Jewish Contribution to the Medical Sciences
The invention of local anesthesia by Carl Koller and the discovery of Novocaine by Alfred Einhorn.
The discovery that pancreatic dysfunction is the cause of diabetes by Oskar Minkowski (together with Joseph von Mering+) and subsequent work on the involvement of the islets of Langerhans by Moses Barron. The work of the Canadian team that isolated insulin (Banting+, Best+, Collip+, and Macleod+) was based on these two prior discoveries. Earlier work on the use of pancreatic extracts in the treatment of diabetes by Israel Kleiner in the US and Georg Zuelzer in Germany had come close to discovering insulin.
The discovery of the ABO and other human blood groups and of the Rh factor by Karl Landsteiner. (The M, N, and P blood groups were co-discovered with Philip Levine and the Rh factor was co-discovered with Alexander Wiener). Landsteiner received the 1930 Nobel Prize for this work, which made safe blood transfusions possible for the first time. Landsteiner is also considered to be one of the giants of immunology, having made major contributions to the understanding of the chemical basis of antigen-antibody interaction.
The development of the sodium citrate blood storage technique by Richard Lewisohn. Prior to Lewisohn’s work in 1913, blood could not be stored and had to be transfused directly between donor and recipient. The use of sodium citrate as an anticoagulant, together with the use of refrigeration (introduced by Richard Weil), permitted creation of the first blood banks. Lewisohn and Karl Landsteiner (see above) are considered to be the two researchers most responsible for the invention of modern blood transfusion, which is estimated to have saved in excess of one billion lives since the 1950s alone, making it the single greatest lifesaving medical advance in history
The invention of blood plasma fractionation by Edwin Cohn. Cohn, a professor of physical chemistry at Harvard Medical School, invented the Cohn process for separating blood plasma into its constituent components, thereby permitting much greater efficiency in the usage of blood donations. Used initially during World War II to extract serum albumin for treating shock, thereby saving the lives of countless thousands of wounded soldiers, the process was subsequently used to separate out the gamma globulins, used for conferring passive immunity to epidemic disease; fibrinogen and thrombin, used for producing surgical sealing agents and for treating hemophilia; the isoagglutinins, used for rapid blood typing; as well as many other therapeutically critical blood plasma components. “Convalescent plasma,” an anti-viral therapeutic used in the COVID-19 pandemic, is an example. The Cohn process remains the foundational technology of modern blood plasma fractionation. Cohn’s laboratory was awarded the 1953 Lasker Group Award for this work. The fractionation of whole blood into its plasma and red, white, and platelet blood cell constituents was pioneered by Edmund Klein and Isaac Djerassi.
The introduction of the side-chain theory of antibody formation by Paul Ehrlich, which has evolved into clonal selection theory, the central paradigm of modern immunology. Ehrlich shared the 1908 Nobel Prize with Élie Metchnikoff for their independent contributions to immunology. Ehrlich is also considered to be the founder of modern chemotherapeutic medicine. His development of Salvarsan (1909) and Neosalvarsan (1911) constituted the first effective treatment for syphilis and, in the words of Sir Alexander Fleming+, “the beginning – and a magnificent beginning – of bacterial chemotherapy.”
The isolation and development of penicillin by Sir Ernst Chain. Chain shared the 1945 Nobel Prize for this work with Sir Alexander Fleming+ and Sir Howard Florey. It was Chain who recognized the potential of Fleming’s nearly forgotten discovery of the antibacterial properties of Penicillium molds (one of many agents then known to have such properties). Chain, a biochemist, was able to isolate the active antibacterial substance, viz., penicillin, and to work out its molecular structure (later confirmed in the Nobel-Prize-winning x-ray diffraction work of Dorothy Crowfoot Hodgkin+). Using samples that Chain produced, Chain and Florey+ demonstrated penicillin’s stability, nontoxicity, and effectiveness against staphylococcal, streptococcal, and clostridial infections in laboratory animals and humans.
The development of streptomycin by Selman Waksman and Albert Schatz. Waksman received the 1952 Nobel Prize for this work, which created the first antibiotic effective against tuberculosis, for which (in combination with other drugs) it remains a therapeutic mainstay.
The development of isoniazid by Herbert Fox and Harry Yale. Although isoniazid, the leading drug used in the treatment of tuberculosis since the mid-1950s, was first synthesized in 1912 by Josef Mally+ and Hans Leopold Meyer (who later died in the Nazi concentration camp at Terezín), its anti-tubercular properties were not discovered until the early 1950s, when it was independently re-synthesized and clinically explored by three separate groups. These were headed, respectively, by Fox at Hoffmann-La Roche, Yale at Squibb, and Gerhard Domagk at Bayer. Isoniazid, used early on in combination with streptomycin and a third drug, para-amino salicylic acid (PAS), and more recently in combination with other drugs, has saved over a hundred million lives since the 1950s. (PAS was developed by Jörgen Lehmann+ in Denmark, based on studies carried out by Frederick Bernheim in the US. In these studies, Bernheim established the metabolic role of salicylic acid in the tubercle bacillus. PAS is basically designed to interfere with these salicylate-dependant metabolic processes, ultimately impairing or killing the bacillus.) In a related, but separate development, iproniazid, an isoniazid derivative first synthesized by Fox in 1951 as a potential anti-tubercular agent, was found to have powerful anti-depressant effects. It subsequently became the basis for the MAOIs (mono-amine oxidase inhibitors) that revolutionized the treatment of clinical depression in the post-war period.
The isolation of cortisone by Tadeus Reichstein. Reichstein shared the 1950 Nobel Prize with Edward Kendall+ and Philip Hench. Reichstein and Kendall+ were recognized for having independently isolated and characterized the hormones of the adrenal cortex, the most important of which was cortisone.
The chemical synthesis of cortisone by Lewis Sarett, Max Tishler, and Carl Djerassi. Sarett, working under Tishler at Merck, achieved the first chemical synthesis of the compound. With subsequent improvements by Tishler, Sarett’s synthesis made cortisone a commercially available drug for the first time. Further advances achieved independently by Djerassi and by Percy Julian made economically viable, large-scale production possible. Sarett, Tishler, and Djerassi were all awarded US National Medals of Science (in 1975, 1987, and 1973, respectively).
The development of aspirin by Arthur Eichengrun and Felix Hoffmann+. Aspirin is an artificially modified form of salicylic acid, a naturally occurring substance that can be obtained from the bark of willow trees, whose analgesic properties have been known since antiquity. Salicylic acid is, however, very poorly tolerated by the digestive system, which greatly limits its medicinal value. Early attempts to reduce its toxicity through acetylation failed to yield acetylsalicylic acid of sufficient purity to be medicinally useful. The first successful synthesis of pure acetylsalicylic acid was achieved in 1897 by Felix Hoffmann+, working at F. Bayer & Co. in Germany. Recently developed evidence indicates, however, that credit for this development should have gone equally, or even predominantly, to Hoffmann’s+ Jewish supervisor, Arthur Eichengrun.
The discovery of prostaglandins by M. W. Goldblatt. (Also discovered independently by Ulf von Euler.) Sir John Vane* was awarded the Nobel Prize in 1982 for demonstrating that the anti-inflammatory and analgesic action of aspirin-like drugs was via their inhibition of prostaglandin production. Vane also discovered the vasodilator prostacyclin, which led directly to the development of the ACE inhibitors that are widely used in the treatment of hypertension, heart failure, and other vascular diseases. The development of the COX-2 selective inhibitors (such as the “super-aspirin” Celebrex, widely used by severe arthritis sufferers) was largely the work of Philip Needleman.
The discovery of neurotransmitters by Otto Loewi. Loewi shared the 1936 Nobel Prize with Sir Henry Dale+ for their independent work on acetylcholine. Sir Bernard Katz and Julius Axelrod shared the 1970 Nobel Prize with Ulf von Euler for advanced work on neurotransmitters. Their work led directly to the development of the class of anti-depressants that includes Prozac, Zoloft, and Paxil. Axelrod, together with Bernard Brodie, Leon Greenberg, and David Lester, was largely responsible for the development of the pain reliever acetaminophen (Tylenol).
The discovery of endorphins and enkephalins by Solomon Snyder and Hans Kosterlitz, respectively. The discovery by Snyder of the opioid receptors in the mammalian nervous system led to the further discovery of endorphins and enkephalins, endogenous opioids that help to control mood and pain. The opioid receptors play a large role in the action of pain killers such as morphine. This new understanding of opioid action has in turn led to the development of synthetic pain killing substitutes with diminished potential for addiction. Snyder and Kosterlitz shared the 1978 Lasker Award in Basic Medical Research for this work.
The development of Narcan (naloxone) by Jack Fishman and Mozes Lewenstein. Developed as an opioid antagonist more than sixty years ago, Narcan is a life-saving medication that can reverse the effects of drug overdoses due to opioids, such as heroin and fentanyl. It is estimated to have saved the lives of several hundred thousand people in recent years.
The discovery and characterization of growth factors by Rita Levi-Montalcini, Viktor Hamburger, and Stanley H. Cohen. Levi-Montalcini and Cohen shared the 1986 Nobel Prize for their identification and isolation of the nerve and epidermal growth factors, respectively. Growth factors (others of which were subsequently discovered) are protein molecular “signals” emitted by cells to control growth and differentiation in neighboring cells. Cohen also elucidated the biochemical pathways through which growth factors act after binding to receptors on the outer membranes of target cells. Growth factors play a large role in embryonic development and are thought to have potential medical application in nerve regeneration, accelerated wound healing, and in the understanding and control of tumor cell proliferation. The “blockbuster” drug Herceptin for treating breast and other cancers is based, in part, on Cohen’s epidermal growth factor research.
The elucidation of the biosynthesis, metabolism, and control of cholesterol by Konrad Bloch, Michael Brown, Joseph Goldstein, and Alfred Alberts. Bloch shared the 1964 Nobel Prize in medicine with Feodor Lynen for their independent roles in mapping the 37-step chemical pathway involved in the biosynthesis of cholesterol. Brown and Goldstein shared the 1985 Nobel Prize in medicine for their joint work on cholesterol metabolism and the role of low-density and high-density lipoprotein (LDL and HDL) cholesterol in atherosclerotic cardiovascular disease, which is the primary cause of most heart attacks and strokes. Brown and Goldstein also identified the statins as potential LDL cholesterol lowering compounds. These drugs, which interfere with critical steps in cholesterol synthesis, are now among the world’s most widely prescribed pharmaceuticals. Studies indicate that in high-risk individuals, they lower the incidence of heart attack and stroke by as much as 50%. Lovastatin, the first statin drug to be approved for wide usage, was developed at Merck under the leadership of Alfred Alberts.
The development of Warfarin (Coumadin) anticoagulant therapy by Shepard Shapiro. Warfarin is the most commonly used anticoagulant for the prevention of heart attacks and strokes. It is also one of the most widely prescribed medications in the world. It was discovered in 1946 by Karl Paul Link, who developed it as a rat poison. Its identification and development for use in human anticoagulant therapy resulted from the work of Shapiro in the early 1950s. Previously, in the early 1940s, Shapiro had pioneered the clinical use of the anti-clotting agent methylene dicoumarin (dicoumarol), which was also discovered by Link.
The development of oral contraceptives by Gregory Pincus, Carl Djerassi, and Frank Colton.
The development of the Salk and Sabin polio vaccines by Jonas Salk and Albert Sabin, respectively. The resulting worldwide near-eradication of polio is estimated to be preventing over one-half million new cases of lifelong paralysis each year. The discovery that the causative agent in polio was, in fact, a virus was made in 1908 by Karl Landsteiner and Erwin Popper.
The development of the hepatitis-B vaccine by Baruch Blumberg and Irving Millman. Blumberg received the 1976 Nobel Prize, in part for this work, which has saved an estimated six-to-seven million lives.
The co-invention of mRNA vaccines and much of the seminal work underpinning them by Drew Weissman, Jon A. Wolff, Robert Langer, and others. These revolutionary vaccines, which can be very rapidly
produced, trace back to the 1990 demonstration by Wolff and colleagues that mRNA injected into muscle tissue results in the production of associated proteins. The two major obstacles that needed to be overcome in order to develop this potential in vivo antigen/antibody production process into a vaccine were suppression of the strong inflammatory reaction frequently encountered and the rapid degradation of mRNA by the body’s endogenous enzymes and immune system. Katalin Karikó+ and Drew Weissman, who are considered the inventors of mRNA vaccines, addressed the first of these challenges by attempting to replace one of the mRNA nucleotides with a substitute molecule. They found such a molecular substitute for which the resulting modified mRNA was still able to induce production of the desired protein antigens, but without triggering any significant allergic response. Efficient delivery of the mRNA molecules to targeted cells was solved through nano-encapsulation of the molecules. Nano-encapsulation of nucleic acids and proteins for efficient drug delivery stems from the revolutionary work of MIT chemist Robert Langer. Beginning in 1976, Langer showed, in the face of almost universal skepticism, that therapeutic molecules encapsulated in synthetic polymer micro- and nano-particles could be safely and efficiently delivered to their cellular destinations. Langer and others subsequently showed that the addition of polyethylene glycol (PEG) to the surface of such nano-particle carriers enhanced their robustness and that PEG-enhanced lipid nano-particles, which are used in mRNA vaccines, are particularly efficient for nucleic acid delivery. Langer, a co-founder of Moderna, one of the COVID-19 vaccine developers, is an Institute Professor at MIT and one of the ten most cited researchers in history. His inventions are licensed by over 300 companies and he is a recipient of more than 220 major awards, including the Priestley Medal and the Wolf and Dreyfus Prizes in chemistry; the Gairdner Foundation Award and the Breakthrough and Albany Medical Center Prizes in medicine; the Draper, Kyoto, Millennium, and Queen Elizabeth Prizes in engineering and technology; and both the US National Medals of Science and of Technology and Innovation. (See also the bullet below on the discovery of RNA and major contributions to the elucidation of its structure and function.) Unlike the mRNA vaccines developed by Moderna and Pfizer/BioNTech, the COVID-19 vaccines developed by AstraZeneca/Oxford and Johnson & Johnson are based on adenoviral vector technology. Viral vector technology, a nucleic acid delivery technique, was invented by Paul Berg, who was awarded the 1980 Nobel Prize in chemistry for work in recombinant DNA.
The co-discovery of interferon by Alick Isaacs (in collaboration with Jean Lindenmann). The large-scale production of recombinant interferon for medical use (a market currently in excess of $15 billion annually) is based largely on the work of Charles Weissmann and Sidney Pestka. Pestka received the US National Medal of Technology in 2001. Interferons are widely used in the treatment of multiple sclerosis, leukemias and lymphomas, melanomas, and hepatitis B and C.
The co-invention of monoclonal antibodies by César Milstein. Milstein shared the 1984 Nobel Prize with Georges Köhler+ for this work. Four of the top ten “blockbuster” anti-cancer drugs, including the top three, are now based on monoclonal antibody technology. The development of all four drugs was based on the application of this research to other research conducted by Jewish scientists. Specifically, Rituxan is based on the non-Hodgkin’s lymphoma research of Ronald Levy; Avastin is based on the angiogenesis research pioneered by Judah Folkman; Herceptin is based on the the epidermal growth factor research of Stanley H. Cohen and the HER-2/neu protein research of Robert Weinberg, Jeffrey Drebin, and Mark Greene; and Erbitux is based on research by Michael Sela and John Mendelsohn. The combined annual sales of these four drugs are in excess of $20 billion. (Of the remaining six “small molecule” drugs among the top ten blockbuster anti-cancer agents, at least two are based on the research of Jewish scientists. Specifically, Velcade is based on work by Julian Adams, Alfred Goldberg, Avram Hershko, Alexander Varshavsky, Aaron Ciechanover, and Irwin Rose; and Gleevec is based, in large part, on the research of Brian Druker and Owen Witte.) The COVID-19 antibody treatments developed by Regeneron and Eli Lilly are based on monoclonal antibody technology.
The invention of cancer chemotherapy by Louis Goodman, Alfred Gilman, and Sidney Farber. In the early 1940s, Goodman and Gilman discovered the effectiveness of mechlorethamine (“nitrogen mustard”) in the treatment of lymphatic malignancies. In the late 1940s, Farber produced the first chemically induced remissions from leukemia using the folic acid inhibitor aminopterin, which led to the development and widespread adoption of the folic acid antagonist amethopterin, or methotrexate. Eventually mechlorethamine and methotrexate, used in combination with other anti-cancer agents (mechlorethamine is the “M” in MOPP and methotrexate is the “M” in POMP – see bullet on combination chemotherapy below) and radiation, would lead to cures for many previously fatal lymphomas and leukemias, respectively.
The co-development of 6-MP (6-mercaptopurine or Purinethol) by Gertrude Elion, which used in combination with methotrexate and other drugs, has led to cures for most forms of childhood leukemia. Elion was also the co-developer of azathioprine (Imuran), the immunosuppressant that made organ transplants possible between individuals other than identical twins, and of acyclovir (Zovirax) for the treatment of herpes viral infections. Elion and George Hitchings+ received the 1988 Nobel Prize for their joint work.
The co-invention of combination chemotherapy for cancer by Emil Freireich and James Holland (together with Emil Frei III). The effectiveness of combination chemotherapy was preliminarily demonstrated in the treatment of leukemia by Sidney Farber in the 1950s. In 1965, Freireich, Holland, and Frei introduced the POMP combination chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia, which eventually rendered this otherwise rapidly fatal disease curable, revolutionizing cancer chemotherapy in the process. For this work, the three researchers shared the 1972 Lasker Award for Clinical Medical Research. (In POMP, “P” <=> 6-MP, also known as Purinethol, “O” <=> Oncovin, “M” <=> methotrexate, and the last “P” <=> prednisone. Replacing methotrexate with mechlorethamine and 6-MP with procarbazine, MOPP was soon devised as an analogous regimen for use in successfully treating both Hodgkin’s and non-Hodgkin’s lymphomas.)
The discovery and development of cisplatin by Barnett Rosenberg, which has led to a complete reversal in the prognosis for testicular cancer, a malignancy that had almost always been fatal and is now roughly 90% curable. The chemotherapeutic protocols for the use of cisplatin in the treatment and cure of testicular cancer were developed by Lawrence Einhorn (who supervised the successful treatment of Tour de France champion Lance Armstrong).
The revolutionizing of radiation oncology by Henry Kaplan. Kaplan, the long-time head of radiology at Stanford Medical School, introduced the use of megavolt x-ray therapy in the 1950s, using linear accelerators (LINACs) to generate the required high-energy radiation. The medical LINAC is now the primary tool used in radiation oncology worldwide. Since the 1950s, an estimated forty million cancer patients have received such radiation treatments. (Currently about half of all cancer patients receive radiotherapy, primarily from LINAC-generated x-rays.) Even more significantly, Kaplan and his associates demonstrated that radiotherapy could be employed as a curative, rather than a merely palliative, cancer treatment. By the late 1970s, using radiotherapy protocols largely developed by Kaplan and his group, cure rates of 70%-80% were being achieved in patients with early-stage Hodgkin’s lymphoma, which had previously been a uniformly fatal disease. Kaplan and Saul Rosenberg were the first to apply chemotherapy as an adjunct to radiation therapy in Hodgkin’s disease, their regimens achieving initial cure rates in the late 1970s of 30%-40% in late-stage Hodgkin’s disease. (With subsequent dramatic improvements in chemotherapy, the primary and secondary roles of radiation and chemotherapy have been reversed; cure rates are now 98% in early-stage Hodgkin’s disease and 85% in advanced disease.) Kaplan and his associates were also responsible for the clinical trial studies that established the utility of the histopathologic classification scheme for non-Hodgkin’s lymphomas proposed by Henry Rappaport in 1956. Although not widely accepted at the time, the Rappaport classification (with subsequent modifications) has become the most widely used in the staging and treatment of non-Hodgkin’s lymphomas. For his pioneering work in radiation oncology, Kaplan became in 1969 the only biomedical scientist to be awarded the prestigious Atoms for Peace Award.
The co-discovery of oncogenes by Harold Varmus and the elucidation of their role in human cancer by Robert Weinberg, Michael Wigler, Bert Vogelstein, Arnold Levine, and others. Varmus shared the 1989 Nobel Prize with Michael Bishop+ for this work.
The discovery of retroviruses and their associated reverse transcriptase enzyme by David Baltimore and Howard Temin. Baltimore and Temin shared the 1975 Nobel Prize for their independent discovery of these viruses, which are implicated in AIDS and in some cancers, and whose existence disproved the “central dogma” of molecular biology.
The development of AZT, protease inhibitors, and other drugs used in the treatment of AIDS by Jerome Horwitz, Samuel Broder, and Irving Sigal. AZT (Retrovir), which was originally synthesized by Horwitz for use as an anti-cancer agent, proved to be the first of the reverse transcriptase inhibitors found effective against HIV. Its identification as such in clinical trials was largely the result of efforts led by Broder, who also co-developed two other reverse transcriptase inhibitors (ddl and ddC). Sigal, who was senior director of molecular biology at Merck prior to his death in the 1988 bombing of Pan Am Flight 103 over Lockerbie, Scotland, was the first to demonstrate the effectiveness of protease inhibitors against HIV. Used in combination, the various reverse transcriptase and protease inhibitors have dramatically improved the outlook for AIDS patients.
The elucidation of the biochemistry of cellular metabolism by Otto Warburg, Otto Meyerhof, Gustav Embden, Jacob Parnas, Sir Hans Krebs, Fritz Lipmann, Herman Kalckar, Carl Neuberg, Gerty Cori, Konrad Bloch, and others. This includes much of the basic work on glycolysis (Embden-Meyerhof-Parnas pathway), the urea and citric acid cycles (Krebs cycles), the pentose phosphate pathway, and oxidative phosphorylation and the role of ATP, as well as significant contributions to the characterization of glycogen and fatty acid metabolism. Warburg, Meyerhof, Krebs, Lipmann, Cori, and Bloch all received Nobel Prizes.
The invention of radioisotopic tracer techniques by George de Hevesy, Friedrich Paneth, Rudolf Schoenheimer, David Rittenberg, Martin Kamen, William Hassid, and Samuel Ruben. Hevesy and Paneth introduced the general technique, for which Hevesy won the 1943 Nobel Prize in chemistry; Kamen and Ruben discovered the long-lived carbon-14 radioisotope, which has had widespread application in biology (and is also the basis of radiocarbon dating). Konrad Bloch employed several different radioisotopes in elucidating the biosynthesis of cholesterol, for which he was awarded the 1964 Nobel Prize in medicine. Melvin Calvin employed carbon-14 to elucidate the so-called dark reactions of photosynthesis, for which he was awarded the 1961 Nobel Prize in chemistry. (Others who made major contributions to the understanding of photosynthesis include Daniel Arnon, George Feher, and the Nobel laureates James Franck, Richard Willstätter, and Otto Warburg.)
The invention of radioimmunoassay by Rosalyn Yalow and Solomon Berson, which has revolutionized clinical and research practice in such fields as endocrinology and blood banking. The technique, which can be made exquisitely sensitive to trace amounts (nano- and pico-molar concentrations) of specific blood substances, is employed in measuring the levels of most hormones, screening donated blood for hepatitis-B virus, and in allergy and drug level testing. Yalow and Berson used radioimmunoassay’s ability to measure insulin levels in the blood, which had previously been impossible, to revolutionize the understanding of type 2 diabetes. They showed that it was not caused by too little insulin production by the pancreas, as had been long assumed, but rather by the development of insulin resistance by the cells of certain tissues. The pancreas responds to this resistance by pumping out higher levels of insulin. Fat tissue, which tends not to become insulin resistant, responds strongly to the increased insulin levels, leading to the nexus between type 2 diabetes and obesity. Yalow received the Nobel Prize in 1977 for the invention of radioimmunoassay. (Berson died in 1972.)
The determination of key components of the experimental basis for the double helix model of DNA by Phoebus Levene, Erwin Chargaff, and Rosalind Franklin. In 1929, Levene discovered that DNA contains a sugar called deoxyribose and that it consists of a chain of what he termed “nucleotides,” units composed of the deoxyribose sugar, a phosphate group, and one of four purine or pyrimidine bases. (The purine and pyrimidine molecular base constituents of DNA were discovered by the German biochemist Albrecht Kossel+.) Levene incorrectly concluded that all four bases were present in equal proportions. Chargaff, however, showed that the four bases were, in fact, present in specific pairwise ratios ([adenine]=[thymine] =/= [guanine]=[cytosine]), implying both structural base pairing and base coding of the genetic information. Finally, Rosalind Franklin’s x-ray crystallographic studies of DNA provided the clear evidence for a double helical structure. The theoretical model of Watson and Crick was largely based on the experimental data provided by the aforementioned chemical and structural analyses.
The breaking of the genetic code by Marshall Nirenberg. Nirenberg and Har Gobind Khorana shared the 1968 Nobel Prize for their independent determinations of the code.
The co-discovery of the basic mechanisms of gene regulation by François Jacob, Walter Gilbert, Mark Ptashne, Andrew Fire, Gary Ruvkun, Howard Cedar, Aharon Razin, Michael Grunstein, and Michael Levine. Jacob shared the 1965 Nobel Prize with Jacques Monod for their joint work on the development of the operon-repressor model of gene regulation, which was experimentally confirmed by Gilbert, who isolated the lac operon repressor (but whose 1980 Nobel Prize in chemistry was in recognition of other work), and by Ptashne, whose exploration of the phage lambda switch greatly elucidated the process by which regulatory proteins (repressors) switch on and off gene expression. Fire co-discovered RNA interference, an RNA-based gene control process, for which he shared a Nobel Prize in 2006. A second RNA-based gene control mechanism involving short strands of RNA called microRNA was co-discovered by Ruvkun. Cedar and Razin shared the 2008 Wolf Prize in Medicine for their role in the discovery of DNA methylation, which together with histone modification, co-discovered by Grunstein, forms the basis of the new field of epigenetics, which deals with the molecular mechanisms involved in gene activation and suppression by environmental influences. Levine’s work on the organization and function of the homeobox genes (which he co-discovered) “has done for animal development what the work on the lac operon and phage lambda did for understanding gene regulation in simpler organisms.”11 The discovery of these master genes and their role in development has “shattered our previous notions of animal relationships and of what made animals different, and opened up a whole new way of looking at evolution.”
The discovery of RNA and major contributions to the elucidation of its structure and function by Phoebus Levene, François Jacob, Sydney Brenner, Matthew Meselson, Sol Spiegelman, Sidney Altman, Sir Aaron Klug, Alexander Rich, Leslie Orgel, Andrew Fire, Gary Ruvkun, Roger Kornberg, Ada Yonath, and others. RNA was first identified as a nucleic acid distinct from DNA by Levene in the course of his seminal studies of the nucleic acids in the early part of the twentieth century. The concept of messenger RNA (mRNA) as an information-bearing DNA-to-ribosome intermediary in protein synthesis was first formulated by Jacob and Jacques Monod in 1961 and subsequently verified in experiments conducted by Brenner, Jacob, Meselson, and Spiegelman. The surprising catalytic properties of RNA were independently discovered by Altman and by Thomas Cech+, supporting the concept of a pre-biotic “RNA world,” first proposed in 1963 by Rich and, independently a few years later, by Orgel and others. Definitive x-ray diffraction studies of RNA structure were first carried out independently by Klug and by Rich. Rich co-discovered double helical RNA and went on to discover the more general process of nucleic acid hybridization, whose further development would “become the technical foundation of modern molecular biology.”13 Nucleic acid hybridization, e.g., lies at the heart of the polymerase chain reaction (PCR), which has revolutionized molecular biological research practice. Double helical RNA has recently been found to play a role in the control of gene expression in a process called RNA interference (RNAi), which was co-discovered by Fire. Another RNA control process regulating gene expression that involves very short, single-stranded RNA molecules called microRNA (miRNA) was co-discovered by Ruvkun. In recent years, sophisticated x-ray crystallographic analyses using synchrotron radiation sources were developed and employed by Kornberg to elucidate the structural dynamics of RNA-polymerase-directed DNA-to-mRNA transcription. Cryo-crystallographic and synchrotron radiation techniques were also developed and used by Ada Yonath to elucidate the structural dynamics of the process of translation, i.e., ribosomal protein synthesis, which involves mRNA, rRNA (ribosomal RNA), and tRNA (transfer RNA). These studies have revealed the ribosome to be, in fact, a very complex ribozyme (RNA enzyme). Jacob, Brenner, Altman, Klug, Fire, Kornberg, and Yonath were all awarded Nobel Prizes. Rich received the US National Medal of Science in 1995.
The co-invention of gene splicing by Stanley N. Cohen. Cohen and Herbert Boyer’s+ invention opened up the new field of genetic engineering. Cohen and Boyer+ were recipients of both the US National Medal of Science and the US National Medal of Technology. The latter award cited them “for their fundamental discovery of gene splicing techniques allowing replication in quantity of biomedically important new products, and beneficially transformed plant materials. This discovery of recombinant DNA technology has transformed the basic science of molecular biology and the biotechnology industry.” Other major contributors to genetic engineering include Paul Berg, Walter Gilbert, and Daniel Nathans, all of whom received Nobel Prizes for their work.
The invention of cotransformation by Michael Wigler, Saul Silverstein, and Richard Axel. Also known as the Wigler method, cotransformation is the eukaryotic cell analog of recombinant DNA processes in prokaryotic cells (see the above item on gene splicing). It permits any prokaryotic or eukaryotic gene to be introduced into the genome of any mammalian cell, including those that can be grown in tissue culture, thereby transforming such tissue cultures into factories for the production of the corresponding proteins. This is of enormous importance, since recombinantly transformed bacteria frequently cannot produce fully functional human proteins. Recombinantly cotransformed mammalian cells can not only produce such fully functional proteins, but in many cases they, unlike bacteria, can also be made to secrete them. The three top “blockbuster” cancer drugs (Rituxan, Avastin, and Herceptin – see the above item on monoclonal antibodies) rely in part on cotransformation for their production, as do many other breakthrough drugs including the “clot-busting” tissue plasminogen activators (tPAs), which have revolutionized the emergency treatment of myocardial infarctions and strokes. The Axel patents on cotransformation, granted in 1983, 1987, 1993, and 2002, have earned nearly $800 million (mostly for Columbia University, the parent institution of the technique’s three inventors). After mammalian cell lines and bacteria, the third major platform for production of genetically engineered biopharmaceuticals is yeast, which was largely developed as such by Gerald Fink. Recombinantly transformed yeast is extensively employed in the production of human insulin.
The discovery of nuclear magnetic resonance (NMR) by I. I. Rabi. Rabi received the 1944 Nobel Prize in physics for the demonstration of NMR in molecular beams. Felix Bloch shared the 1952 Nobel Prize in physics with Edward Purcell+ for their independent inventions of condensed matter NMR spectroscopy, which is important in biomolecular structure studies, as well as being the basis of the MRI diagnostic imaging technique.
The invention of the flexible endoscope by Basil Hirschowitz, which has revolutionized surgery by greatly reducing the complexity and invasiveness of many surgical procedures. (This work, undertaken in the mid-1950s, led to the production of the first glass-clad optical fibers, which later revolutionized modern telecommunications.)
The co-invention of LASIK eye surgery by Samuel Blum (together with Rangaswamy Srinivasan and James Wynne).
The invention of phacoemulsification cataract surgery by Charles Kelman, which is the technique most widely used for cataract removal worldwide. More than two hundred million such operations have been performed. It has revolutionized the procedure by completely eliminating the need for hospitalization, which had previously averaged one week. Kelman was a recipient of both the US National Medal of Technology in 1992 and the Lasker Award for Clinical Medical Research in 2004 (posthumously).
The co-invention of the first artificial heart valve to achieve widespread use by Albert Starr. Together with Lowell Edwards, Starr invented the Starr-Edwards heart valve, which he used in 1960 to successfully perform the first human mitral valve replacement. In 1963, he used the valve to successfully perform the first human triple (aortic, mitral, and bicuspid) valve replacement. At the same time, Starr pioneered the cardiac intensive care unit to provide post-operative care for his valve replacement patients. For his role in the development of prosthetic heart valves, Starr shared the 2007 Lasker Award for Clinical Medical Research.
The invention of the cardiac defibrillator, external pacemaker, and cardiac monitor by Paul Zoll. Zoll (and, independently, Wilson Greatbatch ) later invented the implantable cardiac pacemaker. Michel Mirowski and Morton Mower were two of the four inventors of the automatic, implantable cardiac defibrillator.
The invention of the Heimlich Maneuver by Henry Heimlich.
The co-invention of the basic technique used worldwide for the controlled chlorination of drinking water supplies by Abel Wolman. Wolman and Linn Enslow’s invention resulted in a dramatic reduction in the incidence of such waterborne diseases as cholera, dysentery, and typhoid fever; as such, it was arguably the single most important contribution to public health in the twentieth century. The number of lives thereby saved has been variously estimated as running into the hundreds of millions. Wolman received both the Lasker Award for Public Service in 1960 and the US National Medal of Science in 1974. The Abel Wolman Municipal Building, one of the largest buildings in Baltimore, MD (where he taught at Johns Hopkins), was named in his honor.