by Douglas Birch
A few months back, Sivaprakash Ramalingam, PhD, focused his microscope on a crowded clump of human stem cells and saw a reddish glow—a chemical signal he had successfully inserted a gene into a “safe harbor” site in the cells’ DNA where it wouldn’t interrupt vital functions.
It was a crucial step in a drive by the postdoc and his advisor, Environmental Health Sciences (EHS) Professor Srinivasan Chandrasegaran, PhD, to develop a practical cure for sickle cell disease. The painful and debilitating genetic illness affects millions of people around the world, including in the U.S. and some of the poorest regions of India.
Ramalingam, 34, began his life on a small plot of land near the Bay of Bengal in southeastern India. While his father toiled in the family’s banana grove, sugar cane field and rice paddy, young Siva helped out by milking the family cow.
Today, Ramalingam works with his mentor Chandrasegaran—also a native of the southern Indian state of Tamil Nadu—on the frontiers of genetic medicine, trying to find gene-based cures for major health challenges like cystic fibrosis and HIV, as well as sickle cell disease. In their common quest, it’s hard not to see a torch passing from one generation of scientists to the next, from basic science to applied medical research and from Western institutions to young researchers from the rapidly advancing scientific institutions of the developing world.
The two public health scientists are collaborating with stem cell expert Curt I. Civin, MD, of the University of Maryland, on the sickle cell project. They are racing with labs around the world pursuing similar goals. In May, the Maryland Stem Cell Research Fund awarded Ramalingam one of 17 grants worth up to $200,000 over the next two years for his sickle cell work, as part of a program to support Maryland scientists pursuing novel approaches to stem cell therapies.
Ramalingam and Chandrasegaran say the painstaking research could take two or three more years before it is ready for testing in animals, in preparation for human trials. Asked whether they worried about the intense competition, Ramalingam admits that he sometimes loses sleep over the publication of an important paper by a rival lab.
Chandrasegaran just smiles. The 30-year veteran scientist, who pioneered the development of man-made gene-editing tools called zinc finger nucleases, takes a philosophical approach. “If you’re asking me, do you want to be first? Yes. But it’s not in our hands. If others do it, we will be happy that it was done since it will help a lot of people,” he says.
There is no guarantee of success in this latest assault on the scourge of sickle cell. Except for mice and yeast, the DNA of most animals, including humans, is notoriously difficult to fiddle with and many efforts to repair human genes have failed.
Some early gene therapy patients died when viruses carrying engineered DNA inserted it at random locations on the genome and switched on genes that caused cancer.
Chandrasegaran says he’s leery of overselling his lab’s progress. “I want to keep it low-key,” he says. “Let’s take it one step at a time, and do careful science.”
But for Chandrasegaran, as for many other scientists, the relatively recent discovery that stem cells can be “induced” or derived from adult cells has opened exciting new avenues for medical research. “I hope that I can see it in my lifetime,” he says. “I’d like to see people cured of HIV, cured of sickle cell—any monogenic disease where you can replace the cells. It will help a lot of people, and that’s the ultimate goal.”
“I want to keep it low-key. Let’s take it one step at a time and do careful science.”
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