[Editor's note: It's not easy to assess a study's ramifications from press releases, three of which caught my eye this month. I asked Phil Schwartz, a neural stem cell expert at Children's Hospital of Orange County, California, to help me understand the gap between study and therapy. I also asked authors from each paper to respond. This article is one of three resulting from this process.]

Research summary by Nature Reports Stem Cells: Eight people with spinal cord injury received surgeries that included removing scar tissue, untethering the spinal cord and receiving infusions of cells collected from their own bone marrow. Four received the procedures within 40 days of their injuries; four received the procedure more than six years after their injuries. A series of case studies, published in Cell Transplantation, were conducted at the Luis Vernaza General Hospital in Guayaquil, Ecuador, by a team led by Francisco Silva, head of stem cell company DaVinci Biosciences, based in Costa Mesa, California. Patients were assessed for quality of life six months, one year and two years after the study, according to measures of bladder function, mobility and sensation. To avoid bias, the neurologists who conducted the assessments were not the neurologists who recruited the patients for the procedure. Almost all the patients reported some level of improvement on the measures assessed1.

News coverage: Two versions of a press release were sent out. The first, from the journal, was put into a release service for science journalists. I found the second, from DaVinci, through FierceBioResearcher, an industry newsletter, and it is downloadable from DaVinci's website. This release quotes praise for the study from the journal's editor without identifying him as such.

Schwartz's take: It's a very interesting study, but it suffers from a problem that a lot of human clinical trials suffer from: What do you use as an appropriate control for these types of studies? Arguments have been made that doing a sham surgery for a highly invasive procedure is unethical. On the other hand, there are also studies that show patients when they had a sham surgery versus [when patients actually had] the fetal tissue put in the brain2. When the patients thought they had the real thing (that is, the transplant of the fetal tissue) they did better. So the placebo effect is real.

Over and above that, with these particular patients, the researchers do cite references to show that spinal decompression doesn't alter the course of the injury. But the manipulations they did were over and above spinal decompression. There were a number of manipulations they did — including untethering the spinal cord and removing scar tissue — and none of them were controlled for. So a basic question is: To what extent does just untethering the scarred spinal cord or removing glial scar tissue have a significant beneficial effect?

It's been shown in animal models that scar tissue does prevent axons from growing across the injured site. So although they've shown that putting the cells in is feasible and safe, they have not shown that it has any kind of efficacy, and they don't have proper controls to do so.

Author reply:

Nature Reports Stem Cells (NRSC): Before DaVinci, you were an executive at another stem cell company, PrimeGen [in Irvine, California], which has issued press releases of advances described as extremely promising but without publishing the results in peer-reviewed journals. Do you think this is appropriate?

Silva: It is obvious that when they released their claims in 2008 [they were] not well received. PrimeGen Biotech had a corporate strategy regarding publishing their work, which differed from my belief that peer review is a required and needed process providing validation and transparency. As a result, I left [the company] in 2007.

NRSC: Why are there two versions of the press release? Why did the longer one quote Paul Sanberg praising your study without identifying him as the editor of the journal in which [the study] was published? Do you think readers will understand that Sean Morrison's quote refers to a study other than your own?

Silva: There are two versions of the press release because one was issued independently by Cell Transplantation and the other was issued by DaVinci Biosciences. Paul Sanberg was asked to comment on the study based on his expertise in neuroscience. If you read the press release, [it states,] “Up to 400,000 people in the United States are estimated to live with spinal cord injuries, according to the Christopher and Dana Reeve Foundation. On January 23, 2009, The Food and Drug Administration approved the first U.S. clinical trial to use human embryonic stem cells in paralyzed humans. In a recent ABC News story on this FDA approval, Dr. Sean Morrison, director at the University of Michigan Center for Stem Cell Biology was cited as saying that even if this study could restore partial spinal cord function or bladder function that it would be a really important advancement.”

It clearly states that the quote is relating to the FDA-approved ESC [embryonic stem cell] trial.

NRSC: How can you be sure that your observations [in the paper] reflect the administration of cells rather than improvement over time or other effects of the procedure?

Silva: The end points of this study were to determine if the surgical procedure and injection of autologous bone marrow stem cells into the site of injury via multiple routes were safe and feasible. The only way to truly determine this would be to include a control group; since this study did not have an end point to determine efficacy, it would have been inappropriate to have a control group and expose the patients to a surgical procedure where safety had not yet been determined. In our preclinical work that we performed using a spinal cord injury animal model, we did find that our control group — which did not receive cells — had no functional improvement.

[Editor's note: I sent the following follow-up question but had received no reply after two days, when this article went to web production:

Can you tell me more about the animal testing of autologous bone-marrow in spinal cord injury? (I reread what I thought would be the relevant section of your paper, and the only reference was Keirstead's work on hES-derived oligodendrocyte cells. What am I missing?)]

NRSC: Did any patients pay for the procedure? What was the cost?

Silva: None of the patients paid for this procedure; the study was funded 100% by a grant from the Junta de Beneficencia de Guayaquil, a nonprofit organization in Ecuador.

NRSC: Have you done any animal or other testing on how many bone marrow cells stay in or survive in the spinal cord?

Silva: Before initiating this trial, extensive animal testing was performed in order to determine the feasibility of using autologous bone marrow [cells] for spinal cord injuries. What is interesting is that we found that survival and engraftment were more efficient in acute injuries versus chronic injuries.

NRSC: What population of cells from the bone marrow do you think is active?

Silva: Our bone marrow preparation contains several cell types that have been found to have therapeutic potential; in particular we are studying the role of endothelial progenitor cells and their role in neovascularization.

NRSC: What do you think the bone marrow cells do in the spinal cord?

Silva: It has been well documented that cells found within the bone marrow population have angiogenic properties resulting in neovascularization and triggering a cascade of events leading to endogenous repair. The human body has an amazing mechanism to repair itself after stress or injury — using stem cells is complimentary to this and may help jump-start the repair process.

NRSC: What are you doing to try to figure out how the cells might be working?

Silva: We are continuing to work on our spinal cord injury animal models using labelled cells to determine their course of action and mechanism.

We have been working toward filing an IND [investigational new drug application] with the FDA to initiate a multicentre trial in the United States. Having completed our strategic milestone of completing and publishing this safety and feasibility study, we believe that it will bring us closer to an FDA-approved study performed within the United States.

[Editor's note: Schwartz's comments are transcribed from an interview. Silva's responses reflect e-mailed replies to e-mailed questions.]