Drawing the Human Blueprint : $3-Billion Project Could Bring Cures for Cancer, Diabetes

SAN DIEGO — When scientists first proposed a 15-year, $3-billion project to identify the 3 billion individual chemicals in the human genetic blueprint, critics scoffed.

The project was too big to accomplish in that period, it would cost much more than proposed and, most important, it would have to be conducted in large laboratories, thereby shutting out most biologists.

But now, three years later, scientists are speeding along in what has been termed the largest and most important project in the history of biology.

Researchers meeting here last week concluded that those early objections are being overcome. New technology is greatly speeding up the process by which the individual chemicals can be identified and is also lowering the cost.

Most heartening, that new technology is enabling even the solitary biologist to participate in the formidable project.

“The objective is, to say the least, heroic,” said Nobel laureate James D. Watson, of the National Institutes of Health in Bethesda, Md. “It’s to find out what being human is. Humans are the most exciting things we can learn about.”

Researchers believe that deciphering this blueprint, known as the human genome, will greatly speed up the search for the cause of genetic diseases and thereby the development of new therapies. As many as 4,000 diseases are caused by single genetic defects and many others, such as cancer, diabetes and alcoholism, are caused by many genes working together.

The results from the genome project “are sure to revolutionize the practice of medicine,” according to Charles Cantor of the Lawrence Berkeley Laboratory, who is head of the U.S. Department of Energy’s genome project. “We can’t think that every gene (identified) will lead to a cure,” said Watson, head of genome research at NIH, “but if we (identify) enough, some of them will lead to cures.”

The human genome is the full complement of genetic material in a human cell. It is “the complete set of instructions for making a human being,” said biochemist Robert Sinsheimer of UC Santa Barbara.

Genetic information is encoded in DNA, or deoxyribonucleic acid. DNA is organized into small units called genes, which are bundled into much larger units called chromosomes. Humans have about 100,000 genes in 23 pairs of chromosomes.

The uniqueness of individual humans is due to the uniqueness of each person’s set of genes. Surprisingly, differences among individuals are caused by quite small differences in their genes, and deciphering one person’s genes will tell researchers a great deal about every other person’s.

Like the Alphabet

DNA is composed of four distinct chemicals called bases. The 3 billion bases in the human genome are strung together like pearls on a necklace to form genes and chromosomes in the same fashion that letters of the alphabet are strung together to form words, sentences and books.

If the DNA in one human cell could be uncoiled and stretched out in a straight line, it would form a fragile thread more than 5 feet long and less than 50-trillionths of an inch across.

The ultimate goal of the Human Genome Initiative, as the project has now been dubbed, is to identify the position of each of the 3 billion bases, a process called sequencing. U.S. researchers hope eventually that other countries will join the project and contribute funds.

To date, research on identifying genes has been carried out in bits and pieces by small groups of biologists scattered over the landscape. Even so, there have been some exciting developments.

One recent success was the discovery of the cystic fibrosis gene, reported in August by geneticist Francis Collins of the University of Michigan and his colleagues.

But the cost and time--$120 million and 10 years--consumed by that project are typical problems in genetic research.

The Human Genome Initiative is viewed as a way to reduce overall costs of identifying and sequencing genes by developing new technology and by enabling researchers to work more efficiently.

The biologists involved in the project hope to find new, more effective ways to identify or create genetic markers as well as to locate the position of individual genes. Most important, however, they want to reduce the cost of sequencing.

Currently, said geneticist Raymond White of the University of Utah, it costs between $5 and $10 per base to sequence a gene, and a researcher can sequence perhaps 20,000 bases per year.

To achieve the goals of the Human Genome Initiative, it will be necessary to use new chemistry and automation to get that cost down to no more than 50 cents per base, and perhaps as low as a few cents per base, Watson said.

Complex Machines

Biologist Leroy E. Hood and his colleagues at Caltech have already developed robotic machines that can sequence 10,000 bases per day at a cost of less than $1 per base. He and other researchers, particularly at the Energy Department laboratories, are working on the development of more complex machines that could sequence as many as 1 million bases per day, a level many feel is necessary to achieve the goals of the initiative.

Critics of the Human Genome Initiative have feared that the project would be dominated by large laboratories and would dry up funding for conventional biology in the same way that the recently approved Superconducting Supercollider is projected to drain funds from physicists working on smaller projects.

This dichotomy between big and small science has been one of the most controversial aspects of the genome initiative, and one of the biggest sources of opposition. The 800 scientists at last week’s meeting were thus cheered by a new proposal that would enable small groups to play a much bigger role in the project.

The proposal would involve a fundamental shift in the way researchers handle DNA.

From the inception of the genome project, researchers have envisioned the creation of a massive “physical library” of the genome.

But the costs of maintaining the cultures needed for the library and sharing them among researchers would be prohibitive for small laboratories. Overall, it could cost as much as the $3-billion budget of the project.

But a group of four researchers led by Maynard Olson of Washington University has proposed a far simpler and cheaper expedient that they call sequence-tagged sites.

Under the proposal, each research group working with a specific fragment of DNA would sequence the first 200 or so bases and enter that information in a computerized database.

Information Available

Any researcher who wanted to look at that same fragment of DNA would get the information in the database and then synthesize a DNA fragment containing the first 20 bases, at a cost of perhaps $100. The researcher would then add this primer to his own sample of human DNA and, using a recently developed biochemical technique called polymerase chain reaction, produce the entire fragment.

The whole procedure, in addition to being cheap, would take only a day or two. And everybody’s results would be expressed in the same scientific terms. One of the difficulties in the past is that people were reporting their results on the locations of new genetic markers in different manners, Cantor said.

“We had a flood of data in different languages,” he said. “What this gives us is a common currency.”

For the last year NIH and Department of Energy have shared direction of the genome project, a collaboration that Cantor said has been running “very smoothly.”

NIH’s Watson plans to establish 20 genome centers around the country, and the first proposals for such centers are due in February.

The Energy Department is developing technology to automate the sequencing project and “grinding out maps and sequences,” Cantor said.

For the coming fiscal year, Congress is expected to give NIH $63 million for the genome project and Energy Department $27 million. That’s up from only $2 million two years ago.

Watson hopes the funding will rise to $200 million per year when the 15-year project officially starts on Oct. 1, 1990.

But funding by other countries is much smaller. “There is a fear in Congress that we will do all the work and give the knowledge away,” Watson said.

Most of the Research in U.S.

That fear may not be unfounded because, according to Johns Hopkins University geneticist Victor McKusick, at least 75% of the work on the genome is occurring in the United States.

U.S. officials are trying to pull other countries into the project, but if they don’t sign up, “there will be strong pressure” to keep the results from other countries, Watson said.

In a ringing conclusion to the meeting, Watson proclaimed: “I’m for peace, but if there will be war, I will fight it.”

Genetic Blueprint In the Human Genome Initiative, biologists hope to learn the identity of each of the 3 billion chemicals that make up the human genetic blueprint, known as the genome, in order to identify the causes of genetic diseases. Nucleus Each cell of the human body (except red blood cells) contains 23 pairs of chromosomes, each a packet of compressed and entwined deoxyribonucleic acid (DNA). Genes The 46 chromosomes contain about 100,000 short segments of DNA, called genes, that define all the characteristics of each human. The genetic information contained in each gene is encoded in the sequence of four repeating chemicals, called bases, in the same way that information in words is encoded in the sequence of letters. The four bases are called adenine (A), thymidine (T), cytosine (C), and guanine (G).