Chinese researchers become the world's fifth most prolific contributors to regenerative medicine

Enforcing new Chinese rules for clinics may impact lucrative stem cell therapy tourism but improve international credibility, confidence

Chinese researchers have become the world's fifth most prolific contributors to peer-reviewed scientific literature on clock-reversing regenerative medicine even as a skeptical international research community condemns the practice of Chinese clinics administering unproven stem cell therapies to domestic and foreign patients.

According to a study by the Canadian-based McLaughlin-Rotman Centre for Global Health (MRC), published today by the UK journal Regenerative Medicine, China's government is pouring dollars generously into regenerative medicine (RM) research and aggressively recruiting high-calibre scientists trained abroad in pursuit of its ambition to become a world leader in the field.

And its strategy is working: Chinese contributions to scientific journals on RM topics leapt from 37 in year 2000 to 1,116 in 2008, exceeded only by the contributions of experts in the USA, Germany, Japan and the UK.

The accomplishment is all the more astonishing given that China's international credibility has been and still is severely hindered by global concerns surrounding Chinese clinics, where unproven therapies continue to be administered to thousands of patients.

New rules to govern such treatments were recently instituted but need to be strictly enforced in order to repair China's global reputation, according to MRC authors Dominique S. McMahon, Halla Thorsteinsd-ttir, Peter A. Singer and Abdallah S. Daar.

They drew their conclusions after having gained unprecedented access to almost 50 Chinese researchers, policy makers, clinicians, company executives and regulators for interviews. The research was made possible by funding from the Canadian Institutes of Health Research.

"When you look at the issue of stem cells in China, you see the Yin-Yang of a scientific powerhouse mixed with controversial clinical application of stem cell therapies," says Dr. Singer, MRC's Director. "The overall picture at the moment is ambiguous but in the future, given the measures that have been put in place, the science can be expected to rise and the controversy to fall."

Regenerative medicine an interdisciplinary field of research and clinical applications focused on the repair, replacement or regeneration of cells, tissues or organs to restore impaired function resulting from any cause, including congenital defects, disease, trauma and aging. It uses a combination of several converging technological approaches, both existing and newly emerging, that moves it beyond traditional transplantation and replacement therapies. The approaches often stimulate and support the body's own self-healing capacity. These approaches may include the use of soluble molecules, gene therapy, stem cell transplants, tissue engineering, and the reprogramming of cell and tissue types.

MRC researchers report that until May 2009 clinical trials to determine the effectiveness of stem cell therapies were not required. Now proof of safety and efficacy through clinical trials is required by China's Ministry of Health for all stem cell and gene therapies.

The change was made after international experts, joined by top Chinese researchers, protested that treatment centers were acting "against commonly accepted principles of modern scientific research" and successfully called on China to regulate new treatments and ensure patient safety.

Despite the new rules, however, stem cell treatments are still available at over 200 hospitals across China to patients of diseases such as ataxia, Lou Gehrig's disease, traumatic brain and spinal cord injury, diabetes, Parkinson's, multiple sclerosis, autism, cerebral palsy, stroke, optic nerve hypoplasia and many others.

"To our knowledge, Chinese policy makers and ethicists are working out the regulation details,- says Ms. McMahon, the study's lead author. "Once that is accomplished, we still expect a delay, during which the therapies currently administered by clinics and hospitals will be evaluated individually to determine whether they meet the criteria of China's Ministry of Health."

"It is hard to say what impact these new clinical regulations will have in China, although certainly they show the government's commitment to changing the way things are done," she adds.

Beike Biotechnology Inc. (Shenzhen) is the largest of the Chinese therapy centers and claims to have treated over 5,000 patients to date, including more than 900 foreigners, offering stem cell injections into spinal fluid, for example.

The Stem Cell Center affiliated with Tiantan Puhua Neuroscience Hospital in Beijing, meanwhile, claims to activate and multiply the body's own neural stem cells through oral and intravenous medications and rehabilitation. It also offers a lumbar puncture or brain injection of bone marrow stem cells, fetal neural stem cells, or other stem cell types to allegedly improve symptoms of stroke, cerebral palsy, spinal injury, Parkinson's disease or other neurological diseases.

Controversial stem cell therapies provided at Beijing Xishan Institute for Neuroregeneration and Functional Recovery, involve injecting cells from aborted fetuses to treat spinal cord injury and a variety of central nervous system diseases. About 1,500 patients have received this treatment, including roughly 1,000 foreigners.

MRC authors say this latter stem cell therapy is the only one discussed in high-impact peer-reviewed academic journals. One study documented a spinal cord injury patient's early motor and sensory improvement, another found no improvement in seven spinal cord injury patients. Another recent publication found the therapy improved some spinal cord injuries in animals but its effectiveness in humans "is not yet established."

Despite the absence of randomized clinical trial evidence that these stem cell therapies work, an "increasingly popular but controversial" tourism industry has grown up around them.

"This is a matter of international importance, as increasing numbers of foreign patients travel to China to seek unproven stem cell therapies not available in their home countries," according to the MRC. "The International Society for Stem Cell Research (ISSCR) strongly condemns the administration of unproven stem cell therapies - and has written a handbook to help doctors and patients make informed decisions about available stem cell therapies."

As for advice to last-resort patients considering Chinese clinic stem cell treatments: "This is not a medical study," says Dr. Singer. "Instead we urge such patients to consult their own medical professionals. The International Society for Stem Cell Research has certainly made their stance clear."

"These therapies are sought out by desperate, no-option patients seeking marginal improvements in their quality of life. People should get as much information as possible before committing to any procedures. Each clinic provides a different therapy for a variety of different ailments and there is no systematic evidence that these therapies work."

While unorthodox activities at Chinese clinics and controversial drug approvals have raised eyebrows both in and outside China, dedicated researchers in the country's labs have been making remarkable contributions to the field.

Among the country's scientific firsts:

• By transferring the nucleus of a human skin cell into the immature ovum cell of a rabbit, researchers from a Shanghai hospital successfully produced embryonic human cells (a finding popular scientific journals held off publishing for two years due to skepticism and of mistrust Chinese scientific integrity).

• China to date has created at least 25 human embryonic stem cell lines (some estimate over 70 stem cell lines), four of which are of a specialized type that at that time only two other groups worldwide had managed to create.

• A Shanghai hospital cultivated and reintroduced human brain tissue in 2002 after taking a sample from the end of a chopstick implanted in a patient's frontal lobe following a disagreement at a restaurant.

• Several human tissue types created artificially include blood vessel, tendon, bone, cartilage, skin, cornea and muscle fiber.

Current research of note includes the efforts of ChinaSCINet, a consortium of 27 medical facilities, starting phase 2 clinical trials to test the efficacy and safety of using cord blood stem cells and oral lithium to treat about 40 patients with spinal cord injuries.

Other clinical trials are underway on the use of stem cell therapies to treat patients of heart attacks, artery obstruction, and liver and neural diseases.

Elsewhere in China, studies are underway on the potential use of stem cells to treat Type 1 diabetes, Parkinson's disease, heart, liver and blood diseases, eye cataracts, and to combat aging.

Guidelines governing Chinese research are liberal but common to other countries as well.

Chinese regulations prohibit reproductive cloning, the use of human embryos past 14 days post-fertilization, the fusion of human and non-human gametes (cells that fuse during fertilization), or the implantation of research embryos into human or animal uterus.

Researchers are required to obtain informed consent from subjects and institutes must have an ethics review board to approve research involving human embryonic stem cells.

Chinese fertility clinics serve as a source of discarded embryonic stem cells for some research, and cord blood banks may serve as a source of stem cells for clinical applications.

Therapeutic cloning is allowed, as is the use of surplus embryos or discarded fetal cells from abortions as well as embryos created with artificial help.

"What sets China apart from most of the rest of the world is that these regulations do not prohibit the fusion of human genetic material with nonhuman oocytes (cells from which an egg or ovum develops)," the MRC authors say.

As well, the rules for embryonic stem cell research in China are criticized internationally as having limited authority over researchers because they are not legally binding. Adherence is enforced only for those who receive government funding, which applies to most researchers, but financially independent researchers or hospitals must simply answer to their own institution's ethical review board.

MRC authors say that while there is no indication embryonic stem cell research rules are being broken, greater regulatory oversight would help ease international concerns.

Interviewees agreed that regulation enforcement is a key concern. According to one, a lack of inspection capacity cast doubt on regulatory implementation.

Chinese data show the country now generates 400,000 graduates in science and medicine each year and recruits many high caliber scientists from abroad.

China-s gross domestic expenditure on R&D in science and technology has grown from $5.9 billion in 1996 to $44 billion today. Stem cell research, tissue engineering and gene therapy are key areas receiving priority funding, largely centralized in the universities, hospitals and research institutes of China's main urban centers, especially Beijing and Shanghai.

Approximately 78% of China's R&D funding in RM is reserved for product development, with an additional 16.8% for applied research. And China has developed large primate colonies for preclinical testing, and begun clinical trials for a number of therapies.

According to the MRC, China's push for clinical applications, which has allowed it to produce new scientific knowledge quickly, has come at the expense of basic research aimed at, for example, overcoming technical challenges such as controlling how stem cells behave and differentiate.

Only 5.2% of China's budget for research and development is allocated to basic research, compared with 13 to 19% in Japan, Korea and the USA. Even the funds allocated for basic research favor 'strategic basic research' designed to encourage application.

"China has catapulted itself into the field of regenerative medicine in a relatively short time," says Dr. Thorsteinsd-ttir. "The government's policy of attracting highly educated Chinese nationals back to China has contributed significantly to the country's success in the field."

"I was amazed that almost all the top Chinese researchers the regenerative medicine field had been educated in the US and the UK and gained extensive working experience there in cutting edge research," she adds. "This is a policy other countries lacking relevant human resources should consider."

"New regulations may in time help restore international confidence in Chinese stem cell innovations, but it will take time to evaluate their impact," says Dr. Daar. "The creation of new RM therapies needs a clear regulatory path. There should also be a closer connection between applied research and those providing therapy."

"China is an important player in regenerative medicine," says Ms. McMahon, "Despite the media's focus on stem cell tourism, the international community needs to recognize that Chinese researchers are making important contributions to the science of this field, and China should be included in international discourses on standards and regulations."

"Regenerative medicine research in China is a source of national pride," she adds. "The Chinese rightly feel their research discoveries can achieve solutions to many global health problems. If China continues to build on its strengths and overcomes its challenges, successful, internationally acclaimed regenerative medicine treatments and therapies are more than likely."