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The debate heats up over the Genome Project.

Biology's first megaproject is doing more than advancing human genetics. It's also transforming the NIH.

The Human Genome Project (HGP), the first biomedical megaproject ever undertaken, holds great promise for disease curing and prevention for future generations of humans. The goals of the 15-year, $3 billion effort--to map and sequence the human genome--are considered by many researchers as the cornerstone on which most future advances in medicine, biology, and biotechnology will be built.

With the genetic map, researchers expect to be able to find and repair defective genes in humans, to fight such insidious diseases as cystic fibrosis, Huntington's disease, and Alzheimer's. The project also could lead to the development of effective screening tests that can determine the genetic composition of a couple's still unborn child.

"This is the era of molecular medicine," says Thomas Caskey, director of the Institute for Molecular Genetics at the Baylor College of Medicine, Houston. "This is how we will be doing medicine in the future."

Walter Gilbert, a Harvard Univ. geneticist and a pioneer of DNA sequencing, believes the genome project is part of a "changing paradigm" of science that heralds a new age.

"The paradigm of molecular biology is that it was an experimental science," Gilbert said at the Human Genome II conference held in San Diego last October. "There still will be experimentation, but the way we do experiments will change dramatically."

But other prominent biological researchers say the HGP is nothing more than a pork-barrel project fueled by the clout of a small group of politically connected scientists. They say it's a bad idea for scientific and economic reasons.

"In the worse funding year in decades [for NIH] we see a proposal to disburse previously unheard of amounts of research funds to a handful of scientists," said Martin Rechsteiner, cochairman of the biochemistry department at Univ. of Utah, Salt Lake City, before a Senate subcommittee. "The HGP represents an unfair and unwise allocation of precious research funds."

"I feel we do not have adequate evidence that a sequenced-based approach [to the human genome] justifies a crash program," adds Bernard Davis of the Harvard Medical School, Cambridge, MA.

At the core of the criticism is the fact that HGP overrides the normal National Institutes of Health (NIH) grant allocation system. The RO1 system of investigator-initiated proposals and open peer review is a system that many NIH-supported researchers hold dear.

HGP instead relies on a closed group of administrators (within the Dept. of Energy and the NIH, which oversee the project) who will dole out large sums of money to small groups of researchers for the purpose of setting up genome centers. It's big science infiltrating a system that has historically favored small science.

RO1 grants are typically for about $200,000. With genome centers, four of which already have been established by the NIH, the funding amounts are in the millions.

"The centers tend to politicize the scientific endeavor because they come in units [large enough] for politicians to become really interested in them," says Rechsteiner, a harsh critic of the program. "That is dangerous in terms of credible scientific progress."

Some 60% of NIH's research money is disbursed as research project grants, making it politics free, says Donald Brown of the Carnegie Institution, Washington, DC. "Compare that with any other organization, USDA, DOE, or any other agency. How much of their funds are free of politics?"

What frightens Harvard's Davis, who has felt the scorn of Sen. Pete Domenici (R-NM), the genome project's biggest congressional supporter, is the fact that a group of scientists have taken to lobbying for the project.

"This is a very strong effort of the sort that no other area of biomedical research is putting forward," Davis says. "It creates a sense of unfairness that will persist in having one group of scientists using political pressure to advance the support of their area that is out of proportion to the rest of the biomedical sciences."

But supporters of the project, which officially began this past October 1, wonder why there is such a big stink being raised over 1% of NIH's budget.

"Using 1% or 2% of the budget is not going to affect the quality of the RO1s (investigator-initiated grants)," said James Watson, director of NIH's portion of HGP, during a press conference at the Genome II conference last October. "They want it to sound like we are trying to shut down the [NIH] budget. We aren't trying to shut down anything."

The genome project's centralized and targeted structure, says Tony Carrano, director of a DOE genome center at Lawrence Livermore (CA) National Laboratory, "is a much more cost effective way to identify and map genes than the RO1 funding mechanism.

"For independent and creative research the RO1 mechanism is extremely good," Carrano adds. "But when you are dealing with specific goals and milestones, you have to have everybody working toward a common goal, and the way to do that is to centralize its funding."

The genome project's two primary goals are to map and then sequence the human genome. To accomplish these goals the project is drawing from NIH-supported scientists and researchers from DOE labs.

This odd set-up, the pairing of the big centralized science at DOE with the freethinking and more creative approaches by NIH, is the product of the genome project's history.

Today's genome project actually grew out of DOE's insistence on using genetics as a way to make the link between the effects of radiation exposure and causes of disease.

"It is a pork barrel project," Rechsteiner charges. "Few will deny that it has its origins in New Mexico with a powerful senator [Domenici] and Los Alamos lab."

In FY91 NIH has been given $85 million for the genome project, DOE $48 million.

Proponents and most critics agree that the mapping portion of the project is a worthwhile scientific endeavor. The technology for mapping the genome is at hand.

A map will provide the diagrams that depict the order and spacing of genes relative to one another on any of the 24 chromosomes. Genetic linkage maps will provide rough approximations of gene locations by determining how frequently certain traits are inherited. Physical maps will convey location more precisely by showing the actual distance between genes.

The ultimate physical map of the genome, however, is its nucleotide sequence. This sequence will look much like rows of the letters A, T, C, and G (for andenine, thymine, cytosine, and guanine), the four basic nucleotides of DNA.

But within a molecule there are long stretches of DNA whose function is unknown. This "junk DNA" constitutes from 95% to 98% of the total genome. To many scientists it is genetic gibberish. But others believe that the spacing between regions of interest could be the way genes regulate their activity. Not knowing the importance of the junk DNA regions made early proponents of the project push for sequencing the entire genome from A to Z.

Mapping without sequencing the genome, Watson said, "is like saying 'I will marry you with no sex.'"

"Mapping will show us all of the genes we know and will show us where the genes are," says Glen Evans, an associate professor at Salk Institute, La Jolla, CA. "But the sequence will give us the information necessary to make a human being. We may not know how to interpret all of it, but even if we interpret a small percentage of it, it will revolutionize the way science is done."

But the critics don't agree.

"The real goal [ought to be] understanding the genome," says Harvard's Davis. "Not sequencing it per se, not recording it like 77 sets of Encyclopaedia Britannica."

"I don't object to finding and exploring genes that cause major diseases," says Utah's Rechsteiner. "But there are more medically important things to do [than sequencing the entire human genome]."

The current plan for HGP is to spend the first five to eight years mapping the genome and developing better technology. At that point, the project's progress will be evaluated.

The sequencing portion of the project will begin with regions of chromosomes known to hold clues to diseases. But even sequencing the interesting regions will require advances in technology.

With some three-billion base pairs of information hidden within the body's 100 trillion cells (excluding red blood cells), decoding the DNA molecules will take a Herculean effort. It also will require technical advances in cloning, sample preparation, sequencing chemistries, automation and robotics, and computers.

For sequencing, researchers will have to break down and analyze large portions of the base pairs. New techniques have been devised to isolate and analyze DNA segments.

Gene cloning, for example, enable scientists to isolate specific pieces of DNA and make numerous copies of them, thus producing the large quantities needed to study gene structure and function. Through a number of methods clones can be realigned in the order in which they originally occurred in the chromosomes, resulting in a map of DNA segments. Scientists can then learn the relative location of the DNA segments that they are studying.

"The promise to deliver the total sequence is based on the presumption that we will improve our methods by at least a factor of 10," says Lawrence Berkeley Lab's Charles Cantor, director of the DOE side of the project. "The cheaper sequencing becomes, the faster it will be done."

The current going rate for sequencing is about $1.50 a base pair. Genome administrators hope technological improvements will get sequencing costs down to 15 cents to 50 cents a base pair.

Researchers working on sequencing spend much of their time performing routine tasks necessary for obtaining original DNA clones containing the gene of interest, subcloning, and handling the DNA prior to sequencing reactions. In addition, significant time and expense are devoted to gel electrophoresis and analysis.

One promising method for simplifying these tasks is polymerase chain reaction (PCR) technology, which amplifies single segments of DNA. PCR, pioneered at Cetus Corp., Emeryville, CA, could provide preparation of vector segments of 10,000 to 100,000 base pairs, compared to the current rates of 300 to 500 base pairs.

The method could help to alleviate much of the sample preparation for sequencing. Because PCR would be able to handle much larger vectors, researchers would be able to link them up quickly, facilitating labeling, and rapidly providing materials for sequencing.

"PCR will allow you to make large clones without ever having biological clones," says Norton Zinder a professor of molecular genetics at Rockefeller Univ., New York City, and the chairman of the genome advisory committee to NIH. "Long-distance PCR would be one type of technological breakthrough that would give you a long adjunct to many areas of the study, to mapping, to connecting things together, to checking for clones, for closing over regions."

Newer techniques being explored include fluorescent-based sequencing. Applied Biosystems Inc., Foster City, CA, and Pharmacia, a Swedish-based company, are developing systems in this area.

The fluorescent-based devices can provide a resolution that allows reading of tracks up to 500 base pairs and 24 lanes simultaneously. A single overnight run can produce a 10,000 base sequence, says Carrano. But the cost is high, roughly $1 to $1.50 per base pair.

DOE researchers are exploring more exotic technologies which, if successful, could revolutionize sequencing.

At Brookhaven National Laboratory, Upton, NY, William Studier and John Dunn are working on a statistical method that could simplify determining the sequence of the nucleotide components of DNA. At Livermore lab, researchers are using scanning tunneling microscopy to image strands of DNA. Los Alamos researchers are working on a method called flow cytometry, which uses laser beams and fluorescence to read bases one at a time as they are clipped off the end of a long DNA chain.

These technologies are at least five years away, and each has its own problems. In the meantime, the project will require armies of post-doctoral students to perform the actual mapping and sequencing of the genome.

This brute-force approach to sequencing has raised questions as to whether it will turn off more young investigators to the project than it will turn them on to it.

"It is hard to see how this huge amount of repetitious work is going to provide good training of future scientists," says Harvard's Davis.

"All science is boring drudgery," says Salk's Evans. "Sure you'll dread having to sequence some huge map, but I have each post-doc mapping some region that includes something they want to find. There is a pot of gold at the end of the rainbow."

"Initial reaction by young researchers was negative because they dreaded it," says Kay Davies, a Medical Research Council Fellow at John Radcliffe Hospital, Oxford, England. "But now they can see how fast the field is moving, how much more quickly we can do things. This is an exciting phase in human biology."

But Rechsteiner, who with Michael Syvanen of the Univ. of California, Davis, has mounted a letter writing campaign asking that the project be killed, says HGP sends the wrong signal to young researchers.

"The NIH grabs a bunch of money from DOE and they give it to eight to 12 researchers, at the same time thousands of young scientists are starving for research funds," he says. "It is the next generation of scientists who are getting squeezed."

"They say the project is too complex and to do it rapidly and competently you have to target funding," adds Brown. "My argument is it could have been included in the [RO1] system and the two could have strengthened each other."
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Title Annotation:includes related article; Special Report; Human Genome Project
Author:Derra, Skip
Publication:R & D
Date:May 1, 1991
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