TIME: Almanac 1993/TIME Almanac 1993.iso/time/032089/03208900.005

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                                                                                SCIENCE, Page 62

COVER STORIES

The Gene Hunt


Scientists launch a $3 billion project to map the chromosomes
and decipher the complete instructions for making a human being

By LEON JAROFF


    Know then thyself...the glory, jest, and riddle of the
world.
--Alexander Pope

    In an obscure corner of the National Institutes of Health
(NIH), molecular biologist Norton Zinder strode to a 30-ft.-long
oval conference table, sat down and rapped his gavel for order.
A hush settled over the Human Genome Advisory Committee, an
unlikely assemblage of computer experts, biologists, ethicists,
industry scientists and engineers. "Today we begin," chairman
Zinder declared. "We are initiating an unending study of human
biology. Whatever it's going to be, it will be an adventure, a
priceless endeavor. And when it's done, someone else will sit
down and say, `It's time to begin.' "

    With these words, spoken in January, Zinder formally
launched a monumental effort that could rival in scope both the
Manhattan Project, which created the A-bomb, and the Apollo
moon-landing program -- and may exceed them in importance. The
goal: to map the human genome and spell out for the world the
entire message hidden in its chemical code.

    Genome? The word evokes a blank stare from most Americans,
whose taxes will largely support the project's estimated $3
billion cost. Explains biochemist Robert Sinsheimer of the
University of California at Santa Barbara: "The human genome is
the complete set of instructions for making a human being."
Those instructions are tucked into the nucleus of each of the
human body's 100 trillion cells* and written in the language of
deoxyribonucleic acid, the fabled DNA molecule.

    In the 35 years since James Watson and Francis Crick first
discerned the complex structure of DNA, scientists have managed
to decipher only a tiny fraction of the human genome. But they
have high hopes that with new, automated techniques and a huge
coordinated effort, the genome project can reach its goal in 15
years.

    The achievement of that goal would launch a new era in
medicine. James Wyngaarden, director of the NIH, which will
oversee the project, predicts that it will make "major
contributions to understanding growth, development and human
health, and open new avenues for therapy." Full translation of
the genetic message would enable medical researchers to identify
the causes of thousands of still mysterious inherited disorders,
both physical and behavioral.


    With this insight, scientists could more accurately predict
an individual's vulnerability to such obviously genetic diseases
as cystic fibrosis and could eventually develop new drugs to
treat or even prevent them. The same would be true for more
common disorders like heart disease and cancer, which at the
very least have large genetic components. Better knowledge of
the genome could speed development of gene therapy -- the actual
alteration of instructions in the human genome to eliminate
genetic defects.

    The NIH and the Food and Drug Administration have already
taken a dramatic step toward gene therapy. In January they gave
approval to Dr. W. French Anderson and Dr. Steven Rosenberg,
both at the NIH, to transplant a bacterial gene into cancer
patients. While this gene is intended only to make it easier for
doctors to monitor an experimental cancer treatment and will not
benefit the patients, its successful implantation should help
pave the way for actual gene therapy.

    The very thought of being able to read the entire genetic
message, and perhaps alter it, is alarming to those who fear
the knowledge could create many moral and ethical problems.
Does genetic testing constitute an invasion of privacy, for
example, and could it lead to more abortions and to
discrimination against the "genetically unfit"? Should someone
destined to be stricken with a deadly genetic disease be told
about his fate, especially if no cure is yet available? Does it
demean humans to have the very essence of their lives reduced
to strings of letters in a computer data bank? Should gene
therapy be used only for treating disease, or also for
"improving" a person's genetic legacy?

    Although scientists share many of these concerns, the
concept of deciphering the human genome sends most of them into
paroxysms of rapture. "It's the Holy Grail of biology," says
Harvard biologist and Nobel laureate Walter Gilbert. "This
information will usher in the Golden Age of molecular medicine,"
says Mark Pearson, Du Pont's director of molecular biology.
Predicts George Cahill, a vice president at the Howard Hughes
Medical Institute: "It's going to tell us everything. Evolution,
disease, everything will be based on what's in that magnificent
tape called DNA."

    That kind of enthusiasm is infectious. In an era of
budgetary restraint, Washington has been unblinkingly generous
toward the genome project, especially since last April, when an
array of scientists testified on the subject at a congressional
committee hearing. There, Nobel laureate Watson of DNA fame,
since picked by the NIH to head the effort, mesmerized listeners
with his plea for support: "I see an extraordinary potential for
human betterment ahead of us. We can have at our disposal the
ultimate tool for understanding ourselves at the molecular level
. . . The time to act is now."

    Congress rose to the challenge. It promptly allocated more
than $31 million for genome research to the NIH and to the
Department of Energy and the National Library of Medicine, which
are also involved in the quest. The combined appropriations rose
to $53 million for fiscal 1989.

    Even more will be needed when the effort is in full swing,
involving hundreds of scientists, dozens of Government,
university and private laboratories, and several computer and
data centers. With contributions from other Government agencies
and private organizations like the Hughes institute, the total
annual cost of the project will probably rise to $200 million,
which over 15 years will account for the $3 billion price tag.

    The staggering expense and sheer size of the genome project
were what bothered scientists most when the idea was first
broached in 1985 by Sinsheimer, then chancellor of the
University of California at Santa Cruz. "I thought Bob
Sinsheimer was crazy," recalls Leroy Hood, a biologist at the
California Institute of Technology. "It seemed to me to be a
very big science project with marginal value to the science
community."

    Nobel laureate David Baltimore, director of M.I.T.'s
Whitehead Institute, was one of the many who feared that such
a megaproject would have much the same impact on biology that
the shuttle had on the U.S. space program: soaking up so much
money and talent that smaller but vital projects would dry up.
Others stressed that the technology to do the job in a
reasonable time was not available. But by 1986 some opponents
realized they were fighting a losing battle. "The idea is
gaining momentum. I shiver at the thought," said Baltimore then.
Now, however, he approves of the way the project has evolved and
has thrown his weight behind it.

    What really turned the tide was a February 1988 report by
the prestigious National Research Council enthusiastically
endorsing a project that would first map and interpret important
regions of the genome, then -- as better technology became
available -- proceed to reading the entire genetic message. Most
of the remaining critics were silenced last fall when the NIH
chose the respected Watson as project director. Still, some
scientists remain wary of the project. Says David Botstein, a
vice president at Genentech and a member of the Human Genome
Advisory Committee: "We need to test its progress, regulate its
growth and slap it down if it becomes a monster. Jim Watson
understands the dangers as well as any of us."

    The concern, as well as the cost, reflects the complexity
of the human genome and the magnitude of the effort required to
understand it. DNA is found in the human-cell nucleus in the
form of 46 separate threads, each coiled into a packet called
a chromosome. Unraveled and tied together, these threads would
form a fragile string more than 5 ft. long but only 50
trillionths of an inch across.

    And what a wondrous string it is. As Watson and Crick
discovered in 1953, DNA consists of a double helix, resembling
a twisted ladder with sidepieces made of sugar and phosphates
and closely spaced connecting rungs. Each rung is called a base
pair because it consists of a pair of complementary chemicals
called nitrogenous bases, attached end to end, either adenine
(A) joined to thymine (T) or cytosine (C) attached to guanine
(G).

    Fundamental to the genius of DNA is the fact that A and T
are mutually attractive, as are C and G. Consequently, when DNA
separates during cell division, coming apart at the middle of
each rung like a zipper opening, an exposed T half-rung on one
side of the ladder will always attract an A floating freely in
the cell. The corresponding A half-rung on the other section of
the ladder will attract a floating T, and so on, until two
double helixes, each identical to the original DNA molecule, are
formed.

    Even more remarkable, each of the four bases represents a
letter in the genetic code. The three-letter "words" they
spell, reading in sequence along either side of the ladder, are
instructions to the cell on how to assemble amino acids into
the proteins essential to the structure and life of its host.
Each complete DNA "sentence" is a gene, a discrete segment of
the DNA string responsible for ordering the production of a
specific protein.

    Reading these genetic words and deciphering their meaning
is apparently a snap for the clever machinery of a cell. But for
mere scientists it is a formidable and time-consuming task. For
instance, a snippet of DNA might read ACGGTAGAT, a message that
researchers can decipher rather easily. It codes for a sequence
of three of the 20 varieties of amino acids that constitute the
building blocks of proteins. But the entire genome of even the
simplest organism dwarfs that snippet. The genetic blueprint of
the lowly E. coli bacterium, for one, is more than 4.5 million
base pairs long. For a microscopic yeast plant, the length is
15 million units. And in a human being, the genetic message is
some 3 billion letters long.

    Like cartographers mapping the ancient world, scientists
over the past three decades have been laboriously charting human
DNA. Of the estimated 100,000-odd genes that populate the
genome, just 4,550 have been identified. And only 1,500 of those
have been roughly located on the various chromosomes. The
message of the genes has been equally difficult to come by. Most
genes consist of between 10,000 and 150,000 code letters, and
only a few genes have been completely deciphered. Long segments
of the genome, like the vast uncharted regions of early maps,
remain terra incognita.

    To complicate matters, between the segments of DNA that
represent genes are endless stretches of code letters that seem
to spell out only genetic gibberish. Geneticists once thought
most of the unintelligible stuff was "junk DNA" -- useless
sequences of code letters that accidentally developed during
evolution and were not discarded. That concept has changed. "My
feeling is there's a lot of very useful information buried in
the sequence," says Nobel laureate Paul Berg of Stanford
University. "Some of it we will know how to interpret; some we
know is going to be gibberish."

    In fact, some of the nongene regions on the genome have
already been identified as instructions necessary for DNA to
replicate itself during cell division. Their message is
obviously detailed and complex. Explains George Bell, head of
genome studies at Los Alamos National Laboratory: "It's as if
you had a rope that was maybe 2 in. in diameter and 32,000 miles
long, all neatly arranged inside a structure the size of a
superdome. When the appropriate signal comes, you have to unwind
the rope, which consists of two strands, and copy each strand
so you end up with two new ropes that again have to fold up. The
machinery to do that cannot be trivial."


    One of the most formidable tasks faced by geneticists is to
learn the nature of that machinery and other genetic
instructions buried in the lengthy, still undeciphered base
sequences. To do so fully requires achievement of the project's
most challenging goal: the "sequencing" of the entire human
genome. In other words, the identification and listing in order
of all the genome's 3 billion base pairs.

    That effort, says Caltech research fellow Richard Wilson,
"is analogous to going around and shaking hands with everyone
on earth." The resulting string of code letters, according to
the 1988 National Research Council report urging adoption of the
genome project, would fill a million-page book. Even then, much
of the message would be obscure. To decipher it, researchers
would need more powerful computer systems to roam the length of
the genome, seeking out meaningful patterns and relationships.

    It was from the patterns and relationships of pea plants
that a concept of heredity first arose in the mind of Gregor
Mendel, an Austrian monk. In 1865, after studying the flower
colors and other characteristics of many generations of pea
plants, Mendel formulated the laws of heredity and suggested the
existence of packets of genetic information, which became known
as genes. Soon afterward, chromosomes were observed in the
nuclei of dividing cells, and scientists later discovered a
chromosomal difference between the sexes. One chromosome, which
they named Y, was found in human males' cells, together with
another, called X. Females' cells, on the other hand, had two
copies of X.

    But it was not until 1911 that a gene, only a theoretical
entity at the time, was correctly assigned to a particular
chromosome. After studying the pedigrees of several large
families with many color-blind members (males are primarily
affected), Columbia University scientist E.B. Wilson applied
Mendelian logic and proved that the trait was carried on the X
chromosome. In the same manner over the next few decades,
several genes responsible for such gender-linked diseases as
hemophilia were assigned to the X chromosome and a few others
attributed to the Y.

    Scientists remained uncertain about the exact number of
human chromosomes until 1956, when improved photomicrographs of
dividing cells clearly established that there were 46. This
revelation led directly to identification of the cause of Down
syndrome (a single extra copy of chromosome 21) and other
disorders that result from distinctly visible errors in the
number or shape of certain chromosomes.

    But greater challenges lay ahead. How could a particular
gene be assigned to any of the nonsex chromosomes? Scientists
cleverly tackled that problem by fusing human cells with mouse
cells, then growing hybrid mouse-human cells in the laboratory.
As the hybrid cells divided again and again, they gradually shed
their human chromosomes until only one -- or simply a fragment
of one -- was left in the nucleus of each cell.

    By identifying the kind of human protein each of these
hybrid cells produced, the researchers could deduce that the
gene responsible for that protein resided in the surviving
chromosome. Using this method, they assigned hundreds of genes
to specific chromosomes.

    Finding the location of a gene on a chromosome is even more
complicated. But over the past several years, scientists have
managed to draw rough maps of all the chromosomes. They
determine the approximate site of the genes, including many
associated with hereditary diseases, by studying patterns of
inheritance in families and chopping up their DNA strands for
analysis. With this technique, they have tracked down the gene
for cystic fibrosis in the midsection of chromosome 7, the gene
for a rare form of colon cancer midway along the long arm of
chromosome 5, and the one for familial Alzheimer's disease on
the long arm of chromosome 21.

    One of the more dramatic hunts for a disease gene was led
by Nancy Wexler, a neuropsychologist at Columbia University and
president of the Hereditary Disease Foundation. Wexler was
highly motivated; her mother died of Huntington's disease, a
debilitating and painful disorder that usually strikes adults
between the ages of 35 and 45 and is invariably fatal. This
meant that Wexler had a 50% chance of inheriting the gene from
her mother and contracting the disease.

    In a search coordinated by Wexler's foundation, geneticist
James Gusella of Massachusetts General Hospital discovered a
particular piece of DNA, called a genetic marker, that seemed
to be present in people suffering from Huntington's disease.
His evidence suggested that the marker must be near the
Huntington's disease gene on the same chromosome, but he needed
a larger sample to confirm his findings. This was provided by
Wexler, who had previously traveled to Venezuela to chart the
family tree of a clan of some 5,000 people, all of them
descendants of a woman who died of Huntington's disease a
century ago. Working with DNA samples from affected family
members, Gusella and Wexler in 1983 concluded that they had
indeed found a Huntington's marker, which was located near one
end of chromosome 4.

    That paved the way for a Huntington's gene test, which is
now available. The actual gene has not yet been isolated and
since there is no cure at present, many people at risk for
Huntington's are reluctant to take it. "Before the test," Wexler
says, "you can always say, `Well, it can't happen to me.' After
the test, if it is positive, you can't say that anymore." Has
Wexler, 43, taken the test? "People need to have some privacy,"
she answers.

    Tracking down the location of a gene requires tedious
analysis. But it is sheer adventure when compared with the task
of determining the sequence of base pairs in a DNA chain. Small
groups of scientists, working literally by hand, have spent
years simply trying to sequence a single gene. This hands-on
method of sequencing costs as much as a dollar per base pair,
and deciphering the entire genome by this method might take
centuries.

    The solution is automation. "It will improve accuracy,"
says Stanford's Paul Berg. "It will remove boredom; it will
accomplish what we want in the end." The drive for automation
has already begun; a machine designed by Caltech biologist Leroy
Hood can now sequence 16,000 base pairs a day. But Hood, a
member of the Genome Advisory Committee, is hardly satisfied.
"Before we can seriously take on the genome initiative," he
says, "we will want to do 100,000 to a million a day." The cost,
he hopes, will eventually drop to a penny per base pair.

    Hood is not alone in his quest for automation. That is also
the goal of Columbia University biochemist Charles Cantor,
recently appointed by the Energy Department to head one of its
two genome centers. "It's largely an engineering project,"
Cantor explains, intended to produce tools for faster, less
expensive sequencing and to develop data bases and computer
programs to scan the data. Not to be outdone, Japan has set up
a consortium of four high-tech companies to establish an
automated assembly line, complete with robots, that researchers
hope will be capable of sequencing 100,000 base pairs a day
within three years.

    Is there a better way? In San Francisco in January, Energy
Department scientists displayed a photograph of a DNA strand
magnified a million times by a scanning tunneling microscope.
It was the first direct image of the molecule. If sharper images
can be made, the scientists suggested, it may be possible to
read the genetic code directly. But that day seems very far off.

    Even before the Human Genome Project was begun by the NIH,
others were deeply involved in probing the genome. Building on
a long-standing program of research on DNA damage caused by
radiation, biologist Charles DeLisi in 1987 persuaded the
Energy Department to launch its own genome program. In addition
to the sequencer and computer-hardware engineering projects,
Energy Department scientists are focusing their attention on
mapping seven complete chromosomes.

    Victor McKusick, a geneticist at Johns Hopkins University,
was in the game much earlier. He has been cataloging genes since
1959, compiling findings in his regularly updated publication,
Mendelian Inheritance in Man. In August 1987 he introduced an
electronic version that scientists around the world can tap into
by computer. At the end of December it contained information on
all the 4,550 genes identified to date. Says McKusick: "That's
an impressive figure, but we still have a long way to go."
Several other libraries of genetic information are already
functioning, among them GenBank at the Los Alamos National
Laboratory and the Howard Hughes Medical Institute's Human Gene
Mapping Library in New Haven, Conn.

    McKusick also directs the Human Genome Organization (known
informally as "Victor's HuGO"), a group formed last September
in Montreux, Switzerland, by 42 scientists representing 17
nations. "The U.N. of gene mapping," as McKusick describes it,
plans to open three data-collection and -distribution sites, one
each in Japan, North America and Europe.

    Geneticist Ray White, formerly at M.I.T., has established
a major center for genetic-linkage mapping at the University of
Utah in Salt Lake City. In 1980 he began a study of 50 large
families, collecting their blood samples, extracting white blood
cells, which he multiplies in cell cultures, then preserving
them in freezers.


    Working with family pedigrees and DNA extracted from the
cell bank, White and his group have identified more than 1,000
markers, each about 10 million base pairs apart, on all the
chromosomes. They have also been major contributors to the
Center for the Study of Human Polymorphisms, set up in Paris by
French Nobel laureate Jean Dausset to coordinate an
international effort to map the genes. Of the 40 families whose
cell lines reside in CEPH's major data banks, 27 have been
provided by White's group.

    How and if these and other genetic research efforts will be
coordinated with the Human Genome Project is a question being
pondered by director Watson and his advisory committee. "Right
now," says Watson, "the program supports people through
individual research grants. We have to build up around ten
research centers, each with specific objectives, if we want to
do this project in a reasonable period of time."

    The effort will also include studies of genes in other
organisms, such as mice and fruit flies. "We've got to build a
few places that are very strong in mouse genetics," Watson
says, "because in order to interpret the human, we need to have
a parallel in the mouse." Explains Genentech's Botstein:
"Experimentation with lower organisms will illuminate the
meaning of the sequence in humans." For example, genes that
control growth and development in the fruit fly are virtually
identical to oncogenes, which cause cancer in humans.

    One of the early benefits of the genome project will be the
identification of more and more of the defective genes
responsible for the thousands of known inherited diseases and
development of tests to detect them. Like those already used to
find Huntington's and sickle-cell markers, for example, these
tests will allow doctors to predict with near certainty that
some patients will fall victim to specific genetic diseases and
that others are vulnerable and could be stricken.

    University of Utah geneticist Mark Skolnick is convinced
that mapping the genome will radically change the way medicine
is practiced. "Right now," he says, "we wait for someone to get
sick so we can cut them and drug them. It's pretty old stuff.
Once you can make a profile of a person's genetic predisposition
to disease, medicine will finally become predictive and
preventive."

    Eventually, says Mark Guyer of the NIH's Human Genome
Office, people might have access to a computer readout of their
own genome, with an interpretation of their genetic strengths
and weaknesses. At the very least, this would enable them to
adopt an appropriate life-style, choosing the proper diet,
environment and -- if necessary -- drugs to minimize the effects
of genetic disorders.


    The ever improving ability to read base-pair sequences of
genes will enable researchers to speed the discovery of new
proteins, assess their role in the life processes, and use them
-- as the interferons and interleukins are already used -- for
fighting disease. It will also help them pinpoint missing
proteins, such as insulin, that can correct genetic diseases.

    Mapping and sequencing the genes should accelerate progress
in another highly touted and controversial discipline: gene
therapy. Using this technique, scientists hope someday to cure
genetic diseases by actually inserting good genes into their
patients' cells. One proposed form of gene therapy would be used
to fight beta-thalassemia major, a blood disease characterized
by severe anemia and caused by the inability of hemoglobin to
function properly. That inability results from the lack of a
protein in the hemoglobin, a deficiency that in turn is caused
by a defective gene in bone-marrow cells.

    To effect a cure, doctors would remove bone-marrow cells
from a patient and expose them to a retrovirus* engineered to
carry correctly functioning versions of the patient's faulty
gene. When the retrovirus invaded a marrow cell, it would insert
itself into the cellular DNA, as retroviruses are wont to do,
carrying the good gene with it. Reimplanted in the marrow, the
altered marrow cells would take hold and multiply, churning out
the previously lacking protein and curing the thalassemia
patient.

*Except red blood cells, which have no nucleus.