HAS GENE THERAPY STALLED?

Scientist may have pushed too far too fast in a race for breakthroughs.

By Christine Gorman

Like every medical revolution before it, the field of gene therapy began
with the vision of a brighter future. Researchers promise to cure such hereditary
disorders as cystic fibrosis, muscular dystrophy and sickle-cell anemia, not with
conventional medicine but with the magic of genetic engineering, supplanting
defective genes with their normal counterparts. Patients dreamed of a life free
from the diseases they had inherited. Venture capitalist dreamed of untold riches
and backed the leading researchers in the field with millions of dollars of seed
money.

But turning visions into reality has always been the trickiest step in
conducting a successful revolution. In the U.S., for example, five years after the
first approved experiments on human, there are now 600 Americans enrolled in
100 clinical trials. Yet after all the tests and all the hype, there is still no
unambiguous proof that gene therapy has cured-or even helped-a single patient.

No one denies that gene therapy holds extraordinary promise or that it will
eventually yield results. But critics have grown increasingly concerned that the
initial excitement led to a premature rush to get unproved gene therapies out of
the laboratory and into human patients. Researchers are still not sure which are
the best methods to transport gene into affected cells. Nor have they figured out
how to stop people’s own immune systems from rejecting what are, in effect,
microscopic transplants of foreign material.

Even more troubling are signs that financial considerations may have
replaced scientific rigor in determining how and when to use gene therapy.
Nearly every investigator currently running a clinical trial in the U.S. has
relationship of one sort or another with a biotechnology firm. Some critics charge
that businessmen are pushing researches too hard in order to get a quick return
on their investment, and that some doctors have been too hasty, launching
clinical trials early in hopes of “chasing out” when a large drug company buys
they firm.

Now comes word of major technical snags in two areas of gene therapy
that had been regarded as among the fastest along. Reporting in separate
articles in the New England Journal of Medicine last week, researchers concluded
that the most commonly used genetic treatments for cystic fibrosis and muscular
dystrophy had run into a dead end. In both cases, scientist inserting normal
genes into patients with defective ones were not able to elicit corrective changes
in their patients’ bodies.

Quick to put the best face on the discouraging results, investigators

pointed out that they have other research path to pursue. “You don’t usually hit
a home run the first time,” says Dr. Michael Knowles, the University of North

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Carolina researcher who led the cystic fibrosis trial. “You usually make
incremental steps forward, and that’s what this study did.”

Other genetics experts argue that the time has come to re-evaluate the
approach taken by most gene therapist, and perhaps even to redirect their
efforts. Earlier this year Dr. Harold Varmus, head of the U.S. National Institutes of
Health, appointed an independent committee of scientists to look into how NIH
spends its gene-therapy research dollars (some $ 200 million a year) and
whether the government is getting its money’s worth. “I’ve been a bit concerned
that we weren’t fulfilling the promise of gene therapy in any obvious way at this
point,” Varmus explains. “My intuition tells me that we need to emphasize more
basic aspects of gene-therapy research.”

Scientist are, after all, working counter to millions of years of evolution.

The basic goal of gene therapy is to take bits of DNA that did not originate in
patients’ bodies, insert them into the patients’ tissue and somehow get them to
turn on or, in the jargon of the field, “express’ themselves. Yet this is precisely
the sort of biological action that the body’s immune system interprets as a threat
and is primed to fight.

Furthermore, it is not just the immune system that scientists must outwit,
they also have to get cells that are targeted for treatment to open their
molecular locks and allow the foreign genes inside. As Dr. James Wilson, director
of the Institute for Human Gene Therapy at the University of Pennsylvania, points
out, “The basic principles necessary to make gene therapy successful are only
beginning to be defined.”

If real clinical benefits have been slow to materialize, however, that has
not stopped large pharmaceutical firms from buying up the gene-therapy
concerns that seem to show the most promise. “Many, many companies have
scrambled to get into the race,“ notes Ed Hurwitz, an analyst for Robertson,
Stephen & Co. The list of recent mergers, as Hurwitz ticks them off, reads like a
Who’s Who of biotechnology: “Sandoz buys Genetic Institute. Chiron buys
Viagene. Bristol Myers makes a big investment in Vical. Rhône-Poulenc invests in
Applied Immune Sciences and several other gene-therapy companies.”

Some of this is unavoidable. Even the NIH’s Varmus acknowledges the

legitimate role commercial investment plays in moving gene therapy forward.
The danger is that over reliance on commercial investors could change the kind
of science that gets done. “The involvement of privately funded companies is
already moving the focus away from rare genetic disorders,” says Doris Zallen, a
member of the NIH advisory panel that reviews gene-therapy trials for safety.
Private investors tend to be more interested in diseases that affect large
numbers of potential customers.

Commercial pressure has also pushed scientists to test gene treatments

on human subjects as early as possible. No matter how promising a laboratory
result is, clinical trials with real patients are more likely to pique Wall Street’s
interest. The risk is that expectations will be raised so high that the American
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public-and investors-will lose faith in the technology when reversals occur.
Flossie Wong Staal, a molecular biologist at the University of California at San
Diego, says that because “clinical trials, so far, have very little promise of curing
patients,” she prefers to think of her attempts to use gene therapy to boost the
immune systems of AIDS patients as experiments rather than full-fledged clinical
trials. Even if they do not lead to a marketable therapy, she notes, they are still
valuable tools for guiding future investigations.

Nor are basic research and clinical trials mutually exclusive goals.
“Humans are not big mice,” says Dr. Ronald Crystal, who is working on gene
therapy for cystic fibrosis at New York Hospital-Cornell Medical Center. “Unless
we do clinical trials, we never going to learn. You have to test it in the lab on
animals, try it in humans and then go back to the lab. It’s a cyclic process.”

That process could still pay off. This week researchers led by Dr. Donald
Kohn at Children’s Hospital in Los Angeles will publish a report in Nature
Medicine showing progress in using gene therapy to treat babies born with a
disorder called adenosine deaminase deficiency. Three infants whose hereditary
disorder leaves them defenseless against microbial attacks were given healthy
genes using blood from their umbilical cords. Because the doctors were able to
insert the good genes into the babies before their other immune defenses had
fully formed, their bodies did not reject the material as foreign. Doctors do not
claim to have cured the children, but, they note, the genes are “expressing”.

It may turn out that a good strong dose of reality is just what gene therapy
needed right now. Like cancer and AIDS researchers before them, gene therapist
must learn to make medical progress the old-fashioned way-in fits and starts,
with plenty of setbacks.

TIME, October 9 1995, page 32

II. VOCABULARY PARTS

No. Words Parts of Synonym / Use in Sentence

3
 Speech Description

1 Breakthrough N Major advance or Breakthrough captures the joy

discovery of learning

2 Therapy N Non-surgical Therapy is the attempted

treatment of disease remediation of health problem
or disability

3 Hereditary Adj Able to be passed A hereditary monarchy is the

down genetically most common type of
from one generation monarchy that is used by
to another almost all existing monarchy

4 Dystrophy N Defective nutrition Dystrophy is any condition of

abnormal development

5 Anemia N Deficiency of red Anemia occurs when the level

blood cells or their of healthy red blood cells in
hemoglobin the body becomes too low

6 Concerned Adj Involved, Interested Concerned Women for

America is a proud member of
Townhall.com community

7 Premature Adj An occurring or done A premature baby is born

before usual or before the 37th week of
proper time pregnancy

8 Immune Adj A protected against The immune system is made

infection through up of special cells, proteins,
inoculation tissues, and organs

9 Rigor N Feeling of cold with Transparency and rigor are

shivering and a rise urgently needed to show that
in temperature that church is run in a wise
and just manner

10 Hasty Adj Hurried; acting too Hasty pudding is a pudding or

quickly porridge of grains cooked in
milk or water

11 Snag N Unexpected obstacle In forest ecology, a snag

or drawback refers to a standing, partly or
completely dead tree

12 Elicit V Draw out The lawyer elicited a

description of attacker from
the witness last night

13 Emphasize V Put an importance SMAN 1 Malang emphasize

attached to a thing morality education

4
14 Jargon N Words or expressions Jargon has been designed
used by a particular from ground up to make
group or profession programming for the grid as
straight forward as possible

15 Outwit V Be too clever for; Hackers outwit Windows 7

overcome by greater activation
ingenuity

16 Scramble V Clamber; crawl; Scientist scramble to analyze

climb Haiti Quake

17 Reliance N Trust; confidence Reliance is an established

market leader in the provision
of manpower

18 Pique V Wound the pride of; Toni pique on Twitter

irritate Journalist

19 Umbilical Adj Of the navel In placenta mammals, the

umbilical cord is the
connecting cord from the
developing embryo to the
placenta

20 Plenty N Abundance; Plenty is epicurean in the

sufficient quantity or truest sense: living well, living
number sustainably

21 Setback N Reversal or arrest of Pitch is also known as setback

progress; relapse or high-low-jack