From: Gene Ethics <info@...>

Date: 22 November 2006 2:44:43 PM

To: Gene Ethics <info@...>

Subject: ** Review of use - Human Gene therapy: Proceed with caution

------------------------------- GENET-news -------------------------------

TITLE:  GENE THERAPY: PROCEED WITH CAUTION

SOURCE: Technology Review, USA

URL:    http://www.technologyreview.com/BioTech/17727/

DATE:   14.11.2006

------------------ archive:  http://www.genet-info.org/ ------------------

GENE THERAPY: PROCEED WITH CAUTION

In 1983, when only three genetic diseases could be detected effectively by

screening tests and scientists knew very little about how genes were

controlled, Technology Review argued that anticipated clinical trials of

gene therapy would need to follow stringent guidelines, given the

technology's previous failures. As Horace Freeland Judson explains in this

issue (see " The Glimmering Promise of Gene Therapy "), not much has

changed. Caught up in the promise of curing debilitating, life-shortening

diseases by giving patients good copies of defective genes--and, it seems,

eager for the glory of being the first to make gene therapy work in

humans--some gene-therapy researchers have conducted sloppy, and even fatal,

human trials in the intervening two decades.

http://www.technologyreview.com/read_article.aspx?id=17725&ch=biotech

Judson suggests that moving gene therapy forward will require

well-Â-regulated scientific "drudgery." In April 1983, Tabitha M. Powledge

suggested a similar route in her article "Gene Therapy: Will It Work?"

Though she wrote two years before it was possible to mass-produce genes

through the process called polymerase chain reaction (PCR) and seven years

before the Human Genome Project had officially begun, the challenges she

laid out sound familiar--as does the promise of gene therapy.

First, as Bob Williamson of St. Mary's Hospital Medical School at the

University of London has pointed out, there are more than 2,000 single-gene

disorders, and they are so diverse that most will require unique and

idiosyncratic therapies. Furthermore, many are so rare that the benefits of

gene therapy, if it can be achieved, may not warrant the expense, Williamson

says.

Moreover, gene therapy is possible only for diseases for which the defective

gene and its normal counterpart have been identified. Ways must still be

found to copy normal genes in the laboratory so there will be enough to

genetically manipulate and administer.

In addition, the inserted gene must function properly once inside the cell

and direct the production of its normal product in amounts sufficient to

cure the disease without harming the patient. This final step requires

detailed knowledge of how genes manufacture proteins and what turns them on

and off--knowledge that is likely to be some time in coming.

Even when researchers have developed a therapy for a particular disease,

clinical trials in humans can begin only after extensive trials in animals.

All these criteria are likely to be observed stringently, particularly

because previous attempts at gene therapy have been unsuccessful and highly

controversial.

Finally, gene therapy may turn out to be applicable only to genetic

disorders caused by a single defective gene, and only to some of those,

Â-Williamson points out. The technique offers no way of dealing with

abnormalities of entire chromosomes, nor is it likely to be useful for the

most important group of diseases--such as diabetes, heart and circulatory

diseases, and many mental disorders--in which both genes and environment

play a role.

In short, while the first successful gene therapy will probably burst upon

the medical world before long, many scientists are pessimistic. "The

correction of a disease by gene therapy will be worthwhile only if there is

no other simpler and more effective technique available," Williamson says.

Baylor [College of Medicine]'s Thomas Caskey agrees that the uses of gene

therapy will be limited. But he points out that many of the current

treatments are unsatisfactory and do little more than ease the symptoms of

disease.

------------------------------- GENET-news -------------------------------

TITLE:  THE GLIMMERING PROMISE OF GENE THERAPY

SOURCE: Technology Review, USA

URL:    http://www.technologyreview.com/BioTech/17725/

DATE:   14.11.2006

------------------ archive:  http://www.genet-info.org/ ------------------

THE GLIMMERING PROMISE OF GENE THERAPY

Its history is marred by failures, false hopes, and even death, but for a

number of the most horrendous human diseases, gene therapy still holds the

promise of a cure. Now, for the first time, there is reason to believe that

it is actually working.

By the late 1960s, molecular biologists had erected an overarching

explanation of how genes work--their substance, their structure, their

replication, their expression, their regulation or control. Or at least they

had done so in outline, for prokaryotes, the simplest single-celled

organisms (which include bacteria), and for the viruses, called

bacteriophages, that prey upon them. The leaders of the field were now

looking to a far more difficult problem: doing it all over again for higher

organisms.

What this new generation of molecular biology demanded, and what was

developed in just a few years, was a set of methods for investigating and

precisely manipulating the genetics of eukaryotes, including animals and

plants. With reverse transcriptase, which was discovered independently by

Howard Temin and David Baltimore in 1970, genes encoded in RNA could be read

back into DNA. With Daniel Nathans's and Hamilton Smith's work on

restriction enzymes, segments of DNA could be snipped out at chosen sites.

In a rush, from laboratories chiefly at Stanford University, came ways to

link together genetic material from disparate sources. "We will be able to

combine anything with anything," one senior scientist told me at the time.

"We can combine duck with orange." The initial purpose was to get at the

most basic questions of cellular biology, to find out exactly what

individual genes do and how they do it. Immediately, though, a shining hope

dawned: that this toolbox could be carrie!

 d from the laboratory to the clinic, to cure hereditary diseases caused by

genetic defects. Already, some scientists were dreaming of gene therapy.

By 1970, some 1,500 genetically determined diseases had been identified in

humans. Some show up in babies; others surface at puberty; a few emerge only

toward the end of the victim's reproductive life. Some can be held in check

by dietary restrictions, a few by drugs. But most cannot be cured or even

palliated by conventional medicine. Though almost all are rare, some

extremely rare, collectively they were coming to be recognized as a

burdensome and costly medical problem. Many are marked by gross mental

impairment. Victims of Lesch-Nyhan disease, for example, suffer severe

mental retardation. They must have their arms splinted, because otherwise

they bite their hands and arms. They die in childhood or early adulthood.

Though scientists had traced fewer than a hundred of these human diseases to

specific genetic deficiencies, they began searching for ways to cure them by

safely inserting correcting genes into people suffering from them.

They were still trying nearly two decades later, when on September 29, 1999,

the front page of the Washington Post carried the headline "Teen Dies

Undergoing Experimental Gene Therapy." Jesse Gelsinger was 18, a recent

high-school graduate from Arizona who had a potentially fatal genetic

disease. He was one of 18 patients taking part in a trial at the University

of Pennsylvania. Viruses carrying a new gene had been injected into one of

the arteries supplying blood to his liver. In gene therapy, an engineered

virus is often used as a "vector," delivering the desired gene to the

patient's cells; in this case, however, the virus apparently triggered a

series of deadly events.

The New York Times picked up the story the day after it ran in the Post. The

National Institutes of Health and the U.S. Food and Drug Administration

started investigations, which moved with commendable speed; more details

came out. Later, the U.S. attorney general got involved. But with those

first newspaper reports, gene therapy seemed dead.

The trial that Gelsinger had been participating in was tainted by

accusations of overconfidence, haste, negligent administration, and conflict

of interest. Yet all this diverted attention from acute and fundamental

problems with gene therapy itself--problems in the science and technology,

problems in clinical exploitation of the technology, problems that were by

no means new but that Gelsinger's death made glaringly evident.

I had been following developments in gene therapy for a third of a century,

watching as hundreds of millions of dollars were lavished on it, as new

hopes cyclically turned to ashes, dramatic claims to sad farce. By 2000,

more than 300 gene-therapy trials had been registered with NIH, involving

more than 4,000 patients, according to an article printed that year in the

Council for Responsible Genetics' magazine GeneWatch. The Gelsinger affair

was the most highly publicized failure. There had been plenty of others.

There were two chief reasons for pessimism about gene therapy. As had been

plain from the start, although the total societal load of illness and

debility caused by genetic defects is considerable, most individual diseases

caused by single-gene defects--the kind that seem most likely to be cured by

gene therapy--are rare. (Sickle-cell anemia and some other hemoglobin

disorders are among the few exceptions.) Everybody in the field acknowledged

this. Nobody seemed to face up to the implications. Because these diseases

have different genetic mechanisms and affect different types of tissue, each

presents a new set of research problems to be solved almost from scratch. As

the millions burned away, it became clear that even with success, the cost

per patient cured would continue to be enormous. And success had shown

itself to be always glimmering and shifting just beyond reach, an ignis

fatuus: from the start, step by step, everybody had underestimated the real

difficulties the sci!

 ence presents.

The history of gene therapy can be told as the repeatedly frustrated search

for viruses that work well as envelopes for gene delivery, paralleled by the

increasingly baffling realization that far more than a few simple genes are

needed to produce the desired proteins successfully. For the gene-therapy

community, the years had been a calendar of failures. "We totally

underestimated the fact that the viruses could present so many

difficulties," Inder Verma--a molecular biologist at the Salk Institute, in

La Jolla, CA--told me in August 2006. "We underestimated the fact that it

took billions of years for the viruses to learn to live in us--and we were

hoping to do it in a five-year grant cycle!" He went on, "You know, the body

is designed to fight viral infections. One hundred percent. Luckily for us!

And here we are putting billions of viruses back into people and hoping that

if we have a good virus, the body will say, ‘It's okay, because we're

bringing the good stuff.'"

The first attempt at gene therapy in human patients began with a fortuitous

observation. In 1959, the physician Stanfield Rogers, at the University of

Tennessee, was working with the Shope papilloma virus, which causes warts on

the skin of rabbits. He reported in Nature that the skin of these warts

contained abnormally high levels of arginase, an enzyme that breaks down the

amino acid arginine. He then found that some scientists who had worked with

Shope virus, even 20 years in the past, had decreased blood levels of

arginine.

The possibility that the virus had introduced its gene for arginase into the

scientists was a curiosity, nothing more--until 1969, when the Lancet

published a paper by Heinz-Georg Terheggen, a pediatrician in Cologne,

Germany, and colleagues. Two little girls had been brought to Terheggen,

deeply mentally retarded and suffering from a form of cerebral palsy, the

British journal reported. Tests showed they had high levels of arginine,

while very little of the enzyme arginase was detectable. This was a new

genetic disease.

Rogers went to Terheggen to urge that he and his colleagues be permitted to

inject the girls with Shope virus, hoping to give them a functioning gene

for arginase. As an essential precaution, they did try inoculating the virus

in a tissue culture of cells from one of the girls. They reported in the

Journal of Experimental Medicine that they found arginase activity,

apparently from the virus-introduced gene. But in the trial, there was no

response, no reduction of arginine, no evidence of arginase activity. After

an interval, they gave one child a larger dose. Still no response. The

general consensus was that Rogers had made a premature attempt, with

inadequate scientific understanding. That judgment was not wrong.

In the spring of 1972, Theodore Friedmann and Richard Roblin published the

first extended study of the possibility of treating genetic diseases through

gene transfer. "Gene Therapy for Human Genetic Disease?" appeared in

Science. Disease by disease and therapy by therapy, the researchers warned

of formidable technical problems; much that they laid out was prescient.

They were the first to analyze the potential risks that gene therapy posed

to patients and the grave ethical concerns it raised.

Nonetheless, the paper was a work of advocacy. With a medical degree from

the University of Pennsylvania, Friedmann had spent three years in the 1960s

at NIH, where, in the laboratory of Jay Seegmiller, he had begun to work on

Lesch-Nyhan disease. Seegmiller had discovered that the disease is caused by

the absence of the enzyme hypoxanthine phospho ribosyltransferase, or HPRT,

owing to a defect in its gene. Friedmann hoped to find a way to put the

correct gene into Lesch-Nyhan cells in culture, perhaps using a virus. His

imagination had been caught by the prospect of gene transfer. Indeed, as an

assistant professor of pediatrics at the University of California, San

Diego, in the early 1970s, he introduced the term "gene therapy."

In January 1983, Friedmann and colleagues announced that they had isolated

the normal gene for HPRT. Inder Verma, with whom Friedmann had struck up a

collaboration in the early 1980s, had a potential viral vector: in this

case, a type of retrovirus--one for a mouse leukemia. In August 1983, the

two researchers reported that they had built the vector and used it

successfully to introduce a functioning gene for human HPRT into rodent

cells in vitro.

After that initial glimpse of success, Verma says, "very quickly we asked,

‘Can we do it in vivo?'" They began experiments on hemophilia in live mice.

The gene defects causing hemophilia were known: the lack of a single protein

could prevent blood from clotting. Working in vitro, adding the correct gene

to cells in culture, "we could produce the protein forever," Verma says.

"And this is where the first surprise came." The moment the cells were put

back into the mice, "they instantly stopped making the protein. And this is

the first limitation we recognized: retro viruses can only introduce genes

when the cells are dividing." Verma adds, "We could take [the cells] out,

grow them in vitro, transfuse them with the virus, put them back--but when

we put them back, they shut off." Why? "We still really have no idea," he

says.

Then, in 1990, an NIH research physician named William French Anderson

announced to heated publicity that he was launching a gene-therapy trial,

treating two young girls for a form of severe combined immune deficiency, or

SCID. People with this disease completely lack a normal immune system. The

precursor cells in their bone marrow that should make white blood cells are

defective, so patients catch all the infectious diseases that white blood

cells should fight off. Mild infections become grave; serious ones kill

them. They die in early childhood. Anderson said the two girls were

suffering from a form of SCID caused by a lack of the enzyme adenosine

deaminase (ADA). He was injecting them with correcting genes carried in

murine-leukemia virus.

Anderson was a flamboyantly effective publicist of gene therapy and of

himself. He announced that the two little girls had been cured. In September

1994, he brought one of them to testify before the Science Committee of the

U.S. House of Representatives. She was eight years old by then, lively and

apparently well. The chairman of the committee reportedly called her "living

proof that a miracle has occurred." Anderson made sure he was known to the

public as "the father of gene therapy," even displaying the title on his

website.

Yet his scientific colleagues and competitors became exasperated, even

contemptuous. In point of fact, the trial with the two girls had failed. All

along, the girls had also been treated with injections of a synthetic ADA.

And Verma and Friedmann had already shown the failure of mouse leukemia

virus to introduce genes in vivo. "There was never production of the ADA

protein--there never was," according to Verma. Even before the girl appeared

in front of the House committee, the failure was known throughout the

medical community.

Since retroviruses presented difficulties in vivo, attention turned to the

adenoviruses--which include the viruses that cause certain types of severe

upper-respiratory infections in humans. They worked. "They were wonderful,"

Verma says. "First of all, you could make billions of virus particles."

Secondly, wherever the particles were introduced, the imported genes would

be expressed. Many researchers switched to adenoviruses. But they turned out

to be highly immunogenic: they are difficult to use safely because they can

provoke strong immune reactions. Next came adeno-associated viruses, AAVs.

Because they have only two proteins, AAVs provoke the immune system less

than adenoviruses do.

In the fall of 1994, Harold Varmus, the director of NIH, became increasingly

skeptical about the quality of gene-therapy research. The agency's

Recombinant DNA Advisory Committee (RAC) was reviewing all protocols for

human trials of gene therapy funded by NIH. The committee's first concern

was safety. But as its recommendations passed across his desk for final

approval, which was normally routine, Varmus realized that the committee was

not systematically evaluating the trials' scientific merits.

It turned out that Anderson's were only the most egregious of many

extravagant and unsupported claims surrounding gene therapy. Although NIH

was giving out $200 million a year for gene-therapy research, and big

pharmaceutical firms and swarms of biotechnology startups were thought to be

spending as much again, not a single success with humans had been reported

in any peer-reviewed journal. In May 1995, Varmus convened a panel headed by

Stuart Orkin, a professor at Harvard Medical School, and Arno Motulsky, a

geneticist at the University of Washington, Seattle, to review the state of

gene-therapy research and assess how funds should be apportioned among

gene-therapy research areas.

Orkin and Motulsky reported in December, at length and scathingly. The

promise of gene therapy appeared great, but its failures had persisted

despite the RAC's approval of more than a hundred protocols. Most clinical

trials were too small and exploratory in nature to evaluate the medical

merits of the treatment; they lacked adequate controls and rigorously stated

goals. Gene therapy, the panelists concluded, had been widely and harmfully

oversold.

The balloon was pricked. The RAC had been considering approximately 15

protocols at each of its regular sessions; but the next meeting, scheduled

for March 1996, was canceled. No proposals requiring public review had been

submitted.

Three years later came Jesse Gelsinger's death.

Gelsinger and the 17 other patients in the trial at the University of

Pennsylvania were being treated for a deficiency of the enzyme ornithine

transcarbamylase, which the liver uses to break down ammonia, a by-product

of protein digestion, into harmless waste products. In its most severe form,

the deficiency kills babies in their first year. Gelsinger had been kept

alive on a strict diet and a regime of pills. When he learned of the

gene-therapy trial, he volunteered.

The trial was carried out at the university's Institute for Human Gene

Therapy, which was headed by James Wilson. It was one of the top such

centers in the country. The corrective gene was loaded into an adenovirus.

The 18 patients were divided into groups that got increasingly large doses.

Gelsinger got the biggest--a culture of 38 trillion virus particles. He

received the dose on September 13, 1999. By September 15, his vital signs

were falling precipitously. With his father's assent, he was taken off life

support, and he died on September 17.

Jesse Gelsinger's death was the first directly attributed to gene therapy.

An alert went out to the hundred or so experimenters using adenovirus

vectors. In the press and in scientific journals, the case was reported as a

disaster for the field.

NIH investigated and called a special public meeting for December 8, 9, and

10. The problem became clearer. The protocol for the trials, as approved

four years earlier by the RAC and the FDA, had called for the adenovirus

vector to be injected intravenously. The FDA had subsequently authorized

direct injection of the vector into the hepatic artery, which was the method

actually used. Nonetheless, Gelsinger's autopsy found that the vector was

widespread in his spleen, lymph nodes, and bone marrow.

Meanwhile, the FDA was conducting its own inquiry. Investigators were

harshly condemnatory. Selection of trial participants had been sloppy at

best: Wilson and his colleagues were unable to produce proof that any of the

volunteers had met the criteria for the trials. Informed-consent procedures

had been grossly inadequate. Federal rules require that benefits and risks

be explained fully and clearly; Paul Gelsinger, Jesse's father, told the New

York Times that the family had been led to think the treatment might help

Jesse, though the trial had been designed only to test the safety of a

treatment being developed for infants. Further, the consent form had failed

to mention that monkeys had died after a similar though stronger treatment.

In 1992 Wilson had founded a private research company, Genovo, in which he

held stock. The company had not put money into this particular study, but it

did contribute a healthy portion of the Institute for Human Gene Therapy's

overall budget.

On January 21, 2000, the agency ordered a temporary stop to all gene-therapy

trials at Wilson's institute. In 2005, Wilson settled with the U.S.

Department of Justice: he was not to lead any clinical trials regulated by

the FDA for five years.

Hope for cures based on gene therapy, it appeared, had all but died with

Jesse Gelsinger. But in February 2000, Friedmann gave the opening talk at a

Monday-morning session of an annual meeting of the American Association for

the Advancement of Science, in Washington, DC. He reviewed the fundamental

difficulties of gene therapy, spoke of the many hundreds of protocols

approved but so far not productive. He reminded his audience of Varmus's

impatient charge in 1995 that the field had been wildly oversold. Then--with

a marked change in tone--he said, "We are on the verge of therapeutic

efficacy."

Two lines of work seemed to him to "have the feel of being correct." A pair

of American laboratories were beginning clinical trials of gene therapy for

hemophilia. Proper blood clotting requires a cascade of responses,

controlled by a series of proteins. Hemophilia A, the most common form of

the disease, is caused by a defect in the gene for one of those proteins,

factor 8; hemophilia B is caused by a defect in the gene for another, factor

9. The study Friedmann thought had that "sense of correctness" came from

work with hemophilia B by Katherine High, a hematologist at the Children's

Hospital of Philadelphia. At Stanford, the gene therapist and virologist

Mark Kay was also working with hemophilia B. Kay and High had combined their

efforts. Their methods worked with animal models of the disease. They were

ready to start human trials.

But the most convincing results, Friedmann said, were just then coming from

a group of pediatricians in Paris. Their leader was a man named Alain

Fischer, a clinician working with small boys who had a form of SCID. Like

the girls whom NIH's Anderson had treated for ADA deficiency, these children

produced no T lymphocytes, the white blood cells that fight infection. But

their disorder was caused by a different gene. The children had been sick;

they were not thriving. Then Fischer and his colleagues tried gene therapy.

"These kids are now to all appearances immunologically reconstituted

entirely," Friedmann said. "All their immune properties seem to be

optimized." He went on, "And the thing that's so impressive about it is,

first of all, that it came from nowhere. It came from left field." Experts

on immune-system disorders "certainly must have known of Alain Fischer and

his group," Friedmann said, but the gene-therapy community was not as

familiar with his work. "And it also !

 is presented in meetings in a very low-key, very modest sort of way,"

Friedmann said. "They say straight out there's nothing new in

method--they've done just a combination of a fortuitously good disease model

[with] a lot of standard retrovirology that's been developed over many

years."

Fischer and a dozen colleagues reported their method, and their success with

their first two patients, in Science on April 28, 2000. They followed up

with a report in the New England Journal of Medicine for April 18, 2002.

Meanwhile, Mark Kay and Katherine High reported that when they injected

their vector into dogs with hemophilia B, the dogs had a therapeutic

response. Avigen, a biotech company headquartered in Alameda, CA,

collaborated with High and Kay to plan clinical tests of the treatment's

safety in people.

In November 2002, the French scientists halted their trials. The number of

patients was up to 10, but now one of those patients who'd gained a fully

normal immune system had come down with a disease similar to leukemia,

out-of-control proliferation of the very white blood cells that had been

restored.

Then the June 4, 2004, issue of Science reported that Avigen had backed out

of the trials of the hemophilia treatment. Two of seven patients had

developed slightly elevated levels of liver enzymes.

On September 28, 2005, I went to see Alain Fischer at the Hôpital Necker, a

children's hospital in Paris. He was direct and clear. "I'm not a specialist

in gene therapy," he said at once. "My real field is immunology and, within

immunology, genetic diseases of the immune system." He had been working with

these diseases for 25 years. "I am a physician. And here there is a clinical

unit where children with immunological diseases are taken care of. So that's

where I'm starting from." What kinds of diseases? "All kinds," he said.

"From deficiencies in T lymphocytes, B lymphocytes, innate immunity, there

are … " He drew breath. "We don't know yet exactly. There are at least 140

different immunological diseases." He added, "They are all very different."

Fischer went on, "We are not going to become specialists in gene

therapy--that is, to try to adapt gene therapy to different diseases. This

is not our goal. We are specialists in these immunological diseases, and

gene therapy is one strategy to try to treat these patients." He was drawn

to gene therapy in the early 1990s, when a new gene was identified that,

mutated, causes a form of SCID. He had encountered patients with the

mutation. "We understood very quickly, within one to two years, the

pathophysiology of the disease," Fischer recalled. "And we realized at that

time that this disease could be the best candidate to test gene therapy."

The need for some type of effective treatment was certainly dire. Like all

forms of SCID, he said, without treatment this one kills within the first

year of life. The only treatment was bone-marrow transplants; but their

success rate plummets unless close to identical immune- system matches can

be found, and that's possible only about 20 p!

 ercent of the time.

The types of cells affected by the disease also made it a good candidate for

treatment with gene therapy, Fischer said. First, when the gene in which the

mutation occurs is functioning properly, it encodes a protein that is vital

if the precursors of T lymphocytes are to survive and proliferate. Second,

unlike other types of immune system cells, T lymphocytes can survive for

decades--sometimes even for an entire lifetime.

These two facts meant that even if the researchers could genetically alter

only a few precursor cells, these cells might develop--or, as the scientists

say, "differentiate"--into a large number of mature T cells that had a

lasting benefit for the patient. "So we had the hope," Fischer said, "that a

very poor technology could--in that context, with that disease--work."

Then came the drudgery. "We made vectors, retroviral vectors, the best

technology of the time, blah blah blah," remembered Fischer. But the tests

went well. By 1998, Fischer and his colleagues were ready to seek approval

to start human trials.

The first trial began on March 13, 1999. "And between '99 and 2002, we had

treated 10 patients," Fischer said. The researchers took bone marrow

containing the lymphocyte -precursor cells from the patients. In cell

culture, they introduced the vector, a disabled retrovirus with the

correcting gene. After several days, they injected the cells back into the

patients. "And in nine out of ten, we were pleased to see that it worked,"

he said.

As Fischer and his team had expected, the number of treated precursor cells

able to generate T cells was very low. However, he said, it was sufficient

to produce a normal number of T cells. "After a few months, these children

could leave the hospital and start to live normally with their parents. And

except for those who had the complication I'm going to describe in a moment,

they are living normally still today."

After the first three years, three of the ten children treated developed a

severe complication, an uncontrolled proliferation of T lymphocytes. "I

would call it a leukemia-like disease," said Fischer. Childhood leukemia can

usually be cured with massive doses of chemotherapy, and that's how Fischer

and his colleagues treated the three patients. One died. "The other two kids

today are doing well, as well as the other seven," Fischer said.

How much did all this cost? "A lot!" Fischer laughed abruptly. "A lot; but

the treatment of a child with such a disease, without gene therapy, costs a

lot, too." Yes, he said, per patient, the cost of the research is huge. But

"the cost of the therapy itself is not that big. Let's assume it's

commercialized. I would assume the cost of the therapy itself, with the cost

of the vector--the cell treatment ex vivo--shouldn't cost more than maybe

somewhere between $30,000 and $50,000, something like that. Per patient."

About the same as a heart transplant? "Exactly!" he said. "As it moves

toward being a kind of, quote, ‘routine therapy,' this is not much higher

than many other therapies."

And those complications? "We'll see when we have enough follow-up to be

sure," he said, adding that if the chances of such a complication were

reduced by a factor of 10, he'd consider the risk-benefit ratio "perfectly

acceptable." Fischer said he does not yet know whether his methods can be

generalized to other types of genetic defects; he is not making any sweeping

claims. His group is moving first to two other immune-deficiency diseases,

involving other genes. "So we want to go step by step from the ones that are

easiest to the most complex."

From the first glimmer of possibility to the present day, Theodore Friedmann

has written and spoken as gene therapy's most ardent advocate. He has seen

medicine enter a new era, which offers "new and definitive approaches to

therapy that were previously only the stuff of dreams and scientific

fantasy." His has also been a voice of caution, of reason. He has had to

warn his colleagues that they must openly address their discipline's

difficulties, its limitations, its failures. Yet he continues to marvel at

the unprecedented possibilities raised by gene transfer. For the first time,

he says, and one can sense his quiet exultation, medicine can do more than

treat the signs and symptoms. It can reach the underlying causes. It can

cure. "It's going to be difficult," he says. "Yet medicine has always had to

work with imperfect knowledge and technology."

Horace Freeland Judson is the author of five books, including The Eighth Day

of Creation, a history of molecular biology that was published in 1979 and

is still in print.