Final Draft
Here it is. I pooped out in the end. There's so much more I could have said regarding Craig Venter, who started shit talking the Human Genome Project in the same issue of science as he published the first bacterial genome. He's arguably as big a character as Watson, but damn it, I've been here all night. I'm calling this thing done and handing it in.
Mary Paniscus - Classics Essay
My field is bacterial comparative genomics. My aim is to decipher biological function from genetic information contained within DNA, the genetic material. Comparative genomics is made possible by basic knowledge on the structure of and function of DNA and the development of sequencing technologies and bioinformatics tools for the construction and analysis of whole genome sequences.
Molecular Structure of Nucleic Acids
James Watson and Francis Crick’s famous discovery of the structure of DNA occupies one modest page in the April 25th, 1953 edition of Science. 1 The authors respectfully point out famous physicist Linus Pauling’s three stranded model of DNA would not be possible with DNA in aqueous solution2 and propose a radically different model. They correctly describe DNA as a double helix containing antiparallel strands of nucleotides bound to the sugar moiety of an alternating sugar-phosphate backbone, and note the bases occupy the inside of the double helix and hydrogen-bond such that A-T and C-G form complementary pairs. The article ends with the speculative quote “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material”.
As a rule, advances in genomic science have been greeted with extreme enthusiasm.3 Watson and Crick’s discovery was recognized as revolutionary very soon after the publication of “Molecular Structure of Nucleic Acids”. Biological advances dominated Science News Letter’s 1953 Science Review which proclaimed the “quiet work of scientists on the innermost structure of living material could very well rank with the great scientific discoveries of all time” and identifies the work as fundamental to “disease conquests of the future”.4 Drs. James Watson, Francis Crick and Maurice Wilkins received the 1962 Nobel Prize in Physiology or Medicine, less than ten years after the elucidation of the structure of DNA. The 1962 Science News Letter press release praises their work with the usual (and still largely unrealized) promises of medical salvation through genetic knowledge and manipulation, positing “the day when man will be able to correct and compensate for genetic deficiencies implicated in killing and crippling diseases.”5
Controversy surrounds the discovery of the structure of DNA, not because of the science behind it, but because of the events surrounding the discovery including Watson’s bestselling tell-all memoir “The Double Helix: A Personal Account of the Discovery of the Structure of DNA”. The book begins with the striking first sentence, “I have never seen Francis Crick in a modest mood” and goes rapidly downhill in an unflattering characterization of the author’s partner in research. Watson originally named the work “Honest Jim”. Indeed, he spoke as candidly about the marital problems, digestive habits, and style of kissing of his colleagues as he did regarding the unethical manner with which he’d acquired Rosalind Franklin’s work and used it without her knowledge to confirm and instruct his efforts in solving the structure of DNA. 6
Soon after the memoir was published, Edwin Chargaff, of Chargaff’s Rule, wrote a scathing review of “The Double Helix”. Chargaff emphasizes the “vulgar” nature of the work writing “habitual readers of gossip columns will like the book immensely” and criticizes Watson for publicizing highly personal details of his colleague’s lives. Much of Chargaff’s review was devoted to criticizing Watson’s attitudes toward Rosalind Franklin which he pointedly implies are socially and psychologically pathological.7
James Watson is widely known for indelicate and often offensive verbal expression. 7-12 His colorful wikipedia article contains a nice summary of offensive things he's said on a variety of topics.10 If they don’t make you cringe, you’ve probably got what he has. Watson's famous quoted suppositions on race and intelligence earned him a suspension as the director of Cold Spring Harbor in 2007. His retirement followed shortly thereafter.
Basic Local Alignment Search Tool
DNA was found to contain a code that dictates the amino acid sequences which fold to become proteins, the molecular machines of life. As sequence data accumulated, the biochemical relatedness of all life became an obvious fact. Biostatisticians proved it possible to align and compare two different sequences and conclude with extreme confidence whether they were related or not.13
Progressive alignment algorithms, the ancestral sequence comparison tools, perform exhaustive calculations to determine the best answer to any particular alignment problem. Later, heuristic methods were developed to overcome limitations of computation speed associated with the search of large sequence databases. Heuristic algorithms do not examine all possible solutions, and thus make no claims to producing the best possible sequence comparison. Therefore instead of perfect solutions, one receives solutions not significantly different from perfect, in much faster time.13
Basic Local Alignment Search Tool (BLAST) made rapid, high quality sequence comparison widely available to the scientific community. It was not the first heuristic algorithm, but it was an order of magnitude more efficient than previous tools.14 BLAST’s influence and popularity is most obviously demonstrated by Altschul et al’s “Basic Local Alignment Search Tool” being the most cited scientific paper in the 90’s with over 10,000 citations.15
Virtually all readers of bioinformatics literature will recognize the name of accidental first author Stephen Altshul, who received the honor by virtue of alphabetical precedence. BLAST was the brainchild of last author David Lipman, the Director of the National Center for Biotechnology Information (NCBI) since 1989. Lipman is a trained physician with no drama in his wikipedia entry and obviously leads a distinguished career.16
Almost twenty years later, BLAST remains a cornerstone tool of bioinformaticians. “BLAST”, like “google”, has become a verb with ubiquitous usage. Molecular biologists and biochemists now routinely identify and examine homologs of genes of interest as a source of functional insight. Since we DNA-based life are remarkably similar metabolically, it’s possible to make a strong guess on the function of genes based on knowledge of another version of that gene in another organism. Virtually all genome annotation relies on the putative commutation of function implied by similarity of a novel sequence to that of another species’ characterized homolog. BLAST continues to be the tool of choice in the identification of such orthologs.13
Whole Genome Random Sequencing and Assembly of Haemophilus influenxae Rd
The first whole genome sequence of a free living organism was completed by a team led by Dr. J Craig Venter. The genome paper on Haemophilus influenxae Rd is a classic, not simply because it gave us the first naked view of a cell’s master blueprint, but because it drove the development of information technology that made it possible to sequence whole bacterial genomes much faster and cheaper than possible previously.17
Sequencing reactions may only capture fragments of the genome. Fragments are necessarily pieced together for determination of the continuous sequence. Different methods were devised over time. At first, genome sequencing used the primer-walking method wherein the genome is sequenced systematically from end to end. Primers for successive fragments of sequence are chosen from the end of the last sequence, until the entire chromosome has been “walked”.
The shotgun method was represented the next innovation in sequencing technology. The method’s name is a direct reference to its approach. Entire viral genomes were fragmented and sequenced randomly. Overlaps in the sequences of fragments allowed the knitting together of these random sequences into entire viral genomes. Bacteria however, have much larger genomes. The assembly problem becomes orders of magnitude worse.17 The NIH chose not to fund Venter’s proposed whole genome shotgun of bacteria as unfeasible. After receiving private sector funding, Venter’s group did indeed prove whole genome shotgun a rapid and effective sequencing method for bacteria. The feat was applauded with Science’s News & Comment title “Bacterial Genome Sequence Bagged”. Whole genome random sequencing methods coupled with powerful assembly algorithms remain the standard for Bacterial Genome Sequencing.
Notes and Citations:
1. J.D. Watson and F. H. C Crick. “Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid”. Nature. Volume 171, Issue 4356, 25 April 1953, pp. 737-738.
2. Pauling’s model assumed the DNA’s phosphate’s hydroxyl groups were hydrogen bonding with each other. Water makes this situation impossible since it would ionize the hydrogens right off those hydroxyls and with them the dipoles making hydrogen bonding possible.
3. Rachel Nowak. “Bacterial Genome Sequence Bagged”. Science. Volume 269, Issue 5223, 28 July 1995, pp. 468-470.
4. “1953 Science Review”. The Science News-Letter, Volume 64, Issue 25, 19 December 1953, p. 391.
5. “Nobel Prize Winners”. The Science News-Letter, Volume 82, Issue 17, 27 October 1962, p. 267
6. The Double Helix. A Personal Account of the Discovery of the Structure of DNA by James D. Watson. Publisher: Atheneum; First Edition edition (January 1, 1968)
7. Erwin Chargaff. “A Quick Climb Up Mount Olympus”. Science. Volume 159, Issue 3822, 29 March 1968, pp. 1448-1449.
8. This last April 6th, I received a humorous happy birthday message which told me, amongst other notable events of that day in history, I shared the same birthday as “geneticist and professional asshole James Watson”. The sender was not a biologist.
9. As I wrote this essay, another researcher, unbidden, expressed her distaste of Watson. She cited his self-portrayal as a skirt chaser in The Double Helix and his attitude toward women in general.
10. James D. Watson. (2009, November 10). In Wikipedia, The Free Encyclopedia. Retrieved 14:21, November 12, 2009, from http://en.wikipedia.org/w/index.php?title=James_D._Watson&oldid=325126352
11. Magdelene So, PhD. Personal communication.
12. S. Mitchell Harman MD, PhD. Personal communication.
13. Bioinformatics: Sequence and Genome Analysis by David W. Mount. Publisher: Cold Spring Harbor Laboratory; 2nd edition (July 2004)
14. Stephen F. Altschul, Warren Gish, Webb Miller, Eugene W. Myers, David J. Lipman. 1990. “Basic Local Alignment Search Tool”. Journal of Molecular Biology. Volume 215, Issue 3, 5 October 1990, pp. 403-410.
15. “Sense from Sequences: Stephen F. Altschul on Bettering BLAST”. Science Watch, July/August 2000, Vol. 11, No. 4
Citing URL: http://www.sciencewatch.com/july-aug2000/sw_july-aug2000_page3.htm
16. David J. Lipman. (2008, September 7). In Wikipedia, The Free Encyclopedia. Retrieved 14:25, November 12, 2009, from http://en.wikipedia.org/w/index.php?title=David_J._Lipman&oldid=236818956
17. Fleischmann, Robert D.; Adams, Mark D.; White, Owen; Clayton, Rebecca; . . . Venter, J. Craig. Whole Genome Random Sequencing and Assembly of Haemophilus influenxae Rd. 1995. Science. Volume 269, Issue 5223, 28 July1995, pp. 496-512.
Mary Paniscus - Classics Essay
My field is bacterial comparative genomics. My aim is to decipher biological function from genetic information contained within DNA, the genetic material. Comparative genomics is made possible by basic knowledge on the structure of and function of DNA and the development of sequencing technologies and bioinformatics tools for the construction and analysis of whole genome sequences.
Molecular Structure of Nucleic Acids
James Watson and Francis Crick’s famous discovery of the structure of DNA occupies one modest page in the April 25th, 1953 edition of Science. 1 The authors respectfully point out famous physicist Linus Pauling’s three stranded model of DNA would not be possible with DNA in aqueous solution2 and propose a radically different model. They correctly describe DNA as a double helix containing antiparallel strands of nucleotides bound to the sugar moiety of an alternating sugar-phosphate backbone, and note the bases occupy the inside of the double helix and hydrogen-bond such that A-T and C-G form complementary pairs. The article ends with the speculative quote “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material”.
As a rule, advances in genomic science have been greeted with extreme enthusiasm.3 Watson and Crick’s discovery was recognized as revolutionary very soon after the publication of “Molecular Structure of Nucleic Acids”. Biological advances dominated Science News Letter’s 1953 Science Review which proclaimed the “quiet work of scientists on the innermost structure of living material could very well rank with the great scientific discoveries of all time” and identifies the work as fundamental to “disease conquests of the future”.4 Drs. James Watson, Francis Crick and Maurice Wilkins received the 1962 Nobel Prize in Physiology or Medicine, less than ten years after the elucidation of the structure of DNA. The 1962 Science News Letter press release praises their work with the usual (and still largely unrealized) promises of medical salvation through genetic knowledge and manipulation, positing “the day when man will be able to correct and compensate for genetic deficiencies implicated in killing and crippling diseases.”5
Controversy surrounds the discovery of the structure of DNA, not because of the science behind it, but because of the events surrounding the discovery including Watson’s bestselling tell-all memoir “The Double Helix: A Personal Account of the Discovery of the Structure of DNA”. The book begins with the striking first sentence, “I have never seen Francis Crick in a modest mood” and goes rapidly downhill in an unflattering characterization of the author’s partner in research. Watson originally named the work “Honest Jim”. Indeed, he spoke as candidly about the marital problems, digestive habits, and style of kissing of his colleagues as he did regarding the unethical manner with which he’d acquired Rosalind Franklin’s work and used it without her knowledge to confirm and instruct his efforts in solving the structure of DNA. 6
Soon after the memoir was published, Edwin Chargaff, of Chargaff’s Rule, wrote a scathing review of “The Double Helix”. Chargaff emphasizes the “vulgar” nature of the work writing “habitual readers of gossip columns will like the book immensely” and criticizes Watson for publicizing highly personal details of his colleague’s lives. Much of Chargaff’s review was devoted to criticizing Watson’s attitudes toward Rosalind Franklin which he pointedly implies are socially and psychologically pathological.7
James Watson is widely known for indelicate and often offensive verbal expression. 7-12 His colorful wikipedia article contains a nice summary of offensive things he's said on a variety of topics.10 If they don’t make you cringe, you’ve probably got what he has. Watson's famous quoted suppositions on race and intelligence earned him a suspension as the director of Cold Spring Harbor in 2007. His retirement followed shortly thereafter.
Basic Local Alignment Search Tool
DNA was found to contain a code that dictates the amino acid sequences which fold to become proteins, the molecular machines of life. As sequence data accumulated, the biochemical relatedness of all life became an obvious fact. Biostatisticians proved it possible to align and compare two different sequences and conclude with extreme confidence whether they were related or not.13
Progressive alignment algorithms, the ancestral sequence comparison tools, perform exhaustive calculations to determine the best answer to any particular alignment problem. Later, heuristic methods were developed to overcome limitations of computation speed associated with the search of large sequence databases. Heuristic algorithms do not examine all possible solutions, and thus make no claims to producing the best possible sequence comparison. Therefore instead of perfect solutions, one receives solutions not significantly different from perfect, in much faster time.13
Basic Local Alignment Search Tool (BLAST) made rapid, high quality sequence comparison widely available to the scientific community. It was not the first heuristic algorithm, but it was an order of magnitude more efficient than previous tools.14 BLAST’s influence and popularity is most obviously demonstrated by Altschul et al’s “Basic Local Alignment Search Tool” being the most cited scientific paper in the 90’s with over 10,000 citations.15
Virtually all readers of bioinformatics literature will recognize the name of accidental first author Stephen Altshul, who received the honor by virtue of alphabetical precedence. BLAST was the brainchild of last author David Lipman, the Director of the National Center for Biotechnology Information (NCBI) since 1989. Lipman is a trained physician with no drama in his wikipedia entry and obviously leads a distinguished career.16
Almost twenty years later, BLAST remains a cornerstone tool of bioinformaticians. “BLAST”, like “google”, has become a verb with ubiquitous usage. Molecular biologists and biochemists now routinely identify and examine homologs of genes of interest as a source of functional insight. Since we DNA-based life are remarkably similar metabolically, it’s possible to make a strong guess on the function of genes based on knowledge of another version of that gene in another organism. Virtually all genome annotation relies on the putative commutation of function implied by similarity of a novel sequence to that of another species’ characterized homolog. BLAST continues to be the tool of choice in the identification of such orthologs.13
Whole Genome Random Sequencing and Assembly of Haemophilus influenxae Rd
The first whole genome sequence of a free living organism was completed by a team led by Dr. J Craig Venter. The genome paper on Haemophilus influenxae Rd is a classic, not simply because it gave us the first naked view of a cell’s master blueprint, but because it drove the development of information technology that made it possible to sequence whole bacterial genomes much faster and cheaper than possible previously.17
Sequencing reactions may only capture fragments of the genome. Fragments are necessarily pieced together for determination of the continuous sequence. Different methods were devised over time. At first, genome sequencing used the primer-walking method wherein the genome is sequenced systematically from end to end. Primers for successive fragments of sequence are chosen from the end of the last sequence, until the entire chromosome has been “walked”.
The shotgun method was represented the next innovation in sequencing technology. The method’s name is a direct reference to its approach. Entire viral genomes were fragmented and sequenced randomly. Overlaps in the sequences of fragments allowed the knitting together of these random sequences into entire viral genomes. Bacteria however, have much larger genomes. The assembly problem becomes orders of magnitude worse.17 The NIH chose not to fund Venter’s proposed whole genome shotgun of bacteria as unfeasible. After receiving private sector funding, Venter’s group did indeed prove whole genome shotgun a rapid and effective sequencing method for bacteria. The feat was applauded with Science’s News & Comment title “Bacterial Genome Sequence Bagged”. Whole genome random sequencing methods coupled with powerful assembly algorithms remain the standard for Bacterial Genome Sequencing.
Notes and Citations:
1. J.D. Watson and F. H. C Crick. “Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid”. Nature. Volume 171, Issue 4356, 25 April 1953, pp. 737-738.
2. Pauling’s model assumed the DNA’s phosphate’s hydroxyl groups were hydrogen bonding with each other. Water makes this situation impossible since it would ionize the hydrogens right off those hydroxyls and with them the dipoles making hydrogen bonding possible.
3. Rachel Nowak. “Bacterial Genome Sequence Bagged”. Science. Volume 269, Issue 5223, 28 July 1995, pp. 468-470.
4. “1953 Science Review”. The Science News-Letter, Volume 64, Issue 25, 19 December 1953, p. 391.
5. “Nobel Prize Winners”. The Science News-Letter, Volume 82, Issue 17, 27 October 1962, p. 267
6. The Double Helix. A Personal Account of the Discovery of the Structure of DNA by James D. Watson. Publisher: Atheneum; First Edition edition (January 1, 1968)
7. Erwin Chargaff. “A Quick Climb Up Mount Olympus”. Science. Volume 159, Issue 3822, 29 March 1968, pp. 1448-1449.
8. This last April 6th, I received a humorous happy birthday message which told me, amongst other notable events of that day in history, I shared the same birthday as “geneticist and professional asshole James Watson”. The sender was not a biologist.
9. As I wrote this essay, another researcher, unbidden, expressed her distaste of Watson. She cited his self-portrayal as a skirt chaser in The Double Helix and his attitude toward women in general.
10. James D. Watson. (2009, November 10). In Wikipedia, The Free Encyclopedia. Retrieved 14:21, November 12, 2009, from http://en.wikipedia.org/w/index.php?title=James_D._Watson&oldid=325126352
11. Magdelene So, PhD. Personal communication.
12. S. Mitchell Harman MD, PhD. Personal communication.
13. Bioinformatics: Sequence and Genome Analysis by David W. Mount. Publisher: Cold Spring Harbor Laboratory; 2nd edition (July 2004)
14. Stephen F. Altschul, Warren Gish, Webb Miller, Eugene W. Myers, David J. Lipman. 1990. “Basic Local Alignment Search Tool”. Journal of Molecular Biology. Volume 215, Issue 3, 5 October 1990, pp. 403-410.
15. “Sense from Sequences: Stephen F. Altschul on Bettering BLAST”. Science Watch, July/August 2000, Vol. 11, No. 4
Citing URL: http://www.sciencewatch.com/july-aug2000/sw_july-aug2000_page3.htm
16. David J. Lipman. (2008, September 7). In Wikipedia, The Free Encyclopedia. Retrieved 14:25, November 12, 2009, from http://en.wikipedia.org/w/index.php?title=David_J._Lipman&oldid=236818956
17. Fleischmann, Robert D.; Adams, Mark D.; White, Owen; Clayton, Rebecca; . . . Venter, J. Craig. Whole Genome Random Sequencing and Assembly of Haemophilus influenxae Rd. 1995. Science. Volume 269, Issue 5223, 28 July1995, pp. 496-512.