Neurological Recovery

Thank you. It is my honor to be here to present to you. This talk will cover two parts. In the first part, I will give you an overview of the new science community at UTMB. The second part will focus on my own stem cell research and give you a piece of how scientists are working with stem cells.

The first part was originally scheduled to be presented to you by Dr. Claire Hulsebosch. Unfortunately, she cannot be here. She asks me to send her regrets for her absence. So I will be here on behalf of her and the hundreds of neural scientists, faculty, and staff in UTMB who are working with this institute for neurological recovery.

At UTMB we have a large population of neural scientists and clinicians, both nationally and internationally recognized research scientists and clinical programs. We have over ninety faculty members and several hundred staff located in four UTMB schools. We have 127 research projects and - funded by NIH - federal grants of more than $40 million. Our promise is to restore life, restore hope, and restore neural malfunction.

Our mission is to expand the frontiers of outstanding care for patients with neurological traumas or dysfunctions. The way to achieve that goal is through progressive research contributions, aggressive clinical trials, and accelerated development of new treatments. For that, of course, we need leveraged program funding. Without funds we cannot do too much to advance our knowledge and technology.

Why is it so important to focus on neurological recovery? I will give you several examples. One in every 1,000 people in the United States (mainly younger age groups) suffer from spinal cord injury due to car accidents. That healthcare cost is over $3 billion per year. Traumatic brain injuries also happen in 1 in every 1,000 people in United States (also mainly the younger age groups). That healthcare cost is over $10 billion per year.

Strokes are mainly in the older population. Every 53 seconds someone dies because of stroke. Another example is 1 of every 3 people over 60 years old is at risk of having a stroke attack. The healthcare cost is over $30 billion a year.

Our research and our goal is to make the wheelchair obsolete. We will do that by revolutionizing recovery through intellectual synergy, faculty recruitment, and fostering collaboration. At UTMB we have long history of good collaborations; everybody works with each other. We want to support new areas of research, including stem cell research. We have very good faculty and the facilities to train tomorrow's scientists and clinicians.

There's the old dogma that the central nervous system cannot regenerate. Shown here, are healthy nerve cells. If damaged, the old dogma says they cannot go back. But after decades of neural research and clinician practice, this is no longer true. We can actually help damaged nerve cells recover.

However, the best neural scientists in our school, in the world, cannot make dead cells alive again. So we use the stem cell as a source. Fortunately, the advances in stem cell technology really help us to get the stem cells working.

Our goal is to use stem cells to replace lost nerve cells, so they become healthy nerve cells and reconnect the wiring. Hopefully, not too far away, we will no longer have this old dogma. Our central nervous system can regenerate.

Along this line UTMB neural scientists have pioneered discoveries. This includes Dr. Claire Hulsebosch. Unfortunately, she's not here today. About a decade ago she led a group of scientists to isolate stem cells from human spinal cord.

They found that these cells were actually small floating cells. Previously, people threw the medium away, they were throwing the stem cells away. Now we find actual stem cells floating there. And these stem cells can differentiate and become nerve cells, both in culture dishes and in the spinal cord.

Dr. Hulsebosch also pioneered the process to engineer stem cells and let them express and deliver a lot of neuroprotective molecules. One is BDNF, one is serotonin. They found that when these stem cells are delivered to the surface of spinal cord, they can release BDNF and serotonin. The delivery of BDNF and serotonin can help improve motor and sensory function.

This is the work of Dr. Hulsebosch. She is Vice Chair and Professor in the Neuroscience and Cell Biology Department, director of UTMB's Spinal Cord Injury Program, and also director of Mission Connect, which is a Gulf Coast consortium consisting of five institutes, including TIRR, Baylor Medical College, UT Houston, and IBT Texas A&M, and UTMB. She has led this group to be the first to find that nerve cells and nerve stem cells can grow in the culture; they can be grafted to the spinal cord and the brain to improve function and to also use that stem cell to be a mini-pump to deliver neuro-protective vectors.

Dr. Hulsebosch was the past president of the National Neural Trauma Society, which has over 270 manuscripts. Her three findings are actually now in Phase 1 clinical trials at UTMB, so it is really great to have her on campus. She is leading the Central Nervous System Injury Program and with a group of scientists working on recovery from spinal cord injury.

Dr. Donald Prough, who is professor and chairman of the Department of Anesthesiology, is a world-renowned scientist and clinician for traumatic brain injury. He leads a team studying how to help patients recover from traumatic brain injury.

Dr. Ronald Lindsey, as the chair of the Department of Orthopedic Surgery and Rehabilitation, leads a group of scientists in working on neurological recovery and rehabilitation.

We have very strong program on campus that is targeting drug addiction. Dr. Kathryn Cunningham, who is the professor and vice-chair of the Department of Pharmacology and Toxicology and director of the newly established Center for Drug Addiction, is working on the mechanism of cocaine and Ecstasy dependency.

We also have a world-class pain research team led by Dr. William Willis, who is the Green Distinguished Chair, professor, and past chairman of Department of Anatomy and Neuroscience, and also professor of Department of Physiology Biophysics. Dr. Willis's team focuses on the pain function and pain pathways and how to control pain.

In addition, we have many scientists working on the neurodegenerative diseases. Those diseases include Alzheimer's disease, Parkinson's disease, Huntington's, and spinocerebellar ataxia. Dr. Tetsuo Ashizawa is the professor and chairman of the Department of Neurology and leads both a strong research and a clinical practice toward these diseases.

Dr. Bernard Godley has recently been recruited as a professor and chair of the Department of Ophthalmology and Visual Sciences He is a world-renowned scientist in macular degeneration, ocular nutrition, and retinal health.

Recently we established at UTMB the George and Cynthia Mitchell Center for Alzheimer's Disease Research. Dr. Claudio Soto is the new director of the Center. We have a group of scientists working together to attack this disease, not only Alzheimer's but also Parkinson's disease, Lou Gehrig's disease, Huntington's, and mad cow disease. We are also currently recruiting new strong candidates as faculty for research and clinical practice.

Now I'm going to focus on my own research: human stem cells that repair damaged brain or spinal cord. First, I want to give you a brief introduction. I assume most of you or all of you are already very familiar with stem cells. Especially the political issues of stem cells. There are three types of stem cells: embryonic stem cells, fetal stem cells and adult stem cells. Embryonic stem cells derive from one-week-old human embryos. At that stage there is a ball structure called blastocyst with an outer cell layer and the inner cell mass. The inner cell mass can be isolated and cultured. They can become any type of cell in the human body. Embryonic stem cells are the cells restricted by President Bush policy for federal funding.

Fetal stem cells are derived from discarded tissue of fetuses that are usually above eight-weeks-old. As adults, every tissue organ has a small number of stem cells. They're called adult stem cells, including bone marrow stem cells, umbilical blood stem cells, and they are also in your liver, fat, skin ‑ you name it.

There are some differences in the percentage of cells being stem cell in the tissue. In the inner cell mass 100% of cells are stem cells. That means every single cell can become any type of cells in the human body. Only 1-10% of fetal tissue have stem cell characteristics. I will come back later to tell you the characteristics of stem cells. Adult stem cell percentages are even lower. As cells become more differentiated to perform their functions, the stem cell population gets smaller and smaller. This makes difficulty for scientists to derive stem cells from adult tissue.

There are two characteristics of stem cell. The first one is called self-renewal, meaning that they can reproduce an exact copy of themselves. Embryonic stem cells have a self-renewal capability definitely. Fetal and adult stem cells have limited self-renewal capacity. Another characteristic is the multiple potential to become different type of cells. An embryonic stem cell is considered to have truly multiple potential, they're actually pluripotential. They can become any type of cells in the human body. Fetal stem cells and adult stem cells have restricted differentiation potential. They can become only certain types of cells in the body.

There is another characteristic of embryonic stem cells. They can form tumors, while fetal and adult stem cells have less likelihood to form tumors. So although the embryonic stem cells have the most incredible potential to become any type of cell, they do have a tumor risk. And scientists have been working on that to reduce the formation of tumor.

There are two main challenges in stem cell research. The first one is how to grow the stem cell. Scientists can’t do anything with a few thousand cells or a couple of hundred cells, it's just not enough. It is even more limiting in clinical studies. A couple of thousand cells won't be able to cure any disease. So the quantity of the cells is very critical.

So how to grow the stem cell? In our case we use a human fetal neural stem cell that's derived from a discarded human brain. It’s shipped to us in a vial. This is about thousand cells.

It took us four years to come up with the best medium recipe to expand them. Like we need to eat food, these cells also need to eat their food. Their food is in this medium. The orange medium has amino acid, protein, carbohydrates, vitamins; everything they need. They also have growth factors. We find there is a combination of three growth factors that can make these cells grow. Otherwise they just stay there not growing and not replicating themselves.

So using this new medium we got the cells to grow from one cell into a ball structure of hundreds of cells in what we call a neural SPEAR. If you can see that line on the surface, that is indicating they're healthy, they're happy, they're growing. I have to shake them every day once a day. Otherwise they stop growing; they're on strike. We can freeze the cells into vials and then store them in liquid nitrogen indefinitely. We can then recover them and expand them again. This allows us to have a lot of cells to work with. We don't have to always go back to original human tissue, but we have cells.

So the second challenge is how to make them become specific types of cells, in our case nerve cells, because human stem cells have the potential to become any type of cells. But for any disease we only lost one or two types of cells. We don't need all the other cells. We don't want to grow skin in our brain. Right? Nobody wants that.

So the question is how to get specific types of cells from these multi-potential stem cells. This has come from our breakthrough discovery published in 2002. I developed a protein cocktail that can make this human neural stem cell become a specific type of nerve cells. Basically what we do is take that floating neural SPEAR and we culture it on the dishes, on the flat bottom surface. Then we add this priming cocktail, which has two proteins and one sugar molecule. This makes these cells become neurons, or nerve cells, and stained in red on the slide here. So those are the nerve cells. Our discovery was published in Nature, and our story featured in the Houston Chronicle, reported by BBC News, Reuters Health, also in a story by Science Central, and aired on ABC network.

Now I want to give you some sense of how this translates to clinical patients. Our goal, of course, is to use human stem cells to replace lost nerve cells in the brain or spinal cord. I will use this, a diagram, to illustrate how we do it.

This is normal spinal cord, although our normal spinal cord is not that thick. Our spinal cord is about the thickness of finger. We have motor nerve cells, and then they send axons to control the muscle so we can move, we can talk, we can breathe. But under a diseased condition, in neural trauma, degeneration, or Lou Gehrig's disease, these motor neurons are gone. We want to use stem cells to replace the motor nerve cells and then reconnect to the muscle, so they can move again, and the patient can stand up.

I give you two examples here how we did this ‑ how we studied the stem cell potential. The first one is called axotomy animal model. This is a baby rat, and we crushed the sciatic nerve that controls the legs and feet. When this is crushed, it will cause motor neuron degeneration; the motor neurons die. Two months later we grafted a cell ‑ our stem cell - into the spinal cord and into that left leg. Then we did a gait analysis and to check their behavior. One of the scientists put the hind limbs of this rat into the developer solution and then let the rats walk on the x-ray through this corridor. At the end we have a dark box. Since the rats like the dark place, they just walked there. You can see we get their footprints.

As you can see here on the right side, there's a normal footprint with their toes spread apart and their paws standing up. But with a sciatic nerve injury, their toes cannot spread. They clump together. They also have an elongated foot, they kind of drag their feet. This is before a transplantation. Three months after transplantation, we found they had recovered pretty well, the same rats  are very similar on the left side and right side. This is one example.

Another example is through collaboration with Dr. Prough in anesthesiology working with a traumatic brain injury model. This model is called Fluid Percussion Model. Basically, we have rats on the stage connected to a metal tube containing some liquids. At the end there is a piston and also a pendulum on the end. This pendulum can be placed at different heights. The drop of the pendulum strikes the piston and then transduces pressure to shoot the liquid into the skull and hit the brain. This is a very well established model to mimic trauma to brain injury.

Then we did a water maze analysis: one day after injury, we graft the stem cell into the brain, into the injured area. Then we close, let them wake up, and have run them on the water maze. What is this water maze? It's basically a four-feet-large swimming pool for rats. There is a hidden platform under the water that the rats cannot see. We drop the rats into the water. Although they are natural swimmers and swim very well, they hate the water. They circle the edge and try to get out, but find they cannot get out. So they're just swimming through the pool. Finally they hit the hidden platform and immediately get on top of it, escaping from the water. And we record the distance and the time.

Normal rats learn and memorize the location of this hidden platform. They know where it is, so after a couple of trials, the rats they will go to the hidden platform immediately. However, if injured, they don't. With impaired memory, they cannot remember, so they still circle around and only by chance hit the platform. This slide shows the before transplantation and this is after transplantation.

At UTMB we work on cell expansion and cell priming to get stem cell growth and specific growth into specific type of nerve cells. Then we facilitate and collaborate, working on brain injury, spinal cord injury, stroke, Alzheimer's disease, Lou Gehrig's disease and even working on the mad cow disease. Our goal is to develop the technology to the point that it can enter clinical trials and can help to cure patients.

And for our future, I just want to mention this to you, under the leadership of Dr. Stobo, we have plans to expand UTMB. Right now this gray area is existing buildings for research and hospitals. In fifteen years we will double the square footage and have new buildings, shown in white. In particular, this building will be the building of neurological recovery. The idea is to have housed in the same building world-class scientists, students and also animals for a clinical trial laboratory, and then also the clinical patients and physicians. In this format we can facilitate the translation between bench top science to bedside clinics.

Our groups offer strength in basic science research, expertise in clinical application, collaboration and partnership, and a diverse team approach with clear goals and objectives topped off by leadership and vision. Thank you for your attention and for your being here. Now I will answer questions.

Question and Answer:

Audience: Two questions. One, were you affected by Rita and how much of your lab did you have to shut down?

Dr. Wu: That's a good question. Actually the whole lab was shut down for one week. And then, of course, the cells didn’t survive for one week without medium, so we had to discard those cells and then recover a new batch of cells. I said before that we can store the cells in liquid nitrogen, but because they are frozen, they are slowly recovered from liquid nitrogen storage. So my students actually suffered several weeks or even month to get back to our original schedule.

Audience: My other question is a scientific one. I follow you from where you say you can get the stem cell itself to become a neuron. But as you know, neurons themselves are specific; they're adrenergic, dopaminergic. So when you get the neurons, is it by position or location when you place them, for example, in a dopaminergic area? Which would be pertinent to Parkinson's disease versus somewhere else that's adrenergic? How do you get it to then program itself to say, I am a dopaminergic neuron?

Dr. Wu: Very good question. You probably did a lot of research on that. Yes, one critical issue I didn't have time to go into is that if we graft stem cells into adult brain, they usually remain undifferentiated or become glial supporting cells, and do not become specific type of nerve cells. So our finding of the primer was actually to get the stem cells to a certain stage that the cells can then acquire environmental cues, from where they are grafted, to become specific types of nerve cells there. For example, cholinergic neurons, GABAergic neurons, glutaminergic neurons, all according where they are grafted.

Audience: I wonder is there any application for stem cells with mental illness, like schizophrenia? Has there been any work in that area or is that just a totally different application?

Dr. Wu: Yes. At this moment I'm not aware of anybody working on schizophrenia, but, in principle, if you have nerve cell loss, stem cells can play a role to replace lost nerve cells.

Audience: Has there been any application of this work on human beings, and, if not, what is going to have to take place before you will be able to go from the lab to the bedside?

Dr. Wu: Well, in the United States there is no clinical trial for injury or degenerative disease using stem cells. But recently a stem cell company in California gained FDA approval to use human neural stem cells for nervous system diseases due to the deficiency of enzymes in the brain. The clinical trial probably will start soon.

But outside of the United States, in Ukraine, in Peru and in China, there are several places that have already initiated stem cell transplantation into spinal cord injury patients or Lou Gehrig disease patients. So far we don't know what the outcome is and if there is any beneficial effect.

Audience: My question will show my ignorance about medical schools, because this looks to me like wonderful research that you're doing in this very important area of neurology and improvement of nerve cells. But is this usual in medical schools, that they will have projects of this sort for particular diseases or ailments? And, if so, do they specialize, as you have here, in this?

Dr. Wu? You mean, in United States in medical schools?

Audience: Yes the United States in particular, but internationally as well I should think. I'm well acquainted that cancer is under investigation. But does a medical school find some area that they think needs attention and then develop it as a specialization the way you seem to be doing here?

Dr. Stobo: The answer generally is yes.

Dr. Wu: Yes.

Dr. Stobo: In fact, one-half of the money that comes from the National Institutes of Health goes to medical schools to conduct research. Now, some schools have a deeper bench than others. We made a decision here in about 1998 that we didn't have unlimited resources, and we were going to take our scarce and precious resources and only put them into areas that represent its strengths, represent areas of high quality, and represented areas that served important society needs.

And I think you've seen the examples of that in terms of our emphasis in emerging infectious diseases and biodefense and neurologic recovery - and we've got some others. We don't have twelve, but we've got six that are among the best programs in the state or the country and, in the case of emerging infectious diseases, in the world.

Audience: Two questions. Are you doing any work on the neuropathies that occur with advanced diabetes? Number two: I'll give you a little anecdote here. I just had a tragic thing happen in my house. I had a parrot that I bought in 1963, an African gray, that knew 185 words in English and Spanish that were appropriate. He said good morning in the morning, good night at night. He had the name and could imitate the voices of all my six children. He died last week and we had a funeral after forty-seven years of life.

The question I'm asking in relation to this is that here is this parrot with a brain that's less than a gram in size that has all this capability. Now, admittedly, it was not “intelligent,” but I've got mentally retarded kids who have 1,200 gram brains with no knowledge of their families' names, their siblings' names, have no speech. Why is it that a 1,200 gram brain that looks normal, weighs normal, has almost no function and this little tiny, tiny brain does?

Special projects ought to be set aside for special things that needed to be researched. In spite of the fact that a Ph.D. in a particular organization or school wanted their graduate students to do work in that particular field they ought to save a certain amount of dollars for these special kind of projects. And I wonder if that might be a special kind of project?

Dr. Wu: Well, I will answer the first question and let Dr. Stobo answer the second. The first question - the neuropathy - currently we're not working on neuropathy due to diabetes. But we have on campus a Dr. Randy Urban working on diabetes and trying to use human umbilical blood stem cells to replace pancreatic islet cells to try to find a way to cure diabetes. And that's the cause of the neuropathy. If we catch it early enough we'll be able to prevent a neuropathy from growing.

Dr. Stobo: I'm sorry I didn't hear. Maybe after this presentation I can get with you and we can talk about that. Any other questions? Yes.

Audience: Dr. Wu, thank you for a fascinating presentation. You mentioned President Bush's federal restrictions, and I'm wondering if they've impacted your work at all.

Dr. Wu: Well, we are working with fetal stem cells, and those cells are not restricted, fortunately, by President Bush. So our work is currently not affected by the restriction. But in terms of the whole field, the stem cell field, it is. The United States are affected by President Bush’s policy because there are limited cell lines that can be used, and also limited funds that can be used for stem cell research.

Audience: I have a second question. I know that you're a neuroscientist, but you are an expert in stem cell research. Perhaps you could comment on the recent reported successes in using stem cells to treat myocardial injury.

Dr. Wu: I think it's very fascinating - using stem cells to help to treat myopathy. I would like to see the long-term outcome at this point. A couple of years after the treatment will say something and will mean something. But what the long-term outcome is we still waiting to see. But it's very promising.

Dr. Stobo: I want to thank you very much for a really exciting presentation and thank the audience for their attention and patience here at this program.