Stanford University Medical School

Palo Alto, United States of America

Connections Paul Berg | Janet Mertz

At the forefront of many biomedical advances since the Second World War, Stanford University Medical School played a pioneering role in the emergence of gene cloning.

(Photo credit: Stanford Medical History Center)

Stanford University School of Medicine traces its history back to the founding of the first medical school in the western United States in 1858 by the San Francisco surgeon Elias Samuel Cooper. The school went through many changes until 1882 when Cooper's nephew Levi Cooper Lane established a new college and renamed it Cooper Medical College.

In 1908 Cooper Medical College became affiliated to Stanford University and was renamed Stanford University School of Medicine. The School moved into new premises on the main Stanford University campus in Palo Alto in 1959.

The School fosters strong collaboration between medical investigators, engineers and basic physical and biological scientists and is a pioneering centre for biomedical research. Among its notable achievements are the role its scientists played in the development of recombinant DNA which inspired the creation of Genentech, the first dedicated biotechnology company and the development of genetically engineered drugs. The School's scientists were also instrumental in the generation of instruments for the automatic counting and classification of different cells types. Known as fluorescence activated cell sorters, these instruments opened up research into cell structure, function and disease on an unprecedented scale.

Stanford University Medical School: timeline of key events

A physician and bacteriologist, Zinsser isolated the bacterium that causes typhus and developed a protective vaccine against it. In 1935 he published the book 'Rats, Live and History' in which he recounted the effects of typhus on mankind and the efforts to eradicate it. In the book he argued that disease was responsible for more deaths than war. 1878-11-17T00:00:00+0000Beadle, a geneticist, was jointly awarded the Nobel Prize for Medicine in 1958 for discovering the role of genes in regulating biochemical events within cells. He made the discovery in collaboration with Edward Tatum while conducting experiments that exposed Neurospora crassa, a the bread mould, to x-rays to cause mutations. They found that the mutations caused changes in specific enzymes that were involved in metabolic pathways. The work was done at Stanford University.1903-10-22T00:00:00+0000Tatum was a biochemist who shared the 1958 Nobel Prize for Medicine for discovering how genes regulate biochemical events in cells. This was based on some experiments he carried out with colleagues at Stanford University in 1941 which involved crossing normal strains of the pink bread mould, Neurospora crassa, with another strain of the mould they had exposed to X-rays to induce genetic mutations. The offspring were found to inherit the mutation which manifested itself as metabolic defect. This led them to conclude that there was a direct link between genes and enzymatic reactions. 1909-12-14T00:00:00+0000Kornberg was a biochemist renowned for his research on enzymes which create DNA. In 1956 he and his team isolated the first enzyme known to be involved in the replication of DNA. It would be called DNA polymerase I. For this work Kornberg shared the 1959 Nobel Prize for Medicine. The Prize was given for the discovery of the 'mechanisms in the biological synthesis of ribonucleic acid and deoxyribonucleic acid.'1918-03-03T00:00:00+0000Berg is an American biochemist. He first made his name in 1971 by demonstrating it was possible to insert DNA from a bacterium into the a virus' DNA, creating what is called recombinant DNA. This he did as part of his work to study viral chromosomes. He was awarded the Nobel Prize in 1980 for this work. His technique paved the way to the development of genetic engineering and the modern biotechnology industry. Berg was also instrumental in the setting up of the Asimolar Conference on Recombinant DNA, in 1975, which drew up the first guidelines for experiments with genetic engineering. 1926-06-30T00:00:00+0000Falkow was a microbiologist who made his scientific mark by showing how bacteria develop resistance to antibiotics. During the 1960s he demonstrated that bacteria could acquire resistance by swapping genetic material via plasmids, small microbial DNA molecules. Thereafter he focused his attention on how pathogens cause disease and in 1985 helped to identify a single genetic locus in Yersinia pseudotuberculosis, a Gram-negative bacteria, that accounts for its ability to infect cultured animal cells. He later showed that a sub-type of E. coli caused a life-threatening diarrhoea prevalent in many low-income countries. Known as the founder of molecular pathogenesis, Falkow's work paved the way to the development of new vaccines, including for whooping cough. He also helped to devise a uniform nomenclature for bacterial plasmids1934-01-24T00:00:00+0000Cohen is an American physician and geneticist whose research has focused on the biology of bacterial plasmids, independent circular units of DNA found in and sometimes exchanged by bacteria. In 1970 he found a way to make Escherichia coli acquire a plasmid that made it resistant to the antibiotic tetracycline. He also discovered with Herbert Boyer a restriction enzyme that could cleave a circular plasmid at a single site. This laid the foundation for their joint experiment in 1973 which demonstrated the feasibility of combining and replicating genetic information from different species. Their experiment involved inserted a gene for frog ribosomal RNA into bacterial cells which then expressed the gene. Three patents were taken out on their technique. These paved the way to the rise of new start-up biotechnology companies, founded on the back of the promise of genetic engineering for generating new therapeutic products. 1935-06-30T00:00:00+0000An American physician and bacteriologist, Zinsser isolated the bacterium that causes typhus and developed a protective vaccine against it. In 1935 he published the book 'Rats, Live and History' in which he recounted the effects of typhus on mankind and the efforts to eradicate it. In the book he argued that disease was responsible for more deaths than war.1940-09-04T00:00:00+0000George Beadle and Edward Tatum, American geneticists, demonstrate that genes are responsible for the production of an enzyme. 1941-01-01T00:00:00+0000Levy is an oncologist who in 1981 made history by successfully using monoclonal antibodies to treat the first patient with lymphoma. This work laid the foundation for the development of Rituxan, the first monoclonal antibody drug approved by the FDA for the treatment of cancer. Levy is now focused on the development of cancer vaccines. 1941-12-06T00:00:00+0000The breakthrough was made by Hubert Loring and Carlton Schwerdt. They managed to isolate the virus with 80% purity. The work paved the way for the team to create the first vaccine in August 1947. Schwerdt continued to improve the technique and by 1953 had managed to isolate 100% pure polio virus with Bachrach Howard, which paved the way for Jonas Salk to create a safe vaccine in 1955. 1947-01-10T00:00:00+0000Kornberg is a biochemist whose research is focused on working out the mechanism and regulation of transcription, which is the first step in the pathway of gene expression. In 2006 he won the Nobel Prize for working out the protein pathway that a cell's genetic information takes when transferred to a new cell. He showed how information is carried from the genes and converted to molecules called messenger ribonucleic acid (RNA). This he worked out by mapping out the process in yeast. Kornberg was the first to work out how transcription works at a molecular level in eukaryotes, a group of organisms, including humans, whose cells have a well-defined nucleus. 1947-04-24T00:00:00+0000Fire is a biologist, pathologist and geneticist. In 1998 he and other colleagues working at Carnegie Institute reported in an article in Nature the discovery of tiny snippets of double-stranded RNA dsRNA) that appeared to silence specific genes which destroyed messenger RNA, a molecule involved in the production of proteins. They hypothesised that this was caused by a catalytic process. In 2006 he shared the Nobel Prize for Medicine for helping to show the mechanism that controlled the flow of genetic information. 1959-04-27T00:00:00+0000Mehran Goulian and Arthur Kornberg managed to assemble the genome using one strand of natural antiviral DNA. The two scientists announced their achievement to a press conference as part of an effort to increase the American public's appreciation of government funded scientific work. It, however, generated debate about whether life should be created in a test tube. The achievement was an important stepping stone to the development of recombinant DNA. 1967-12-14T00:00:00+0000Ray Wu and A.D. Kaiser report on the partial sequence of bacteriophage lambda DNA in the Journal of Molecular Biology, 35/3 (1968), 523-37. 1968-01-01T00:00:00+00001968-01-01T00:00:00+0000This was developed by Peter Lobhan, a graduate student of Dale Kaiser at Stanford University.1969-01-01T00:00:00+0000The FACS instrument automatically separates cells. Its sorting mechanism relies on antibodies coupled with fluorescent tags. The FACS was first outlined in HR Hulett, WA Bonner, J Barrett, LA Herzenberg, 'Cell sorting: automated separation of mammalian cells as a function of intracellular fluorescence' Science, 166 (1969), 747–49. By 1971 the FACS could sort 5,000 cells per second. The performance of the instrument was greatly improved by the development of monoclonal antibodies which provided a standardised reagent for the machine. Between 1971 and the early 1980s the number of FACS being used in laboratories increased from half a dozen to over 500. FACS provided a critical tool for investigating cellular structures and functions, measuring processes in cells and determining how viruses infect cells. On the clinical front they provided a means of counting white blood cells, a routine test for assessing the efficacy of chemotherapy in diseases like leukaemia. 1969-11-07T00:00:00+0000This was done in Dale Kaiser's laboratory by Douglas Berg together with Janet Mertz and David Jackson1971-01-01T00:00:00+0000Robert Pollack contacted Paul Berg to raise concerns about the potential biohazards of experiments Mertz, his doctoral research student, planned to do involving the introduction of genes from the oncovirus SV40 in the human gut bacteria, E. Coli. Following this Berg self-imposed a moratorium on experiments in his laboratory involving the cloning of SV40 in E-Coli.1971-06-01T00:00:00+0000The observation was made by Hugh McDevitt and colleagues using two methods of genetic mapping to determine the immune response in immunised mice. The work suggested predictable, inherited susceptibility to some diseases. It was published in HO McDevitt, BD Deak, D Shreffler, J Klein, JH Stimpfling, GD Snell, 'Genetic control of the immune response', Journal of Experimental Medicine, 135 (1972), 1259-78. 1972-02-07T00:00:00+0000The recombinant DNA was made by Paul Berg and colleagues. It was generated by cutting DNA with a restriction and then using ligase to paste together two DNA strands to form a hybrid circular molecule. The method was published in D A Jackson, R H Symons, P Berg, 'Biochemical Method for Inserting New Genetic Information into DNA of Simian Virus 40: Circular SV40 DNA Molecules Containing Lambda Phage Genes and the Galactose Operon of Escherichia coli', PNAS USA, 69/10 (1972), 2904-09.1972-10-01T00:00:00+0000It was based on their finding that when DNA is cleaved with EcoRI, a restriction enzyme, it has sticky ends. JE Mertz, RW Davis, 'Cleavage of DNA by RI restriction endonuclease generates cohesive ends', PNAS, 69, 3370–3374 (1972). 1972-11-01T00:00:00+0000The work was carried out by Stanley Cohen and Annie Chang at Stanford University in collaboration with Herbert Boyer and Robert Helling at the University of California San Francisco. They managed to splice sections of viral DNA and bacterial DNA with the same restriction enzyme to create a plasmid with dual antibiotic resistance. They then managed to insert this recombinant DNA molecule into the DNA of bacteria to express the new recombinant DNA. The technique showed it was possible to reproduce recombinant DNA in bacteria. It was published in SN Cohen, ACY Chang, HW Boyer, RB Belling, 'Construction of Biologically Functional Bacterial Plasmids In Vitro', PNAS USA, 10/11 (1973), 3240-3244. 1973-11-01T00:00:00+0000JF Morrow, SN Cohen, ACY Chang, HW Boyer, HM Goodman, RB Helling, 'Replication and Transcription of Eukaryotic DNA in Esherichia coli', PNAS USA, 171/5 (1974), 1743-47.1974-05-01T00:00:00+0000Her thesis focused on methods to isolate and characterise mutant variants of SV40 1975-01-01T00:00:00+0000Tatum was an American biochemist who shared the 1958 Nobel Prize for Medicine for discovering how genes regulate biochemical events in cells. This was based on some experiments he carried out with colleagues at Stanford University in 1941 which involved crossing normal strains of the pink bread mould, Neurospora crassa, with another strain of the mould they had exposed to X-rays to induce genetic mutations. The offspring were found to inherit the mutation which manifested itself as metabolic defect. This led them to conclude that there was a direct link between genes and enzymatic reactions.1975-11-05T00:00:00+0000American geneticist and biochemist, Leonard Herzenberg and Argentinian biochemist, Cesar Milstein, devise monoclonal antibodies for use on an automatic fluorescence-activated cell sorter, FACS. This improves the reliability of the FACS allowing the instrument to go on to become a major tool not only for cell sorting and cellular biology but the diagnosis of disease. The work is done in collaboration with the American geneticist and immunologist Leonore Herzenberg and Vernon Oi, then a graduate student in genetics at Stanford University. 1977-01-01T00:00:00+0000The American scientists Stanley Cohen and Herbert Boyer are awarded the first US patent for gene cloning.1980-01-01T00:00:00+0000Philip Karr, a patient with lymphoma, is treated by Ron Levy at Stanford University with a customised monoclonal antibody. It marks the first time a monoclonal antibody successfully treats cancer in a patient.1981-01-01T00:00:00+0000Two teams of scientists publish methods for the generation of chimeric monoclonal antibodies, that is antibodies possessing genes that are half-human and half mouse. Each team had developed their techniques separate from each other. The first team was lead by Michael Neuberger together with Terence Rabbitts and other colleagues at the Laboratory of Molecular Biology, Cambridge. The second team consisted of Sherie Morrison and colleagues at Stanford University together with Gabrielle Boulianne and others at the University of Toronto. 1984-12-01T00:00:00+0000 GJ Spangrude, S Heimfeld, IL Weissman, 'Purification and characterization of mouse hematopoietic stem cells', Science, 241 (1988), 58-62. 1988-07-01T00:00:00+0000Jasin, M, Berg, P, 'Homologous integration in mammalian cells without target gene selection', Genes Development, 2/11 (1988): 1353-63.1988-11-01T00:00:00+0000Beadle, an American geneticist, was jointly awarded the Nobel Prize for Medicine in 1958 for discovering the role of genes in regulating biochemical events within cells. He made the discovery in collaboration with Edward Tatum while conducting experiments that exposed Neurospora crassa, a the bread mould, to x-rays to cause mutations. They found that the mutations caused changes in specific enzymes that were involved in metabolic pathways. The work was done at Stanford University.1989-06-09T00:00:00+0000European Committee for Proprietary Medicinal Products recommends the approval of Centoxin (Nebacumab) , a drug originally developed by Henry Kaplan and Nelson Tang at Stanford University and prepared for market by Centocor. Based on this recommendation the drug was subsequently approved for market in The Netherlands, Britain, Germany and France between March and December 1991.1991-03-01T00:00:00+0000Ritxuan (rituiximab) is approved for the treatment of non-Hodgkin Lymphoma. The drug arose out of Ronald Levy's research for three decades to find a way of harnessing the power of the body's own immune system to fight cancer. 1997-01-01T00:00:00+0000Kornberg was an American biochemist renowned for his research on enzymes which create DNA. In 1956 he and his team isolated the first enzyme known to be involved in the replication of DNA. It would be called DNA polymerase I. For this work Kornberg shared the 1959 Nobel Prize for Medicine. The Prize was given for the discovery of the 'mechanisms in the biological synthesis of ribonucleic acid and deoxyribonucleic acid.'2007-10-26T00:00:00+0000The procedure, tried out in clinical trials, involved the injection of modified human, adult stem cells from bone marrow directly taken from two donors into the brains of 18 chronic stroke patients. The trials were led by Gary Steinberg at Stanford University School of Medicine. The 18 patients were selected for treatment from 379 patients. Most had suffered a stroke a year before treatment, and had damage to their motor function. Twelve of the patients were treated at Stanford the remaining six were treated at the University of Pittsburgh. A number of the patients previously confined to wheelchairs were able to walk after receiving the treatment. Many of the patients sustained their improvements for more than one year and some for two years. 2016-06-02T00:00:00+0000CTJ van Velthoven, A de Morree, I M Enger, J O Brett, T A Rando, 'Transcriptional Profiling of Quiescent Muscle Stem Cells In Vivo', Cell Reports, 21/1 (2017), 1994-2004. 2017-11-14T00:00:00+0000C T Charlesworth et al, 'Identification of Pre-Existing Adaptive Immunity to Cas9 Proteins in Humans', bioRXiv (2018), https://doi.org/10.1101/2433452018-01-05T00:00:00+0000Falkow was an American microbiologist who made his scientific mark by showing how bacteria develop resistance to antibiotics. During the 1960s he demonstrated that bacteria could acquire resistance by swapping genetic material via plasmids, small microbial DNA molecules. Thereafter he focused his attention on how pathogens cause disease and in 1985 helped to identify a single genetic locus in Yersinia pseudotuberculosis, a Gram-negative bacteria, that accounts for its ability to infect cultured animal cells. He later showed that a sub-type of E. coli caused a life-threatening diarrhoea prevalent in many low-income countries. Known as the founder of molecular pathogenesis, Falkow's work paved the way to the development of new vaccines, including for whooping cough. He also helped to devise a uniform nomenclature for bacterial plasmids2018-05-05T00:00:00+0000
Date Event People Places
17 Nov 1878Hans Zinsser was born in New York City, USAZinsserColumbia University, Stanford University, Harvard University
22 Oct 1903George Wells Beadle was born in Wahoo NE, USABeadleCalifornia Institute of Technology, Stanford University
14 Dec 1909Edward L Tatum was born in Boulder CO, USATatumStanford University, Yale University
3 Mar 1918Arthur Kornberg was born in Brooklyn NY, USAKornbergStanford University
30 Jun 1926Paul Berg was born in New York NY, USABergStanford University
24 Jan 1934Stanley Falkow was born in Albany, New York, USAFalkowGeorgetown University School of Medicine, University of Washington School of Medicine, Stanford University
30 Jun 1935Stanley Norman Cohen was born in Perth Amboy, NJ, USACohenStanford University
4 Sep 1940Hans Zinsser diedZinsserColumbia University, Stanford University, Harvard University
1941Genes shown to regulate biochemical events within cellsBeadle, TatumStanford University Medical School
6 Dec 1941Ronald Levy was born in Carmel, California, United StatesLevyStanford University
10 Jan 1947First time polio virus was isolatedLoring, SchwerdtStanford University
24 Apr 1947Roger D Kornberg was born in St. Louis, MO, USAKornbergStanford University
27 Apr 1959Andrew Z Fire was born in Stanford CA, USAFire Carnegie Institute, Johns Hopkins, Stanford University
14 Dec 1967Functional, 5,000-nucleotide-long bacteriophage genome assembledGoulian, KornbergStanford University, Chicao University
1968The first partial sequence of a viral DNA is reportedWu, KaiserCornell University, Stanford University Medical School
1968Paul Berg started experiments to generate recombinant DNA moleculesBergStanford University
1969New idea for generating recombinant DNA conceivedLobhanStanford University
7 Nov 1969Fluorescence activated cell sorter (FACS) publishedHerzenberg, Hulett, Bonner, BarrettStanford University
1971First plasmid bacterial cloning vector constructedBerg, Mertz, JacksonStanford University
June 1971Janet Mertz forced to halt experiment to clone recombinant DNA in bacteria after safety concerns raisedMertz, Berg, PollackStanford University
7 Feb 1972Immune response genes discoveredMcDevitt, Deak, Shreffler, Klein, Stimpfling, SnellStanford University, University of Michigan, Jackson Laboratory
1 Oct 1972First recombinant DNA generatedBerg, Jackson, SymonsStanford University
November 1972Janet Mertz and Ronald Davis published first easy-to-use technique for constructing recombinant DNA showed that when DNA is cleaved with EcoRI, a restriction enzyme, it has sticky endsMertz, DavisStanford University
1 Nov 1973First time DNA was successfully transferred from one life form to anotherCohen, Chang, BoyerStanford University, University of California San Francisco
1 May 1974Recombinant DNA successfuly reproduced in Escherichia coliMarrow, Cohen, Chang, Boyer, Goodman, HellingStanford University, University of California San Francisco
January 1975Mertz completed her doctorate MertzStanford University
5 Nov 1975Edward L Tatum diedTatumStanford University, Yale University
1977Monoclonal antibodies developed for automatic fluorescence-activated cell sorter Milstein, Herzenberg, OiLaboratory of Molecular Biology, Stanford University Medical School, University of Toronto
1980First patent awarded for gene cloningCohen, BoyerStanford University Medical School
1981First patient successfully treated with anti-idiotype monoclonal antibodyLevyStanford University Medical School
1984First chimeric monoclonal antibodies developed, laying foundation for safer and more effective monoclonal antibody therapeuticsNeuberger, Rabbitts, Morrison, Oi, Herzenberg, Boulianne, Schulman, HozumiLaboratory of Molecular Biology, Stanford Univerity Medical School
1 Jul 1988The first hematopoietic stem cells were isolated in miceSpangrude, Heimfeld, WeissmanStanford University
November 1988Gene targeting technique shown to be efficient in modifying DNA in mammalian cells which can be adapted for other systems. This is the first time genome modification appears possible. Jasin, BergStanford University
9 Jun 1989George Wells Beadle diedBeadleCalifornia Institute of Technology, Stanford University
March 1991Monoclonal antibody drug approved in Europe for the treatment of septic shockKaplan, TangStanford University Medical School, Centocor
1997FDA approved the first monoclonal antibody cancer drug for the American marketLevy, RastetterStanford University Medical School, Idec Pharmaceuticals
26 Oct 2007Arthur Kornberg diedKornbergStanford University
2 Jun 2016Stem cells reported to provide substantial recovery in patients disabled by strokeSteinbergStanford University
14 Nov 2017Stem cells in the body found to have significantly different gene-expression profile than stem cells isolated and cultivated in the laboratory van Velthoven, de Morree, Enger, Brett, Rando, Stanford University
5 Jan 2018Researchers identify pre-existing antibodies targeting CAS9 proteins raising possibility of immune responses undermining utility of CRISPR-Cas9 for gene therapyCharlesworth, Deshpande, Dever, Dejene,Gomez-Ospina, Mantri, Pavel-Dinu, Camarena, Weinberg, PorteusStanford University
5 May 2018Stanley Falkow diedFalkowGeorgetown University School of Medicine, University of Washington School of Medicine, Stanford University

17 Nov 1878

Hans Zinsser was born in New York City, USA

22 Oct 1903

George Wells Beadle was born in Wahoo NE, USA

14 Dec 1909

Edward L Tatum was born in Boulder CO, USA

3 Mar 1918

Arthur Kornberg was born in Brooklyn NY, USA

30 Jun 1926

Paul Berg was born in New York NY, USA

24 Jan 1934

Stanley Falkow was born in Albany, New York, USA

30 Jun 1935

Stanley Norman Cohen was born in Perth Amboy, NJ, USA

4 Sep 1940

Hans Zinsser died

1941

Genes shown to regulate biochemical events within cells

6 Dec 1941

Ronald Levy was born in Carmel, California, United States

10 Jan 1947

First time polio virus was isolated

24 Apr 1947

Roger D Kornberg was born in St. Louis, MO, USA

27 Apr 1959

Andrew Z Fire was born in Stanford CA, USA

14 Dec 1967

Functional, 5,000-nucleotide-long bacteriophage genome assembled

1968

The first partial sequence of a viral DNA is reported

1968

Paul Berg started experiments to generate recombinant DNA molecules

1969

New idea for generating recombinant DNA conceived

7 Nov 1969

Fluorescence activated cell sorter (FACS) published

1971

First plasmid bacterial cloning vector constructed

Jun 1971

Janet Mertz forced to halt experiment to clone recombinant DNA in bacteria after safety concerns raised

7 Feb 1972

Immune response genes discovered

1 Oct 1972

First recombinant DNA generated

Nov 1972

Janet Mertz and Ronald Davis published first easy-to-use technique for constructing recombinant DNA showed that when DNA is cleaved with EcoRI, a restriction enzyme, it has sticky ends

1 Nov 1973

First time DNA was successfully transferred from one life form to another

1 May 1974

Recombinant DNA successfuly reproduced in Escherichia coli

Jan 1975

Mertz completed her doctorate

5 Nov 1975

Edward L Tatum died

1977

Monoclonal antibodies developed for automatic fluorescence-activated cell sorter

1980

First patent awarded for gene cloning

1981

First patient successfully treated with anti-idiotype monoclonal antibody

1984

First chimeric monoclonal antibodies developed, laying foundation for safer and more effective monoclonal antibody therapeutics

1 Jul 1988

The first hematopoietic stem cells were isolated in mice

Nov 1988

Gene targeting technique shown to be efficient in modifying DNA in mammalian cells which can be adapted for other systems. This is the first time genome modification appears possible.

9 Jun 1989

George Wells Beadle died

Mar 1991

Monoclonal antibody drug approved in Europe for the treatment of septic shock

1997

FDA approved the first monoclonal antibody cancer drug for the American market

26 Oct 2007

Arthur Kornberg died

2 Jun 2016

Stem cells reported to provide substantial recovery in patients disabled by stroke

14 Nov 2017

Stem cells in the body found to have significantly different gene-expression profile than stem cells isolated and cultivated in the laboratory

5 Jan 2018

Researchers identify pre-existing antibodies targeting CAS9 proteins raising possibility of immune responses undermining utility of CRISPR-Cas9 for gene therapy

5 May 2018

Stanley Falkow died