Steps on the Road to Modern Day Biotechnology...
through summer of 2000
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
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