Stem Cell Research – Interview with Dr. Kierstead

While it never quelled the commitment of researchers, treatments for complex diseases such as paraplegia, Parkinson’s and Multiple Sclerosis were elusive, if not seemingly impossible. These perceptions changed when three years ago, Dr. Genie Compton at the University of Wisconsin discovered the first stem cells in humans. This remarkable, breakthrough discovery of human embryonic stem cells, unspecialized cells that give rise to specific specialized cells, offers extraordinary potential and has transformed many views in the biomedicine research arena, bringing hope for the further development of new treatments for various diseases.

Dr. Compton’s promising discovery compelled many scientists to initiate research projects utilizing human embryonic stem cells. One such pioneer in the human embryonic stem cell research arena is Dr. Hans Kier stead, a graduate of the University of British Columbia in Vancouver, Canada. Dr. Kierstead’s doctoral thesis concentrated on his invention of a unique method for regeneration of damaged spinal cords. His work ultimately resulted in the first demonstration of functional regeneration of the injured adult spinal cord.

During his four years of post-doctoral studies at the University of Cambridge. Dr. Kierstead was rewarded with both Canadian and British fellowships to support his work. Since that time, he has also received the dis tinct honor of election to two senior academic posts, Fellow of the Governing Body of Downing College and Senate Member of the University of Cambridge. In 2000, he became the assistant professor in the Reeve Irvine Research Center at the University of California, Irvine, a leading center for spinal cord injury research founded by actor Christopher Reeve and philanthropist Joan Irvine. Dr. Kierstead is currently leading a large team that investigates the cellular biology and treatment of spinal cord trauma, Multiple Sclerosis and other dis eases of the nervous system. He is also the President and CEO of Ability Biomedical Corporation. Founded by Dr. Kierstead in 2002. Ability Biomedical Corporation hopes to bring spinal cord and Multiple Sclerosis treatments to clinical trials.

ABILITY’s Hope Allen recently spoke with Dr. Kier stead on the latest advancements in stem cell research and the impact it will have on spinal cord injury.

Hope Allen: What is the latest information you can provide on spinal cord research or nerve regeneration?

Dr. Hans Kierstend: I think the most attractive prospective therapy going today is the use of cells derived from human embryonic stem cells. The human cells have been ‘pushed’ in culture dishes to become first brain cells, and then a sub-type of brain cell that the field knows to be beneficial for repair The use of these derivatives of human embryonic stem cells is the most attractive therapy available right now and has the potential to successfully treat spinal cord injury.

HA: Is that what you are working on in your lab?

HK: Yes, absolutely. I work at the Reeve-Irvine Research Center established by Christopher Reeve and Joan Irvine, of Irvine, California. Our lab I’m told, or should I say my lab, is the only lab in North America with human embryonic stem cells for spinal cord injury research, although I suspect there are a couple of other groups in the nation that have them now. HA: Have you heard about “Embryos ‘R’ Us?”

HK: Right, right. (laughs) Funny. There are actually several groups that have the cells, that are either growing them for the sake of learning how to play with them in dish cultures, or are using them for Parkinson’s dis ease and Huntington’s and things like that. There are very few groups that have them for spinal cord injury research, in North America at least.

HA: Can you address how stem cells are an answer to the controversy of utilizing tissue from aborted fetuses?

HK: Well, the use of human embryonic stem cells as a source of tissue for cellular replacement strategies really grew out of a need for a solution other than the use of fetal tissue. It is unfortunate the term ’embryonic is used within human embryonic stem cells because the populace generally thinks they are derived from fetuses. As a matter of fact, the use of embryonic stem cells is an answer to the use of fetal tissue to replace lost cells after trauma. There have been studies done in Miami. for instance, and also in Europe, where the tissue from several aborted fetuses was used to treat brain or spinal cord traumas. In those studies. 11 aborted fetuses were used to treat a single human. In Miami there were nine humans treated in this way. That is an amount of tissue that needs to be processed in order to treat a large human. Of course there are supply issues, not to mention the ethical and political controversy.

Human embryonic stem cells are created by a method whereby the cells are multiplied adinfinitim. We can take one cell and make a pint glass of identical cells in a very short time. That is extremely important because we need a lot of tissue to treat sites of trauma. So now that we have that pint glass of cells, we have a homogenous population of cells that we can control. This is accomplished by making them first into brain cells and then a sub-type of brain cell in order to treat injuries.

HA: Where are they derived from?

HK: They are derived from the discards of fertilization clinics. So pre-mom and pre-dad go to a fertilization clinic and they take a dozen or so eggs from the woman and a few million sperm out of the man. Those are unit ed and usually there are about eight or so fertilized eggs that come about for the in-vitro fertilization. Generally they implant a few cells, maybe three or four, into the uterus and if they take, then they kill the rest of them by deep freezing them-discarding them basically. Human embryonic stem cells are derived from what has been discarded at the fertilization clinics. The mom and dad sign a waiver which says. “You may use our excess,” and from those cells the embryonic stem cells are derived.

When they are put into the uterus, they are a three day old union of the sperm and the egg. That is about 150 cells and it is shaped sort of like a tennis ball, a very miniature little tennis ball, and inside that tennis ball are just a handful of human embryonic stem cells. What we do is split open that tennis ball and take out the human embryonic stem cells. Now without the instruction of the tennis ball, these cells can never form a human, even if you put them into a uterus. All they can do is divide and divide and divide. In fact, they are the best cells that science knows of for this purpose. The next best divider is a cancer cell and of course we don’t want to be looking at those. We have discovered that these stem cells are the only cell on the planet that divide and replicate themselves as an exact copy over and over. They have not been mutated or genetically altered at all; they are just pure, natural embryonic stem cells that have now been dividing for over three years since they were extracted.

HA: This is the same batch from three years ago?

HK: That is right.

HA: What is the legislation regarding the use of them?

HK: In the year 2001, President Bush passed a law saying that federal funds may be used to work with the 63 human embryonic stem cell lines that were registered prior to August 2001. Bush declared that no federal funds could be used to research cell lines generated after that date. At that time there were the original 63 cell lines. That is 63 moms and dads who donated their human embryonic stem cells. As it turns out there are only about seven that are any good, the rest are simply uncharacterized and belonged to either scientists or companies that submitted their cells prior to the cutoff date in the hopes of getting another registered cell line. Geron Corporation owns many of the seven and I have established a contract research agreement, basically a collaborative research agreement between Geron and my laboratory at the Reeve Irvine Research Center at UCI, in order to provide me with the cells. Funding has been matched by the BioSTAR program of California in order to conduct the research on spinal cord trauma using these cells.

HA: Then the cells that are in these lines will multiply indefinitely as long as they are maintained properly?

HK: That is correct.

HA: So if the science is done properly, we would not need any more cells?

HK: You ask a very important question, “Is there a need to derive more lines?” Well, my answer to that is, “We do not know what the potential for all of the good seven is.” We have to do the research and I’m researching on two of the lines now; it is going to take a little while to get around to doing all seven…but I’m only one laboratory. Now, just like you are different from me, you are better at some things than I am and I am better at some things than you are…

HA: No, you’re not.

HK: (laughs) Humans are diverse, so these cell lines are diverse. Surely it is reasonable to presume the cells are going to respond differently. Just like humans have different faculties, these cells have different biological properties. Some of them may be better than others at dividing or inducing regeneration of an injured central nervous system. It is possible that some may even migrate after we transplant them. I think it is important actually to try many cells and make sure that we have the best cells available. Now, that is my pitch for “let’s have more cells.” And that is how I stand. I think we should actually have more cells made available to us just because of the preliminary evidence of the extraordinary potential of human embryonic stem cells.

I’ve had these cells for almost two years now; I have been working with them in pushing them to become the right type of brain cell and I have succeeded. I have transplanted them into spinal cord injured adult animals and I have preliminary evidence that they are extraordinarily beneficial at invoking regeneration following spinal cord injury. This evidence is really looking very. very promising. The preliminary evaluation has to be repeated: my laboratory and other laboratories will have to be peer reviewed and published, but I will repeat that the transplantation of human embryonic stem cells is looking extremely promising as a treatment for spinal cord injuries.

HA: With California’s history as a more liberal state, is it less restrictive for this type of research?

HK: I gave two pitches to the California Senate prior to last September when a bylaw was passed. This bylaw made California a “stem cell-friendly state” in complete contradiction to the position of the federal government. That series of pitches to the Senate, given not just by myself, but also by other scientists pitching on behalf of the cells, was enough to convince senators that the potential of these things is incredible. I think that the potential of human embryonic stem cells for healthcare medicine is akin to what the jet engine did to the airline industry. They are incredible. If they continue to work as well as they seem to be working now, they are going to be good not only for spinal cord injuries, but any cellular replacement strategy; Parkinson’s disease. Alzheimer’s disease, Multiple Sclerosis, brain trauma, a whole host of diseases where you need more tissue.

HA: The embryonic stem cells will then allow research which had originally depended on fetal tissue to move forward.

HK: It has been proven in the literature that fetal tissues can benefit trauma and disease. Many different diseases, but primarily Parkinson’s and Huntington’s could be treated to advantage. Unfortunately, to move forward on that front is simply not possible for ethical reasons. political reasons and supply reasons. These cells represent a way to generate, not only enough tissue, but also pure tissue on cell type. They are much more clinically relevant and also not as mired in ethical controversy as the fetal tissue. So I really see them as the answer to a very promising work previously done with fetal tissue. One couple generated the H-1 cell line which has now been growing for three years. I’ve treated well over 150. to 200 animals with it and it just keeps on growing, pro viding me with enough tissue to conduct a lot of very detailed experiments. Hopefully one day I will treat an even greater number of people.

HA: You must have a difficult time keeping the growth at a constant without either over or under growing.

HK: No, the conditions to grow stem cells have been well worked out. Since stem cells in rodents were dis covered ten years ago, I have been able to basically lean on the shoulders of scientists that have come before me who have really worked out the conditions for growth. Our lines have been growing for three years and they do not show genetic drift or mutation. They just keep on growing and they are exactly the same unless we specifically treat them to force them to mature.

HA: What kind of time frame are we looking at before any of these developments can actually be realized by individuals with spinal cord injuries?

HK: You know, I wish I could tell you. I’m really not copping out by not giving you a timeline. What has to be done now is that the studies have to be replicated again and it generally takes about four to five months. Then dosing studies have to be done: are we using the right amount? We have to repeat it several times with different dosages. Here is the big one: toxicology studies have yet to be done. We have to figure out if these things are having any serious side effects on the animal. The toxicology studies involve looking at the heart, the liver, the bloodstream and the immune system, and make sure that our treatment is not doing harm. We don’t know how long toxicology is going to take because if it doesn’t do any harm, it is completed very quickly. If it does do harm, then we have to figure out why and eliminate the components that cause the harm and then start up again. That is the black box.

The next step, which is also a black box, is regulatory affairs. As you create standardized vials of cells to be put into humans, the FDA becomes extraordinarily involved. What is in that vial? Do you know everything that is in that vial? What conditions led to the development of that vial? It’s called regulatory development and again, we don’t know the answers because we haven’t gotten to that stage yet.

HA: If the cells are inserted and begin to grow to accommodate the location where they’ve been introduced, where does the toxicity come from?

HK: Let me just give you a doomsday scenario: you put cells into people, the immune system fails to recognize the cells and starts to destroy them. Right? And now you’ve got a permanently altered immune system that is hyper sensitive to these cell types. Maybe then you get an inflammation that causes sickness in the host so we have to do Immunol suppression to quiet down the immune system. Another bad scenario: maybe the cells don’t stay where they are put. Maybe they wander… possibly into some environment in the brain where they then form a tumor. That is what we call toxicity.

HA: That same type of toxicity where you mutate and grow two heads?

HK: Right! (laughs) We have to make sure that there is no tumor growth, and so far we have never seen a tumor, but the FDA will require us to test many animals and look for tumors in a very, very specific manner, because they might be small and therefor easily missed.

HA: How do you program that cell to regenerate or grow exactly where the host needs the new material?

HK: We put it exactly where we want it.

HA: It’s controlled solely by the placement?

HK: It’s just by placement. We stick it straight into the spinal cord at the exact location where it is needed.

HA: And then you water it?

HK: (laughs) That’s right. You know what is really nice? My whole premise in working with cells is, “Don’t pretend that you are smarter than the central nervous system.” The brain and spinal cord are a lot smarter than we are, so if you put a multi-potential cell like the human embryonic stem cell into a site of trauma, what is it going to become? The cell you want it to become? No, it’s going to become whatever the central nervous system dictates that it is going to become. If it’s making scar at that time it’s going to trick those little guys into becoming more scar. So what we have done is pre-differentiate the cells so that they are committed to becoming only the type of cell we want them to become. Then when we introduce them into the central nervous system they can’t wander.

HA: That sounds very interesting!

HK: Yes! Very interesting. Pre-differentiation. So there is less opportunity for them ever to form tumors, for example, because the cell is too immature in its developmental path to become a tumor.

HA: Do you do that in-vitro?

HK: Yes, we manipulate them before we put them into the animal, to mature them into becoming a precursor of the cells that we want. Plus, it is as simple as you pictured it to be: you put them in and you let them do their magic. You’d be shocked at how perfectly it actually does work.

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