Hans Keirstead - Stem Cells
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Hans Keirstead
As Tom Chappell, MD, the managing health editor of ABILITY Magazine, approached Oakley’s sportswear manufacturing plant last summer, he felt like he was entering the fantasy game Dungeons and Dragons. He found the Foothill Ranch, California, structure imposing. On the face of it were a pair of protruding conical orbs, and the whole building appeared to be held together by metallic bolts and stanchions.

The lobby bustled with scientists, noted athletes with spinal cord injuries, television personalities and supporters of spinal cord injury research. Hans Keirstead, PhD, of the University of California at Irvine Reeve Spinal Cord Injury Research Center was the scheduled speaker. The topic was stem cell research for the treatment of spinal cord injury.

The presentation included colorful photographs and video—taken through a microscope—of paralyzed experimental rats recovering from spinal cord injury, with the aid of stem cell treatments. FIXFor 20 minutes, Kierstead Delivered the fascinating findings from the research center.

What we did in brief, Kierstead said, was establish a 42-day protocol in which we simulated what happens inside a rat embryo when its in its mother’s uterus. During early development, many types of cells are being formed. But all of them start out as stem cells, tantamount to a blank canvas. None of these new cells have been assigned a specific task in the body as yet.

One adult cell type that we are particularly interested in is called an oligodendrocyte [oh-li-GOH-den-droh-site]. It’s a 50-cent word for an important cell in the nervous system that supports the neurons. Neurons are nerve cells, the cells that carry messages from our brains to our spinal cords. These particular cells make an important protein called myelin. The oligodendrocyte cells wrap themselves around neurons and the myelin serves as insulation, much like that in electrical wire.

We began to research what other scientists know about what stimulates the stem cells to become oligodendrocytes. We found that there were certain molecules that seemed to influence the process. We were thus able to obtain some of these molecules and put them on stem cells in just the right combination, at just the right time. Our lab is now able to start with stem cells and produce volumes of oligodendrocytes.

One cell splits into two, which splits into four, which doubles to eight, and then 16, continuing on until they form little spheres; little floating balls in liquid. Initially, some of them look yellow, black or clear. What we did next was suck them out of the Petri dish, where they initially formed, one at a time. Ultimately we found that the oligodendocytes are the yellow ones. Then we developed a way to purify (or isolate) the yellow cells, removing the black and the clear ones.

Then we developed a way to purify those yellow cells. We can place the purified oligodendrocytes on a sticky surface for growing cells, and they start spreading out. There are millions of cells. This is a method of achieving high purity of the cell type and a large volume of cells. We can actually tag them prior to putting them into animals with a little bit of iron and then use what’s called magnetic resonance imaging (MRI) to view the cells inside the animal to show that the cells are surviving and spreading up and down the spinal cord.

Let me tell you about an experiment we did. The spinal cord of a rat is exposed surgically and then bruised with a blow from a small, blunt object to simulate spinal cord injury in humans. After the injury, the animal is unable to use its hind legs. It can move them a bit because the injury is not complete, just as is the case sometimes in humans. But it is dragging its belly, since there’s no consistent coordination between its front and hind paws.

After a spinal cord injury, many neurons—the cells carrying the information from our brain to our body—are lost forever. Others simply lose their insulating cells aka oligodendrocytes. Now those ‘wires,’ so-to-speak, cannot conduct ‘electricity,’ or signals from the brain, hence the paralysis. That’s why we took human embryonic stem cells and influenced them to become human oligodendrocytes that make myelin to protect those signals. When we transplant them into the rat’s injured spinal cord, it restores the function of the neurons that are still alive, but lost their insulation as a result of the injury. In the case of the rat, it’s enough to restore the animal’s ability to walk again. And it’s awesome to be in a laboratory when it happens.

The rat is not playing soccer, but her belly is off the ground, she’s supporting her weight, she displays locomotion with coordinated front to back movement of her front and hind paws, her tail is up—that’s an amazing degree of recovery.

[It is important to note that animals that are much lower on the biological hierarchy than humans, such as rats, have a much greater capacity to recover from a brain or spinal cord injury than humans do.]

After we did this treatment, we went on to do safety studies to determine if the transplant might cause harm. We’ve since determined that the treatment in rats is not harmful to them. Moreover, the experiments were repeated in other laboratories around the world and confirmed our results.

California voters approved Proposition 71 in November of 2004 to raise $3 billion for stem cell research in California. Prop 71 authorizes state bonds to create the California Institute for Regenerative Medicine. The Institute provides funding to stem cell researchers at universities, medical schools, hospitals and research facilities.

I can’t tell you how much flak our laboratory took for coming out with this treatment, playing a role in Prop 71, going to the senate on both the state and federal levels, and talking about it. We took so many hits, it was unbelievable. But then four other good laboratories from around the world repeated and confirmed our work, and all of a sudden everybody’s asking me to give talks.

On the other hand, we know that nothing happens after transplanting cells into a rat with a chronic (or old) spinal cord injury. There is no recovery in the rat if too much time has passed since the injury. I didn’t ever expect it to. We designed it to work on subacute injuries—meaning up to a week or so after the trauma first occured. In a chronic injury you’ve got scar tissue. That is the problem in a chronic spinal cord injury that an acute (just happened) injury and a subacute (recent) injury does not have.

So we had to design another treatment for chronic injuries. What we decided to do was induce the stem cells to become motor neurons. Motor neurons make muscles move. So now, instead of focusing on the insulating cells (oligodendrocytes), we began culturing the actual working cells of the brain and spinal cord. Although we developed this specifically for chronic spinal cord injury, it turns out that there are other diseases for which this could be helpful, such as ALS (Amyotrophic Lateral Schlerosis) aka Lou Gehrig’s disease. Spino-muscular atrophy is another one. Nothing can be done for these diseases. People who have them lose the motor neurons that control breathing and pumping of their heart. Eventually they waste away and die.

So we sought to generate motor neurons from stem cells, and we got lucky. In humans, the progenitor—or precursor cell that becomes the human motor neuron—can also become an oligodendrocyte, and we didn’t know this when we started. We just influenced them with chemicals to become a particular cell type. There are a number of chemicals that can tell this progenitor to either become an oligodendrocyte or a motor neuron.

We can place them on sticky surfaces in culture dishes, and we can persuade them to become adult neurons, not the just the sheath cells (oligodendrocytes), but the actual neurons of the brain and spinal cord.

Now, a motor neuron that we generate might look, smell and feel like your average motor neuron, but we need proof that it is also functional. The way that you prove this is you make it move muscle, right? That’s what a motor neuron does. In a person with a spinal cord injury, the muscles don’t work because the motor neurons have been destroyed.

We had to coax the stem cells to become muscle cells. When you go to the gym and work out, your muscles get big because of the progenitor cells in them called myoblasts. They divide and make more muscle cells. Our lab poked our graduate students with a hypodermic needle and take some muscle cells out. Then we learned to induce the muscle cells mature into muscle fibers, and then we incubated our motor neurons with these muscle fibers.

A sheet of human muscle that shouldn’t be contracting at all does because we put a sheet of human muscle with human motor neurons. This proves beyond a shadow of a doubt that human motor neurons that we’ve cultured from stem cells are functional. They actually make the muscle contract. That’s a tremendous breakthrough. It’s only the second time in the world that a high-purity population of any cell type has ever been developed from stem cells.

Now we move on to the animal experiments for those motor neurons that we developed from stem cells. What we’ve done is modeled the human cervical (neck) spinal cord injury by bruising the rats in the same area. Then we transplant our human motor neurons into the injury site in the rat. The brown-stained cells are our human motor neurons, and they’ve actually situated themselves where they should be. We’re extremely excited about this.

But we’ve got a few more tricks to do. If you just put human motor neurons into a spinal cord injury, they’ll probably just sit there and do nothing. They might grow a little branch, but what you really want them to do is connect all the way out to the muscle that moves the thumb, for example. If you can make the thumb work again in a patient who is quadriplegic, that is a tremendous increase in useful functioning. From there, imagine if we could eventually get that whole arm, or eventually, the legs to work? But one thing at a time.

So what we’ve done is devise more tools. In the muscle that we want to work again, we put an attractant so that the motor neuron will grow out and connect to that muscle again. Frankly, the sexiest thing that a motor neuron has ever seen in its life is the GDNF (Glial cell line-Derived Neurotrophic Factor). If you were a motor neuron and there was a GDNF in the parking lot, you’d be gone. (laughter)

‘When we transplant our motor neurons, they are able to induce the lost branches of the brain cells that come down the spinal cord to start growing again. Eventually, the brain cells can then, theoretically, connect with the new motor neurons.’

Our team started using viruses. Viruses can take other genes into their own. That’s what they do really well. However, to effectively use a virus in an animal or human, it has to be damaged first, so that it can infect a cell only one time before the virus itself dies. Otherwise, it will multiply and cause infection. The virus inserts itself into the gene of a cell that we choose. In this case, we want the gene that makes the GDNF in the muscle that we want our motor neurons to connect to.

Then we enhance the growth of the motor neuron by giving the patient, hypothetically speaking, a drug that causes the motor neurons to grow much more than they normally would. The growing branches of the motor neurons are then attracted to the GDNF in the muscle. The idea is to get the motor neurons to grow to the muscle cells. (The virus is no longer there, because it’s died.) Only the muscle cells are making the GDNF because the virus put the gene for GDNF into the DNA of the muscle cell. The hope is that a connection will be made that will allow impulses in the motor neuron to move the muscle. That’s the project that’s going on now.

At this time, we theoretically have healthy functioning new motor neurons in the injured spinal cord that can connect with and control muscles in the body. We still have a big missing link, however. There is still no connection between the brain and the new motor neuron in that spinal cord.

Sharon in our lab has been doing a number of really cool experiments to address this problem. What she does is take brain cells that might normally connect to the motor neurons in the spinal cord and put them in a Petri dish. If she just leaves them there, they grow little branches. But if she adds the substances produced by our human motor neurons, they grow much faster. We’ve identified a number of molecules that our motor neurons release, which cause brain cells to branch out and grow.

That’s great news. It means we got lucky: When we transplant our motor neurons, they are able to induce the lost branches of the brain cells that come down the spinal cord to start growing again. Eventually, the brain cells can then, theoretically, connect with the new motor neurons. Since these neurons have the potential to reconnect with the muscle, the circuit is theoretically complete: the brain should be able to control the muscle as it does in a normal situation.

At this point, you’re thinking: ‘This is not so tough.’ Ah, but the problems have only begun. We’ve developed the experimental treatment and we want to get it into people with spinal cord injuries, but we can’t. All the experiments have to be repeated by other researchers and they have to get the same results to prove that what we did wasn’t a fluke or faked. But what laboratory wants to repeat someone else’s work? They’re busy doing their own thing. Besides, we already have the glory of publishing these results and a grant to continue the work. So now we have to raise money to pay other scientists to repeat our work. That’s been very hard.

After that, safety tests have to be done to make sure the cells don’t migrate away from where they’re supposed to be, make sure that they don’t form tumors, or do anything to the blood or cause pain. We’ve done these studies for the oligodendrocytes, and we’re sure that none of those safety concerns exist. Now we’re doing safety tests on the motor neurons. This is all in animal models, of course.

To complicate matters further, there are tremendous debates. A lot of scientists say, ‘Slow down. Do more experiments. Show me that it works in several animal models.’ We have to balance that against the urgent need to get the treatment to humans. If we know it’s safe in rats, then why should we be required to do it in cats and dogs and pigs and monkeys, waiting five years per species? How do we balance the information we’re gonna get from continuing to study various animals against the need of getting to patients with spinal cord injuries sooner?

Following the presentation, Jamie Little, action sports and motorsports reporter for ESPN, ESPN 2 and ABC led an Q&A with MotoCrossriders and others in the audience with spinal cord injuries. The group included David Bailey and Ernesto Fonseca, both former MotoCross champions.

Little: David, you’ve been paralyzed and in a wheelchair for 20 years. You’ve heard and seen it all. I know you had pretty much closed the door on the whole idea that you would ever walk again, but I heard recently that you changed your mind?

David Bailey: Well, I can see Hans is on top of this. Most doctors say it’s impossible for people with spinal cord injuries to walk again, but he’s not taking no for an answer. He’s pressing on. He’s got a great team. They’ve made progress and accomplished what Hans told me he would back in 2001—doing stem cell injections into people and getting drug companies involved. Everything he said he was going to do, he’s done.

He’s proven to me that he’s not like some of the physicians I’ve spoken with since I first got injured. They keep talking about treatment being five or ten years out. So I had put it on the back burner. Way back. Not only did I think it was not possible for this to happen in my lifetime, but if it did, I’d be too old to benefit from it. Now I know I’m going to see this happen and affect my life. And the funding isn’t nearly as expensive as I thought it would be. I figured there would be a lot of resistance, or people saying, “We need $10 million to do this.”

Little: This is all new to Ernesto. He was injured about a year and a half ago. Ernesto, please put into perspective what life has been like since you had the accident. What would it mean to you for stem cell treatment get off the ground in the next few years?

Ernesto Fonseca: Early on you think that you’re going to be able to find some doctor or machine or medicine that’s going to make a difference. That’s the fallacy of this injury. People think if you’ve got a strong will or a lot of resolve or just so many other things in your life, that you’re going to be able to make a difference. The truth is that there is no therapy, there is no doctor, and there is no machine that’s going to help.

‘The number one cause of spinal cord injuries is automobile accidents. So the odds are that somebody we know is going to be affected by this. Wouldn’t it be nice if there were some form of treatment to address the effects or turn them around?’

Hans mentioned loss of bowel function. He mentioned loss of sexual function. Imagine when we leave here tonight that these things and many others are lost for you for the rest of your life. That’s a tough one to swallow. So you see me doing the Iron Man, hanging with Ricky James, riding a motorcycle. I still have a good time. I’ve adjusted, but behind the curtain it’s difficult.

The number one cause of spinal cord injuries is automobile accidents. I’m pretty sure you all drove here tonight. So the odds are that one of us or somebody we know is going to be affected by this. Wouldn’t it be nice if there were some form of treatment to address the effects or turn them around?

Little: Ernesto, you were recently introduced to Hans and the breakthrough that hopefully is right around the corner. Talk about the impact your accident has had on you.

Fonseca: I remember it like it was the other day. The moment I crashed, the first thing that came to my mind was: I don’t want to be in a wheelchair. I knew it as soon as I was on the ground. I looked over my left shoulder, and I think I said to one of the guys, “I’m done.” That was the thing that I was most scared of at the time. It’s hard for me to believe it’s going to be better at home, and it’s hard to see my wife dealing with so much stuff. I like to think that someone or something out there might be able to help us.
‘Research happens faster when the dollars flow. That’s just a simple equation. That’s why I moved here to do research. That’s why we’ve gotten so much done in such a short time.’

Little: Dr. Keirstead, obviously there’s been a lot of progress with the treatment for acute injuries. What is the goal once you start trying to treat the chronic cases?

Keirstead: We designed the motor neuron treatment specifically for chronic cases: People who have been paralyzed for years or decades. I would expect the result of this treatment to be that every single moving muscle group in the body would be re-enervated and connected with nerve cells all to the brain, and that they would be under the control of the injured individual.

At first we’ll try to regain control of one particular muscle that’s critical to daily function, to see if the treatment really works. And then we’ll get into all of the rest of the muscle groups until we can restore all of the things that a person really wants in order of priority, including bowel, bladder and sexual functions. We can theoretically seed the muscles that control these areas with attractants to have the motor neurons go there. So it’s going to be a series of steps. We’re actually working with groups of scientists and physicians overseas to recruit huge numbers of injury victims so that we can get through the early stages of treating just one muscle at a time, until there are cases where we are treating 20 muscle groups at a time.

The challenge we have is this middle ground that we’re currently on. For example, when this thing is ready for human testing, California Stem Cell is already waiting to pay for the trial. Once you get to work on patients, companies want in on it. It’s the pre-clinical research, laboratory research, that we’re fighting really hard to fund right now.

Little: Talk a little bit more about the funding and why David and Ernesto brought everyone here tonight. We all know that thankfully Prop 71 passed. There’s a lot of money available in the state of California now for research grants. But how much money is available and how is that money regulated? Why can’t it be used for what we’re trying to do?

The second part of my question is regarding the time frame in getting to human treatment. How long would it take with the normal flow of money, versus if we were able to leave this room tonight with $1.5 million? What would that do for the timeline?

Keirstead: Funding agencies wish to be associated with early discoveries. Their job is to fund laboratories doing this kind of research. Who decides what research gets funded? It’s groups of other scientists that participate in what are called peer-review bodies. These scientists review other scientists’ research proposals. They meet several times a year, and are directed to fund those studies that are a scientific novelty. But after something has been discovered, government agencies don’t exist to put money into development. It’s not their purpose.

So raising the funds to actually get it from the point of discovery into the hands of a company that’s going to pour tens, possibly hundreds of millions of dollars into it is the trick. The average cost of a biological pre-clinical (before it can be used in humans) project is $1 billion to move it from discovery to market. We don’t have to raise that, thankfully, because there are companies out there that will take it on, because they can make money from it. They deserve to, because they’re making the investment to bring new discoveries to the market, where they’ll be available to all who need them.

It’s a fact that research happens faster when the dollars flow. That’s just a simple equation. That’s why I moved to the U.S. to do research. That’s why we’ve gotten so much done in such a short time. We’ve been successful in attracting discovery research grants.

If you’re asking for a particular timeline, how fast can we get there, I can’t give you a solid answer. We’re not gonna know the outcome of our safety study before we do it. If we run into a problem, we have to tweak it and do it again. If a study takes six months and we nail it right the first time, it will take six months, but we might screw up and have to repeat it. That’s just the way science goes. Something might happen that we didn’t understand. But then we’ve got to raise the grant money again and experience another delay.

The path from here to patients with the motor neuron treatment is pretty much laid. Geron Corporation did it using our laboratory research. They have picked up our oligodendrocyte program and poured millions of dollars into developing this treatment. [Geron Corporation develops and produces biopharmaceuticals to treat cancer and degenerative diseases, including spinal cord injury, heart failure and diabetes. It is touted as the world leader in the development of human embryonic stem cell-based therapeutics. The spinal cord injury treatment Dr. Kiersted has developed is anticipitated to be the first product to enter clinical development.]

They’ve done pre-IND (Investigational New Drug) meetings and publicly announced that they are going to go to the FDA for the final IND approval by the end of this year. (An IND or Investigational New Drug permit must be obtained from the FDA or Federal Drug Administration before an experimental treatment can be used in experiments on humans in this country. This is an arduous process.) Clinical trials, in other words, experiments on humans with subacute spinal cord injuries should begin some time in 2008.
The first human embryonic stem cell clinical trial in the world is going to pave the way, because no such trial has ever been done before. Scientists and doctors don’t know how to do spinal cord injury trials, because they’ve never been done, so we have to learn. Similarly, the FDA didn’t know how to approve a spinal cord treatment using stem cells. Everybody’s had to learn. Geron has basically taken a machete and cut a path through the jungle and laid a road so that others can now follow. Subsequent stem cell treatments are going to be able to drive on that road.

The FDA is going to require us to treat Infantile Type I Spinal Muscular Atrophy first. This is a disease in infants that causes all of them to die before one year of age. They want us to start with that population because we can’t do harm to it with experimental treatment; there’s nothing to lose. We’ll have to show that our treatment is at least safe in that population first. Then we’ll still have much more to do before we try it in patients with spinal cord injuries. I can’t tell you precisely how long all of this will take.

Audience Member: Hans, I once asked you how you got into the field and why you were doing what you do. Your response, without a split second hesitation, was, “When I was a teenager, maybe 13, I decided it was going to find a cure for spinal cord injury.” In 2000, you moved down to California from Vancouver. This work is considered by many to be a dead end, a research dead end and a career dead end, yet you still want to do it. Would you speak a about your dedication to this cause and this research?

Keirstead: I have always felt that spinal cord injuries are treatable. I have been shocked and amazed that people don’t believe it and I think now we have proven that there is potential treatment. We now have several laboratories around the world that have shown that there are several different potential treatments. The views have changed over time. I don’t know exactly what the source of my stubbornness is, but you’re right, I’ve had it for a very long time. I’ve gained a lot of faith and support from everybody around that says, “Keep going.” Most of it comes from my students, staff and postdoctoral fellows who keep coming to me the right answers.

Audience Member: As individuals can we donate money to build this fund?

Ricky James, Sr. : Maybe I can answer that. I think there’s really three basic things that all of us can do. One is create awareness of this situation and the work Hans is doing. Two is to build relationships with people who have the ability to give. And three, generate widespread support for this.

UCI has a foundation. This foundation is attached to the university and directly to Hans Keirstead’s work. We’re looking for people who are willing to fund this kind of work. We can set up one-on-one meetings in Hans’s lab. We’d love to give tours of the facility if anyone would like to do that. If there’s more information you need to make the donation, we can give you the answers.

Audience Member: Is there a way to ensure that dollars go directly to research?

James: Yes. All you need to do is write, “Keirstead Lab, unrestricted” with your donation and Hans can use it for research. All donations are tax-deductible.

After the Q&A, the room hummed with the excitement of hope created by the presentation. With any luck, wealthy philanthropists in the audience grabbed donation packets on the way out the door and made good on their intentions.... continued in ABILITY Magazine

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ABILITY Magazine
Other articles in the Laura Innes issue include Headlines — CVS, Red Cross, AT&T Foundation; Humor Therapy — It’s Sad Not Being Happy; George Covington — When Life’s A Blur; Humor Therapy; Senator Letter — Ben Nelson; DRLC — Is Your Health Care System Accessible?; Allen Rucker — Thoughts on the Writers Strike; Green Pages — Save Bucks in the Bathroom; Betsy Valnes — Sticks and Stones; Deaf Cruise — Partiers of the Caribbean; ChairKrazy — The Marcus Ingram Story; Dr. Hans Keirstead — Stem Cell Pioneer; Richard Pimentel — Get A Job (Here’s How); ABILITY's Crossword Puzzle; Events and Conferences...subscribe

Dec/Jan 2007-08

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More excerpts from the Laura Innes issue:

Laura Innes -- Interview

Ricky James — Still Zooming Ahead

Hans Keirstead — Stem Cell Pioneer

Call Me Chairkrazy: The Marcus Ingram Story

Will Downing -- Will Power

UCP — Life Without Limits

Raytheon — Rhodes To Independence

Betsy Valnes — Sticks and Stones

Richard Pimental — Get A Job (Here's How)

 

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