Altering ANDi: Genetic engineering gets a (small) step closer to humans

Two weeks ago in the journal Science, Dr. Gerald Schatten and a team of researchers at Oregon Health Sciences University reported the first successful genetic engineering of a primate, a baby rhesus monkey whose name — ANDi — stands for inserted DNA spelled backwards.

ANDi received worldwide attention, with stories in all major newspapers. I suspect a lot of the attention had to do with the fact that we humans are also primates. Apes and monkeys like ANDi are our close cousins. If their genes are now being successfully engineered, then human genetic engineering is likely not far off. For this reason, the creation of the worlds first genetically-modified primate seems a key scientific advance. Lest anyone miss the point, Schatten was quoted by the Associated Press as saying I think were at an extraordinary moment in the history of humans.

Are we? I dont buy it.

The approach used to introduce a novel gene into ANDis chromosomes was developed over a quarter century ago by researchers studying mice. The gene to be transferred is first introduced into a noninfectious virus that will serve as a piggyback carrier — sort of like putting a package in a mailtruck. Using a very fine needle, a solution containing the engineered virus is carefully injected into an unfertilized egg. The virus moves through the egg cells interior into the nucleus, where it inserts itself — and the gene it carries — into one of the chromosomes. The gene is now part of the eggs genetic endowment. When the egg is fertilized by a sperm, divides to form an embryo, and eventually gives rise to an adult, every cell of that adult will possess the introduced gene.

As a simple and sexy way to demonstrate that the procedure has worked, researchers often select for the experiment a jellyfish gene that makes a protein that glows under a fluorescent light.

However, several decades of using this approach with mice and rabbits has revealed two serious drawbacks:

1. It isnt safe. The virus enters the host chromosome just any old place, and the gene that it inserts itself into is usually damaged (imagine inserting a phrase from Shakespeare into a line of code in a computer program). Said simply, the approach causes mutations, and so almost certainly could cause cancer.

2. The introduced genes dont work. While the genes do get into egg DNA, they are usually silenced and inactive. The cells contain the new gene, but do not use it to make proteins.

Schatten used this traditional approach in his successful attempt to genetically modify a rhesus monkey. First, 224 monkey eggs were mixed with a virus carrying a jellyfish gene. The eggs were then fertilized. From them the researchers were eventually able to obtain 126 embryos. They selected 40 of these, and implanted them in females. This resulted in five pregnancies and three live births. One of these, ANDi, had the added jellyfish gene, a permanent change in his hereditary information that will be passed down to future generations.

Did ANDis tissues glow in fluorescent light? Nope. As a mouse researcher might have predicted, the added jellyfish gene didnt work. The only way Schatten knew he had succeeded in adding a gene to ANDis chromosomes was by using a very sensitive method called the polymerase chain reaction to detect the jellyfish genes presence in cheek, hair, urine, placenta and blood (he seems not to have checked sperm).

So a critic might argue with some force that all Schatten has done is to show that a traditional approach that is unsatisfactory in mice is also unsatisfactory in monkeys.

Make no mistake, this sort of experiment will eventually be made to work. It presents many of the same challenges as gene therapy, only targeted at germ-line tissue. The new kinds of gene-carrying viruses being used in gene therapy today, targeted to safe places on the chomosome, seem a promising bet.

But even if we CAN modify the genes of primates, SHOULD we? The only justification I can imagine is that it will allow researchers to study human diseases in a way that otherwise would not be possible. However, I am not at all sure that introducing a human disease gene into a monkey in this way will improve the study of the disease. The method only leads to animals with added genes, while most human hereditary diseases result from missing or mutated genes. There are other ways to disable specific genes in monkeys, if researchers want to study disease-causing genes.

I find the ethical issues associated with animal research particularly difficult in this case. Absent a clear advantage to using primates, by what right do we condemn ANDi or any other primate to a life of disease? I cannot get from my mind the film of Jane Goodalls chimps, Children of the Forest. These wild African apes are not just another animal. They are our biological cousins, living a rich family life, supporting and loving each other much as we do. It is a close kinship I feel uncomfortable ignoring.

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