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Treating and Controlling HIV

By | February 2, 2004

Figure 1My colleagues and I had been working for a number of years to develop a novel therapeutic inhibitor of the HIV-1 protease enzyme. Eventually, a specific and potent inhibitor, indinavir, was developed and brought into Phase I trials in patients persistently infected with the virus. While sitting at home on a dreary, cold winter night in early 1994, I was staring at the figure that depicted the patient's plasma virus levels while on treatment. I was depressed by the observation that most p

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Painted Embryo

By | January 19, 2004

Courtesy of Walter GehringOn our chromosomal walk to clone the Antennapedia gene, Richard Garber and Atsushi Kuroiwa also cloned the segmentation gene fushi tarazu (ftz). Ernst Hafen and Michael Levine had concurrently developed an in situ hybridization method to tissue sections. Garber joined forces with Hafen to hybridize ftz recombinant DNA to wild-type embryos in order to localize the ftz+ transcripts. A few weeks later, I was seated at my desk when Hafen and Kuroiwa burst into my office and

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BLAST From the Past

By | December 15, 2003

Foundations | BLAST From the Past Courtesy of Warren Gish In late 1994, BLAST was fast, but it wasn't as sensitive as programs that produced gapped alignments, such as Bill Pearson's FASTA. To keep the statistics in sync with the new search algorithm, I conjectured that the statistics of Samuel Karlin and Stephen Altschul might be empirically applied to the interpretation of gapped alignment scores. By early 1995, Altschul at the NCBI [National Center for Biotechnology Information] h

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The Boron Connection

By | December 1, 2003

Foundations | The Boron Connection Click for larger version of measurements (35K) In 1999 we discovered LuxS, an enzyme needed for making a signal molecule (AI-2) that bacteria use for interspecies communication.1 X-ray crystallography allowed us to see that AI-2 is composed of two, five-membered rings. The challenge was to determine which atoms composed the rings. Our initial guess, a mixture of carbons and oxygens, appalled our chemist friends: we had drawn a carbon atom covalently

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DNA Damage Response

By | November 17, 2003

Foundations | DNA Damage Response Courtesy of Stephen J. Elledge In 1986, I was trying to identify a RecA-related protein in Saccharomyces cerevisiae whose abundance increased in response to DNA damage. I expected a recombinase but when I cloned the gene, it encoded ribonucleotide reductase, which cross-reacted with the antibody I used. I was initially depressed by these findings. However, I soon realized this meant that eukaryotes took great care to ensure that DNA replication was protect

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The Birth of the Southern Blot, 1975

By | November 3, 2003

Foundations | The Birth of the Southern Blot, 1975 Courtesy of Ed Southern Gels used for electrophoresis of nucleic acids and proteins are permeable. This obvious fact didn't dawn on me until I tried to dissolve some agarose by floating it on a solution of sodium perchlorate and noticed a bead of liquid form on the top. I reasoned that if DNA molecules were carried through with the flow it would be possible to capture them on a nitrocellulose membrane, using the setup shown in the sketch.

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Pauling, Meselson, and Socrates

By | October 20, 2003

Foundations | Pauling, Meselson, and Socrates The Ava Helen & Linus Pauling Papers, Courtesy of Oregon State University  Pauling sent this telegram to President Kennedy in 1962. Matthew Meselson anticipated a lecture that night in 1954 when he heard Linus Pauling's slippety-slap footfall outside the lab. Meselson, then a graduate student in Pauling's lab at Caltech, had neglected his lab duties to organize scientists against atmospheric nuclear testing. Instead of a dressing-down

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Dance of the Yeast Genome

By | October 6, 2003

Courtesy of University of California, San Francisco The science of yeast genetics was still in its infancy some 30 years ago, and one of its thorniest problems wouldn't go away: How do diploid yeast cells transform themselves into haploid cells, so that they can mate and reproduce through meiosis? A young University of Oregon researcher named Ira Herskowitz proposed that a cassette of DNA dropped out, only to be replaced by a copy of another cassette of DNA, and that this event altered the ve

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Biology's Renaissance Man

By | September 22, 2003

Foundations | Biology's Renaissance Man Courtesy of the College of Physicians of Philadelphia I don't cite papers that are more than one hundred years old, but Joseph Leidy's (1823-1891) name keeps coming up. Although he published more than 400 papers, he's not known today. That's mainly because he never made the sweeping generalizations that tend to make scientists famous. He was a paleontologist, botanist, zoologist, medical doctor, and anatomist. For us, though, his most important contr

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Little Green Bacteria

By | September 8, 2003

Foundations | Little Green Bacteria Click for larger version of notes (68K) When I first heard Paul Brehm [then at Tufts University] mention green fluorescent protein at a seminar in the late 1980s, I got excited; I knew it had the potential to be an expression marker. I talked with Doug Prasher, who was trying to isolate a gfp cDNA, and we promised to keep in touch. But we lost track of each other after I married and went to do my sabbatical at my wife's university. In September 1992, I

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