Part 1. The Early Years of Genetics
(go to Pt 2)
1859 Charles Darwin publishes The Origin of Species, establishing the Theory of Evolution and its mechanism, natural selection, and challenging both the accepted scientific and religious views of Western culture that had been taught for centuries. The first edition sold out on the day it was published. Theologians quickly labeled Darwin "the most dangerous man in England"... Yet, after reading it, Darwin's friend and colleague T. H. Huxley had a different reaction: "How extremely stupid not to have thought of that." Quote
1865 The age of genetics begins when Gregor Mendel, studying inherited traits of pea plants, outlines the basic laws of heredity that still hold true today for all organisms. Mendel's discoveries about "heritable factors" (genes) are not recognized by other scientists for over 35 years.
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 (with Joshua Lederberg).
1952 The "Waring Blender Experiment": Martha Chase and Alfred Hershey use the common kitchen appliance to separate the protein coats of viruses from their DNA to demonstrate that DNA is the substance that transmits inherited characteristics from one generation to the next. Hershey shares the 1969 Nobel Prize (not with Martha Chase but with Max Delbruck and Salvador Luria)
1953 Unraveling the double helix. James Watson and Francis Crick deduce the structure of the DNA molecule - a double helix - without ever doing a single experiment at the 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) [Image]
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.
Part 2. The Birth of Biotech: The 1970's
(go to Pt 3)
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. [Image]
1970 Restriction enzymes discovered. UCSF scientist Herb Boyer, working with bacteriophages, discovers that certain bacteria preferentially fought off (or "restricted") certain phages by producing enzymes that chopped 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 (Hamilton Smith et al.) win the1978 Nobel Prize in Medicine. [Image]
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 "for his fundamental studies of the biochemistry of nucleic acids, with particular regard to recombinant-DNA" (with Walter Gilbert and Fred Sanger below). [Image]
1972 "From Corned Beef to Cloning": In November, 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 desired DNA into bacterial plasmids that would then churn out specific proteins - the basis of the biotechnology industry. Quote
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. The scientists agree to suspend research involving recombinant DNA technology research until potential risks can be evaluated, a "milestone of self-regulation in science. 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".
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 in Chemistry (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 IPO!. [Image] (the Cohen-Boyer patent continued to net Stanford and UCSF royalties of $200 M over the ~20 year course of its life (1980 to 1997). Woo hoo.
1978 Human insulin cloned into E. coli by Genentech scientists. Genentech licenses the human insulin technology to Eli Lilly. In 1982, human insulin, or Humulin, becomes the first recombinant DNA drug approved by FDA. [Image]
1985 Genentech becomes the first biotechnology company to launch its own biopharmaceutical product in 1985, ProTropin - growth hormone for children with growth hormone deficiency.
Part 3. Are You Ready for the Revolution? The Early 1990s
(go to Pt 4)
1986 The Polymerase Chain Reaction (PCR) is conceived by Kary Mullis and revolutionizes molecular biology... PCR uses a thermostable DNA polymerase 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) as well as the scientific establishment (we won't go there), is not 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 (in favor of Promega). [Image]
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). [Great timeline of its own: Exploring our Molecular Selves]
1990 First use of gene therapy to treat human patient. Ashanti DiSilva, a 4-year-old girl with ADA 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 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. [Image]
1996 Announcing Dolly: 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..Sadly, on February 14, 2003: "Dolly the sheep, the first cloned mammal, is dead at age 6 of a lung infection common to sheep raised in barns. (snif!)
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. [Image]
1996 Ag Biotech takes off (quietly and quickly) The development of two important Input Traits (insect resistance and herbicide tolerance) is just what the farmers of the US needed (and wanted). Acceptance of GM crops is swift and quiet, with GM soybeans, cotton, and corn crops dominating US farmlands by 1998. Although worldwide resistance to accepting GM grain puts the squeeze on US farmers, EPA studies consistently reaffirm safety, and "no unreasonable adverse effects" (yikes, scary picture) on non-target insects, the environment, or public health and safety. Safe as baby shampoo!
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".
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. [Click for Image]
Part 4. Speed Matters - Welcome to the Genomics Era: 1998+
(go to Pt 5)
1998 (May) Race for the Genome: J. Craig Venter and Perkin Elmer merge to create Celera Genomics. 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 computing power second only to the Pentagon. Venter calls the plan a "mutually rewarding partnership between public and private institutions."
1998 (September): Google opens its doors in Menlo Park CA. [Fast forward: 22 November 2006 Google’s Shares Climb Above $500: 'Google’s success has made its founders, Sergey Brin and Larry Page, the 12th and 13th richest people in the US, and, at 33, the youngest in the top 400. Their share holdings alone are worth more than $15 billion each, on top of the more than $2 billion each in cash they have received for selling some shares already. Google now has a total value of >$150 billion, exceeding all but 13 American companies — like Exxon Mobil and Wal-Mart. It is worth more than any media company and all the technology companies except Microsoft and Cisco Systems'. Way cool!]
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 human Embryonic Stem (hES) 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.
1999 (September) Shotgun sequencing: 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. [Image]
14 March 2000: Code Red for Biotech Stocks: President Clinton and Prime Minister Tony Blair released a joint statement that genome information "should be made freely available to scientists everywhere". While Clinton and Blair went on to reinforce “the intellectual property protection for all gene-based inventions”, the market reacted to only the first part of the statement, putting stock market investors in a panic. Biotech stocks across the board went into a 'screaming nosedive', dragging down the NASDAQ, which on that day suffered its second-biggest point loss ever! By the end of the day, investors in the biotechnology sector lost over $40 billion. Ouch! Image
26 June 2000 - The Race is Over: President Clinton, Tony Blair, the HGP, and Celera announce the completion of a "working draft" 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 draft expected by 2003 or sooner. Quote (PS. Celera made the announcement to the White House on April 6, 2000, but decides to make a joint announcement with the HGP). Contest: Provide a caption for this photo...
Part 5. Biotech and Politics: 01.26.01 -to- 01.20.09
26 January 2001: Inaugural Indecision: New U.S. President George W. Bush (43) is undecided whether to allow federal funding for stem cell research, despite letters of support from Nobel laureates, support from both conservative and liberal Senators, and a lawsuit by Christopher Reeves and concerned scientists.
February 15 & 16, 2001The simultaneous
publication of the historic Genome Issues of Nature (Collins et. al, Human Genome Project) and Science (Venter et. al, Celera Genomics). The
Biggest Surprise about the Human Genome: 35,000
genes or less*, far fewer than originally predicted for humans.
31 July 2001: Cloning Ban: by a vote of 265 to 162, the US House of Representatives passes the Human Cloning Prohibition Act of 2001 (HR2502), a ban on all human cloning, either for reproduction or for therapeutic cloning. Despite warnings, on August 7th, at a National Academy of Sciences Meeting, 3 privately-funded US / European groups vow to continue their programs on Human Reproductive Cloning.
10 August 2001: The Bush Decision on Stem Cells: In his first address to the nation, Bush approves a compromise on stem cell funding. His decision allows for (a) full federal funding for research on adult and umbilical stem cells, (b) limited federal funding for research on human embryonic stem cells (hES cells) to pre-existing cell lines drawn from surplus embryos created for in-vitro fertilization, (c) no federal funding for research on hES cells from Donor Embryos created specifically for developing stem cells or for research in therapeutic cloning (for genetically identical, and immunologically compatible hES cells).
2001+: Cute, cuddly, and cloned: We'll do a whole lecture on this later in the semester, but in the meantime, here's some cloned animals to love:
- 14 Feb 2002: Cc, the first Cloned Cat is born
- 25 Dec 2001: 5 Christmas piggies: Noel, Angel, Mary, Star, and Joy
- 29 May 2003: Way to go, Idaho!
- 7 August 2003: Prometia: World's first cloned horse, born to its genetic twin.
2002+: Next Generation Genomes. [We'll do a whole lecture on this later in the semester, but in the meantime, here's some highlights and links] An era of very rapid shotgun sequencing of major genomes including the Mouse, Chimp and Dog, Fugu ribripes (pufferfish), Bos taurus (moo) and hundreds of other species, PLUS the completion of Human Chromosomes (in this order) 22, 21, Y, 7, 6, 20, 14, 13, 16, 19, 10, 9, 5, 16, X, 2, 4 , 18, and in 2006:8, 11, 12, 15, 17, 3, and 1 (May 2006!) wow!!! A large percentage of the genomes were completed by TIGR, Venter's first (and non-profit) company in Bethesda MD (run by his very talented scientist spouse Claire Fraser). Check out this impressive (ever-growing list) at A Quick Guide to Sequenced Genomes . The human chromosomes were typically completed by the NHGRI (The Genome Boys: Francis Collins, Eric Lander, et. al) plus the IHGSC).
14 April 2003: The Human Genome Project - fini! BETHESDA, Md., – Said Francis S. Collins, M.D., Ph.D.,"All of the project’s goals have been completed successfully – well in advance of the original deadline and for a cost substantially less than the original estimates." ...and just in time for..... 25 April 2003: Happy Birthday Double Helix! It's DNA Day celebrating 50 years of the double helix.
2004+: Sailing the Genomic Sea (of data)
We'll do lots more on this later, but for now...
- April 2004: The Sorcerer II Expedition: 1 billion bp of DNA, 1.2 million new genes from the Sargasso Sea, all while sailing on Craig's 55-foot yacht ...waayyy cool
- August 2005: Genbank hits 100 Gigabases - From zero to one hundred billion bases (100,000,000,000) in 20 years...! CLICK HERE for graph!
- March 2007: Craig Venter: PLoS Ocean Metagenomics Issue...waayyy cool
- Woo baby...sign me up for the next cruise!
2004+: Ups and downs for stem cells:
We'll do a whole lecture on this later in the semester, but in the meantime, here's some highlights and links from the last few years:
- March 2004: Doug Melton: 17 new hES lines, privately funded
- April 2004: Harvard takes stem cells into the private realm: Harvard Stem Cell Institute
- August 2004: The UK OK's stem cells: Newcastle University
- Nov 2004: California Prop 71: $3B bond measure for CA stem-cell institute
- December 2005: National shame for Korea: (1) Cloning Creates Human Embryos (2004) *(2) Retracted December 2005; (3) May 2006: Cloning Scientist Is Indicted in South Korea
2006+: Very important Stem Cell / Genome Updates of the past year:
- 19 July 2006: Senate Approves a Stem Cell Bill; Veto Is Expected
- 19 July 2006: First Bush Veto Maintains Limits on Stem Cell Use
- 23 August 2006: Human Embryonic Stem Cell Lines Derived From Single Blastomeres
- 7 June 2007: Biologists Make Skin Cells Work Like Stem Cells = We will read this paper later in the semester.
- 13 June 2007: New Findings Challenge Established Views on Human Genome: The ENCODE Research Consortium Uncovers (shocking) Surprises about the human genome!
- 21 June 2007: Bush Vetoes Measure on Stem Cell Research (third veto of presidency)
2006+: Just a last few pretty genome covers to finish up:
26 October 2006
Sea Urchin Genome
10 November 2006
|The Opossum Genome
10 June 2007
The End (for now)
1.Identify Nobel-winning scientists and their research stated above. Why? because every self-respecting Biology major SHOULD!
2.Explain how the Cohen-Boyer partnership resulted in 'the birth of biotech' (aka Cloned beef to cloning), the role of Robert Swanson developing the biotechnology company Genentech
3.Explain the major results of the Cohen-Boyer 1974 PNAS paper. We will go over this paper in class Tuesday evening
4. What were the major recommendations of the 1974 paper "Potential Biohadards of Recombinant DNA molecules? What was the outcome of this manuscript?
5. What were the major conclusions from Asilomar conference and what are their significance in the use of recombinant DNA technology? Be able to discuss the the initial concerns and recommendations that surround this important event.
However, in later discussions, we will focus in on more specific objectives for all the rest of the topics: the Human Genome Project, Cloning Animals, Ag-Biotech, Stem Cells and Stem Cell legislation, Cloning Human Cells, etc.
You will want to keep returning to this timeline to help you study for those particular lectures. Do you have to know dates and the 'order' of particular events? NO, but I will give you essay exam questions that will ask you to recall and discuss specifics about the events, given the dates and historical context. More on this later!
Copyright Kathleen A. Marrs 1998-2009
(1) Nature, January 2003: The Birth of Biotechnology *(from 8/23 readings)
(2) PNAS, May 1974: [PDF] Replication and Transcription of Eukaryotic DNA in E. coli Cohen and Boyer (focus on Intro, Fig 2 and Discussion)
(3) PNAS, July 1974: [PDF]
Potential Biohazards of Recombinant DNA molecules
(4) PNAS, June 1975: [PDF] Summary Statement on the Asilomar Conference
(5) NY Times, 7 June 2007: Biologists Make Skin Cells Work Like Stem Cells
(6) ENCODE 13 June 2007New Findings Challenge Established Views on Human Genome
Optional but interesting:
1. From Corned Beef to Cloning (don't print out...!!! Short pages by Cohen and Boyer)
2. Asilomar and Recombinant DNA (particularly the very last section); by Paul Berg