Lasker Ceremony: Homage Amidst Angst

Shaken but not disheartened by events 10 days prior, some of the world's leading biomedical scientists gathered in New York, Sept. 21, to honor scientific achievement at the 2001 Lasker Awards ceremony. As James Fordyce, chairman of the Albert and Mary Lasker Foundation, welcomed attendees, he asked that they view the World Trade Center wreckage "as a reminder of the precious value of life" and that they "not be deterred" from the life-saving mission of research. Echoing these sentiments through the decorous Cotillion Room of the Pierre Hotel, ABC News co-anchor Dianne Sawyer offered, "Although the audacity of the skyscrapers has been obliterated, the audacity of the ability to soar has not." For the soaring ability of five men--three who developed arguably the most useful tool for studying human disease; one who launched a new era of infertility treatment; and another whose diligence stamped out smallpox and changed the face of public health policy--each received a $50,000 honorarium and an inscribed statue of Nike, the Winged Victory of Samothrace. Three Men and a Mouse The Albert Lasker Award for Basic Biomedical Research went to Mario Capecchi, Oliver Smithies, and Martin Evans, three researchers credited with creating the first knockout mouse. Capecchi, Howard Hughes Medical Institute investigator and distinguished professor of human genetics and biology at the University of Utah, found that some of the most efficient machinery for introducing a gene to a targeted site on a genome already existed within the cell. It was the machinery that aided homologous recombination of a single strand sequence into a cell's genome. "If [a cell] had that machinery," Capecchi tells The Scientist, "maybe we could fool it. If we gave it a piece of DNA, maybe we could fool it into thinking that's something it wanted to play with and exchange information with the crossover copy. Ten years later that [idea] worked." Numerous attempts at inserting a neomycin resistance sequence to disrupt the gene HPRT (which codes for hypoxanthine phosphoryibosyltrasferase) in a viable mouse finally resulted in success in 1987.1 With time Capecchi's lab developed a positive/negative selection process that greatly improved efficiency. He credits much of his success to the values ingrained in him by his former mentor at Harvard University, "I think using selection protocols was pretty much ground into me. That was when I was in [James] Watson's lab ... working with bacterial viruses and bacteria." During his acceptance speech Capecchi said of Watson, who was also in attendance, "He taught us not to bother with small questions, for such pursuits were likely to produce small answers." Smithies, an excellence professor in the department of pathology at the University of North Carolina, Chapel Hill, pegs the outcome of his scientific achievements to a childhood memory: helping his mother with the laundry. The image of the starch jellifying came back to him when he was trying to improve electrophoresis methods. He created a starch gel--a precursor, he says, of polyacrylamide. Some unexpected results of these early globin gene experiments led Smithies in search of homologous recombination. With a homemade electroporator built from a plastic tub and a test tube rack, Smithies found evidence that he could place a corrective copy of the gene for b-globin into the correct locus of mouse erythroleukemia cells in the order of about one in a million.2 "The idea was to repair a sickle cell globin gene, but the frequency was so low that it was pretty clear there was no use for that," Smithies says in an interview with The Scientist. Looking for a more selectable gene that was easier to work with, Smithies too, was drawn to the HPRT gene for the experiments that inevitably led to the creation of his transgenic mouse. While Smithies and Capecchi worked independently on a gene-targeting system, Evans, now head of Cardiff School of Biosciences and professor of mammalian genetics at Cardiff University, Wales, was working out the crucial final piece of the puzzle. Working with mouse embryonal carcinoma (EC) cells, Evans was drawn to their pluripotence, and their first step differentiation that so resembled the inner cell mass of a mouse embryo. From these early embryos, Evans was able to create living mice, but due to abnormal karyotypes, they were sterile. "There was a great possibility that if only we could get a normal cell with a normal chromosome complement, it could go through the germline," Evans says. In 1980, colleague Matt Kaufman, offered a line of haploid cells that had gone through specific delay steps in vivo. Kaufman first provided some normal diploid cells as controls, and when Evans cultured them he immediately saw all of the characteristics he had been looking for. Years of honing the media for EC cells paid off, and mouse embryonic stem cells that could pass their genetic code through the germline became a reality.3 Capecchi and Smithies heard about Evans' technique at a 1985 Gordon Conference. They contacted him independently and with his cells went on to create the first transgenic mice--Smithies correcting a defunct Hprt gene, and Capecchi knocking a working copy out. Since then more than 4,000 strains have been created using their methods. Two Men and a Baby For facilitating the birth of Louise Brown, the first test tube baby born in 1978, Robert G. Edwards, emeritus professor of human reproduction at the University of Cambridge, received the Albert Lasker Clinical Medical Research Award. Patience and perseverance of Edwards, and the now deceased Patrick Steptoe of Oldham Royal Hospital, enabled this historic event which Joseph Goldstein, chairman of the awards jury, lists with Darwin's The Origin of Species as a defining moment in the history of human society. This patience was not only tried by over 100 failed attempts at in vitro fertilization, but also by ridicule and scorn from pundits, ethicists, and colleagues. At the podium Edwards expressed regret that Steptoe, who had adopted the laparoscopy technique by which egg cells could be harvested, could not be there to share the platform; the Lasker Awards are not given posthumously. Edwards also offered his gratitude to the parents of Louise Brown, "who maintained their dignity and common sense throughout very trying times before and after Louise's birth." One Man and a Mission When working to eradicate smallpox in Africa, William Foege would have cohorts in small villages announce that the tallest man in the world was coming. He used the publicity to explain about vaccines and get the natives immunized. A giant in stature, and also in public health, Foege, presidential distinguished professor, department of International Health, Rollins School of Public Health at Emory University, received the Mary Woodard Lasker Award for Public Service. Under the directives of the Centers for Disease Control and Prevention (CDC), Foege developed a technique by which smallpox was eradicated ahead of schedule and under budget. As director of the CDC, Foege helped to discover that an alarming rash of toxic shock syndrome in young women was due to a tampon that served as a breeding ground for certain types of bacteria. He also stood strong against pharmaceutical companies when aspirin was identified as a risk factor of Reye's Syndrome in children. Since his time at the CDC, Foege has worked with the Carter Center and the United Nations Task Force for Child survival. He has combated River Blindness and other diseases, and he currently acts as senior medical advisor for the Global Health program of the Bill and Melinda Gates Foundation spearheading programs against what he calls, "the triad: AIDS, tuberculosis, and malaria." In his acceptance speech Foege spoke most poignantly of the ultimate directives of all science: to alleviate misery and torment. He expressed gratitude not for his recognition, but for the recognition of global health, what he calls "the sum total of science and the successful application of that science." He concluded, "For recognizing the coalitions that make it possible, from bench scientists to field workers, the millions working anonymously, the optimists in millions of communities: On their behalf, thank you very much." Brendan A. Maher can be contacted at bmaher@the-scientist.com. References 1. K.R. Thomas, M.R. Capecchi, "Site-directed mutagenesis by gene targeting in mouse embryo derived stem cells," Cell, 51[3]:503-12, 1987. 2. O. Smithies et al., "Insertion of DnA sequences into the human chromosomal b-globin locus by homologous recombination," Nature, 317:230-4. 1985. 3. M.J. Evans, M.H. Kaufman, "Establishment in culture of plurpotential cells from mouse embryos," Nature, 292:154-6, 1981.

Lasker Ceremony: Homage Amidst Angst

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