Hello, my name is Dr. Jeffrey Gelsinger. I am a gene therapist at the Anderson Institute for Gene Therapy (AIGT), named after W. F. Anderson, the father of gene therapy. I specialize in the genetic treatment of ornithine transcarbamylase (OTC) deficiency in newborns up to one month old. Wow, you may be thinking, that is a pretty loaded opening statement! So let me take the time to explain a little bit more to you about who I am and what I do.
To begin, even my name, Gelsinger, needs an explanation. Anyone who is familiar with the early problems of gene therapy is familiar with this name. In September 1999, a healthy, eighteen-year-old boy named Jesse Gelsinger volunteered to participate in a gene therapy trial at the University of Pennsylvania that led to his unexpected death. The death of Jesse Gelsinger marked the beginning of a dark period for genetic therapy as the public became aware of misleading informed consent forms and previously unreported adverse effects of treatments. People felt that the scientists involved had no regard for the participants in their studies when they heard that scientists were calling Jesse's death "'a pothole' on the road to gene therapy" (Gelsinger 1) and excusing it by saying, "in a busy laboratory like this 'sometimes things fall through the cracks'" (Fall through the Cracks 1). The University of Pennsylvania's gene therapy program was shut down for about two years as a result of Jesse's death, and many people felt that the science behind genetic therapy should be better understood before scientists advanced any further with the testing of animals. Jesse Gelsinger was my great-uncle, and he is the reason that I became a gene therapist.
I already mentioned that I specialize in treating OTC deficiency in infants. I chose this specialty because that is the disease Jesse had been living with. One of the by- products of the body's metabolic functions is the breaking down of ammonia in the body. OTC deficiency prevents this breakdown from occurring. Jesse was an exceptional case because he was born with only a mild form of the disease, and so he was able to keep it under control through drug treatment and a strict non-protein diet (Fall through the Cracks 1). When the disease runs its normal course it usually causes death soon after birth. The gene therapy trial that Jesse volunteered to participate in was not likely to benefit him at all, but he wanted to be a part of it anyway because he wanted to give newborns with this disease the chance to live a full and happy life. Even after his death, my grandfather, Paul Gelsinger, stated in his letter to the United States Senate Health, Education, Labor and Pensions Subcommittee on Public Health that "I am not against gene therapy. I recognize it holds so much promise for so many people. But we cannot allow what happened to Jesse to happen again" (Gelsinger 3). I felt that by entering into the field of gene therapy, I would be able to help work towards Jesse's goal of helping infants born with OTCand fulfill the wish of my grandfather that Jesse's death would not be in vain. That is exactly what I did.
In their Preliminary Findings concerning the death of Jesse Gelsinger, the Institute for Human Gene Therapy (IHGT) reported that it was "the injection of the vector [that] triggered the sequence of events that led to Mr. Gelsinger's death" (IHGT 1). In one form of gene therapy, a gene is spliced into a viral vector and this virus is then injected into a patient. The virus targets and infects specific cells and inserts the gene that it is carrying into the cell’s DNA, thereby correcting the genetic disorder. In Jesse's case, the vector was a modified cold virus called adeno-associated virus (AAV), and it was injected into him in such large amounts that it caused his immune system to flare up in response to the perceived foreign invader. According to the IHGT, Jesse's genetic defect rendered him unable to handle the sudden activation of his immune system, leading to an accumulation of ammonia in the blood, coma, and the onset of Adult Respiratory Distress Syndrome, which then led to his death (IHGT 1). The manner of Jesse's death is an example of the biggest problem with which gene therapists were faced, the delivery of the gene into human cells.
In 2013, the human genome was completely mapped and sequenced, and by 2027, an international committee that had been working to establish the functions of all of the human genes had presented its findings. Suddenly gene therapists were faced with a Rosetta Stone for reading DNA and they were able to rapidly develop very specific vectors to be used in the treatment of genetic diseases. They no longer had to worry about inserting genes into important DNA stretches where they would interrupt normal functioning or into dormant stretches where the gene would not be expressed (Gibbs 2). They knew exactly where the defective genes appeared on the chromosome and they knew how to correct the problem without otherwise altering the functioning of the cell.
The first breakthrough in the treatment of genetic diseases in humans came in 2033 with the perfection of the "Naked" DNA (N-DNA) treatment that had been pioneered by Dr. Jeffrey Isner at the St. Elizabeth Medical Center in Boston in 1999. In N-DNA therapy, copies of a human gene that serve a specific organ-related function are placed into a saline solution and injected directly into the affected organ. Isner had used the VEG-F gene to grow blood vessels that would allow the heart to bypass clogged arteries that medicine and surgery had not been able to correct, but after the technique was perfected it was able to treat a variety of organ-specific diseases (Jaroff 3). Today N-DNA treatment is able to correct certain lung, liver, and kidney diseases by injecting genes that were responsible for growing certain parts of the organ tissue when that organ was originally formed, back into the organs. Once the gene is, in a sense, "reactivated," normally functioning tissues are produced that act in place of the tissues that had been damaged by disease. Once the new tissues are working properly, the older damaged tissues become inactive.
Intramuscular injection of N-DNA is another way that scientists today use the N-DNA technology to treat genetic diseases. This method is used to treat a variety of serum protein deficiency diseases such as anemia, hemophilia, and diabetes (Gibbs 2). In this case, healthy genes in saline solution are simply injected into a muscle in the same way that vaccines are administered. The genes seek out their respective cells and begin to function to produce the serum that the existing genes are not producing. N-DNA therapy provides an excellent way to treat genetic diseases, but it does so by introducing a new gene to compensate for the gene that was not working. In 2033, gene therapists were still about fifty years away from one of their ultimate goals—to be able to repair, rather than replace, defective genes.
That goal was attained in 2080, and I am proud to say that I played a major role in its occurrence. I was fresh out of the two-year gene therapy program that gene therapists were required to attend after medical school and I had been assigned to a committee in AIGT's clinical laboratories that was working on the development of viral vectors. In 2074, we were conducting experiments to see how the vectors worked across a range of genetic diseases, including Huntington's Disease (HD), sickle cell anemia, and OTC deficiency. When I entered the project, the committee had completed the animal testing for HD and sickle cell anemia and having received positive results, they were moving into Phase I of research with human participants. During Phase I trials we are mainly interested in finding out if there are adverse effects associated with the gene therapy. We work with very small groups of people and administer a very low dosage of the vectors in order to test for toxicity. We were using the adeno-associated virus (AAV) that had been used in the Gelsinger trials in 1999 and we were having good success. In the previous tests with mice and monkeys, the virus had not elicited a severe inflammatory response of the immune system and the gene had become firmly established in the nuclei of the cells (Jaroff 2). When it came to OTC deficiency, however, we had not seen the same results. When the otherwise benign modified cold virus was injected into an animal subject with this disease, the ammonia levels in the blood skyrocketed as a result of the slight immune system response and there was a complete organ shutdown. It was clear that no matter how successful AAV was in some treatments, a different type of vector was needed for OTC deficiency.
I had studied the workings of retroviruses in great detail during my two-year gene therapy program and I suggested that perhaps a modified version of the Human Immunodeficiency Virus would be best in the treatment of OTC deficiency. It takes the immune system longer to respond to HIV than to a cold virus, so I hoped that it would be just enough time for the virus to find its way into the liver cells before the immune system reacted. I first went through the routine practice of removing the genes that made HIV dangerous. Next, I spliced the gene that would produce the enzyme that OTC deficient patients lacked into the DNA of HIV. The last thing that I did was something that had not been attempted in previous trials. I found a way to suppress the expression of all the viral genes except the OTC corrective gene I had spliced in. Thus my vector was unable to produce viral proteins and thus should be almost invisible to the immune system. My vector was ready by February of 2077. The treatment succeeded beautifully in the tests with mice and the same positive results were achieved when we moved on to the testing of monkeys.
It was in September of 2080, eighty-one years after Jesse's death, that I received permission to proceed with my second Phase I trial involving human participants. The first Phase I trial, with four subjects and a very small dose, produced no adverse effects, but there was no significant increase in the production of the key enzyme. It was now time to up the dose. We would never make it to Phase II without a jump in enzyme production. But would the larger innoculum induce a catastrophic immune response? I was very nervous, but I informed my participants ofall the possible risks that they faced if they decided to participate in the trials and I answered any questions that they had about the procedures. They were provided with all of the information that was available at that time concerning similar gene therapy trials performed on mice and monkeys as well as on other humans. Out of the fifteen people who had been asked to participate, thirteen people decided to go through with it. After their initial consent, the participants were given an additional week before the trials were to begin in case they decided to change their minds.
By the first week of October 2080, we were ready to begin the trials. We made sure that all of the patients' ammonia levels were well below permissible limits, and ensured that we were ready to detect the slightest bit of inflammation in the liver that would suggest the activation of the immune system. We began the procedure on October 7th, at 9:00 a.m. The patients were injected with millions ofcopies of the viral vectors, and the vectors began to attack the cells in the liver. Everything went as planned, and, as I had hoped would happen, the immune system was taking awhile to detect HIV. At 10:30 a.m. on October 8th, we measured a slight immune response in four patients. The antibodies in the liver began to build up, but not any more than they had in the animal trials. We just hoped that the gene had established itself and that the non-expression of viral genes would prevent further immune system complications. The trial was a complete success! By noon on October 10th the necessary enzyme was being produced in low levels in ten of the thirteen participants, and by October 13th the livers of these ten people were producing the enzyme at the same level as the liver of a person without OTC deficiency!
While the gene did not express itself right away in three of the participants, the deactivation of the virus had prevented any adverse effects, and there was still the chance that the gene would begin to express itself before the end of the trial period. Even if the gene never expressed itself in these last three patients (which it did before the end of the trial period), I had succeeded in my goal. The babies would be saved just as Jesse had hoped and my grandfather could rest assured that his son's death was not in vain. My modified HIV vector, which I called the Jesse Gelsinger Vector (JGV), was easy to make, it delivered genes at high efficiency, it could infect non-dividing cells, and it transferred the therapeutic gene into the chromosome (Jaroff 4). It was a gene therapist's dream come true—a practically perfect vector. As time progressed we learned that genes that were transmitted using JGV continued to express themselves until the death of the person. The vector allowed the gene to become a permanent part of the patient's DNA, so newborns can receive one treatment that will last their lifetime.
Looking back on the development of that vector, I see it as a landmark in gene therapy. After the completion of the OTC deficiency clinical trials, we knew that we had a sure-fire way to repair defective genes without eliciting a drastic immune system response that would endanger the lives of our patients. JGV proved to be more efficient than AAV for the treatment of HD and sickle cell anemia, and is currently used to treat a host of other single gene disorders. The science of the JGV vector has become so exact in the twenty years since it was first introduced that scientists feel comfortable enough with it to start testing its efficacy in the fetal environment. The results of the animal trials of 2100 were positive, but the experimenters are still waiting for permission to begin Phase I testing with humans. The only hurdle of gene therapy that we have not yet overcome is gaining a complete understanding of multigene disorders. While we do know for sure what genes are involved in a multigene disorder such as cancer, we are still not able to pinpoint exactly what role the environment plays in the development of this and other diseases.
Of course being right in the midst of the rapidly advancing genetic technology, I saw many changes take place in response to ethical dilemmas that arose out of the new developments. One ethical problem that has actually diminished as an issue is the safety of human participants in gene therapy trials. Once gene function was understood scientists were able to be more exact in their treatment of genetic diseases, and after the development of JGV they had a 100% safe and effective mode of delivering the gene therapy. There was practically no risk involved in participating in a gene therapy trial after the development of JGV in 2080.
I use the word "practically" because there are still the unforeseen problems that can occur if a certain genetic deficiency interactscatastrophically with the slight inflammatory response of the immune system induced by the therapy. When the chance of this unexpected response is coupled with over-confident scientists who know they have the means and the knowledge to correct any defective gene that they are faced with, it could create a formula for disaster. The advanced technology and our eagerness to cure another disease made it really easy for us to become blinded to the fact that something could still go wrong. To lessen the chance of overlooking small details that could be detrimental to the trials, there were some slight changes made to the regulations regarding the protocol for administering experimental gene therapy. While we had always been required to monitor the specific danger areas associated with a genetic disease during treatment (i.e., Jesse's ammonia levels associated with his OTC deficiency), it was done simply for our own observation. In order to ensure that scientists would not overlook these vitally important details in their very realistic race for the cure, it was required by law after 2090 to designate one member of their team to do nothing else but closely monitor and record the person's reactions to the therapy. These records were then required to be included in the reports that were submitted when the scientists wished to move their experiment from one phase to the next. I personally thought that this change was a good one because it reminds us, as scientists, that no matter how advanced our knowledge and technology is, no science is exact and gene therapy is no exception. No two people and no two diseases are exactly alike and therefore there is always the possibility of an unexpected, never-before-seen reaction.
Another ethical issue that I feel to be extremely important to the advancement of the field of gene therapy is the high cost that is associated with the treatments. We are making amazing discoveries every day with the hope that we are going to be able to save millions of people from unnecessary pain and suffering, but the high costs limit those to whom these novel treatments are made available. There is currently a bill circulating through the House of Representatives that, if passed, will require insurance companies to pick up the costs of gene therapy. However, there are still people who are against this policy. The people who are for the bill say that by not covering the costs of genetic treatment, insurance companies are in a way giving certain people a chance to live and condemning others to death. The proponents argue that if triple bypass heart surgery for a thirty-year-old person who has eaten fatty foods and not exercised all his or her life is covered by insurance, then the same coverage should be granted to a three-year-old child with a rare genetic heart disease. Those who are against the bill argue that not every genetic abnormality is life threatening, and that some genetic diseases, such as color blindness, are simply nothing more than an annoyance. They say that a general bill requiring insurance companies to cover all gene therapy will not do, and they say such a bill will not pass until it is geared more specifically to the genetic diseases that really matter. I ask, who are they to say that one disease is more or less important than another one?—but that is just my own personal opinion. I, as a gene therapist, came into this field to help people and I am very angered that something as insubstantial as money prevents me from giving anyone the chance at a better life.
It's when I sit back and consider issues like this that I wonder whether or not society is really better off because of all these advances, and I've come to the conclusion that whether I think so or not depends on my mood. On a good day, I think about how much we have accomplished and in so little time. I think of how the feats of gene therapy in the past one hundred years can inspire young scientists to keep working towards what seem to be unattainable goals. I reflect on how the knowledge that has been acquired through the study of genetics shows the unlimited powers of the human mind, and I amaze myself thinking about how much farther we can go. On a bad day, I remember the greedy investors and the sloppy scientists who are interested only in the money and the prestige that come along with curing a disease, who have no regard for human life at all. I also think about those who can't afford to treat their genetic diseases. People who have to wake up every day to the reality that they live in a world where their economic status determines whether they live or die, suffer or live painlessly. Sometimes I even consider the statement that our technological fixes have made about genetic disease—that it is bad and needs to be eliminated. As a geneticist and a moderately religious person I worry that God has molded us into what we are now through natural selection. Gene therapy interferes with natural selection and genes that He did not intend may pass from generation to generation. Will we like what we have become in a thousand years? I do not know.
On a more personal level, however, no matter what kind
of a mood I am in there is one thing that constantly reminds me of all
the good that gene therapy has brought into the world. The one thing is
the feeling that I get every time I treat a newborn with OTC deficiency.
When I look into that baby's eyes, I do not want to change anything that
would prevent me from being able to give that baby the gift of life. I
cannot explain the fulfillment that I feel and, do you know, to this day,
I still see Uncle Jesse looking up at me from each baby's face saying,
"Thanks, Jeff. Thanks for saving the babies."
Gibbs, W. Wyat. (1996, October.) Gene therapy. Scientific American. (VaST 254 Supplementary Readings.)
Jaroff, Leon. (1999, January 11.) Fixing the genes. Time, 153, (1). (VaST 254 Supplementary Readings.)
Sometimes things fall through the cracks: The death of Jesse Gelsinger and what it means. htm://www.sandxford.techie.org.uk/gelsinger.htm (2001, April 25).
University of Pennsylvania Health System—The Institute
for Human Gene Therapy (1999, December 2). Preliminary findings reported
on the death of Jesse Gelsinger. htm://www.med.upenn.edu/ihg.tLfindings.html