INTERVIEW

The pioneer who conducted the first human gene therapy is looking toward gene
transfer to treat diabetes and heart disease and maybe even double life span.
In a thousand years, he adds, you may have to augment your DNA

W. FRENCH ANDERSON

He always knew what he wanted to do. In the late Fifties, before recombinant
DNA technology was drawing-board theory, he vowed to cure hereditary disorders
by repairing faulty genes. His Harvard professors laughed at the aspiring
genetic surgeon with the Okie accent and cowboy boots. But W. French Anderson,
now chief of the Molecular Hematology Branch at the National Heart, Lung, Blood
Institute in Bethesda, Maryland, never wavered in his mission to bring gene
therapy from the laboratory bench to the patient's bedside. And in September
1990, Anderson and his colleagues ushered in a new era of medicine with the
first human gene procedure aimed at correcting a hereditary disease.

The patient, a four-year-old girl, was born with an adenosine deaminase (ADA)
deficiency. She lacked the same key immune cell enzyme as David the bubble boy,
whose defenses were so impaired that he was forced to live inside a germ-free
capsule. Anderson and collaborators R. Michael Blaese and Kenneth Culver of the
National Cancer Institute (NCI) combined some of the girl's white blood cells
with those of an engineered virus. These genetically modified cells were then
reintroduced into her bloodstream, where it was hoped they would multiply over
the coming months, gradually restoring the functioning of her immune system.

Although still too soon to predict the ultimate success of this much-heralded
trial, the physicians are very encouraged by the child's progress. She is
better clinically and many of her immune function studies are improving, some
into the normal range. Another ADA patient, a nine-year-old girl, began
treatment on January 31, 1991. Early results suggest that she, too, is
improving thanks to gene therapy. The investigators now believe this general
strategy promises to have applications far beyond the treatment of rare
hereditary diseases. Since genes code for vital body chemicals, Anderson thinks
gene transfer techniques will eventually be used to "trick" cells into releasing
drugs useful in the treatment of almost any disorder-from AIDS and cancer to
heart disease and ordinary aging. Inserting the gene for insulin into the B
cells of the pancreas might enable the diabetic patient to synthesize his own
internal source of the hormone, eliminating the need for daily injections.

Raised at the edge of the dust bowl in Tulsa, Anderson was a prodigy. His
passion for science burgeoned at age three, and by the end of grade school, he'd
consumed every technical book he could find, including college-level medical
texts. As a Harvard University senior at seventeen, he took one of the first
courses linking DNA to genetics. The instructor was James Watson, the Nobel
laureate who only four years earlier had codiscovered the chemical structure of
DNA with Francis Crick. A year later, Anderson went to Cambridge, England, to
continue his genetic studies with Crick. He completed his M.D. at Harvard in
1963 and two years later moved to the National Institutes of Health, where he's
been ever since.

At NIH Anderson discovered the specific factors cells use to initiate protein
synthesis, while his clinical studies led to breakthroughs in the treatment of
deadly hereditary diseases. He championed the use of iron chelators for removing
excess iron from the blood of thalassemia victims, which dramatically extended
the lives of these patients. With the advent of gene-splicing techniques in the
Seventies, Anderson intensified his efforts to devise better ways to get genes
into cells. Using a hair-thin needle guided under a microscope, he pioneered the
microinjection of genes. From the mid-Eighties on he used retroviruses to ferry
genes into human chromosomes. And most dramatically, he has brought gene
therapy to clinical use.

Whether confronting a problem in scientific technique or an obstacle in personal
life, Anderson won't let go of a challenge until he's brought it to ground. A
story from his youth is telling: To overcome a terrible stutter, he joined a
debating team. Surviving this baptism by fire, he emerged as a champion debater
in Oklahoma. Later, he took up Tae Kwon Do, a form of Korean karate, and
attained a fourth-degree black belt. In 1988 he accompanied the American Tae
Kwon Do team to the Seoul Olympics as their chief sports physician.

Kathleen McAuliffe first interviewed Anderson in his office, and later in the
more relaxed environment of his home. Well. . . relaxed for French Anderson.
Afterward, he went to his cellar gym to practice karate, demonstrating once
again his iron will-and iron fist.

Omni: Tampering with genes--even for treating diseases-has aroused widespread
concerns. Do you think those fears are inflated?

Anderson: It's clearly an emotional issue. Jeremy Rifkin [outspoken critic of
genetic engineering] has fanned those concerns by exaggerating the risks. But
he wouldn't attract so much media attention if society didn't have fears in the
first place. Yes, I am concerned. My mother is concerned. The athletes I
accompanied to the Olympics are concerned. It's bad enough to have your mind
manipulated through advertising, or into eating artificial substances in foods.
So the notion of manipulating genes-which make us who we are-is frightening. I
feel strongly that gene therapy should be applied only for the treatment of
disease. Very firm lines should be drawn to ensure that genetic engineering is
used for no other purpose. That's been my position for twenty-five years.

Anderson: I believe an excellent system is in place for reviewing protocols and
that doctors in this area are following a very ethical path. The long, involved
process of gaining approval for the first human gene therapy trial is testimony
to the numerous safeguards in place. This [he points to a document bigger than
a Manhattan phone book] was the earliest draft of the protocol for the
experiment. The Recombinant DNA Advisory Committee and half a dozen other
regulatory committees studied it. Several reviewed the experiment twice, and
numerous public hearings took place with TV crews present. In the end,
virtually every reviewer voted to proceed with the experiment. Even Rifkin
complimented us on the care we took in preparing the Informed Consent Document
that lays out for the patient all the risks and benefits of the procedure.

Omni: Why did you choose a patient with ADA deficiency, a very rare disorder,
for the first gene therapy trial?

Anderson: In the Seventies I initially targeted a more common hereditary
disorder--thalassemia--for the first trial. Kids with the disease produce
abnormal hemoglobin [the blood molecule that transports oxygen]. Those pictures
on the wall are of Nick and Judy, my first two patients with thalassemia. It's
a fatal disease, and both died years ago. Unfortunately, thalassemia turned out
to be too great a challenge for us then because the instructions for producing
hemoglobin are encoded in several different genes.

Omni: Isn't it distressing talking to these desperately ill children?

Anderson: I'm much more comfortable with children than adults, who tend to
maintain a protective front. Kids talk about things important to them. Death
and suffering are very real issues. Yes, I'm very comfortable talking to them
about dying, I interact well with sick children. I can just feel with them.

Omni: Why was ADA deficiency a better disease to target than thalassemia?

Anderson: ADA, which stands for the enzyme that malfunctions in these children
as a result of their genetic defect, involves only one gene. Without adenosine
deaminase, the body cannot produce new T and B lymphocytes. So ADA kids suffer
from severe combined immunodeficiency and need to be protected from infections.

Omni: How is gene therapy done?

Anderson: We withdraw the children's white blood cells and put into each cell a
healthy copy of the gene for the ADA enzyme. We'd already genetically modified
monkeys' immune cells, and after we reintroduced the white blood cells
intravenously, the animals actually produced human ADA in their bloodstreams.
That positive result convinced us we were ready to begin treating a human with
the disease.

Omni: Could you be guilty of rushing ahead too quickly, as critics claim?

Anderson: Some patients with ADA might have been helped had we proceeded three
years earlier. Richard Mulligan [at the Whitehead Institute for Biomedical
Research in Boston] is the main scientist opposing our group. And from his
perspective, he is right. But as a Ph.D., he doesn't have the experience of an
M.D. doing rounds on a pediatric ward every day who knows that ninety percent of
medicine is an art-not a science. That makes a scientist uncomfortable. So he
felt our ADA gene protocol was premature. But the science was actually much
further developed at the outset than is the case for most successful therapies.

Omni: Were you nervous on the day of the trial?

Anderson: Extremely. Even though the event itself was very anticlimactic. I
mean, hanging up a bag of blood cells and intravenously dripping them into a
patient happens ten times a day in that intensive care unit. And that's just
one of many medical wards here, and we're just one of thousands of hospitals.

Omni: Didn't you worry she might die?

Anderson: Not from anything related to the procedure. I did worry that she
might get a blood clot in her lungs or develop some other rare, life-threatening
condition during the trial, which would have been an absolute disaster. I mean,
if the first patient died while genetically modified cells were going into her
body, who would agree to be the second patient? It could have set gene therapy
back a decade.

Omni: What are the indications that the gene treatment helped?

Anderson: At this stage, there is every indication she is doing well. No, better
than well-she is doing beautifully in every way we can measure she is improving.
Her parents are delighted because she is no longer sick all the time. In fact,
she's just been sick once and that was when the whole family came down with flu.
She was the first to get better! Her parents couldn't believe it. They were
still sick in bed and she was running around playing. They say she smiles and
laughs a lot more than before. As far as laboratory measurements are concerned,
her T cell count is normal for the first time in her life, most of her immune
function studies are improving, and some are now in the normal range. And we
can isolate gene-corrected cells making ADA directly from her bloodstream. She
has never shown any serious side effects from any of the infusions. We could
not be happier about the way things are going. Our second patient, a
nine-year-old girl, has had two infusions. She is also doing very well and the
first preliminary data on her appear to show that she is improving.

Omni: How many more patients are you going to treat? Anderson: That's Mike
Blaese's decision, since he is the PI [principal investigator) on the protocol.
But our plan is to add another patient at the end of the summer and maybe one
more at the end of the year.

Omni: Does the treatment carry risks for problems later on?

Anderson: To introduce genes into the patient's cells, we use a vector derived
from a retrovirus that can cause leukemia in mice. We snip out most of the
retrovirus's genetic material so it can't cause disease, But there is always a
remote possibility that when the new gene is inserted inside the patient's cells
the process might cause cancer many years later.

Omni: Before the ADA trial, your group introduced a foreign gene into ten adults
with advanced melanoma. The gene itself was not intended to have therapeutic
benefits, so was this early trial done basically to show that gene transfer was
safe? Anderson: In part, yes, since the risk to a terminal patient is almost
infinitesimal. But another major motivation was to obtain information that
could help medicine better develop cancer treatments in the future. Mike
Blaese, our ADA expert at NIH, saw that our gene transfer techniques could help
Steve Rosenberg at NCI refine his new cancer therapy and got us all together.
Rosenberg removes cancer-fighting white blood cells called TILs [tumor
infiltrating lymphocytes] from the patient's tumor. In the lab those cells are
multiplied ten-thousandfold using the growth factor interleukin-2. Then the
TILs are given back to the patient. About forty percent of patients show at
least a fifty percent reduction in tumor size. Ten percent have a complete
response; there's no evidence of any remaining tumor.

Omni: For terminal patients, isn't that an incredible response?

Anderson: Yes. But why does the treatment work for some and not others?
Rosenberg needed some way to get a handle on what was happening inside the body.
He needed to know where those TILs were going. What they were doing. That's
where our technology could help. We tagged the TILs removed from the patients
with a retroviral vector carrying a bacterial gene. When those gene-marked cells
were returned to the body, they functioned a lot like a radio transmitter
attached to a dolphin. We followed the TILs, saw how long they lived, where
they went. It worked beautifully and perhaps has helped us to identify a
subpopulation of lymphocytes more effective in fighting tumors. These findings
may help us develop more powerful treatments against some types of cancer.

For example, Steve Rosenberg has already started treating two patients with
advanced malignant melanoma by infusing TILs that contain the gene for tumor
necrosis factor, an anticancer compound. Although it's too early to see any
clinical response-we are still in the phase one safety trial-these patients have
shown no toxicity from the gene transfer. Other approaches for using gene
transfer to treat cancer are now being developed.

Omni: When did you know retroviruses would work in gene therapy?

Anderson: By around 1983, I became convinced that they were the way to go. It
was not a sudden revelation. I'd been talking with Ed Scolnick, then at NCI,
about retroviral vectors since 1979-1980. But there were so many apparent
problems with them. By late 1983, thanks to the work of Gilboa, Mulligan,
Verma, Friedmann, Miller, Bernstein, and others, I developed a deep instinctive
conviction that retroviral vectors could be made to work in human gene therapy
protocols.

Retroviruses normally carry genetic information into cells; that's how they
reproduce themselves. They evolved to do just that, so they're much more
efficient than micro-injection. With retroviruses we could get into millions of
cells in one step, I should make it clear that I'm not the only person to have
this idea. But, yes, most of the rest of the world thought we would never make
it work in patients. Of course there were technical problems. There always are.
But to me, the important thing was that I knew what ought to be done .

Omni: Why are you so confident your experiments will work?

Anderson: I've always had that ability. My conscious mind isn't so bright. I
have trouble following lectures unless I know something about the subject. But
when I get really interested in a problem, I take in all the information and
totally immerse myself in it. My subconscious works on it all the time, and
sooner or later it comes out. Sometimes I'll wake up at three A.M. with the
idea for an experiment.

Omni: And it works?

Anderson: Ninety percent of your "brilliant" ideas don't work the first time.
And don't work for a long time-the experiment may drag on for months or years.
Francis Crick once said if there's a conflict between theory and data, the
theory's more likely to be correct. Most scientists think just the opposite,
but I'm more like Crick. If an experiment ought to work, I'm convinced it will
work, and stick with it until it does.

I'll tell you something more bizarre. Molecules have minds. They can tell if
you're not comfortable with them, if you're not really in control. So they just
won't work. You have to get inside the minds of molecules and master them.
Sooner or later they will give up and do what you want them to. You can try and
try to no avail. But once you finally get the system working, you can drop the
experiment on the floor, scrape it up, and it will still work.

Omni: How did you see the idea for gene therapy so long before, the advent of
genetic engineering technology?

Anderson: By my junior year in high school I was already thinking about the idea
in its broadest outlines. I wrote on my application to Harvard that I wanted to
study the molecular basis of human disease. Nobody even knew what a gene was at
that stage. By my senior year in college, however, we knew about this slimy
stuff, DNA, that could alter the appearance and function of bacteria. Working
with Julie Marmur, I'd irradiate DNA with ultraviolet light, causing mutations
in the molecule, and then introduce it into bacteria. This experimental
manipulation would often change a basic property of the bacteria. So it
occurred to me then: If I can change how a bacterium functions by giving it new
DNA, it ought to be possible to use the same strategy to help people suffering
from hereditary disorders. I began to study human genetic disease at NIH,
joining [Nobel laureate] Marshall Nirenberg, who was working out the final
stages of the genetic code in E. coli. When that project was completed, I
announced I wanted to study hereditary diseases in man. Marshall was aghast.
So little was known about human genetics then, he thought I was throwing my
career away. It was only if you couldn't make it in E. coli genetics that you
worked on humans. But that's what I wanted to do. So I said, "If you won't let
me do what I want to do, I quit." Marshall did his best to talk me out of it but
finally gave in and let me spend fifty percent of my time doing human work,

Omni: What sorts of advances can we look forward to in the future?

Anderson: We're trying to transfer genes into other types of human cells:
hepatocytes [a type of liver cell]; endothelial cells [lining blood vessels and
the heart]; and bone marrow stem cells. A host of potential applications could
come out of this work. Endothelial cells are especially attractive targets
because any protein produced by them will be secreted directly into the
bloodstream. One protein we'd like these cells to produce is the anticlotting
factor TPA [tissue plasminogen activator]. When a clogged or injured blood
vessel needs to be replaced, doctors will graft in an artificial vessel. About
three hundred thousand grafts are performed yearly in the United States, and one
hundred thousand of them fail because a clot forms in the artificial vessel.
David Dichek in my lab plans to line the artificial vessel with endothelial
cells that have been genetically manipulated to produce TPA. We've done it with
rabbit cells, and others have been successful with pigs and dogs. But the cells
tend to wash off after a couple of days. When we find a better way to anchor
them, these techniques will improve the success of blood-vessel grafts in
humans.

We also hope to engineer insulinproducing cells for the diabetic, or antitumor
agents for the cancer patient. Perhaps someday we might genetically engineer
cells to produce neurochemicals needed by psychiatric patients.

Omni: So gene transfer could provide a new drug delivery system?

Anderson: Yes. Drug companies now churn out millions of vials of drugs with
half-lives of minutes or hours. Some must be injected several times a day or
week. Today even diabetics who closely monitor their blood sugar levels still
suffer debilitating problems, such as the retinopathy leading to blindness.
Perhaps they can't regulate the drug dosage closely enough. By transferring a
properly regulated gene for insulin into the B cells of the pancreas, we might
avoid such serious complications. We hope to get the body to manufacture and
release the appropriate amount of insulin at the appropriate time-the way a
healthy body does. Within twenty years gene transfer techniques will give us
another drug delivery vehicle.

Omni: Could gene therapy transform us into a new species?

Anderson: No. We have a hundred thousand genes, and even after the Human Genome
Project is completed, all we'll know is the sequence of these genes. We won't
know what they do in the body; at what stage in our life cycle the gene is
expressed; or how one gene interacts with others. The total amount of
information contained in the human genome is truly overwhelming. Comparing that
knowledge to an ocean, all we're doing is scooping water out of a tiny lagoon.
And with each scoop, the inlet fills up with more water. The idea of creating a
new species of human any, time in the next century is about as likely as
traveling at warp speed to a galaxy millions of light-years away.

Omni: If ninety-eight percent of our DNA matches the chimpanzee's, perhaps you'd
have to change only a few genes to transform the species. Anderson: That's
misleading. That figure is based on how much of our DNA will bind to, or
"hybridize," with a complementary strand of DNA from a chimp. If you actually
look at the bases [the basic components of the genetic code], only about seventy
percent of our DNA exactly matches the sequence of a chimp. We probably differ
by twenty to eighty million base pairs. That's an enormous difference when you
consider that gene therapy usually involves the correction of only one or two
genes, or what amounts to a few thousand base pairs.

Omni: Still, by introducing extra copies of those genes that possibly encode for
enzymes that repair damage done to DNA as we age, couldn't we, say, double our
life spans?

Anderson: You're not talking about creating a new species now. The scenario
you're presenting is more than possible--it very well may happen over the next
hundred years.

Omni: Would it be ethical to alter our genetic endowment to live one hundred and
fifty years?

Anderson: No, because society isn't ready to handle the problems that this
development would engender. As it is, we can barely care properly for people
living into their eighties or nineties. Also a gene that expands our life span
may have twenty other detrimental effects. These individuals may live
longer--but might be worse off in terms of their vigor, health, intelligence,
memory, and so on. Say, parents of short children might want their offspring to
receive the gene for human growth hormone so they could become basketball stars.
But who knows what problems that might cause later in life?

Let's say, however, that our knowledge progresses to the point that we can
safely expand the human life span, or make kids taller, or who knows. Maybe
someone will discover a gene coding for a neurochemical that enhances memory.
Then there's the whole issue of equality: Who gets the gene? Who decides who
qualifies? And by what criteria? Do we give the memory-booster gene to mentally
retarded children, because they need it the most? Do we give it to smart kids,
who could make the most use of it? Who deserves to live longer? Be taller? Our
society has no answers. I don't think we should use a powerful technology just
because it exists.

Omni: Once the technology exists, won't there always be genetic doctors who'll
perform surgery for the right fee?

Anderson: Yes, based on what we know is a thriving black market for steroids
among athletes.

Omni: We have cosmetic surgery, and a system for deciding who gets it-namely,
money. Why is this different?

Anderson: It's considerably more fundamental, something that strikes at the core
of who we are. Surgery on the breasts or face is very superficial in the real
sense of the word. Why doesn't society permit Olympic athletes to take steroids
if what we want is people who can jump higher, run faster, lift more weights?
The reason is only partly because of the dangerous long-term health
consequences. Steroids give people an unfair advantage.

Omni: What could be more unfair than our genetic endowment at birth?

Anderson: True. And society quite legitimately is concerned that the richest,
most powerful, most famous, will get the good genes first. Elite groups could
become even smarter, better looking, and richer than people disadvantaged from
day one, That's why society is more comfortable with the idea of offering
genetic surgery to individuals who, through no fault of their own, suffer from
severe diseases. Then it is morally justifiable to at least try to bring them
up to a minimum level of quality of life. To take an acceptable quality of life
and try to enhance it would be more disruptive to society than beneficial.

Omni: Would it be ethical if we could boost everyone's intelligence or life span
or physical prowess through gene transfer?

Anderson: Yes. If it turned out everyone could have a marvelous quality of life
for one hundred and fifty years, then everybody ought to have it. But now we're
getting into the argument of how many angels can stand on the head of a
pin-because for the next fifty years it's not going to be possible to
genetically engineer the whole population.

Omni: How do you decide what constitutes a disease? How short is too short? How
fat is too fat?

Anderson: You start out with severe cases: the child who'd grow up to be under
three feet tall. If the procedure proves safe and effective, then you would
gradually extend treatment to people with less serious conditions. Until gene
therapy is well accepted by society, we should err on the side of being too
conservative and restrict treatment to the most medically needy.

Omni: Might a future generation view gene therapy like cosmetic surgery?

Anderson: If we continue to destroy our ozone layer and pollute the environment
with toxins and carcinogens, everybody may need gene therapy in another thousand
years-extra genes for DNA repair enzymes to protect against harmful radiation
from the sun, extra genes to boost the number of liver enzymes that can detoxify
dangerous compounds. A New Yorker cartoon shows a spokesman outside a nuclear
reactor saying to a TV crew, "Not to worry. The genetic damage caused by the
nuclear accident can be corrected by genetic engineering." I hope that day never
comes to pass, but one cannot be encouraged by how we're handling our
environment now. What happens with gene therapy in the long run depends on the
risk-benefit ratio to society. But what society does five hundred years from
now is not for us to decide. They wouldn't care what we have to say any more
than we care what people in 1600 thought about how we should spend our lives.
Ethics, after all, is contextual. To a future society, gene therapy may not
only be acceptable--it may be essential for its survival.