Piet Borst
Netherlands Cancer Institute
For an exceptional 50-year career of scientific discovery, mentorship, and leadership
The 2023 Lasker~Koshland Special Achievement Award in Medical Science honors a physician-scientist for an exceptional 50-year career of scientific discovery, mentorship, and leadership. Piet Borst (Netherlands Cancer Institute, Amsterdam) boldly and repeatedly ventured into new territory in the laboratory, and he made seminal discoveries in multiple fields. His work revealed how parasites evade the human immune system, and it provided insights into the molecular pumps that underlie cancer drug resistance. He illuminated an unanticipated metabolic pathway, unveiled a novel DNA building block, and pinpointed the biochemical basis of an inherited disorder. With vision and fortitude, he shepherded the Netherlands Cancer Institute to world-class status. His contributions have extended far beyond his home establishments, as he has guided prominent scientific organizations and prize committees in Europe and beyond. He has trained scores of investigators who have gained international renown, and he has directed his passion for science and no-nonsense attitude toward educating the public as well.
From mitochondria to trypanosomes
During a career that has spanned more than five decades, Borst has demonstrated a healthy disrespect for planning and authority. In his research and administrative posts, he has seized opportunities to pursue fruitful paths even when they veered from an obvious trajectory or grated against the status quo.
Six months into his medical internship at the University of Amsterdam, Borst’s undergraduate advisor, Bill Slater, contacted him. A collaborator had abandoned a project and Slater wanted Borst to pick it up. Borst put his medical training on hold and embarked on a PhD program, eventually overturning the popular hypothesis that tumor cells contain defective mitochondria. He also discovered an unanticipated system, the malate-aspartate shuttle, which helps eukaryotic organisms extract energy from sugar. This process was initially dubbed the Borst cycle and is now standard textbook fodder.
In 1965, he joined the University of Amsterdam as an associate professor. His mitochondrial expertise occasioned an invitation to a meeting that was discussing, among other things, the unusual mitochondrial DNA of African trypanosomes, which cause sleeping sickness. Borst wound up launching a research program on these parasites. They multiply in the mammalian bloodstream, where the tsetse fly picks them up and transports them to the next victim. To combat the pests, mammals make antibodies that target a surface protein. Before all of the microbes die, a subpopulation emerges that displays a different protein. This process, called antigenic variation, repeats and allows the pathogen to persist.
In collaboration with George Cross (now at The Rockefeller University), Borst isolated genes that encode different versions of the surface protein from trypanosome variants. He showed that the parasite eludes the immune system by replacing the existing coat-protein gene with a new one at an active spot in the genome. This work led to additional important findings, including the trypanosome telomeric DNA sequence, which he published back-to-back with an independent report of the same observation by Elizabeth Blackburn (2006 Albert Lasker Basic Medical Research Award). Borst also uncovered an unusual DNA building block called base J, which had never before been seen in any organism. Base J is a chemically modified version of thymine, a standard nucleic acid subunit, and Borst showed that it plays a crucial role in terminating growing RNA chains in trypanosomes and other parasites.
Administrative finesse
In 1983, the Netherlands Cancer Institute recruited him as Director of Research. Its core grants were being cut, productivity languished, and inefficiency reigned. The governing board was keen to stop the slide and pinned Borst to solve the problem, in part because he had rescued a flailing institute at the University of Amsterdam and accomplished other impressive management feats there.
The institute had a council that held tremendous power and a pronounced egalitarian bent. Some members viewed Borst’s attempts to change policy as repressive and elitist, and his ideas encountered stiff opposition.
Conflict came to a head when Borst tried to eliminate tenure for graduate students. He thought that including newly enrolled students in the organization’s “no firing” rule was wildly misguided. Some career researchers had never completed their PhDs, disliked experimental work, and remained in positions that left them underperforming and unhappy. Furthermore, because jobs and space were limited, this situation burdened the institution, as turnover stalled.
Borst inaugurated a system in which scientists had to complete a postdoc before being considered for a permanent position, but the council challenged this proposal in court. Borst convinced the judges that a cancer institute could not function if graduate students are hired into lifelong jobs. Losing the argument would have left him impotent as a leader, and he would have resigned. Instead, the council backed off, and Borst was liberated to implement other innovations, such as English-speaking research discussions, which were necessary in order to include foreign students. He also installed stringent internal reviews of grant applications before they were submitted; funding rates jumped. The organization’s atmosphere improved and output increased. Morale rose, as did the quality of the science and recruitment capacity. Borst thus transformed this struggling enterprise into the outstanding cancer research center that it is today.
Pumping progress
After he moved to the Netherlands Cancer Institute, he began studying genes that underlie mammalian resistance to chemotherapeutic agents. He made numerous findings in this area, particularly with respect to the proteins’ normal physiological roles. He discovered, for example, that a particular member of the P-glycoprotein family of molecular transporters guards the brain by expelling certain toxins. This same protein also resides in the intestinal membrane, where it performs a similar job. Consequently, certain oral medications are not absorbed and require intravenous administration. This revelation helped fuel a strategy for circumventing the problem: inhibiting the molecular pump while giving the desired anti-cancer drug.
These transporter proteins led Borst to an inherited human disorder, pseudoxanthoma elasticum (PXE). The genetic defect maps to errors in another one of the transporter genes, causing calcium to accumulate in the eyes, skin, and blood vessels. Although researchers had demonstrated its genetic underpinnings, the underlying biochemical pathology remained murky. Borst’s experiments pointed to a culprit: dearth of the metabolite pyrophosphate, which normally blocks calcification. This finding has laid the groundwork for possible therapeutic approaches.
Generous statesmanship
The breadth of Borst’s background and his leadership experience prepared him to help shape many eminent institutions, including the Basel Institute for Immunology, the Imperial Cancer Research Fund, the Swiss Institute for Experimental Cancer Research, the Institute of Molecular Pathology in Vienna, and the Scripps Research Institute. He has served on advisory boards for these establishments and chaired those for the European Molecular Biology Laboratory and the Pasteur Institute, where his diverse interests were a boon as he steered meetings that covered wide-ranging topics.
In numerous ways, Borst has cultivated the scientific enterprise in the Netherlands. For example, he joined the Innovation Platform, a small think tank led by the Dutch prime minister. He staunchly promoted basic research and pushed back against a bloc that sought to fund primarily applied work that had to be conducted in collaboration with industry. He has delivered a major impact on modernizing Dutch biomedical science.
He has also led prestigious scientific award juries with his hallmark clearsightedness about what needs to change and his humorous touch while nudging people in new directions. When he took the reins of the Louis-Jeantet Prize in 1997, he found the atmosphere too factional and formal. The French huddled with the French, the British with the British. In response, he seated members in alphabetical order and introduced the use of first names, thus enhancing collegiality. He also drafted women to the group, starting with Nobel Prize winner and Lasker Award recipient Christiane Nüsslein-Volhard.
Popular science
From 1993 to 2016, the NRC, the Dutch newspaper of record, ran a column by Piet Borst in which he explained new discoveries and illuminated the scientific process. Earlier this year, Borst was invited for a three-article comeback, two of which are shown here: Pseudowetenschap en kwakinnovatie (left; “Pseudoscience and quack innovation”) appeared on March 11, 2023; Succes, geen verdienste (right; “Success without merit”) on February 4th, 2023.
Transmitting wisdom
Borst has consistently instilled in his students devotion to carefully constructed experiments that produce unambiguous results and, of course, the value of independent thinking. In keeping with his skepticism of authority, he introduced a prize—a Dutch chocolate bar—for any lab member who disproved one of his cherished hypotheses.
More than 20 of his trainees have gone on to chair their own academic departments. At least five have distinguished themselves as members of the Royal Netherlands Academy of Arts and Sciences, four as Royal Society Fellows, and seven as National Academy of Sciences members. One—Alec Jeffries (Emeritus, University of Leicester)—won a Lasker Clinical Medical Research Award, and two—Titia de Lange (The Rockefeller University) and Roeland Nusse (Stanford University)—received the Breakthrough Prize in Life Sciences.
Borst’s influence has transcended academia. As head of the Netherlands Cancer Institute, he frequently appeared on TV and radio, and since the beginning of his career, he has stepped up to be interviewed about contentious issues such as the recombinant DNA controversy of the 1970s. He has encouraged Dutch citizens to take science seriously as an endeavor that can benefit society.
In 1993, the Dutch daily newspaper of record, the NRC, invited Borst to write a column. For 23 years, he explained new discoveries and railed against the dangers of quackery. This past year, he was asked to return and fill in. In his three-article comeback, he laid out the argument that success arises from talents and circumstances that an individual cannot control. He encouraged his readers to express solidarity with those who are less fortunate. He discussed the science of longevity and the pseudoscience of bleach to fight not only Covid-19, but also cancer, HIV, autism, and malaria.
Borst’s intellect, moxie, peppy nature, and interpersonal gifts have earned him appreciation, admiration, and reverence from colleagues and compatriots alike. He serves as an inspired and inspiring model.
by Evelyn Strauss
Selected Publications – Piet Borst
Recollections
Borst, P. (2006). How I became a biochemist. IUBMB Life. 58, 177-182.
Borst, P. (2006). From cancer cells to trypanosomes and back again. Cell. Mol. Life Sci. 63, 745-754.
Borst, P. (2020). Looking back at multidrug resistance (MDR) research and ten mistakes to be avoided when writing about ABC transporters in MDR. FEBS Lett. 594, 4001-4011.
Borst, P. (2020). The malate-aspartate shuttle (Borst cycle): How it started and developed into a major metabolic pathway. IUBMB Life. 72, 2241-2259.
Articles
Borst, P. (1963). Hydrogen transport and transport metabolites. In: Karlsson, P., editor. Springer Berlin, Heidelberg. Funktionelle und morphologische Organisation der Zelle. p. 137-162.
Hoeijmakers, J.H., Frasch, A.C., Bernards, A., Borst, P., and Cross, G.A. (1980). Novel expression-linked copies of the genes for variant surface antigens in trypanosomes. Nature. 284, 78-80.
Boothroyd, J.C., Cross, G.A., Hoeijmakers, J.H., and Borst, P. (1980). A variant surface glycoprotein of Trypanosoma brucei synthesized with a C-terminal hydrophobic ‘tail’ absent from purified glycoprotein. Nature. 288, 624-626.
De Lange, T., and Borst, P. (1982). Genomic environment of the expression-linked extra copies of genes for surface antigens of Trypanosoma brucei resembles the end of a chromosome. Nature. 299, 451-453.
Bernards, A., Michels, P.A., Lincke, C.R., and Borst, P. (1983). Growth of chromosome ends in multiplying trypanosomes. Nature. 303, 592-597.
Van der Ploeg, L.H.T., Liu, A.Y.C., and Borst, P. (1984). Structure of the growing telomeres of trypanosomes. Cell. 36, 459-468.
Van der Ploeg, L.H., Cornelissen, A.W., Michels, P.A., and Borst, P. (1984). Chromosome rearrangements in Trypanosoma brucei. Cell. 39, 213-221.
Smit, J.J.M., Schinkel, A.H., Oude Elferink, R.P.J., Groen, A.K., Wagenaar, E., Van Deemter, L., Mol, C.A.A.M., Ottenhoff, R., Van der Lugt, N.M.T., Van Roon, M., Van der Valk, M.A., Offerhaus, G.J.A., Berns, A.J.M., and Borst, P. (1993). Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell. 75, 451-462.
Gommers-Ampt, J.H., Van Leeuwen, F., de Beer, A.L., Vliegenthart, J.F., Dizdaroglu, M., Kowalak, J.A., Crain, P.F., and Borst, P. (1993). b-D-glucosyl-hydroxymethyluracil: a novel modified base present in the DNA of the parasitic protozoan T. brucei. Cell. 75, 1129-1136.
Schinkel, A.H., Smit, J.J.M., Van Tellingen, O., Beijnen, J.H., Wagenaar, E., Van Deemter, L. Mol, C.A.A.M., Van der Valk, M.A., Robanus-Maandag, E.C., te Riele, H.P.J., Berns, A.J.M., and Borst, P. (1994). Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 77, 491-502.
Borst, P., and Elferink, R.O. (2002). Mammalian ABC transporters in health and disease. Ann. Rev. Biochem. 71, 537-592.
Van Luenen, H., Farris, C., Jan, S., Genest, P.A., Tripathi, P., Velds, A., Kerkhoven, R.M., Nieuwland, M., Haydock, A., Ramasamy, G., Vainio, S., Heidebrecht, T., Perrakis, A., Pagie, L., Van Steensel, B., Myler, P., and Borst, P. (2012). Glucosylated hydroxymethyluracil (DNA base J) prevents transcriptional read-through in Leishmania. Cell. 150, 909-921.
The Secret to a Successful Career in Science—According to Magritte
There is no shortage of words of advice on how to become a successful scientist.
Award Presentation: Harold E. Varmus
Successful scientists make discoveries that reveal how the world works. Those discoveries sometimes improve the human condition and occasionally win Lasker Prizes. But a few great scientists are more than discoverers. They also have generous impulses to nurture discoveries by others; a history of extensive service to the scientific community; or a drive to learn and teach about the promise and perils of science.
Since 1994, the Lasker Foundation has awarded a biannual prize to such individuals, people who have made outstanding discoveries in the medical sciences, but have also displayed characteristics that inspire, in the prize’s memorable phrase, “deep feelings of awe and respect.” Today I have the pleasure of introducing you to Professor Piet Borst, who embodies those rare traits and is this year’s recipient of the Lasker-Koshland Special Achievement Award in Medical Science.
Piet’s qualities
Piet cuts a very large figure. He is a polymath of biomedical science, making waves in disparate fields: biochemistry, molecular biology, parasitology, and clinical genetics. He is renowned for his service to institutions, colleagues, trainees, and the public. And he is revered for the integrity, humor, loyalty, and frankness that are emblematic of his character. My job today is to summarize these awe-inspiring virtues.
Piet himself has attributed his success to good luck. Born with more than just a good brain, he was the son of a greatly admired academic physician in a place, The Netherlands, that has for centuries produced some of the world’s most prominent artists, philosophers, entrepreneurs, and scientists. Piet has spent nearly his entire life in Amsterdam, while influencing science globally. Despite his global reach, he has remained deeply and distinctly Dutch. But much more than his good luck or his essential “Dutchness” explain why the Lasker Jury has selected Piet for this award.
His Science
Piet’s accomplishments as a scientist are legion, a result of his insatiable curiosity, his fearless excursions into difficult domains of biomedicine, and his mastery and invention of many technologies.
When he enrolled as a student at the University of Amsterdam, his interests ranged broadly from literature and history to medicine. But when his clinical curriculum offered a break that permitted laboratory work, he took an unusual path. Bill Slater, a charismatic biochemist imported from Australia, persuaded Piet to characterize mitochondria in normal and cancerous mammalian cells. Although this ultimately revealed little about cancer, he solved a long-standing enigma about energy generation in mitochondria, discovering what is still sometimes called the “Borst shunt,” a pathway for electron transfer employing components of the sugar metabolic cycle. That success triggered his life-long fascination with mitochondria and other cellular organelles that tend to receive much less attention than the nucleus.
Yet, when another opportunity to get exposed to laboratory science arose after his time with Slater, Piet moved in yet another direction, learning molecular biology and virology with the Nobel Laureate Severo Ochoa—here in New York, at NYU—finding and characterizing the enzyme that duplicates the RNA genome of a bacterial virus.
After these successes, Piet was emboldened to abandon the idea of medical practice and accept an offer from Slater to join the biochemistry department at the University of Amsterdam, combining his new skills in nucleic acid research with his earlier interests in mitochondria.
His attention was soon drawn to trypanosomes—the single cell parasites that include the cause of sleeping sickness—because of their strangely configured mitochondrial DNA. So when he heard from George Cross, at Cambridge University, that trypanosomes can evade an immune attack by changing the major protein on their surface, he was ready to act.
To learn how the surface proteins varied, Piet and his trainees uncovered and explored several amazing phenomena: how surface protein genes move from many places in the parasite’s chromosomes to places near chromosomal ends (the telomers); how their messenger RNAs are spliced in an unexpected way; and how the short, repeated sequences at trypanosomal telomers, sequences that proved to be identical to human telomers, expand and shrink.
While this spectacular work was in progress, Piet moved his lab from the University to the Netherlands Cancer Institute, where he took on leadership responsibilities that I’ll describe in a moment. This change encouraged him to take up some form of cancer research, pursuing a new topic deliberately, rather than serendipitously. Soon—and without abandoning his beloved trypanosomes—he became well known for his work on novel proteins that can mediate resistance to cancer drugs and for discoveries of surprising things those proteins can do in normal tissues.
At about the same time, he and his students found, in trypanosomes and some other organisms, what few expected: a new component of DNA, adding new base—J— to the bases that everyone learns in high school—-A, C, G, and T. With tenacity, over many years, culminating just over a decade ago, Piet learned how that new base is made and how it affects cell behavior by terminating synthesis of RNA.
On top of all this, Piet had not forgotten clinical medicine. By determining the biochemical basis of two uncommon inherited diseases, Piet and his colleagues turned medical mysteries into solvable metabolic disorders.
His Service
As his prominence rose in medical science, Piet also became widely known for his enthusiastic service to science—-as a generous advisor to many institutions and funders and as an insightful leader of prize committees.
Like his father, he was also famous as a university teacher, sometime delivering more than a hundred lectures per year, energizing students about science, and bringing many undergraduates into his lab for their first exposures to research. Dutch scientists populate many of the leading research institutions around the world, and Piet is rightfully viewed as the father of the Dutch diaspora.
This extensive service pales, however, in comparison to two of Piet’s other accomplishments. In the early 1980’s he was persuaded become the Research Director of the Netherlands Cancer Institute (NKI), which, by many accounts, had become a sleepy, undistinguished institution. Within a very short time, Piet had used several strategies— recruiting talent astutely, encouraging changes in faculty behavior, and setting a personal example—to turn the organization into one of the world’s best centers for cancer research. On top of all this, for several decades, Piet wrote a column for one of Amsterdam’s leading newspapers, explaining and defending scientific work, challenging questionable medical practices, and urging public support for the scientific enterprise.
His Character
Much of what I have already said pays tribute to Piet’s character: his intellectual integrity, his passion for science, his loyalties to students and institutions. But you need to experience Piet’s personality at closer range to appreciate fully his droll humor, his intensity, and his frank—even blunt—views of so many things.
Consider one example: the advice that Piet delivered openly, a few years ago, to a colleague turning 80: “…the only jobs that will [now] come your way are the jobs that require wisdom, a euphemism for cognitive decline.”
Piet Borst is one of a kind. But I note, in closing, that there is at least one literary precedent— the lean, serious Clerk from Oxford, one of Chaucer’s pilgrims to Canterbury, a student of logic, who spoke…
“…with formality and reverence,
And short and quick and full of elevated meaning;
His speech was always consistent with moral virtue,
And gladly would he learn, and gladly teach.”
Thanks for listening and for honoring Piet Borst with your presence.
Acceptance remarks by Piet Borst
My path to science was a straight and obvious one. My mother was a smart dentist, who taught her six children the elementary Dutch virtues: swimming, ice skating, healthy ambition, and playing an instrument, in my case the cello. My father was an ideal role model, professor of internal medicine, charismatic physician and fanatic clinical researcher. The only downside of my youth was the Second World War. My father in a concentration camp; little food. In the winter of 1944-45, I ate sugarbeet remnants and tulip bulbs, not your standard Lasker lunch. It left no scars in me.
I had the privilege to get into science at the start of the golden age of biology. The fields in which I worked, mainly cancer and tropical diseases, have seen spectacular advances. When I started my PhD we knew so little about cancer that I spent 3 years to show that tumor mitochondria were not defective, in contrast to what the great Otto Warburg had postulated. Thanks to revolutionary advances in methods to study gene expression—and thanks to clever scientists—we now know what cancer is and how it arises. The Netherlands Cancer Institute even suggested in 2013 that 90% of all cancers would be cured or turned into a chronic condition with good quality of life within 25 years. This prediction was ridiculed in 2013, but I now think we may get there, given the recent advances in targeted therapy, immunotherapy and anti-cancer vaccination.
Knowledge of parasitic diseases, my other scientific interest, lags behind that of cancer, but I predict that this will not be the case forever. Whereas the differences between normal cells and cancer cells are small, the metabolism of parasites differs radically from that of our cells, providing ample opportunities for selective chemotherapy. The exotic and interesting biochemistry of parasites is going to be their downfall, eventually, and the basis for more Lasker prizes.
Whereas science has provided us with more powerful methods than ever to get at the truth, pseudo-science, conspiracy theories, and quackery flourish. I spent part of my life ridiculing all this nonsense in columns and interviews. However, at a time when Tony Fauci needs protection against death threats, and an American president uses prime time TV to promote bleach as a therapy for Covid, ridicule does not suffice. What then? Bruce Alberts has suggested the need to teach all kids the scientific method. I am in favor, but will that work for simple, not so smart people, bombarded by misleading information? Our challenge is to convince these people that science works, not only for us scientists, but also to solve their problems. I hope that Lasker prizes highlighting the power of science will contribute to that goal.
