Somewhere in the world an unborn baby suffers from a rare genetic disease that -- if left untreated -- will claim its life within months after birth. But next year, a dramatic new medical technique called gene therapy may enable this baby to survive. If gene therapy works -- and there is growing evidence to suggest that it could -- a new era of medicine will be opened, one that could have promising applications for such wide-ranging, fatal diseases as sickle cell anemia, heart disease and even cancer.
Sometime next year, it is expected that this infant -- perhaps at about 6 months of age, maybe slightly older -- will be wheeled down a hospital corridor to an operating room. The baby -- whose body lacks an enzyme necessary for proper immune system functioning -- will be placed under general anesthesia and turned gently on his or her stomach. Doctors will take a large needle, insert it into the infant's hip and extract some bone marrow. Up to 10 percent of the child's bone marrow will be removed, placed in a sterile flask and carried quickly to a nearby laboratory.
There the bone marrow will be spun in a specially equipped centrifuge to select out cells called stem cells. Scientists will try to repair the genes of those cells with a modified virus.
The virus has been altered to carry the missing human gene. It now contains just enough viral machinery to "infect" the baby's stem cells with the gene, but contains none of the other qualities of a virus. The baby's stem cells and the altered viral particles will be combined in a petri dish.
Twenty-four hours later, the "infected" bone marrow will be returned to the child's body intravenously, just like a blood transfusion. About two days after that, the child will go home.
And then everyone -- doctors, parents, researchers -- will wait.
If blood tests within a few weeks to a few months show that the missing enzyme is present, the child will have beaten a disease that claims most victims by age 2. The doctors will have performed a successful and historical experiment, and modern medicine -- well, modern medicine will be at the threshold of what normally cautious researchers call a revolution.
Gene therapy is upon us. It will be a far cry from the cloning techniques described in "Brave New World" -- although some critics cite the Aldous Huxley tale as an example of where this new technology could lead. Nor is gene therapy likely to be the stuff of "The Andromeda Strain" -- the scary virus from outer space that wreaks havoc on unsuspecting humans before mutating to a benign form.
What gene therapy will be is a chance to treat severe -- and usually fatal -- diseases by altering the very fabric of life: the DNA molecules that make up chromosomes and genes. This is the chemical material that dictates a vast array of genetic information, from the type of metabolic enzymes present in our bodies to the color of eyes, hair and skin. Information in the chromosomes determines whether a baby will be male or female, how tall someone will be and even whether he or she will be susceptible to heart disease or diabetes. In short, the chromosomes are the master blueprints of the body, and for the first time in history, gene therapy will allow scientists to attempt to correct the architectural, inborn errors of nature.
"Things are going very rapidly," Dr. W. French Anderson, chief of the National Heart Lung and Blood Institute's laboratory of molecular hematology, told a recent meeting of that institute's advisory council. "We are very encouraged."
Although so far gene therapy has been limited to experiments in mice and monkeys and to a test or two on human white blood cells in laboratory test tubes, Anderson said, "We think that in the not-too-distant future we should be able to get the efficiency of this procedure sufficiently high that we could comfortably plan to carry out human gene therapy . . .
"It is possible, if the work that I tell you about today continues to go well, that perhaps as early as the end of the year, very probably by the beginning of next year, it will be possible to submit a protocol for review."
The first humans, Anderson announced recently, are likely to be treated "sometime in 1986 and very possibly in the early part of 1986."
The tool for this genetic renovation is the virus. Researchers like Dr. Michael Blaese, chief of the Cellular Immunology Section at the National Cancer Institute's Metabolism Branch, are harnessing viruses to work for, instead of against, human health.
A virus, he says, is simply "an infectious group of genes." Strip a virus of its genes of reproduction, and it can't make more viruses. It is no longer a threat. What remains is the virus's ability to infect a cell. In the place of the removed viral genes, scientists drop human genes, just like a cassette goes into a tape player.
"What we've done," says NCI's Blaese, "is to take the genes out of the virus and put in the [human] genes that we want."
The recombined virus is still capable of slipping inside a cell and delivering its genetic material to the cell's nucleus. But the difference is that now the virus inserts a human gene into the cell's own DNA (deoxyribonucleic acid). This new gene can then override the inborn error that causes a genetic disease.
The most likely candidate for the first gene therapy will be an infant with a rare disease called ADA deficiency. Only eight to 10 people in North America are afflicted with this type of immune deficiency, a condition similar to the one that killed David -- the famous "Bubble Boy" -- in Houston last year. People who suffer from ADA lack an enzyme called adenosine deaminase. Without it, the amount of a chemical, deoxyadenosine, rises to abnormal or toxic levels in the blood, preventing white blood cells, specifically T-cells, from dividing, multiplying and, ultimately, from fighting infection.
Matched bone marrow transplants from a sibling have an 80 percent or better chance of curing these youngsters. Unfortunately, only one in four ADA victims has a sibling whose bone marrow is a close enough match to use. "If we can't offer this kind of therapy," says NCI's Blaese, "90 percent of kids with this disease will be dead by 15 months of age."
But there are other reasons for targeting ADA for the first attempt at human gene therapy. For one, the gene to correct ADA is available, having been separated and cloned by University of Cincinnati researcher John Hutton, among others. For another, stem cells extracted from a patient's bone marrow will mature into T-cells, which are easily accessible to researchers. This means that these cells can be extracted, treated with viral particles containing the ADA enzyme gene and reinserted into the body -- a feat possible for only several dozen of the more than thousands of genetic diseases.
There's also an indication that infecting just a small percentage of these stem cells with the corrective gene may be enough to colonize the body with normal T-cells -- unlike other genetic diseases, says Anderson, which may require "50, 60 or 70 percent infection rates."
Something else that makes ADA a likely disease for pioneering gene therapy is that researchers won't have to tamper with the patient's bone marrow -- other than to remove a small portion of it. Future targets for gene therapy will probably require destruction of old bone marrow cells with radiation to make room for new cells. In those cases, if the gene therapy doesn't work, the patient would be left with a very depressed immune system -- perhaps a far deadlier condition than the genetic disease itself.
Also, "ADA is the most simple-minded of any of the genetic diseases we might hope to address," says embryologist Martin Eglitis, part of the team working with Anderson and Blaese at the National Institutes of Health.
"If gene therapy doesn't work in ADA deficiency, then it's unlikely that it will work [at all]," adds Anderson. "If it works in ADA, that opens up a whole range of other genetic diseases."
The list of genetic diseases that harm, cripple and in many cases kill their victims runs into the thousands. Yet for most of these illness, "there is very little that you can do now," says NHLBI's Anderson. "We are still back at the first revolution in medicine. We can sit by the bedside and talk to the family, but we really can't do much."
What gene therapy could mean, Anderson says, is that "15 to 20 years from now, a wide range of lethal, genetically disabling diseases, might be cured."
Think of it. Sickle cell anemia, a blood disease causing abnormal hemogloblin production in many blacks. Tay-Sachs, a disorder of fat, or lipid, metabolism that produces blindness and mental retardation in the first few years of life. Lesch-Nyhan, a severe neurological illness that causes uncontrollable self-mutilation in its victims. PKU, or phenylketonuria, a defect that causes the buildup of an amino acid in the blood, and within days after birth produces irreparable brain damage. Thalessemia, or Cooley's anemia, which results in an abnormal type of hemoglobin -- the important oxygen-carrying protein in the blood. And cystic fibrosis. Hemophilia. Diabetes.
The key to overcoming any one of those disorders will be an important, historical step for medicine, and with it, an improvement for public health.
Small wonder, then, that the race to attempt the first gene therapy in a human patient is a competition reminiscent of the drive to unravel the structure of DNA -- the feat pulled off by James Watson, Francis Crick and the often-overlooked Maurice Wilkins. Gene therapy, it is said in scientific circles, will not only open up vistas for new medical treatment, but it is the stuff that helps pave the way to Stockholm and the Nobel prize in medicine.
History could be made by half a dozen research teams around the world in hot pursuit of the key to human gene therapy. But at the head of the pack are two teams in particularly close contention: an NIH-Princeton University-Memorial Sloan Kettering team headed by Anderson and Blaese and Dr. Arthur Nienhuis of NIH, molecular biologist Eli Gilboa of Princeton, and Dr. Richard O'Reilly from New York; and another team in Boston, directed by Harvard University researcher Dr. Stuart Orkin and molecular biologist Richard Mulligan of MIT.
All these teams have performed gene therapy experiments in mice -- with promising results. But only one, the Anderson group, has attempted experiments in monkeys -- a fact he says puts them "the closest to doing this therapy in humans."
In reporting on the status of his group's monkey experiments to a recent NHLBI Advisory Council meeting, Anderson said: "The procedure that we tried to do is exactly as we would do in a patient, and we immediately found with the first animal that going from a mouse to a monkey was an enormous problem and we failed on our first several tries. Now we're learning how to run the protocol so that in fact we are able to infect, to a low percentage, somewhere between a tenth and 1 percent of cells . . . The results show that, yes, we can get a very small number of stem cells infected. It does express what appears to be the human ADA gene and the neo gene [another kind of marker gene scientists use to determine if gene transfer has been effective]. But the total efficiency of the procedure simply going from mouse to monkeys has gone very low.
"Where we stand at the present time is that . . . we have a mouse system which works very effectively [90 percent of removed cells are infected], we have gone into a number of monkeys . . . We are able to get a low level of expression and activity of the gene. We need to get that much more efficient."
In addition, Anderson and his colleagues also have conducted test-tube experiments using recombined viruses on T-cells drawn from a patient with ADA. On their first try, the team was able to infect 15 percent of the cells, "which is good," Anderson told the Advisory Council, "though not as high as we think we can get it." These results demonstrate it is possible for the virus to carry the ADA gene into the cell and turn on the enzyme.
"It tells us," Anderson says, "that those cells are corrected. That's nice, and it certainly indicates promise."
But it will still take more studies before the first genes are implanted in humans. "As excited as I am about gene therapy, I want to be convinced in my heart that this is the best option I can give to these patients," says NCI's Blaese. "We have got to do more experiments before I can say that . . . We have had so many exciting tidbits of information coming down the line just in the last two months. It's exciting, very positive data that's been coming out, and that's just tremendous. If it continues to go this way, gene therapy is really going to be something that I can recommend very enthusiastically."
Adds Dr. Philip Kantoff, an NIH medical fellow and a key player on the Anderson gene therapy team: "When you discover a new star, it may be important to be first, but in this type of thing, I feel, it's nice to have company there. You're dealing with people, and you want to make sure that you're doing everything right and not making any mistakes. It's important not only to be first, but to be right."
The drive to do gene therapy in the first human is a bit like the space race. Every step must be practiced again and again. Researchers are now rehearsing with monkeys, and -- since a monkey is about the same size as an infant -- transplanting genes into the primates gives the scientists a chance to develop contingency plans for every conceivable problem.
"What would you do if a [test] tube breaks?" says Anderson, who is one of eight members of the gene therapy group also known as the "gene team." "What would you do if you dropped a tube? What would you do if you have your cells and they get infected with a fungus or something? What if the bone marrow cells themselves are contaminated in some way?
"When you're first setting these things up, you're just trying to see if it will work and you don't worry about anything else. Once it looks like it's working, then you have to look for all the potential problems."
In the past two monkey experiments, Anderson and his team have been operating as if the animal were a human baby. "Just the increased tension of thinking of this as human bone marrow, I found that my hands shook and that even getting lids on didn't go as easily, that things don't work as well, because you are afraid that you might contaminate something," Anderson said. "It's really going to take experience to have done it enough times, so that you know you can [still] do it if anything bad or unexpected happens."
Even when the experiment can be done perfectly every time, the final decision about when gene therapy can be performed in humans will not be left solely up to scientists. An elaborate set of committees -- comprising lawyers, medical ethicists, physicians, laymen and researchers -- has been set up to review the scientific data and to consider a protocol, or proposed treatment plan, for this new therapy. Among those who must approve the therapy are at least four different NIH institute-level committees, two overall NIH committees (the Recombinant DNA Advisory Committee, or RAC, and its advisory working group the Food and Drug Administration and NIH director Dr. James Wyngaarden.
This complex approval process arises out of an awareness of the magnitude of what is being approached. As Judith Areen, associate dean of Georgetown University Law Center, speculates in an upcoming law journal article: "It will no doubt will be difficult to achieve appropriate control of gene therapy or of any technology of comparable power . . . gene therapy raise[s] at least the possibility of ending the human race as we know it."
Such concerns are being well addressed by the various advisory groups, including RAC, she writes.
But not everyone is comfortable with the prospect of gene therapy.
"Up to now, reproduction has been a crapshoot, a lottery," says Jeremy Rifkin, president of the Foundation of Economic Trends and an opponent of genetic engineering of all types -- including gene therapy. Gene therapy, Rifkin says, "is not just another extension of the medical and surgical procedures used since the beginning of time. It's not like an organ transplant.
"We're walking steadfastly," he warns, "into Brave New World."
But even Rifkin recently has tempered his criticism -- at least for the type of treatment that would be used for genetic diseases like ADA. Known as somatic cell therapy, this type of gene therapy corrects the chromosomes of body cells only. It does not affect the sperm or the eggs, which would pass the gene on to future generations. Rifkin remains adamantly opposed to this second form of treatment, called germ line gene therapy. Germ line therapy, he says, could lead to "eugenics" -- the science of improving a race or species by the careful selection of parents. "Germ line gene therapy raises extremely complex social and moral questions," he says.
Rifkin also worries that the human race could face a new scourge of diseases from a recombined form of virus created by these genetic manipulations. But scientists say both these fears are unwarranted.
The present gene therapy technique is still terribly crude, and years from being even close to germ line therapy. "It's quite likely that 50 years from now, people will look back at this stuff and it will seem like the Wright brothers' airplane," says Martin Eglitis, an embryologist at NIH. In addition, today's treatment is limited to using one type of virus, and they are stripped of all their reproductive genes.
"I would point out the fact that what we are introducing is the remnants of the virus," says Princeton University's Eli Gilboa. "It's not virus. Whatever is done to it, there will be no virus floating around in the patient . . . I honestly don't see any reason for concern."
One possible risk is accidentally turning on special genes -- called oncogenes -- inside the patient's cell that could lead to cancer, Gilboa says. "The very fact that it [the new gene] integrates in the cell means that it may be able to activate adjacent oncogenes [and cause cancer] . . . The likelihood is small, but existant . . . Then you have to weigh the risk for the patient and the benefit of gene therapy. And obviously, in the case of a child who is dying, you won't care about that risk."
To help guard against that remote possibility, Gilboa and other researchers also are trying to develop new ways of delivering genes to the cell that would eliminate even the outside chance of activating an oncogene.
For the future, gene therapy may be used to fight cancer.
There are some cancer drugs that cannot be used because they are toxic to bone marrow, NCI's Blaese says. "One could theoretically take the gene for resistance to that drug, put it into bone marrow, and the bone would be resistant to the drug and you could get much, much more drug to treat the cancer someplace else in the body, and the bone marrow would survive such a treatment."
Over the next 20 years, Blaese says, gene therapy "is going to allow us to manipulate a lot of these things, to make a lot of these genetic disorders treatable."
Right now, explains NIH fellow Kantoff, scientists have discovered in gene therapy a "crude key" able to unlock only a few of the molecular-sized doors in the genes. "But once we find the right key . . . "