By Marilyn Chase Illustration by Michael Reingold August 22, 1988 Article includes, in order mentioned: Thomas Rogers, Monsanto scientist Michael L Riordan, the founder and CEO of Gilead Sciences Samuel Broder, National Cancer Institute associate director Claude Helene, scientist at France’s National Institute for Health and Medical Research Paul Miller, Johns Hopkins professor Laure Aurelian, University of Maryland professor Jack Cohen, National Cancer Institute scientist Makoto Matsukura, National Cancer Institute scientist Len Neckers, National Cancer Institute scientist Peter Dervan, California Institute of Technology professor Douglas Melton, Harvard professor Hal Weintraub, Hutchinson Cancer Research Center principal scientist

1. THE WALL STREET JOURNAL.
Promise Seen in 'Anti-Sense' Medicine
Approach Aims
At Neutralizing
Harmful Genes
By MARILYN CHAsE
StaffReporter of THE wALL STREET JOURNAL
Frog eggs, a mouse's ear and slime
mold.
They sound like ingredients in a
witches' brew. But they are actually the
subjects of early laboratory experiments
investigating a radical new way of treating
genetically based diseases.
Tests involving these three homely
items indicate that it may be possible one
day to halt a host of cancers and viral ills
by blocking the genetic messages that
cause them. To the wizards of molecular
genetics, this is known as the "anti-sense"
approach. It means using an inverted piece
of the gene code to lock onto potentially
dangerous genetic messengers, canceling
their ability to do harm.
In its simplicity and specificity, anti­
sense is utterly unlike mainstream biotech­
nology, which involves splicing a new gene
into a medium such as bacteria to produce
a de.sired protein that will combat a dis­
ease. Nor is it like "gene therapy," which
aims to splice in a good gene to compen­
sate for a defective one. The new science
looks to target and block bad genes-such
as cancer-causing oncogenes-much as
correcting tape blocks out a typographical
error.
The field-is exploding, thanks in part to
burgeoning information about gene se­
quences in computerized data banks, and
to a generation of new machines th.at auto·
mate the once tedious task of synthesizing
and sequencing genes. More and more aca­
demic labs are exploring anti-sense, along
with such companies as Monsanto Co.,
Bristol-Myers Co., Enzo Biochem Inc., Mi­
croprobe Corp. and the Lifecodes Inc. unit
of Quantum Chemical Corp.
Provocative Precision
"It gets people excited," says Thomas
Rogers, a Monsanto scientist. "It's unique
among therapeutic approaches-something
that's that selective."
Blocking the Mess�ge �
Cell / �1-rotetn
Ordinarily, the double
cyio
(
plum- �
helix of DNA is trana-
/
cribed into messenger DNA
RNA, containing genetic
instructions that are M-nser
translated into the
RN
production of a protein.
lllullratloft by Mic!-f �
One of the most striking examples of
the trend is Gilead Sciences Inc. in Foster
City, Calif., a company devoted exclu­
sively to genetic targeting. Incorporated
just a year ago, Gilead is named for the
biblical site of a healing balm. Michael L.
Riordan; its founder and l)resident, is a
fonner venture capitalist with an M.D.
from Johns Hopkins University and an
M.B.A. from Harvard University. After a
year of researching the field, he persuaded
his mentors at the venture-capital firm
Menlo Ventures to provide $2 million in ft·
nancing-half of which he collected the
day before his 30th birthday last August.
"Probably 80% to 90% of all disease is
The"anti-sense"molecule,
designed to bind with
and block a specific piece
of messenger RNA, halts
the translation of its
genetic instructions and
prevents the production
of protein.
traceable to the functioning of one or more
deleterious genes," Dr. Riordan asserts.
"It seemed to me an enormously powerful
tool if you could knock out a gene responsi­
ble for a virus or cancer." If successful, he
argues, anti-sense could usher in a new
therapeutic era comparable to the advent
of antibiotic drugs in the 1940s.
However, no one has yet proved that
anti-sense will work in the human body.
Scientists must devise agents that are sta­
ble, that can be delivered effectively to the
tight cells, that can withstand attack from
the body's defense mechanisms and that
can be produced at a tolerable cost.
"Anti-sense is exciting and aesthetically

2. THE WALL STREET JOURNAL MONDAY, AUGUST�.
pleasing," says Samuel Broder, associate
director for clinical oncology at the Na­
tional Cancer Institute. "But it would be
wrong to raise public expectations that a
therapy is right around the comer." In·
deed, it is likely to be a couple of years be·
fore human testing even begins.
A gene, of course, is a unit in the hered­
itary code, made up of a unique sequence
of four chemical elements-labeled A, C, T
and G. Like primary colors blending into a
rainbow of hues, these elements are ar­
ranged in the various patterns that encode
the genes for all living organisms. Paired
in spiraling steps to form the double helix
of DNA (deoxyribonucleic acid), this mate­
rial later gets transcribed to RNA (ribonu­
cleic acid), which then produces a protein.
An anti-sense agent is, literally, a syn­
thetic strand of DNA that duplicates in re­
verse the order of elements in the RNA. It
binds to the gene's messenger and cancels
the message, thus preventing cells from
following its instructions.
Natural outgrowth
Anti-sense is a natural outgrowth of
gene-probe technology, which similarly
employs a chain of nucleic acids comple­
mentary to the sequence of a specific gene.
The aim of a probe, though, is not to wipe
the gene out but to zero in on it for pur­
poses of identification and diagnosis.
Anti-sense may be simpler than gene
therapy,whichinvolvesinstalling an intact
and functional good gene in the organism­
a much more complex biological chal·
lenge. "To kill something, to tum it off, is
much simpler than doing something posi­
tive," says Monsanto's Mr. Rogers.
While the state of the art in anti-sense is
still embryoni..:, a number of scientists re­
ported early successes at a crowded meet­
ing on the topic sponsored by the National
Institutes of Health last fall in Annapolis,
Md. For example, Claude Helene, a scien­
tist at France's National Institute for
Health and Medical Research (INSERM),
said his test-tube studies show that an anti­
sense molecule can block a gene crucial to
the life cycle of trypanosomes. These para­
sites, passed to humans by the bite of the
tsetse fly, cause African sleeping sick­
ness.
Paul Miller, a scientist at Johns Hop­
kins and one of the pioneers of anti-sense
research, reported on progress in the de­
_velopment of an anti-sense molecule
against the herpes simplex virus. He said
that, in an experiment he termed "very
preliminary," his colleague, University of
Maryland researcher Laura Aurelian, had
incorporated the molecule into an ointment
that cleared herpes lesions when swabbed
·on the ear of an infected mouse.
On the AIDS front, National Cancer In­
stitute scientists Jack Cohen and Makoto
Matsukura told the meeting of their pro­
gress in testing an anti-sense molecule
against human immunodeficiency virus, or
HIV, which is believed responsible for
AIDS. The compound they used, a phos­
phorothioate that nullifies a gene essential
to HIV's replication cycle, was found to in­
hibit significantly HIV's replication and
cell-killing power in the test tube.
Dr. Cohen also reported that Len
Neckers, another cancer institute col­
league, had achieved "significant inhibi·
tion" of an oncogene called myc in cell
culture using an anti-sense compound. A
great variety of cancers are linked to the
myc oncogene, including leukemia, lym­
phoma and certain cancers of the colon
and lung.
While such bright beginnings don't
guarantee clinical success, they inspired
Dr. Riordan to pursue his notion of devot­
ing an entire company to the science. Join­
ing him on his three-man board of direc­
tors are H. DuBose Montgomery, manag­
ing partner of Menlo Ventures; and Donald
Rumsfeld, former U.S. Secretary of De·
fense and former president G.D. Searle &
Co., the pharmaceutical company;
Scientific Advisers
After a yearlong study of anti-sense and
its major players, Dr. Riordan courted
three researchers, who joined him as core
scientific advisers to Gilead and its staff of
16: Peter Dervan, a professor of chemistry
at California Institute of Technology;
Douglas Melton, professor of biochemistry
and molecular biology at Harvard; and
Hal Weintraub, principal scientist in the
geneticsdivision of Seattle's Fred Hutchin·
son Cancer Research Center.
Prof. Melton, a pioneer in using anti­
sense to block gene function in frog-egg
cells, says anti-sense has now been proved,
not only in the test tube but also in living
organisms including yeast, flies, frogs,
slime mold and tomatoes. Such tests set
the stage for much bigger studies.
Although the details are still under
wraps, Gilead's general game planis to at­
tack serious viral illnesses and cancers.
Dr. Riordan notes that AIDS will be one
early target. Gilead already has a license
agreement with the federal government to
develop the cancerinstitute's phosphoroth­
ioate compound for use against AIDS and
similar viruses.
Laying the groundwork for its cancer
work, Gilead recently got a license to a pa­
tent held by Massachusetts Institute of
Technology on anti-sense inhibition of on­
cogenes. Conservatively, at least 30 onco­
genes have so far been linked to a variety
of malignancies, says Dr. Weintraub. He
believes a likely first target may be the so­
called ras oncogene, which has been linked
to certain tumors of the nerve cells, gas­
trointestinal tract, bladder and breast.
Gilead also wants to reach beyond anti­
sense, which targets the gene's RNA mes-
senger, to the more difficult and unproven
task of locking directly onto the double he­
lix of DNA itself, in a strategy called "tri·
pie helix." A direct strike against DNA,
the master copy of the gene, would allow
scientists using smaller doses to reach la­
tent viruses hiding silently in their host's
DNA. If this proves possible, it will be a
breakthrough in fighting AIDS infection
and other slowly smoldering viruses.
"It's too early to say this Is a major
thrust, and we don't know that it works in
cells," Dr. Riordan cautions. "But," he as­
serts, "we'll be the first to know."
Advantages Over Btotech
Because genetic targeting marries so­
phisticated organic chemistry with molecu­
lar genetics, Gilead says it sidesteps some
of the messier problems of conventional
biotechnology-particularly the manufac­
ture of human proteins. Proteins are very
large and infinitely variable, whereas the
smaller anti-sense molecules can be pre­
cisely defined as chemical formulas. More­
over, anti-sense molecules can be synthe­
sized in a lab. Conventional biotech, by
contrast, requires big fermentation vats­
like those used in breweries-to cook up
the bacterial broth that churns out recom­
binant proteins.
But for Gilead, as for others in the field,
challenges abound. The major technical
hurdle is figuring out how to deliver the
anti-sense molecule into the right cell. The
molecule may need modifications-such as
making it "lipophilic," or fat-soluble-to
get it to penetrate the cell membrane.
Another problem is that the synthetic
DNA strands are inherently unstable. They
break down and get chewed up by enzymes
called nucleases. Finally, the making of
anti-sense molecules is prohibitively costly
right now; a single human dose would re­
quire tens of thousands of dollars of rea­
gents. Better stability and delivery could
drive down that cost.
Whether scientists can solve these prob­
lems, turning an elegant laboratory tool
into a weapon against cancer or AIDS, is
still a point of debate. Dr. Riordan says he
wrestles with chemical formulas in his
dreams, like Jacob with the angel.
"Mike is driven, almost �. by
the concept that anti-sense can be applied
to therapy," says Harvard's Prof. Melton.
"He is absolutely convinced that tb1s ls go­
ing to happen. I'm about 90o/o sure."
MONDAY, AUGUST 22, 1988