scientists, and federal funding of biomedical sciences.
I was elected to the FASEB Board of Directors in 2003, vice president of science policy in 2010, president-elect in 2011, and president in 2012. With Howard Garrison as chief of public affairs, terrific staff members, and volunteer scientists from all our member societies, we had a voice (a seat at the table) at federal and state agencies and funding agencies (particularly NIH and the National Science Foundation) when important decisions were being made about research and education. FASEB represented 130,000 scientists and engineers, and these numbers gave us more influence than the individual societies alone. I was president during FASEB's centennial year (2012). Joe LaManna, the immediate past president, and I presided over several events that celebrated the achievements and activities of the federation. Kenny Offermann, M.D./Ph.D., who was one of my first graduate students, succeeded me as president. FASEB served the scientific community for more than 100 years despite many challenges. It is amazing to me that I had the good fortune to be president of both ASBMB and FASEB during their centennial years.
Chairing academic departments
After being promoted to professor in 1985, I was asked to consider the position of head of the Department of Biochemistry and Nutrition at Virginia Tech (VT) in Blacksburg, Virginia. I had made several trips to Blacksburg in the 1980s to present seminars and collaborate with Mark Failla, a faculty member there. Mark was an expert in trace metal analysis, and we worked together on arginase and meprin projects. My husband encouraged me to explore the VT position, even though it would mean we would have a commuting marriage. I received Virginia's Outstanding Scientist Award from the Science Museum of Virginia in 1988 (Fig. 10), was chair of the NIH Biochemistry Study Section by that time, and was ready for a new challenge. In addition, Dean Nichols in the VT College of Agriculture and Life Sciences (CALS), made the position attractive with new faculty positions and a startup package. I accepted the position, set up my new laboratory, and purchased a condominium in Blacksburg. VT was a real learning experience for me (somewhat out of my comfort zone). First of all, I was the first woman chair in the 150-year-old CALS, and there was some noticeable discomfort on the part of my colleagues and faculty members. Second, as a girl brought up in Brooklyn, New York, I knew nothing about agriculture, and, as VT is a land-grant university, there were significant interactions with farmers of Virginia—a new world for me. My husband initiated a program to teach me about the difference between a Holstein and Guernsey cow. Third, I found there are significant differences between the formal and informal interactions of individuals in colleges of medicine versus colleges of agriculture, as well as urban versus rural cultures. Fourth, the department I was chairing was responsible for teaching a large undergraduate population and a smaller graduate student group, which was a change from my experience with graduate and professional school students. Last, I would have to live on my own during the week and commute back to Richmond to be with my family on weekends. My mother was particularly worried about my living alone in the “Wild West” and would check up on me often. Despite all these problems, I learned to love this new world. We were able to hire new faculty, renovate a laboratory, and buy new equipment. My colleagues and I became less uncomfortable as we worked together for common goals. I found the farmers of Virginia to have a healthy interaction with the university and to be quite knowledgeable about and accepting of biotechnology. The quality of the students and postdocs was excellent, and I was able to assemble an outstanding research group myself. The work with meprins became increasingly exciting, and I received a MERIT Award from the NIH, which was an honor as well as providing sustained funding (1989–1997). In addition, it was a pleasure working with the undergraduate biochemistry students at VT. Their enthusiasm and intelligence were heartening and inspired optimism for the future of science and the USA. Overall, getting out of my comfort zone turned out to be a very positive move.
As a consequence of becoming an academic department chair (or head, as they called it at VT), I joined a group of biochemistry department chairs called the Association of Medical and Graduate Departments of Biochemistry (AMGDB). This group meets annually in January to discuss issues relating to education, research, and public policies that affect our profession. I found it very useful to share experiences with other chairs, meet new chairs, stay current with national trends, and get to know colleagues with common interests. I was elected president of AMGDB in 1998 and joined the group as an ex-chair in 2019 for its 50th anniversary.
In the 1990s, I felt my work would benefit from medical school expertise, and, unfortunately, VT did not have this at that time. In addition, there were changes in the leadership of VT and a determination to strengthen the undergraduate programs, which I felt was at the expense of the graduate school programs. So, despite all the positive outcomes of the move to VT, when an opportunity arose for a position in a medical school, I became interested. The position was as Chair of the Department of Biochemistry at Penn State University's College of Medicine (PSUCOM) in Hershey, Pennsylvania. Jim Jefferson was Chair of Physiology there, and he and Dick Courtney, Chair of Microbiology and Immunology, and Dean Mac Evarts recruited me to PSUCOM. I knew Jim from when we were postdoctoral fellows at Vanderbilt University. In the early 1990s, PSUCOM and the Hershey Medical Center were doing very well financially and expanding their faculty and facilities. Chairs in the basic sciences were expected to have strong research programs, and the recruitment package seemed very beneficial to the department faculty and my own research program. It did mean that I would have to continue a commuting marriage as my husband was in Richmond (200 miles from Hershey, same as from Blacksburg). But we had managed that for four years, and I can recommend this lifestyle once children are grown. I moved my research group to Hershey in the summer of 1992. Again, there was the excitement of hiring new faculty, renovating laboratories, acquiring equipment, and establishing new collegial relationships. One of the first things we did was change the name of the department to Biochemistry and Molecular Biology, which followed a national trend and was important for attracting graduate students. My research flourished in this environment with a combination of the trainees from VT and new trainees (Fig. 4, B–D). My research continued to be primarily basic but now also included medical aspects (renal and intestinal disease and cancer). I felt welcomed and comfortable in the medical school; however, there were challenges. I was the first female chair at PSUCOM, and there were instances of “the only woman in the room” not being heard. There were stresses in the department—for example, when the administration wanted medical education to move to small group, case-based learning rather than lecturing, a battle ensued between faculty and administration. I sympathized with faculty members in that they should be decision-makers in education; however, there was also value in experimenting with innovations that were trending across the country. A hybrid way of teaching was accepted after several years. Faculty members also felt the administration put too much value on external research funding, especially in hard times for obtaining funding. Nevertheless, we hired some excellent faculty members, and there was growth in the department and individual research programs.
Chairing academic departments provides opportunities for leadership in the broader institution, and I had the privilege of participating in several PSUCOM and university initiatives. One was the expansion and formalization of the M.D./Ph.D. program. Dean Evarts appointed Tom Krummel, Chair of Surgery, and I as co-chairs. Tom and I knew each other from MCV/VCU and worked well together. We assembled a strong group of faculty members for the steering committee from different departments and applied for NIH Medical Scientist Training Program funding. NIH funding is important for these programs, not only because it helps the institution support an expensive program, but also because it brings national recognition to the program. It was known to be difficult to get into the system, as there were limited slots available and a lot of competition, so it was a great victory when we obtained the funds. The program has grown substantially in the past 25 years, is now directed by devoted leaders (Leslie Parent and Bob Levenson), and has produced excellent physician-scientists.
Another PSU initiative I had the pleasure to contribute to was the Life Sciences Consortium (LSC). The purpose of this consortium was to enhance the research and graduate education by forming programs that spanned the University Park (UP) Campus and Hershey Campus. There were strong research programs on both campuses, and it was felt they could advance together to a new level. Importantly, the university leadership was willing to invest in the LSC. The two campuses are 100 miles apart, a two-hour drive, but there were substantial collaborations between faculty members, and different expertise existed in the core facilities of these campuses, and there was also the capability to communicate and teach courses through the Internet. Nina Federoff was hired as director of the consortium, and Bob Matthews, a professor of chemistry at UP, and I were designated as co-directors of graduate education for the LSC. A number of graduate programs were formed in areas such as chemical biology, cell and developmental biology, immunology, and neuroscience, providing students on both campuses more choices for laboratory experiences and didactic courses. The consortium was key in attracting new graduate students, acquiring high-end, sophisticated equipment, and fostering collaborations across the university. The LSC has now evolved into the Huck Institute.
During my last years at PSUCOM, a group of faculty members became interested in outreach activities. One initiative aimed to attract minority college students to PSUCOM to prepare them for careers in biomedical research. In 2007, we obtained a grant from the NIDDK that enabled us to bring minority students to our college for summer research experiences. The program was funded through an R25 mechanism and called “Short-Term Education Program for Under-represented Persons” or STEP-UP. I was the principal investigator of this program, with a group of faculty members designing individual projects for ∼25 students each summer for five summers. The students learned to present their work and brought talent, energy, and a sense of balance to the college (Fig. 11).
Another initiative undertaken by PSUCOM faculty aimed to work with teachers and students in local high schools in the Hershey, Pennsylvania, area to encourage the students to think about careers in biomedical science. For this program, we partnered with high schools that served lower middle-class students from Middletown. We obtained funds from the National Center for Research Resources of the NIH from an R25 mechanism called “Science Education Partnership Award” (SEPA). I was the principal investigator for this program, and a very dedicated group of faculty from PSU and the high schools designed summer laboratory experiences for students. We learned that most of the students from these high schools had no role models for a career in science and had never envisioned themselves in professional careers. We have learned of some notable successes.
You are blessed if your path leads to some fulfillment and, as Confucius said, “Find something that you love to do, and you'll never work a day in your life.” I feel I have been fortunate—for finding a profession that I have loved, finding people to share that passion with, contributing to the science of the day, communicating knowledge to trainees, working with trainees, mentors and colleagues, and representing scientists to larger circles of the community. There is so much pessimism and negativity currently and discouraging words about careers in research and in academia. By contrast, there is so much promise for fulfilling careers in science, as well as potential and enthusiasm in the trainees in biomedical sciences. There is great satisfaction in finding something unique, having a front seat to seeing a story unfold, always having new questions to answer, fringe benefits of travel and having friends and colleagues around the world, and watching students take ownership of their projects and find success in their own careers. I encourage those who love problem solving and have a genuine interest in science to go for it.
I dedicate this “Reflections” article to the memory of Herb Tabor, who passed away at the age of 101 as I was in the last stage of writing it. Herb was a quiet giant in biochemistry circles who encouraged me, as well as many others, to record their reflections in the JBC. His leadership and commitment to the JBC, and support of ASBMB, over many decades inspired and motivated many of us. He will be missed and remembered.
An essential histidine in the catalytic activities of 3-phosphoglyceraldehyde dehydrogenase.