<b>September 15 2003</b> – A movie Superman and three laboratory Supermen have won the 2003 Lasker Awards for their various contributions to supporting biomedical research, eukaryotic RNA polymerase research, and work in rheumatoid arthritis therapy using anti&#8211;tumor necrosis factor (TNF).
Christopher Reeve, who played Superman in three films, will be given the Mary Woodard Lasker Award for Public Service in Support of Medical Research and the Health Sciences for his work bolstering public support of research into paralysis since a 1995 horseback riding accident left him quadriplegic. Reeve is the chair of the Christopher Reeve Paralysis Foundation, which is expected to spend $7.4 million in grants for neuroscience in 2003 and more than $600,000 in Quality of Life awards.
In a telephone interview with The Scientist, Reeve said he has tried to challenge the once-strong belief that spinal cord injuries are intractable and irreversible. "Beginning with that attitude of&#8230; denial and simply not wanting to be told why progress couldn't be made, over the years I've acquired some knowledge of the biology involved and the approaches being developed around the world," he said. "Now I'm even more hopeful based on awareness than I was based on ignorance."
Reeve has also tackled such charged issues as embryonic stem cell research, challenging lawmakers to consider the weight of their decisions. "I'm doing my best to keep politics and religion from having an undue influence over the progress of research," he said. "I believe that scientists can be held to ethical standards that are acceptable to society."
In the basic research category, Robert G. Roeder of Rockefeller University will receive the 2003 Albert Lasker Medical Research Award for studies that characterized the eukaryotic RNA polymerases and transcription factors opening gene expression study to biochemical analysis. Roeder came to the bench nearly 40 years ago, and, in his last months as a graduate student in William Rutter's University of Washington lab, his work paid off. In February 1969, Roeder finally solubilized polymerase from the chromatin to which it was bound and identified three distinct types of activity he dubbed I, II, and III. The finding, published later that year, "broke the logjam of the enzymatic participation in mammalian cell transcription," James Darnell, fellow Rockefeller researcher and 2002 Lasker laureate, told The Scientist.
Roeder subsequently characterized the actions of the three RNA polymerases (Pols): Pol I transcribes the bulk of ribosomal RNAs; Pol II transcribes premessenger RNAs; and Pol III transcribes transfer RNAs and some ribosomal RNA. But this only began to explain the forces that initiate transcription. Roeder went on to define the first gene-specific activator, TFIIIa, required for Pol III transcription of 5S genes, and to define various transcription factors and accessory proteins&#8212;some of the more than 40 polypeptides minimally needed for gene recognition of the transcription start site and RNA synthesis. Work from Roeder and others "has shown that what we thought we knew about transcription 25 years ago coming out of the simple systems with bacteria were just wholly inadequate to explain how transcription occurs in mammalian cells," said Darnell.
Roeder, now the Arnold and Mabel Beckman Professor at Rockefeller, continues to interrogate transcriptional initiation through biochemistry. He champions the biochemical approach, citing a recent study linking histone H2B transcription, a cell cycle&#8211;dependent phenomenon, to metabolic state. It was something, he told The Scientist, that could never have been discovered through genomics, proteomics, or even genetics. "The biochemical approach was really what launched this field," he said. "We still think it's going to be useful for mechanistic analysis."
In the clinical research category, Marc Feldmann and Ravinder N. Maini of the Kennedy Institute of Rheumatology at Imperial College London will receive the award for their codiscovery of anti-TNF therapy as an effective treatment for rheumatoid arthritis. Feldmann and Maini collaborated on the first clinical and commercial success of targeted therapy for the disease. The two won the Crafoord Prize in 2000.
Feldmann, who was born in Poland at the end of World War II but grew up in Australia, first studied medicine in Melbourne. He went on to pursue a PhD at the Walter and Eliza Hall Institute, he told The Scientist, because, he realized, "we didn't understand much about disease processes, disease mechanisms." Maini, a clinician, told The Scientist that he left a brief foray into cardiac investigation because, he said, "it was too mechanical." The two shared an interest in autoimmune disorders and began working together in the early 1980s. "Undoubtedly, it was something that clicked&#8230; We were able to share the challenges and the risks and have fun out of doing it," Maini said.
Maini also credits choosing a field and a molecule that produced many reassuring results. A 1989 study showed that blocking TNF-alpha using specific antibodies stopped interleukin-1 production. This study and others posited TNF-alpha as a cytokine "master regulator," refuting a common perception that there were simply too many proinflammatory cytokines involved in rheumatoid arthritis to make blockage practical.
Though it was considered a high-risk strategy, Maini and Feldmann pursued clinical trials using chimeric TNF antibodies in humans. Alone and in combination with other treatments, their studies showed success and helped spur approval of such drugs such as Remicade, Humira, and Enbrel, a soluble TNF receptor fusion protein. TNF-squelching drugs are expensive and require continued use, but the response rate is generally greater than 60%, and side effects such as&#8212;predictably&#8212;proneness to infection, are, said Feldmann, "more manageable than anyone had thought." Remicade, which Maini and Feldmann began working with in 1992, has recently also been approved to treat severe Crohn disease. "It's dramatically improved what we can offer to patients with rheumatoid arthritis," H. Ralph Schumacher, chief of rheumatology at the Veterans Affairs Medical Center in Philadelphia, told The Scientist.
Although anti-TNF therapies are effective for some autoimmune disorders, Maini, now retired as a principal investigator but still taking part in lab discussions, laments that the therapies are not a cure. "It doesn't restore the loss of homeostasis that has led to the disease in the first place," he said. Nevertheless, "it has set the stage for dissecting out other components of the inflammatory process," said Schumacher, who is also editor of the Journal of Clinical Rheumatology.
The four winners will be presented with a replica of the Winged Victory of Samothrace&#8212;the Lasker Foundation's symbol of victory over disability, disease, and death&#8212;at an awards ceremony on Friday, September 19, at New York City's Pierre Hotel. The clinical and basic science categories also carry a $50,000 prize, while the public service award carries no financial purse.
<b>Links for this article</b>
Christopher Reeve
http://www.christopherreeve.org/christopherreeve/christopherree vemain.cfm
"Superman"
http://us.imdb.com/title/tt0078346/
Christopher Reeve Paralysis Foundation
http://www.apacure.com/
Robert G. Roeder
http://www.rockefeller.edu/research/abstract.php?id=144
R.G. Roeder, W.J. Rutter, "Multiple forms of DNA-dependent RNA polymerase in eukaryotic organisms," Nature, 224:234-237, October 18, 1969.
A.M. Ginsberg et al., "Xenopus 5S gene transcription factor TFIIIA: characterization of a cDNA clone and measurement of RNA levels throughout development," Cell, 39:479-489, December 1984.
L. Zheng et al., "S Phase activation of the histone H2B promoter by OCA-S, a coactivator complex that contains GAPDH as a key component," Cell, 114:255-266, July 25, 2003.
Marc Feldmann
http://wwwfom.sk.med.ic.ac.uk/med/about/divisions/kennedy/peopl e/m.feldmann.html
Crafoord Prize 2000
http://www.hammersmithresearch.com/specialty/article.asp?Specia lty=Bones&art_id=68
F.M. Brennan et al., "Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis," Lancet, 2:244-247, July 29,1989.
H. Ralph Schumacher
http://www.med.upenn.edu/rheum/rheum_bio_schumacher.html
