As Dr David Baltimore rose to speak a smoke and thunder of voices rattled the doors at the back of the Great Hall at the University of the Witwatersrand in Johannesburg. Protestors outside had threatened to disrupt his presentation of the third annual Nelson Mandela Science Lecture.
Baltimore is the President Emeritus and Robert Andrews Millikan Professor of Biology of the California Institute of Technology. His work on the identification of reverse transcriptase â€“ the mechanism by which retroviruses, like HIV, infect cells – earned him the 1975 Nobel Prize in Physiology or Medicine at the age of 37.
Baltimore is in South Africa at the invitation of the Africa Genome Education Institute to speak on his experiences in searching for solutions to HIV.
Africa, with 10% of the world’s population, has 60% of its infections. In 1994 South Africa, at the dawn of transition to majority rule, already had 850,000 people infected with HIV. In 2007, largely as a result of government negligence and the promotion of “alternative” remedies such as garlic and beetroot, there are 5.5 million South Africans who are HIV positive.
The discussion of HIV and AIDS in South Africa is not without controversy.
The people outside the Great Hall, held back by campus security, were students. And they weren’t concerned about AIDS. They were protesting the university’s decision to raise fees and expressing their displeasure by emptying garbage out of bins and interrupting lectures.
Inside the hall a student yelled to Baltimore, “You’re my hero! You rock!” Baltimore laughed.
Africa is where chaos goes for its vacation.
HIV was identified in 1981 and is now the most studied virus in science. It is also history’s most destructive, estimated to have been responsible for the deaths of 25 million people.
All obvious solutions have been studied. 23 anti-viral HIV drugs have been created. People all over the world, from both public and private institutions, collaborate on studying it. Yet HIV persists.
Three years ago the Gates Foundation offered grants for the study of audacious new approaches to combating HIV. Baltimore was one of the recipients for a gene therapy approach and he is now building the tools necessary for it to work.
“If you are going to think about complicated issues in science then you must be prepared to be wrong,” he says. That doesn’t ameliorate the awful disappointment at the failure of the Merck vaccine trial.
Merck stopped their phase II trial of a potential HIV vaccine, based on an adenovirus vector, after interim results showed that it was ineffective. Merck’s vaccine was hoped to stimulate an immune response in the body’s CD8 T killer cells and allow them to recognise and destroy HIV.
“There is no obvious solution,” says Baltimore, “but the T cell vaccine was a bit of a ‘Hail Mary’.” In other words, a wild stab at a solution without any obvious signs that it would succeed.
The great difficulty for researchers is that none of their laboratory standards (chimpanzees or mice) are affected by HIV in the same way as humans. Successful testing of vaccines on them gives no indication of how we will respond.
For this reason, and to complement his research on gene therapy, Baltimore has completed the creation of a chimeric mouse which has a human immune system. One-day-old mice are injected with CD34+ stem cells that then supplant the mice’s own immune systems. An infection protocol is still in development.
Gene therapy requires that new genes be incorporated into the human genome to express new proteins to combat HIV in novel ways. “Interestingly,” says Baltimore, “the virus that is a natural for this role is HIV itself.”
What constitutes a novel gene that may do the job?
Retroviruses operate by integrating themselves into their host’s DNA. The enzyme responsible for kicking off the process that synthesises a DNA copy of the RNA virus is reverse transcriptase. Interfere with the operation of reverse transcriptase and HIV is unable to function. Many of the anti-viral therapies for HIV have taken this approach.
There is also a certain circularity in Baltimore building genes to target the enzyme the identification of which earned him his Nobel Prize.
How does one target the action of reverse transcriptase?
“Micro RNA is a very exciting new discovery,” says Baltimore, of one approach. Micro RNA (miRNA) are tiny lengths of RNA, containing no genes, which regulate gene expression directly. The miRNA is complementary to messenger RNA (which carries the code for protein production) and acts to dampen gene expression. In other words, it is an off switch.
Novel miRNAs could be produced to interfere with HIV RNA synthesis to DNA.
500 miRNAs have been identified and there is an enormous amount of work still to perform. Baltimore has just been appointed to be head of a scientific panel advising a new business looking into this.
Another area is histone modification. Histones are proteins which act as spools around which DNA winds, and play a role in gene expression. They could be used to turn whole regions of genes on or off.
Gene approaches run risks in terms of how patients respond.
Amgen, a company where Baltimore is a director, has a drug called Vectibix. It is used for the treatment of colorectal cancer and inhibits the epidermal growth factor receptor (EGFr). They have recently discovered that only 15% of patients respond to the therapy. It appears that the bulk of patients have EGFr genes with mutations downstream of the gene that are sufficient to prevent the efficacy of the drug.
It could be that a gene therapy approach to HIV runs into similar complications. This opens up the necessity for pharmacogenetics where remedies are targeted to specific expressions of particular ailments.
“It may be that I can’t pull off the gene therapy approach,” says Baltimore,”but I think we will. The Gates Foundation only wants to fund things that are a great challenge. If you spend a lifetime in research doing this you’ll probably never get funded. But, occasionally, you’ve got to be willing to take a giant leap.”
Dr Baltimore was interviewed by Gavin Chait. Dr Baltimore met briefly with Nelson Mandela immediately prior to his presentation at the University of the Witwatersrand. He is next travelling to Cape Town to join a gathering of grantees of the Gates Foundation and will then fly to Rwanda at the invitation of their ministry of Health. His full Nelson Mandela Science Lecture is available at the AGEI website.
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