March 10, 2003 | FEW SCIENTISTS or commentators can summon the chutzpah to lecture on the topic of "What remains to be discovered" and get away with it. But Sir John Maddox, editor emeritus of Nature and author of a book of the same title, did just that in his closing address at the Miami Nature Biotechnology Winter Symposia last month. The meeting marked the 50^th jubilee of the discovery of the double helix, as well as the founding of the University of Miami School of Medicine.

While Nature's prestige was indubitably sealed by the famous 1953 publication of Watson and Crick's 900-word letter, Maddox consistently upheld the journal's lofty reputation during his two stints as editor, from 1966-1973 and 1980-1995, not only publishing a steady stream of cutting-edge research but also jumping enthusiastically into the trenches to tackle and/or exacerbate controversial issues such as the viral cause of AIDS, cold fusion, animal telepathy, and the alleged homeopathic memory of water. In an extraordinary episode known as the Benveniste affair, Maddox elected to publish results (under the heading "Hypothesis") purporting to show that water could retain the structural imprint of proteins. He then accompanied his friend, the Amazing Randi, to Paris to investigate and ultimately debunk the research.

John Maddox echoes the call for a new initiative in systems biology.

Despite the remarkable progress in DNA research, genetic engineering, and the genome project, Maddox maintains that many unresolved questions remain in molecular biology. The process of reading genes, or transcription, remains a puzzle: How does the DNA, so tightly packaged in chromosomes, disentangle itself to allow individual gene sequences to be read? How do the DNA motifs that constitute gene promoters and enhancers work at the chemical and genetic level? And why do some genes have to be edited in the nucleus — surely evolution should have discarded such an inefficient process by now? The stage is set for rapid advances in the field of evolution. "Darwin didn't tell us how species differ from each other, but geneticists now can."

In cell biology, Maddox marveled at the sophisticated 3-D pictures of complex molecular structures so commonly displayed at meetings, such as the nuclear pore complex and ribosomes (the sites of protein synthesis). The cellular machinery will be sorted out in the next 10 years, Maddox predicted, after which it will become boring. But what chemical principles govern protein function and complex formation? And how are molecular machines, composed of dozens of discrete proteins, actually assembled?

Maddox also echoed the call of Leroy Hood, who spoke earlier at the conference, for a new initiative in systems biology. "It's high time molecular biology became quantitative," Maddox said. "It cries out to a physicist — as I used to be — for modeling. Modeling isn't a crutch ... it's the opposite; it's a way of suggesting experiments to do, gaps in your understanding."


Malfunctions of the Mind 
Major questions remain unanswered in other areas, too. 2003 also happens to be the 50th anniversary of Stanley Miller's classic synthesis of organic compounds from rudimentary ingredients, but advances in explaining the origin of life since then have disappointed. The function of the brain remains a mystery — particularly the formation of memories, how the brain makes decisions, and the molecular underpinnings of consciousness.

Maddox spoke passionately against the curiously entrenched public acceptance of genetic determinism. One of the embarrassing oversimplifications of the genome era is the mistaken assumption that genes control all human traits, a list that might include avarice, bad temper, tardiness, the inability to get out of bed, and more. While most if not all disease genes for single-gene (monogenic) disorders such as cystic fibrosis have been identified, Maddox doubts that the public readily appreciates the polygenic nature of most common diseases, such as diabetes.

Trials and Frontiers

Bio·IT World will present two symposia at the Bio-ITWorld Conference & Expo in Boston (March 25-27). On the afternoon of March 25, please join us for either a session on e-clinical trials (hosted by Forrester Research analyst Michael Barrett) or a session exploring post-genomic frontiers. Both will feature five outstanding speakers, addressing two vital aspects of bio-IT. Details can be found at www.bioitworldexpo.com.

This is a concern, particularly as research into complex diseases, notably mental illness, starts to pay dividends. Maddox has helped the British mental health charity SANE build the Prince of Wales International Centre for SANE Research in Oxford, dedicated to schizophrenia and other malfunctions of the mind, which officially opened last month. One intriguing possibility under investigation is that schizophrenia may have arisen as a consequence of the evolution of language in humans, suggesting that genomic differences between humans and chimps might reveal a genetic culprit.

Musing on the perennial issue of nature versus nurture, Maddox implored researchers to pay more attention to the role of the environment in shaping behavior. His own family is a case in point. His wife, Brenda, the highly regarded biographer of Rosalind Franklin, is turning her attention from the dark lady of DNA to the iron lady of the U.K.: Margaret Thatcher. His daughter Bronwen is the foreign editor for The Times. And his son Bruno, the Harvard-educated former editor of the now defunct Spy magazine, is wrapping up his second book, a modest little number provisionally entitled TB2, said to be a sequel to The Bible.

Kevin Davies, Ph.D.
Editor-in-Chief
Bio·IT World