WASHINGTON — As the young microbiologist Richard C. Mulligan delivered a speech about human gene therapy before an Institute of Medicine conference here on Oct. 15 of last year, W. French Anderson sat in the audience, listening intently.
Mulligan, after all, was talking about something Anderson had been feverishly pursuing for years.
I want to win, I want to be the first to do human gene therapy, Anderson had often said. Director of the laboratory of molecular hematology at the National Heart, Lung and Blood Institute, he had already managed to put a new gene into monkeys--the ADA gene, which codes for an enzyme that protects immune system cells from deadly poisons. Now he wanted to try the same with humans.
Must Use Stem Cells
Unless you can put a gene into the human bone marrow's stem cells, Mulligan was saying, the whole game is doomed. Getting into more mature, already developed cells was no good--when those cells died out, so would the transplanted gene. The gene would only proliferate if you got it into the self-renewing stem cells that replenish the entire system.
French Anderson's lab, Mulligan declared, could not have gotten the ADA gene into their monkeys' stem cells. The gene's enzyme activity in the monkeys had lasted only a short time.
We need a test to show we can get into stem cells, Mulligan said. That would be the appropriate final test before going into humans. If we can't develop that test, a critical decision will have to be made about what to do next.
Anderson stared at Mulligan as he spoke and slowly shook his head.
Anderson did not so much disagree with Mulligan as he viewed the matter from a different angle. Mulligan, an MIT associate professor and lab director at the Whitehead Institute for Biomedical Research in Cambridge, Mass., after all, was a basic researcher pursuing knowledge. Anderson was a medical doctor, a clinician geared to treating sick patients.
Critical Decision Looms
Anderson agreed that without the needed test for stem cell infection, a critical decision loomed. But unlike Mulligan, he was not inclined to search any longer for that test, for he did not think it could be found. He was ready to make the critical decision Mulligan spoke of.
There finally was only one way to find out if you could get into stem cells and stay in: go into a human patient, a human ADA-deficient patient. See there if you got results that lasted.
Others would argue that he should first get those types of results in a monkey. Then the leap to humans would be much shorter.
That's not possible, Anderson would respond.
You could not do in a monkey what you could do in a sick, ADA-deficient human patient, Anderson reasoned. That was so because only in the human system would your new cells have a selective advantage.
At the heart of Anderson's impassioned endeavor was his belief in this theory of selective advantage.
Even if they got the ADA gene into only a few cells of an ADA-deficient patient, he reasoned, that would be enough, for those cells would have a selective advantage over all the other cells that lacked the ADA gene. They alone would be immune to the body's poisons. They would proliferate while the others died out.
Selective advantage could not be tested in monkeys, though, or any other animal. Animals have their own ADA gene, their own ADA enzyme activity. They aren't sick, as the human patient would be. So the newly inserted cells would have no advantage over the monkey's own cells.
Others, Mulligan included, thought Anderson's selective advantage idea was not just a speculative theory, but a poorly thought out one at that, full of basic flaws. How, for example, could Anderson assume the stem cells in an ADA-deficient patient were the defective ones? If they weren't, newly infected stem cells would have no advantage over all the others.
Everything Anderson was shooting for, though, hinged on the idea of selective advantage. If it wasn't right, gene therapy was a long way off. For the patients, for his own goals, the theory just had to be right.
It is here, where the pursuit of science turns on matters of theory and what a lab investigator desires, that the differences between the clinicians and the molecular biologists become most sharply apparent.
Trained in Labs
Molecular biologists do not traffic much in theories and desires. Trained in labs amid test tubes, not patients, they talk a complex language, one deeply rooted in the hard nuggets of science. They keep their eyes on the cells.
They see so many unanswered questions.
Which donor cells really get taken up into the body's system? How can we be sure those cells even existed in the marrow obtained from patients and infected with vectors? What if there is something wrong with the cells the vectors are supposed to infect--maybe there won't be anything for the vector to hook onto. How do you know you won't have to kill off some of the patient's own cells to make room for the ones you were giving him? How dangerous would that be?