Steps on the Road to Modern Day Biotechnology...
through summer of 2004

many of the photographs used herein are from the
 Access Excellence - National Health Museum Website
and are used here for non-commercial, educational use by teachers and students.

1865:  The age of genetics begins
when Gregor Mendel, studying inherited traits of pea plants, outlines the basic laws of heredity. Mendel's discoveries about "heritable factors" (genes) are not understood until early 1900's.

1910: Chromosomal theory of inheritance proposed: Thomas Hunt Morgan establishes that genes are located on chromosomes by physically tracing a specific gene to a specific chromosome. Morgan wins the 1933 Nobel Prize in Medicine.

1941: One gene, one enzyme: George Beadle and Edward Tatum establish that one gene makes one enzyme or protein, and share the 1958 Nobel Prize in Medicine.

1952: Martha Chase and Alfred Hershey use radioactive isotopes of 35S and 32P and a common kitchen appliance to separate the protein coats of viruses from their DNA to demonstrate that DNA is the genetic substance that transmits inherited characteristics from one generation to the next. Hershey wins the 1969 Nobel Prize.

1953: Unraveling the double helix. James Watson and Francis Crick decipher the structure of the DNA molecule - a double helix - without doing any "wet" biochemical-like experiments at the lab bench. In a classic "race to the finish", Watson and Crick submit a one-page paper to the journal Nature, starting with "We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.)", and ending with the subtle understatement: "It has not escaped our notice that the specific pairing that we have postulated immediately suggests a possible copying mechanism for the genetic material". Their work is recognized with the 1962 Nobel Prize, shared with Maurice Wilkins (Rosalind Franklin died 4 years earlier)


1967: Cracking the the genetic code. Har Khorana, Robert Holley, and Marshall Nirenberg decipher the mechanism that enables DNA to be translated into proteins. Nirenberg, Khorana, and Holley share the 1968 Nobel Prize.

1968: Stanley Cohen, studying bacterial disease at Stanford, determines that bacteria carry genes for antibiotic resistance on plasmids, extrachromosomal circles of DNA. Cohen learns how to purify plasmids and reinsert them into other bacterial cells, transferring antibiotic resistance in the process.
[a late-night talk in a deli meals sparks a DNA revolution: in his own words]   


1970: Restriction enzymes discovered. UCSF scientist Herb Boyer, working with bacteriophages, discovers that certain bacteria preferentially fight off (or "restrict") certain phages by producing enzymes that can chop up the phage's DNA, leaving "sticky ends" on the cut strands. Boyer isolates the "Big Daddy" of restriction enzymes, EcoR1. In the ensuing years, hundreds of different restriction endonucleases are found that cleave DNA at specific sites. Earlier investigators studying restriction enzymes win the 1978 Nobel Prize in Medicine. [in his own word's]


1972: Recombinant DNA technology begins: Stanford biochemist Paul Berg splices together two blunt-ended fragments of DNA from the SV40 virus and E. coli, creating recombinant DNA. Berg shares the 1980 Nobel Prize in Chemistry with Walter Gilbert and Fred Sanger (below). [In his own words]


1972: "From Corned Beef to Cloning": In November 1972, at a scientific meeting in Hawaii, Cohen hears Boyer describe his work with EcoR1 and his findings that the sticky ends of DNA can be linked together or "spliced" with DNA ligases. Cohen and Boyer meet at a Waikiki Beach Deli, where they discuss ways to combine plasmid isolation with DNA splicing. They form the idea of inserting foreign (non bacterial) DNA into bacterial plasmids that would then churn out specific proteins - the basis of the biotechnology industry.
[in their own words]


1974: First recombinant gene spliced: Stanley Cohen, Annie Chang, and Herb Boyer splice DNA from a frog into the bacterium E. coli,  which becomes the "lab rat" of recombinant DNA research.

1975: Asilomar Conference: Pacific Grove CA: Paul Berg organizes an international conference on recombinant DNA technology with over 100 other scientists to discuss what they knew (and didn't know) about recombinant DNA and to draw up guidelines that would let the science proceed without undue risk. Although recombinant DNA technology turned out to be much more harmless than many had suspected, Asilomar remains an important scientific landmark, a rare instance of scientists independently questioning and successfully regulating their own work. The scientists agree to suspend research involving recombinant DNA technology research until potential risks can be evaluated, a "milestone of self-regulation in science". [in their own words]

1975: DNA sequencing developed: Walter Gilbert and Allan Maxam of Harvard University and Fred Sanger of Cambridge University simultaneously come up with two techniques for determining the exact sequence of bases that make up a gene. Gilbert and Sanger share the 1980 Nobel Prize (also with Paul Berg).


1975: Cesar Milstein, Georges Kohler and Niels Jeme develop monoclonal antibody technology by fusing immortal tumor cells with antibody-producing B lymphocyte cells to produce "hybridomas," that continuously synthesize identical (or "monoclonal") antibodies. Milstein, Kohler and Jeme are awarded the 1984 Nobel Prize in Medicine.


1976: Big bucks for Biotech: The commercial potential of using cells as factories for hormones and proteins to produce "biopharmaceuticals" is not lost on the business world. Robert Swanson, a 29-year-old Silicon Valley venture capitalist, and Herb Boyer team up to form Genentech, Inc. (for "GENetic ENgineering TECHnology") with the goal of cloning human insulin. Genentech goes public on Oct. 14, 1980, offering one million shares of stock for $35 a share - and makes $35 million in an afternoon. By the end of the day, Genentech's stock makes market history by hitting a high of $89, a record for an initial public offering. [Genetech's Web pages]


1978: Human insulin cloned into E. coli by Genentech scientists. Genentech licenses , the human insulin technology to Eli Lilly. In 1982, human insulin, Humulin, becomes the first recombinant DNA drug approved by FDA. [Humulin]


1985: Genentech becomes the first biotechnology company to launch its own biopharmaceutical product in 1985, ProTropin - growth hormone for children with growth hormone deficiency. [ProTropin]


1986: The Polymerase Chain Reaction (PCR) is conceived by Kary Mullis and revolutionizes molecular biology. PCR uses a thermostable DNA polymerase, from a thermophilic bacteria,  to amplify any given DNA segment billions of times in a few hours. Taq polymerase is chosen as the 1989 Molecule of the Year by the journal Science. Kary Mullis, having parted ways with his employer (Cetus Corp.) as well as alienated himself from the scientific establishment, is not even mentioned in the Science article. However, Mullis is awarded the 1993 Nobel Prize in Chemistry and goes on to become a best-selling novelist. A long, bitter "David vs.Goliath" patent struggle between Hoffman-LaRoche and Promega Biotech over ownership of PCR technology and the key enzyme,Taq polymerase, was at last resolved in 1999.


1989: The Human Genome Project (HGP) begins. An ambitious plan to "map, sequence and render accessible for further biological study" all ~100,000 human genes by the year 2005, initially led by director James Watson. Human chromosomes are parceled out to labs around the world, with new genomic sequencing technologies springing up to meet the need for faster sequence analysis. Anticipated cost: $3 billion (NIH / DOE).

1990: First use of gene therapy to treat human patient. Ashanti DiSilva, a 4-year-old girl with ADA (adenosine deaminase) deficiency is the first recipient of gene therapy. William French Anderson and colleagues at the NIH insert a normal ADA gene into the girl's T-cells and re-introduce the T-cells into her bloodstream. Injections of corrected T-cells every 2 months restores 25% of her immune system function, allowing her and others with ADA deficiency to lead a normal life.

1994: Brave new foods ­ On May 18, the Food and Drug Administration announces the arrival of Calgene's FlavrSavr tomato, the first transgenic food, to the supermarket shelves. FlavrSavr had undergone a decade of testing, costing $525 million, before being approved safe by the FDA. Engineered to remain firm even as it turns red and ripe, FlavrSavr "provides summertime taste year round". Although delicious, the FlavrSavr suffers from consumer resistance, high price and a boycott by chefs. Calgene, heavily in debt before the tomato hit the market, declares the FlavrSavr dead on the vine in 1997. [Time Magazine story on "Killer Tomatoes"]

1996: First mammal cloned from adult cells: A surrogate mother sheep gives birth to Dolly, a lamb cloned from an udder cell of an adult sheep born 6 years earlier. Ian Wilmut and colleagues at the PPL Theraputics and the Roslin Institute in Scotland quietly announce the birth of Dolly in February, 1997 in the journal Nature, after which, all hell breaks loose...[MSNBC - History of Cloning]


1996: Development of the GeneChip®: The Department of Biochemistry at Stanford and Affymetrix introduce a technological breakthrough in gene expression and DNA sequencing technology with the introduction of DNA chips, small glass or silica microchips that contain thousands of individual genes that can be analyzed simultaneously. Since then, DNA Chip technology has become a growth industry as new tools for making, probing, imaging, and analyzing arrays are introduced almost daily. [Gene Chip uses]


1997: Three Cloned Mice: Dolly is joined on October 3, 1997 by the cloned mouse "Cumulina" and, shortly afterward, by 22 of her cloned siblings (some of whom were cloned from clones) using the 'Honolulu Technique' of nuclear transfer. Author Teruhiko Wakayama concludes that "contrary to previous opinion, mammals can be reproducibly cloned from adult somatic cells". [Story of Cumulina & her sisters]


1997: First Human Artificial Chromosome: Scientists at Athersys in Cleveland OH use a combination of natural and synthetic DNA to create a "genetic cassette" that can potentially be customized and used in gene therapy. Genes on the artificial chromosome are expressed and replicated in cells for over 6 months. [Synthetic Microchromosome Technology]


1998 (May):  Race for the Genome: J. Craig Venter and Perkin Elmer merge to create Celera Genomics, The Company's goal: sequence the entire human genome by December 31, 2001 - 2 years before the completion by the HGP, and for a mere $300 million. The company is massive genomics sequencing facility with a capacity greater than that of the current combined world output, and second only to the Pentagon in computing power. Venter calls the plan a "mutually rewarding partnership between public and private institutions." [Celera Genomics]


1998 (October):  Human Genome Project on 'Fast Track' for Early Completion: The DOE and NIH approve new 5-year goals aimed at completing the Human Genome Project in 2003, generating a "working draft" of the human genome DNA sequence by 2001. PS. "It's NOT a race"

1998  (November):
Two research teams, led by James Thompson (UW Madison) John Gearhart (Johns Hopkins) succeed in growing Embryonic Stem (ES) cells, pleuripotent, self renewing cells with the demonstrated ability to differentiate in vitro into all three embryonic germ layers. Science selected stem cell research and technology as the 1999 "Breakthrough of the Year." The research was funded by and is licensed to Geron Corporation.
[August 23, 2000: NIH Publishes Final Guidelines for Stem Cell Research]
                           [January 2001: Guidelines updates]

1999 (September):  Speed Matters: Celera announces completion of the Drosophila genome sequence (With Gerry Rubin et. al. of Howard Hughes Medical Institute) on September 9, and immediately begins sequencing the Human genome. Critics had predicted that (a) the full sequence would not be able to be deciphered and (b) that Celera would not release the sequence to the public, neither of which proved to be the case. Science reports the full scoop.

2000 (June 26th):  The GENOME Race is Over:
President Clinton, Tony Blair, the HGP, and Celera announce the completion of a "working draft" of the sequence of the human genome. The achievement provides scientists with a road map to the location and sequence of an estimated 90% of genes on every chromosome, with all HGP data freely available on the Internet. Although the draft contains gaps and errors, it provides a high-quality reference genome sequence -- with the final fully-completed draft expected by 2003 or sooner. Knowledge about genes will speed the understanding of how genetics influences disease development, aid researchers looking for genes associated with particular diseases, and contribute to the discovery of new treatments. (PS. Celera made the announcement to the White House on April 6, 2000, but decides to make a joint announcement with the HGP). [Image]      The HGP Press Release Web Pages
     Free access to the Human Genome is promised by President Clinton and Prime Minister Blair. In 2000 all of human chromosome #21 (with 33.5 million base pairs, but only 300 genes).

2001:  IHGSC Formed.  The International Human Genome Sequencing Consortium is announced to serve as a joint research endeavor (6 countries & 16 research institutions) to work on the completion of the Human Genome sequence.

2003: Working draft of mouse genome sequenced. In April the IGHSC published in Nature a complete draft of human Genome Sequence.

2004: (October) The IGHSC published build 35 in Nature of the finished complete Human Genome Sequence with 2.85 billion nucleotides and only 341 small gaps not sequenced. Surprisingly, only between 20,000 and 25,000 genes seem to be present in the human genome. The relative sizes on organisms genomes is a surprise to many - figure