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EXPLORING HUMAN GENETIC DESTINY
REVIEWED BY STEPHEN K. RITTER
Global chaos is the central theme of many novels and motion pictures in the techno-thriller genre. Science has to play a major supporting role in such works so that the hero, against unbelievable odds, can save the world for the good of humankind. For the most part, though, the details of the hard science involved are passed over for a hand-waving treatment so that most people can follow along and the action doesn't slow to a crawl.
In "Ninth Day of Creation," a first novel by physicist Leonard Crane, the author forgoes the hand waving and lets the science deliver a solid performance without compromising the story. Crane, a specialist in quantum optics, earned his Ph.D. in 1993 from the University of Queensland, in Australia. He later was a postdoc at California Institute of Technology and now works at Random Mouse Software, a small Web software development firm in Pasadena, Calif.
Crane takes an intriguing look at what possibly could happen after a researcher announces out of the blue that he has developed a cure for AIDS. Many scientists have spent the past two decades looking for an effective way to combat HIV, the virus that causes AIDS. It's been a daunting challenge, mainly because of HIV's ability to mutate and thus sidestep drugs that have been developed thus far to slow its progression.
Defeating HIV and AIDS has more recently taken a backseat in most people's minds because of the moderate success of the current suite of drugs. But some thought-provoking facts still remain: 36 million people worldwide are now infected with HIV, and 22 million people have already died from AIDS or HIV-related illnesses [The Sciences, 41, No. 1, 20 (2001)]. And still there is no cure for AIDS, let alone the elusive goal researchers are really after: an AIDS vaccine, which by some researchers' estimates is still a decade or more away.
In the novel, young research biochemist Richard Kirby stands up at a World Health Organization (WHO) conference and announces an AIDS cure. Kirby works at a small San Diego biotech company that mainly produces vaccines for the U.S. military. His ultimate goal, like real-life researchers, is to develop a vaccine to prevent AIDS, but in the meantime he has made an antiviral drug that cures AIDS. The early part of the book brings out piecemeal the details about the new drug, Triphylactin.
Chemists will be pleasantly surprised by Crane's unabashed use of the words "chemist" and "chemistry" to describe much of the science. And a nice aspect of the book is Crane's intermittent sections where he takes the time--either in the narrative or through his characters--to explain the basic science behind a technique or method. He describes the polymerase chain reaction and gel electrophoresis, for example, as well as how one can use a virtual reality protein-folding computer program to visualize structure and hence reactivity. The book even includes a few graphs, figures, and molecular stereoviews of proteins critical to the story.
For nonscientists, the explanatory forays, although generally well written, might make for slow reading. To compensate, Crane livens up the action by having Kirby's announcement at the WHO conference be a trigger for a series of world events that quickly cascade into the aforementioned global chaos.
Myriad plot lines ensue, among them repercussions from an earlier ecological disaster, an ongoing political refugee problem, car chases, kidnappings, assassination attempts, helicopter chases, industrial espionage, murders, and a riveting naval battle. And of course, in the penultimate moment before all hell breaks loose, calm is restored by the actions of Kirby and his colleagues.
The kicker that spurs the chaos is Kirby's discovery of secret research at his own company to develop synthetic viruses based on human genome information--research dubbed virotechnology. The viruses would be invisible to the human immune system and could deliver a synthetic or natural gene where desired for essentially any purpose. Although such viruses could be used in many positive ways, one target of the secret research is sinister: development of a synthetic flulike virus for the Army that could be used covertly and selectively against an indigenous population.
The science that underpins "Ninth Day" is part of Crane's goal to bring realism to the page. And the research developments he writes about all seem plausible. To portray science well in a fictional setting, Crane says, an author probably needs to be a trained scientist. His book includes insights gleaned from discussions with researchers and from the scientific and technical literature, with a list of references as an appendix.
Crane hopes "Ninth Day" will be an incentive for closet scientist-writers to have a go at a novel. He warns, though, that the two years it took him to write the book were "very difficult."
Crane's attention to scientific detail shows. In his WHO talk, for example, Kirby points out the trouble with the current antienzyme approach to combat HIV. "It's a problem in structural chemistry," Kirby says. "Usually we design these drugs to have a particular shape that allows them to glom directly onto the enzymes and 'glue up the works.' But by making small modifications at the level of the gene, a virus can effect relatively large structural changes in the enzymes it codes for. Large enough changes to render our drugs useless."
Currently, the first line of defense for HIV infection is usually a drug to inhibit reverse transcriptase, an enzyme HIV uses to convert its single-stranded RNA into double-stranded DNA, which is then incorporated into the genome of a host cell to begin the cycle of infection. The drug is often coupled with a second one that inhibits protease, a scissorslike enzyme that works inside infected cells to cut up strands of genetic material used by the established virus to replicate itself.
About a dozen companies currently market a few dozen HIV drugs or drug combinations. The antienzyme drugs have had some success in slowing down the progression of HIV/AIDS, but none of them is free from sometimes debilitating side effects and none so far is completely effective because of mutating strains of HIV.
Kirby goes on in his talk to explain that structural chemistry can only "take us so far." What's needed are drugs that work at the level of the gene, not the protein, he says. "Instead of structural chemistry, what we ought to be dealing with is the informational chemistry of HIV. We should be designing drugs that recognize the viral gene sequences directly, and not the products of host gene sequences, as we have been doing."
Kirby's Triphylactin works directly on the gene coding for an enzyme to stop the enzyme from being built in the first place. To achieve this, Kirby had to design a set of man-made bases that could be incorporated into a third strand of material that could bind to DNA to form a triple helix. His artificial bases--designated L and O--combine with the natural bases cytosine (C) and thymine (T) to produce a four-letter alphabet called CLOT in recognition of what it does. Strands of synthetic DNA made from these four bases can wrap around any selected gene sequence.
The resulting drug doesn't rely on a single molecular interaction, as enzyme inhibitors do, that can be foiled by a mutating HIV strain. Instead, it contains artificial genelike segments that are programmed to home in on and wrap around the corresponding HIV gene sequences. "For HIV," Crane writes, "Triphylactin literally presents the virus with a molecular straightjacket against which even mutation provides no hope of defense."
In many ways, "Ninth Day of Creation" is a cross between the novels of Tom Clancy and Michael Crichton, with a bit of Ian Fleming thrown in. A bonus for scientists is that the book combines nearly every conceivable element of science into the plot: basic and applied research, collegiality, conflicts among workers in a lab, and the ethical bounds of research. The latter is particularly prescient because of current concerns about the consequences of sequencing the human genome. Although this accomplishment has opened a door for many medical advances, there will always be concern that humankind is incapable of controlling the dark side of its "genetic destiny."
The book's minor drawbacks are that the writing is unseasoned in some sections and its editing is patchy in others. Furthermore, the plot sequences, although entertaining, are true to the techno-thriller genre and gradually become more and more unbelievable.
To his credit, Crane instills in his characters the enthusiasm that most scientists have for their research: They relish the glow of advancing the boundaries of science. Crane also does a good job conveying the excitement of an audience upon hearing news of a major scientific breakthrough that may have ramifications for many other research problems.
The book captures well the reality that science today is often politically and certainly financially motivated. It also carries the subtle message that no matter how altruistic an individual scientist's ideas might be, that scientist could easily find himself, as Kirby does, wrapped up in events well beyond his own imaginings.
"Ninth Day of Creation" is an ambitious work, it's very well thought out, and it has something for most everyone to like about it. Crane's book is one of what will certainly be many science-in-fiction novels that focus on the consequences of sequencing the human genome. For chemists, it's a good place to start. *
Stephen K. Ritter is a Washington, D.C.-based senior editor at C&EN.
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