The play between chemistry and technology has allowed Arun Ghosh (below) to arrive at new treatments for diseases such as Alzheimer’s

Arun Ghosh may have worked in the world’s foremost laboratories for nearly two decades, but he is still bedazzled by science and what scientists are able to achieve. He is amazed at the advances in genetic engineering, and the ways in which biologists manipulate genes to make animals as pliant as plasticine. More importantly, Ghosh is stunned by his own field of chemistry, and the ways in which technology lets him play around with molecules.

“It is absolutely amazing what I can do these days,” he says, thinking not of himself but of the machines and methods that are available in a topnotch laboratory. Ghosh is also dazzling others, because his work is leading to potential treatments for dreaded diseases.

Ghosh, who grew up in Calcutta, is now professor of organic and medicinal chemistry at Purdue University. Exactly a year ago, on June 23, 2006, a compound he had synthesised was approved by the US Food and Drug Administration (FDA) as the frontline treatment for drug-resistant HIV infection. A few days ago, on June 18, the FDA approved for clinical trials another compound he had synthesised — it is one of the few, if not the only, serious candidates for treating Alzheimer’s disease. There is no conclusive method yet to diagnose or cure this disease.

Ghosh had stumbled on this work in the year 1999, through his friend and former collaborator Jordan Tang, head of the protein research programme at the Oklahoma Medical Research Foundation. Tang and Ghosh had collaborated in the development of the drug Darunavir against multi-drug resistant HIV. In 1999, Tang discovered an enzyme that he named memapsin. It was a set of five proteins he had discovered at that time.

Later, it turned out that this enzyme was involved in the early stages of Alzheimer’s disease, suggesting that a molecule that could disable it could be a potential drug. Tang was a biologist, while drug development was mostly a chemist’s job. “Once Ghosh heard about memapsin, he needed no persuasion to design a drug against it,” says Tang.

Alzheimer’s disease is one of the most resistant diseases to diagnosis or treatment. Clinicians use their experience and several tests to diagnose the disease, but none of the methods are conclusive; the only way to establish the disease is through an autopsy. Although a few drugs have been approved for Alzheimer’s, none make a significant difference to the quality of life of the patient or retard the progression of the disease. “In spite of considerable research, we haven’t been able to improve significantly the methods of diagnosis or treatment of Alzheimer’s disease,” says T.S. Sridhar, neurologist and professor of molecular medicine at St John’s Hospital in Bangalore.

This is the reason why experts now predict a huge increase in the incidence of the disease. A recent study by researchers at Johns Hopkins University in Baltimore showed that more than 26 million people worldover suffer from Alzheimer’s disease. By the year 2050, this number will quadruple to more than 106 million, out of which 63 million of the affected will be in Asia. By that time, 43 per cent of the people would need the special care of a nursing home.

“The rate of growth of the risk is the same wherever you are,” says Ron Brookmeyer, professor of biostatistics at Johns Hopkins and the lead author of the study. A drug that could postpone the disease progression by even one year can reduce the number of cases by 12 million in 2050.

Scientists have been speculating about a protein called beta-secretase that was involved in the early stages of Alzheimer’s disease. Tang did not originally know the function of memapsin, but it later turned out that it was actually the beta-secretase that scientists were looking for. Memapsin cuts a protein called amyloid precursor protein, whose chopped up bits through a chain reaction produce the amyloid plaques that are characteristic of the disease. It is not the plaques themselves that cause the disease; the accompanying reactions produce toxic substances and destroy nervous tissue. A molecule that could block memapsin could be a potential drug because it will stop this chain reaction.

After Ghosh and others started work on finding a memapsin blocker, scientists discovered another enzyme similar to memapsin. This was called memapsin-1, and the first one memapsin-2. Now Ghosh was confronted with a problem. A drug that blocks memapsin-2 could also block memapsin-1. Since memapsin-1 was found all over the body, the drug could lead to blocking vital biological functions. This was when technology came to help. Ghosh used X-ray crystallography to get pictures of memapsin-2 attached to the candidate drug. X-Ray crystallography is an old technique, but only recently became good enough to look at protein-drug complexes. “We knew then exactly what we needed to do to the drug to make it bind only to memapsin-2,” says Ghosh.

Animal trials showed that a single dose could reduce amyloid levels by 30 per cent in mice. Biologists also made mice — through genetic engineering — that do not have memapsin-2. “All that these mice showed was a slight reduction in curiosity,” says Tang.

That is not a serious trade-off in treating Alzheimer’s patients. In any case, the researchers do not expect to turn off memapsin-2 completely. The technology for the drug has been transferred to a San Francisco-based company called CoMentis. The clinical trials will begin soon.