MAPPING THE HUMAN GENOME:

Imagine that you are trying to solve a jigsaw puzzle. If you can put all the pieces of the puzzle together, you will understand many of the mysteries of the human body.

There's only one hitch. this puzzle has quite a few pieces. Over three billion, to be precise.

By the year 2006, microbiologists hope to master just such a puzzle--that of the human genome.

The human genome consists of all the hereditary information of human beings. This information exists in long chains of amino acids known as DNA sequences. Scientists are currently attempting to sequence the entire human genome, in the $3 billion Human Genome Project.

Already, researchers have identified a significant portion of genes on the genome. Earlier this month, scientists at the National Institutes of Health (NIH) reported that they had found one in twenty such genes.

One use of this data will be the diagnosis of disease through the genetic analysis of blood samples. Geneticists will also obtain a wealth of information about how humans function and how they have evolved.

And Harvard's science departments, from biology to virology, are playing an important role in the project's daily discoveries.

The project is a worldwide effort to analyze the structure of DNA, the chemical component of genes, and to determine the exact location of genes in humans and many other model organisms. Scientists are attempting to create a physical and genetic map of the chromosomes of the various organisms.

The last time the federal government funded a scientific undertaking of this magnitude was the Apollo project.

One aim of the project is to form a computer database containing the genetic sequences that have been discovered. This will make the information accessible over computer networks around the world.

"Genetic sequences have been emerging around the world and scientists thought that it would be useful to have an organized base of genetic knowledge," says Loeb University Professor Walter Gilbert, whose lab represents a large portion of Harvard's genome project efforts.

Gilbert says that geneticists hope to learn a great deal about the human body not only for the advancement of medicine, but also for purely scientific purposes.

Scientists are sequencing genes in order to understand the structure of the proteins they encode, he says.

Genes determine most biological phenomena and are key in learning how the body works.

"By elucidating and putting together the 100,000 genes of the human body, we can discover how the body itself functions," Gilbert says.

"Medicine is dominated by the realization that aspects of the human condition are determined by the genes people have," he says. Genetic irregularities can be found at the root of most diseases, including genetic diseases, diabetes, and heart disease, Gilbert says.

Gilbert's lab was one of the first sequencing centers in the country, for his pioneering work, he was awarded the 1980 Nobel Prize in Chemistry.

"Gilbert and I were at the early meetings before the project was started," says Assistant Professor of Genetics George M. Church, who is also involved in the project.

Both scientists received grants to conduct research in the project early on, he says.

The project is jointly funded by NIH, through the National Center for Human Genome Research, and by the Department of Energy. Contributions to the project have also been made by other countries such as England and Italy.

The current research initiative, begun last year, will proceed through three five-year plans until 2006.

The U.S. government is spending approximately $120 million per year on the project.

An NIH report stated, "The information generated by the human genome project is expected to be the source book for biomedical science in the 21st century and will be of immense benefit to the field of medicine."

Gilbert says, however, that although curing and preventing disease is the crux of medicine, scientists have other motivations to experiment in biology.

"We are interested in how living things work and how we work," he says. "The project is also creating a developmental research tool which can be used in the next century to understand biology."

The NIH report also described the project as trying to develop new technology for biological and biomedical research.

New Techniques

Gilbert heads a lab of scientists and technicians who are sequencing the genetic material of Micoplasma capricolum, a small species of bacteria.

This organism's genome consists of approximately one million base pairs of DNA. The bacteria is one of a group of "Model organisms" which are being sequenced along with the human genome to discover new techniques of DNA analysis as well as to acquire knowledge about the organism itself.

Gilbert's lab is working out the sequence for the bacterium and performing computer analyses to identify the genes.

"We have set up a production line, which is a sequence center that makes the process simpler so it can be done on a large fast scale," Gilbert says.

According to Church, chromosomes cannot be analyzed under a microscope or in any simple chemical fashion, but only through the use of specific genetic and biochemical techniques.

Scientists begin to map and sequence genes by amplifying a subset of a particular chromosome, Church says. They then use biochemical methods to divide the subset into smaller fragments, he says.

Technicians map the genes using specific genetic markers such as DNA polymorphisms, which are hereditary traits that have more than one form in humans. They also sequence the amplified DNA by converting it into chemical information specifying the nucleotide bases in the molecule.

Church says that the goals of the genome project are realizable due to great advances in technology.

"The genome project grew out of the realization that there was new technology that could be applied to human disease in different ways than science was able to apply it before," Church says.

Molecular biology procedures have been scaled up and a number of breakthroughs have facilitated the work of all genetic researchers, he says.

"These developments have brought down the cost of the project for the whole community," Church says.

Church's lab focuses on DNA sequencing and automation, using computer analysis of the sequences, he says.

The scientist sequences the genomes of a number of different organisms for the sake of developing new technologies.

"My personal ambitions are to help produce technology to sequence faster and more accurately," he says.

Gilbert and Church say that genetic sequencing will have profound implications for all of science.

"DNA sequencing is not an end, but a means, for so many fields," Church says. "This is an underlying enabling technique and relatively few modern technologies affect so many fields."

Gilbert says the project is part of a movement in science towards an increasingly genetic view of many different biological phenomena--a view which has come under fire in the past from many scientists who do not wish to deemphasize the role environment plays in hereditary determination.

Another by-product of the the project, says Church, is that its wide-reaching nature has mobilized people from many different fields.

Controversy Over Funding

The human genome project has recently been the focus of controversy among microbiologists because of funding changes it may have caused in the field of genetic experimentation.

Some point out that the amount of money now being spent on sequencing all human genes might be more productively spent on researching genes for specific diseases.

Lewis M. Kunkel, professor of genetics in the Medical School's Department of Pediatrics, says he does not approve of the shift in funding priorities.

"This project is directing funds away from disease-oriented research," Kunkel says.

Kunkel's lab cloned the Duschene gene which has been linked to muscular dystrophy, a genetic disease which causes muscles to waste away.

"I don't for the fun of it clone big blocks of DNA. I look for and try to understand specific regions that cause disease," Kunkel says. "I'm targeting a particular part of the genome that might be therapeutically treated in certain individuals."

But Church insists that the proposal has not changed funding policies or wasted money.

"The fact is, we were already spending similar amounts of money on similar activities before the project started," he says.

Scientists should not simply concentrate on sequencing genes for specific diseases, though such findings may seem to give immediate utility to the project, Church says.

"If unknown DNA is mixed in finely with gems, you don't avoid the gems because you don't want the junk," he says.

"Instead you make it cost effective to sequence everything."

Gilbert says that the project grew out of the accumulation of specific sequenced disease genes.

"Scientists know they are going to want all of the genetic sequences sooner or later, so why not do it all at once?" Gilbert says.

The project is a simpler and more efficient way to map genes than concentrating exclusively on specific disease genes, he says.

Professor of Biology Fotis C. Kafatos says he believes both broad global projects and investigator-initiated projects are both important to biological science.

"Biologists [should be] pushing to expand support of science, rather than arguing about shifts of support from this to that," Kafatos says.

Ethics

NIH and the Department of Energy have also jointly formed the Working Group on the Ethical Legal and Social Implications of Human Genome Research to examine ethical issues related to the project.

The committee has focused its discussions on quality of and access to genetic tests, privacy issues involving genetic testing and public and professional education, according to an NIH report.

"This is one of the first big science projects in which ethical considerations were given a lot of attention before it began," Church says.

He says that most ethical issues the committee must confront have come up before in other biological research.

Also, the majority of the project's results will be helpful, and therefore less subject to criticism, Church says.

The benefits to a person of knowing he or she has hypercholesterolemia, a hereditary inability to remove cholesterol from the body, for instance, will far outweigh the chances that it will hurt his or her jobs opportunities if an employer finds out, he says.

Gilbert says that with the knowledge obtained by the project, the U.S. will be forced to move towards much tighter privacy laws.

"At one level, one wants to know about one's own genes and how they affect physical development," Gilbert says.

But, he points out, it may not be desirable for others to know about one's genetic makeup.

"There is a constant battle between the right of the individual human that should be valued, against problems of classification," Gilbert says.

Patenting Gene Sequences

The NIH has filed patent applications for partial gene sequences that have been found, according to a statement by James D. Watson, director of the National Center for Human Genome Research and the director of the Cold Spring Harbor Laboratory in Cold Spring Harbor, New York.

Watson, who won the Nobel Prize in Medicine in 1962 for the discovery of the double helix structure of DNA, says the patenting of sequences has become mired in controversy.

"The issues and implications surrounding patenting partial gene sequences are numerous and complex," Watson says. "I am sympathetic to the views expressed to me by the many members of the scientific community who believe patenting partial gene sequences may not be in the best interest of scientific or economic progress."

Gilbert says the patenting of sequences does not affect science.

"Patenting gives one control over a discovery for eventual commercial use," he says. "Patenting inventions is a good idea, but these sequences don't have great value as inventions."