A Night with Dr. Hans Keirstead

Game-changing discoveries have always been met with resistance. This has been clearly shown by accomplishments achieved by prominent stem cell researcher Dr. Hans Keirstead. Keirstead is an associate professor of Anatomy and Neurobiology and co-director of the Sue and Bill Gross Stem Cell Center at the Reeve-Irvine Research Center at the University of California, Irvine. Keirstead and his lab developed a method using human embryonic stem cells (hESCs) to treat spinal cord injuries and, in 2009, this treatment became the first-ever FDA-approved clinical trial using hESCs.

On June 14, 2010, Keirstead will be giving a presentation at Fess Parker’s Doubletree Inn in Santa Barbara on “Stem Cell Research and Its Application for Treatment of Spinal Cord Injury and Disease.”

During his PhD studies at the University of British Columbia in Vancouver, Canadian-born Keirstead developed ground-breaking methods to regenerate damaged spinal cords. To understand how these methods work, it’s important to have an understanding of how the spinal cord normally functions. Two key groups of cells in the spinal cord are neurons, which transmit information, and oligodendrocytes, which act to protect the neurons and ensure that the information travels properly. (The latter are a type of glial cell, so named for being the “glue” of the nervous system). The main way oligodendrocytes carry out their supportive roles is by insulating neurons in a material called myelin—forming a myelin sheath around the neuron’s axon, a long protrusion from the neuron that conducts electrical impulses. This functions similarly to how an electrical wire must be insulated to work properly.

However, when the spinal cord is injured, oligodendrocytes die en masse and consequently the neurons lose their protective myelin sheaths. Even many oligodendrocytes far from the site of impact can die, increasing the area of the spinal cord that has neurons without myelin sheaths. The absence of the myelin sheaths so greatly disrupts the flow of information across the neurons in the spinal cord that paralysis can result even when the neurons themselves are spared.

Consequently, the main approach Keirstead and others have been taking to regenerate damaged spinal cords is to restore the myelin sheaths to, or “remyelinate,” the neurons. This has been primarily accomplished by introducing new oligodendrocytes to the damaged spinal cord area.

Keirstead continued developing methods of treating spinal cord injuries using oligodendrocytes, but started incorporating human embryonic stem cells (hESCs) into his approaches when he joined the Reeve-Irvine Research Center at UC Irvine. Four years after joining the Reeve Center, in 2005, Keirstead reported that his group could not only create oligodendrocyte progenitors from hESCs, but could also use these progenitors to effectively treat rats with acute spinal cord injuries. (This was published in The Journal of Neuroscience). Specifically, when these rats were injected with oligodendrocyte progenitor cells (termed OPCs) made from hESCs, the rats were able to remyelinate neurons and improve motor functions.

Human embryonic stem cells have immense potential for the field of regenerative medicine because they are seemingly unlimited in numbers and are pluripotent (meaning they can become any type of cell), but they have also been surrounded by ethical debate due to their biological origins. And, other than stem cells from fetal tissues (fetal mesenchymal stem cells specifically, which are from a much later stage in development than hESCs are) or neural stem cells (which are obviously quite limited in supply), hESCs are the only type of stem cell that has been found to be able to become oligodendrocytes (or oligodendrocyte progenitors). Consequently, hESCs are currently the best source of these cells for spinal cord therapies. And they appear to be quite effective.

On January 23, 2009, after submitting very promising data from 24 studies in animals in a 21,000-page application (hopefully it didn’t need to be printed!), Keirstead and collaborators at the biopharmaceutical company Geron received FDA approval for the first-ever human trials using hESCs.

The Phase I clinical trials were to treat patients with subacute thoracic spinal cord injuries by injecting the hESC-derived OPCs (labeled “GRNOPC1”) into the site of injury in the patient’s spinal cord, as this method showed significantly improved neuron remyelination and locomotion in animals for over nine months after a single injection with OPCs. Seven medical centers in the U.S. were selected for the clinical trial, and eligible patients would have to have had a spinal cord injury between the T3 and T10 thoracic spinal segments (near the middle of the spinal cord) and be able to be treated with OPCs only 7 to 14 days after the injury. The short time window of eligibility for treatment is clearly an aspect requiring improvement, but reflects what was observed in the animal models: quick action is needed after injury for these methods to be effective. Hopefully future approaches can be developed, or current ones improved upon, to increase the time window of treatment.

However, in August 2009, before any patients had actually been treated, the trial was put on hold by the FDA. Additional animal data submitted by Geron revealed that small, non-proliferative (they do not grow) cysts were found in the injury site, although the presence of these cysts did not correlate with animals having negative side effects. In late October, 2009 Geron announced that it would reinitiate Phase I clinical trials in patients with thoracic spinal cord injuries, and might expand them to include patients with cervical (the top part of the spinal cord) injuries in the future. The trials are expected to reinitiate by July 2010, while current studies are further characterizing the OPCs in animal studies. Geron is also currently exploring the applicability of the OPCs in treating other neurological diseases, such as Alzheimer’s disease, strokes, and multiple sclerosis.

The University of California at Santa Barbara is becoming a hub for stem cell research that is transitioning to the clinic. Interdisciplinary groups on campus collaborate and use human embryonic stem cells for regenerative medicine applications in the UCSB Center for Stem Cell Biology and Engineering. Additionally, Dr. James Thomson, the researcher who originally isolated hESCs in 1998, holds a joint faculty appointment at the University of Wisconsin and UCSB. Clearly, UCSB is at the forefront of a wave of burgeoning stem cell facilities, and Dr. Keirstead’s talk should find a receptive and motivated audience.

As knowledge and awareness of the uses of these very promising stem cells continues to grow, the resistance they originally met with has already been diminishing. Collaborative efforts with biopharmaceutical companies may ultimately be key to demonstrating the true potential of these cells in treating human diseases and injuries, such as the work done by Keirstead and his Geron collaborators has shown. To hear more about these efforts from Hans Keirstead directly, attend his June 14 presentation here in Santa Barbara .

For more on Dr. Hans Keirstead and his research, see the California Stem Cell’s profile on Keirstead, UC Irvine’s profile on Keirstead, Keirstead’s 2005 paper on using hESC-derived oligodendrocyte progenitors to treat spinal cord injuries, Geron’s press release on the FDA approval for clinically using these cells, the FDA placing the clinical trial on hold in August 2009, or the FDA/Geron announcement to reinitiate the clinical trial in 2010.

Biology Bytes author Teisha Rowland is a science writer, blogger at All Things Stem Cell, and graduate student in molecular, cellular, and developmental biology at UCSB, where she studies stem cells. Send any ideas for future columns to her at science@independent.com.