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Helping immune system to ‘do better and protect’

— Photo: K. Murali Kumar

David Baltimore: “HIV has a set of genes that you do not find in other retroviruses, or in any other virus.”

David Baltimore, the path-breaking American biologist and co-recipient of the 1975 Nobel Prize in Physiology and Medicine, was on a lecture tour in India during January 14-18. He won the Nobel Prize along with Howard Temin and Renato Dulbecco for “discoveries concerning the interaction between tumour viruses and the genetic material of the cell,” which unravelled how cancer-causing RNA viruses managed to infect and permanently alter a healthy cell. The centrepiece of this work was his identification in 1970 of the enzyme reverse transcriptase in virus particles. This provided the evidence for the conversion of (single-stranded) RNA into a (single-stranded) DNA, the reverse of what is known as the ‘central dogma of biology,’ namely that normal transcription of genetic information involved the synthesis of the RNA from the DNA, which in turn was translated into proteins. This work has provided the key to our understanding of life cycles of a whole class of RNA viruses called retroviruses that includes the HIV.

In the following years, Prof. Baltimore has conducted extensive research on the molecular mechanisms in the immune system and how they are controlled, and has contributed a great deal to the understanding of cancer and AIDS. His present research is focussed on control of inflammatory and immune responses to infections. He has launched a major programme called “Engineering Immunity.” The concept, which marks a paradigm shift from the current approaches to treatment and vaccines, could pave the way for “medicine of the future.”

Prof. Baltimore gave a wide-ranging interview on his scientific work to The Hindu’s Science Correspondent, first in New Delhi and then in Bangalore. Excerpts:

The body’s immune system is able to handle most of the infections quite successfully, either by raising antibodies from B-cells or by the action of T-cells. But some important ones are able to evade the immune system and they pose the greatest challenge to medical research: HIV, malaria, and tuberculosis. Cancer is another important disease to which the immune system rarely responds. But it ought to be able to do better and protect. I had a notion about five years ago that you might be able to use gene therapy to protect the immune system against attack by HIV and other things and to allow the immune system to do what it can’t normally do or is not able to do well enough. I call it “engineering immunity” and the programme is related to HIV and it’s also related to cancer. It’s a great challenge but none of it requires brand new science. A lot of this is about engineering. Skirball Foundation funded the project in its initial stages and now we have a big grant [of about $14 million] from the Gates’ Foundation.

Yes. Lot of promise but it has not shown any real effective therapy. And when it has been effective, it’s been dangerous.

Yes, I do.

First of all, we are using different virus vectors than the ones that have proven difficult to carry the genes and our strategy is different. We want to put the genes into the stem cells of the immune system. We know how to do that. I am moderately confident that we can do all of these. The real challenge is to be able to target the virus vectors to specific cells in the immune system and getting them to be smarter. It is a combination of gene therapy, stem cell therapy, and immunotherapy, each one of which has been controversial and does not seem to work separately. But together it seems to work pretty well.

HIV, for instance, has a set of genes that you do not find in other retroviruses, or in any other virus for that matter. Genes encode for proteins and it’s those proteins that have the special properties. We generally infer the sequence of the proteins from looking at the sequences of the DNA and the RNA [of the virus]. And HIV makes proteins that are hidden away from the immune system. They are hidden by a number of tricks. One of which is encoded in the protein instructions that they should have carbohydrates added to them. The carbohydrates then sort of form a whole coating over the [virus] particle and hide it away from the immune system. It physically can’t get inside the carbohydrates to look at the proteins. Viral proteins are thus protected from interaction with the antibodies. But then if you completely surround it, there would be no way for it to bind to the cell. So it has to have some patch, and it does have a patch, but then there are all sorts of things about the detailed structure of that patch that makes it inaccessible for the antibody. In my lab, we try to find ways actually to get to make smaller kinds of molecules that are not as big as the antibodies to get into those crevices that are available on the surface of HIV.

Size is a big thing...Not merely but it’s a big factor.

There are some aspects of the geometry of the binding sites that are important. We actually don’t know it entirely. The problem is that HIV surface protein is a trimer. People have figured out the [three-dimensional] structure of the monomer; they haven’t figured out the structure of the trimer. So we don’t fully understand the surface of the virus and there are people working on it but it’s been very difficult because making stable trimers that you can then determine the structure of has been a real challenge. Now I do know one laboratory that thinks they have it.

Ah! It’s a problem. But there are some aspects of it that we know well enough that you can model. We think it should work.

We are nowhere in the development of a vaccine. Since to make antibodies work is such a difficult thing, we had hoped that you could use another arm of the immune system, T-cells, to protect against the virus. Much of the vaccine work that’s been done over the last five to ten years has been focussed on making a T-cell based vaccine. That’s what Merck did and they just had a total failure of the vaccine and now we are uncertain whether you can make a T-cell based vaccine. I think there will be more tests of it. There are other people trying to do it in somewhat different ways from Merck. But this is a huge setback.

So when I say we are trying to make small protein molecules that go in [to counter the viral protein], the immune system will not make them for us. So our idea is: if we can find these molecules, to actually programme the immune system using gene therapy to make these protective molecules. We are investigating that as a possibility. And it’s a matter of desperation because nobody has ever done anything like what I am suggesting. But because HIV has proven to be so difficult, the idea of attacking it in some very different way is important. So you look for genes that will make those small molecules and try to find one that will bind. The really difficult thing is finding that molecule that will do the trick. You can do that with fragments of antibodies. We are also now working with a new group that I have discovered who can make these binding molecules based on very different structures than antibodies.

No. I have always said since 1986, when I first got involved in this, that a vaccine is at least ten years away. And I still say that it is at least ten years away...It’s awful. Because here we are 20 years later and we are still saying it’s ten years off. But I don’t know if there are many people who would disagree.

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Helping immune system to ‘do better and protect’

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