Inside a plastic flask in a medical school laboratory in Lucknow, clusters of cells extracted from human bone marrow thrive in a broth of proteins. In the colourless liquid, they are invisible to the naked eye. But on a slide beneath a microscope, they look like tiny spindles. From this cellular cocktail, haematologist Sonia Nityanand hopes to pluck a set of cells and coax them to turn into human heart muscle cells ? spare parts for patients who’ve survived their first heart attacks. The cells that Nityanand is trying to exploit are mesenchymal stem cells ? cells from the bone marrow that have the potential to transform themselves into bone, cartilage, tendon, or muscle. “We want to make heart muscle cells from these stem cells,” says Nityanand, a doctor at the Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGIPMS) in Lucknow, who’s among researchers in India trying to hoist stem cell science from the laboratory into clinics.

India’s Department of Biotechnology (DBT) is now spearheading a Rs 25 crore stem cells programme supporting a number of institutions in pursuing the basic biology of stem cells and helping medical institutions inch towards non-controversial clinical trials with stem cells in patients.

Stem cells lack “identity” but have the potential to grow into any of the myriad cells in the body. Insulin-producing cells could help patients with diabetes while brain cells could be used in brain disorders. Most work in Indian laboratories involves adult stem cells derived primarily from bone marrow, muscle, blood or liver.

heart of the matter: India is lagging behind when it comes to clinical trials

Experimental stage

Research on embryonic stem cells is confined to a few select laboratories in India and, scientists as well as policy makers caution that embryonic stem cell therapy is at a much greater distance from clinical trials in the country than is therapy with mesenchymal stem cells from the bone marrow.

“We’re just starting. We are now beginning to multiply these cells under standards that are appropriate for clinical applications,” says Alok Srivastava, co-chair of a national taskforce on stem cells and professor of medicine at the Christian Medical College in Vellore. Srivastava and his colleagues plan to work towards the use of mesenchymal stem cells in the treatment of a variety of diseases including heart, kidney, gastrointestinal, brain and bone diseases.

But researchers caution that it is still premature to discuss clinical applications outside the context of well-designed and monitored clinical trials. “A number of basic questions still need to be tackled,” says Srivastava. Should mesenchymal stem cells be produced on-site ? at the centre where the patient is being treated ? or be batch manufactured at a central facility for people to use as and when needed? There are obvious advantages of mass-producing mesenchymal stem cells ? production would be standardised, product would be ready when needed, and it would avoid duplication of infrastructure for their manufacture.

However, there are also some concerns. Whose mesenchymal stem cells would be used for mass production? Who would be the ideal donor? Do mesenchymal stem cells from different people behave the same way? Would mesenchymal stem cells behave differently at different sites in the body? “This is the kind of basic science that we’ll need to study simultaneously even as we move towards clinical applications,” admits Srivastava.

Better standards

The jump from the laboratory into the clinic would need to be preceded by better standards for the manipulation of stem cells before use in patients. “Clinical trials will be allowed only with mesenchymal stem cells that come from laboratories with good manufacturing practices (GMP)-grade facilities, says Maharaj Bhan, DBT secretary. Nityanand, who’s got a Rs 2 crore grant from DBT, is now setting up a GMP-grade establishment to harvest mesenchymal stem cells.

The DBT has also provided Rs 6.5 crore to the National Centre for Cell Science (NCCS) in Pune. There, biologist Ramesh Bhonde, who has been trying to devise a stem cell-based treatment for diabetes, has just switched from working on mice bone marrow to human bone marrow.

Last year, Bhonde had shown that diabetes in mice might be reversed using stem cells from bone marrow of even diabetic mice. Those results had bolstered hopes that, some day, it might be possible to treat diabetes using a patient’s own bone marrow. Bhonde has now extracted stem cells from human bone marrow and is trying to get them to differentiate into insulin-secreting pancreatic cells.

“The fate of stem cells depends on the microenvironment that we provide them,” says Bhonde. In an appropriate growth medium, only insulin-secreting cells will proliferate. Scientists will then have to find a way to selectively extract and purify only those cells for implantation. “I think we’re still three years away from clinical trials,” cautions Bhonde.

One of the biggest challenges for researchers is to find the right biological tricks to get mesenchymal stem cells to turn, or differentiate, into the specific type of cells that they want for clinical applications. “Though much is known about expanding and differentiating these cells, what is not yet established is what is the ideal or optimal for a particular situation. That’s the challenge,” says Srivastava.

Approval system

Some scientists caution that ethical guidelines and rules have yet to keep pace with the progress towards clinical applications of stem cells. A few stem cell trials in India have already triggered off concerns among researchers about the scientific soundness of studies.

However, in an encouraging step, the DBT has said that it will set up a three-tier approval system to assess the science and ethics of projects that involve the use of stem cells in human patients. Every project would need to be approved by all three committees.

The faster an ethical and regulatory system is in place, the better for India because, scientists caution, as far as clinical trials are concerned, India is lagging somewhat behind countries such as the US. At least 10 leading cardiac centres in the US have initiated stem cell therapy trials to treat patients who have had heart attacks. The adult stem cells from US-based Orisis Therapeutics are mass produced, frozen, and shipped to hospitals around the country where they are stored until needed.

Laboratory studies suggest that mesenchymal stem cells can follow inflammatory signals and move to the sites of injury in the body their own. Such signals from damaged heart muscles are expected to guide stem cells that are infused in patients intravenously. “The beautiful thing about mesenchymal stem cells is that they do not trigger an immune response. So they can be taken from healthy donors and given to patients,” says Nityanand.

Nityanand predicts that in India too, banks that preserve mesenchymal stem cells will eventually emerge. For the moment however, she’s concentrating on finding ways to isolate the sub-population of cells in her flask that will selectively turn into heart muscle cells. Clinical studies, she is hopeful, will begin sometime during the second half of 2007.