A pig heart goes through the de-cellularization process inside a bioreactor at the Texas Heart Institute. (Photo courtesy of Texas Heart Institute)
Doris A. Taylor, Ph.D., director of Regenerative Medicine Research, Texas Heart Institute (THI); director of the THI Center of Cell and Organ Biotechnology, sat down with Texas Medical Center Chief Strategy and Operating Officer and Executive Vice President William F. McKeon to talk about her childhood, stem cell research, and the mantras by which she and her team work.
Will you share with us some memories of your formative years?
Dr. Taylor: As a young child, my father worked for the government and we lived in Germany. We were about to move to Vienna when my father became ill and we moved back to Texas where he died and was buried.
|Doris A. Taylor, Ph.D.|
As my father worked for the government, we always said the Pledge of Allegiance to the flag. I remember being scared to death about moving to the U.S., because I thought it was “one nation under guard.” I thought there were going to be fences everywhere in the United States. It’s hilarious, in retrospect. I was 5, so I didn’t know what to expect.
When my dad died, we moved to Mississippi because my mom’s family was there. So I grew up in Mississippi at a time when many things were happening. My parents had lived around the world and they taught us we could do or be anything we wanted. They also taught me that there are good people and bad people in the world and that it really had only to do with the quality of their character. So I think I grew up not fully understanding everything that was going on around me, but I knew important things were happening.
I grew up in a time when, not only were people talking about change, you were seeing change. So I think seeing all of that, and having lost my dad, I didn’t want anyone else to ever have to go through that. It was the most awful experience of my life and I didn’t want anyone else to have to experience it. I also have a twin brother and he is brilliant, but he is actively schizophrenic. I don’t talk about that a lot. Part of my job in life was protecting him, so I grew up wanting to make a difference and I wanted everyone to have a fair chance.If you can cure disease, everyone has a fair shot.
At what point in your academic training did you decide to dedicate your life to research?
Dr. Taylor: In Mississippi, when I graduated from college, I thought I wanted to go to medical school. So I got an interview, and they said “Why should we let you in? You are just going to get married and have kids. There is no reason for us to let you in.” I still thought that I wanted to go to medical school. It’s funny how it all comes full circle.
I first decided to go to graduate school at Mississippi State because they had a genetics department led by a person nominated for the Nobel Prize for finding B cells. So I went to graduate school for a semester but then received a call from Ross Perot’s company, EDS, asking if I was interested in a job. So I worked for EDS for a couple of years and then decided that I wanted to move toward science or medicine. I got a job at a lab doing cardiovascular work, which eventually led to pharmacology. I loved the big words, like “pathomimesis.” Who wouldn’t want to know what that means? So I got a Ph.D. in pharmacology at UT Southwestern.
Did you have any mentors?
Dr. Taylor: There were several great people in my life, who made a huge difference to me.
In high school, I had a biology teacher who encouraged me to participate in a national science contest. I was one of the people who won for the state of Mississippi. Somebody told me that the inside of ant beds were sterile, so I wondered if that was true, and if so, how? So I learned how to pour agar plates, and then we would streak them with bacteria. Then we would take ants, kill them and put them on the plate and see if they were killing the bacteria, and they were. So we measured the different area for different ants and showed the results. So that was my project, and I got to go to New York, and I saw kids and science projects from all over the country. I even saw my first laser.
The second mentor was a professor in college, Dr. Howell, who I made nuts because I wouldn’t go to class and then I would sit and read the book and pass the course. One day she asked me if I would consider getting a Ph.D., and I thought that sounded awful. I’d be in a lab all day…No! No, no, no. Little did I know, she was right.
I chose to attend Mississippi University for Women over Ole Miss’. I know if I had attended Ole Miss’ I would have deferred to all of the guys in the class. At the University for Women, there was nobody to whom I should defer.
Dr. Taylor: Two things. I really wanted to be a neurobiologist. I really wanted to study the mind…the brain. I thought that was fascinating, how synapses in a dish turn into us having this conversation. I wanted to figure that out. However, I was getting my degree in Al Gilman’s department in UT Southwestern and Gilman said ‘Neuro is 20 years behind everything else. We can’t do molecular biology in the brain, find something else.’
So I ended up doing work on nerve muscle interaction. For my Ph.D., I defined how calcium controlled smooth muscle contraction. It was interesting and I learned a lot. I had go to the slaughter house and get tissues, and heart was one of them. After a few years of grinding up hearts, I really didn’t want to work with animals anymore. I wanted to do molecular biology. So I went to New York and did a postdoc in molecular biology with one of the best people in the field, Leslie Leinwand, and she was doing heart work. I ended up sequencing a few genes from hearts and learned to do sequencing on human muscle cells in a dish and growing heart muscle cells in a dish. The first time we saw heart muscle cells beat in a dish…wow. It changes your whole notion of what’s alive. We knew cells were alive, but somehow they never looked alive. I became fascinated with that.
I learned how to grow viruses, and I had two discoveries out of that. One was that you can’t do molecular biology in a vacuum. A gene has got to be in an animal or it doesn’t mean anything. That’s what made it important. So I was right back to where I had started. Secondly, I was really curious about the fact that everyone said heart cells only divide once after you are born and then they don’t divide anymore. I considered trying to figure out how to make them divide, but that sounded really boring, and there were other people smarter than me working on that. Not the least of whom was Michael Schneider, working here in Houston. So I decided instead to work on gene therapy.
I went to Duke to teach gene therapy. Somewhere along the way it dawned on me and Bill Krauss that if you were going to do gene therapy, you had to get lucky and pick the right gene. And you had to have cells to pick up the gene and do something with it, and that was probably not going to work in a damaged heart where there were no cells. So instead, we said cells are little gene factories, why don’t we use cells instead. We did the first cell therapy in animals and showed that it was possible to improve function. We were the first people to do that in 1998. It took off from there. We did cell therapy for many years and then thought we are probably never going to take people who are at the end of that cell therapy continuum and move them fully backwards. Why don’t we start looking at end stage organ disease and what we can do there? So those are the two things I do.
Over time, men have fewer and weaker stem cells than women. Why is this rarely discussed in research?
Dr. Taylor: If you ask most people if their research was done in male or female animals, they don’t know. Are those cells from a male or a female? They respond, “They are cells. I don’t know.” Most people couldn’t tell you. We started out doing what a lot of people do, using male cells so that we could track them by measuring the Y chromosome. We were going to put male cells in a female so that we could follow them. And we did a control, female cells in a male, to track them. We found that the female cells were acting differently than the male cells, so we had to go back and do the sex matched studies and see. And it turned out the female cells were stronger. There were different cells present in the bone marrow and blood.
Actually, many times, males do worse if they receive female cells. But nobody has really done the right studies to know if that’s because there are fewer of certain cells or more of other cells. We have done a few experiments in animals that suggest there is some degree of imprinting. That whatever you see before puberty is what drives what you need later in life. There were some studies done early on to look at estrogen in men to see if it would be beneficial for men with heart disease and heart failure. And the results were actually very negative. They were actually stopped because there were deleterious effects. I think it’s not that estrogen is beneficial in women and therefore it would be beneficial in men. It has to do more with the loss of estrogen in women and loss of testosterone in men. We have done a little bit of correlative work and gone back and looked retrospectively and as testosterone starts to go down in the 30s, that’s when stem cells start going down in men. There is a very good correlation there. And women only catch up with men in the seventh decade. They start catching up with men in their 50s and over time, by their 70s, they have caught up with men. So I think it’s a loss of whatever hormones you saw previously. With men, it starts early and levels off and with women it starts later and then takes off.
|Following de-cellularization, the heart’s
structure remains and can be re-cellularized
using human adult stem cells. (Photo
courtesy of Texas Heart Institute)
Where are you at now in your research of the “ghost heart,” and what are your hopes for the future for those in need of hearts?
Dr. Taylor: I’m so very lucky to work at the Texas Heart Institute and have the privilege to work with Bud Frazier and Billy Cohn on my animal experiments. Who else in the world can say that?
I think we need to provide a stem cell primer at the Texas Medical Center for the Houston community. What’s a stem cell and why do you care? And we should educate people about stem cells and that they are simply cells that can divide. We all have them, every organ and tissue in your body, and your bone marrow. The world has been doing stem cell transplants since the 60s when we first transplanted bone marrow. I would love to host a program and really educate the community.
We are moving forward with hearts, but one of the preliminary steps is going to be getting enough cells. The other issue is figuring out a regulatory pathway for something like this. If we look back even to when heart transplants started, the assumption wasn’t that the first ones were going to be successful. But today, the FDA holds us to a different standard, even in compassionate use cases. So I think we are going to have to forge a new pathway for doing clinical studies with complex tissues and organs.
We are also moving forward with something simple, like a cardiac patch. To show that a non-human scaffold and human cells in a human is safe. So we really need to convince the regulatory agencies that you can use an unfixed matrix just as we use pig valves.
The first time I saw a calcific valve, I looked at the histology and I thought it looked like mesenchymal cells gone bad. And I think the stiffness of the leaflets in a fixed valve differentiated mesenchymal cells differently than they would have on an un-stiff valve. I don’t think we are that far away from a first in human study on some of this.
You have been an active participant in the strategic planning process across the Texas Medical Center under Dr. Robbins’ leadership. What’s your perspective on the direction?
Dr. Taylor: The Texas Medical Center is unparalleled. But we are not known as the Texas Medical Center. We are known as the Texas Heart Institute, Baylor College of Medicine, MD Anderson…all of which are phenomenal institutions, but which could synergize.
And I think the idea of a single cross-institutional IRB for the Texas Medical Center is outstanding. Moreover, I keep pushing on the same approach for animals. We can’t do research at each other’s facilities. For example, we have to go up to College Station for some things that we ought to be able to do at TMC. I think bringing together the best minds in the Texas Medical Center and joining forces in these institutes is essential. How could anyone in Houston argue against that? I don’t see how anyone in the world could argue against that. In fact, it probably scares the heck out of people across the world, because if we do get together, I think we are fairly unstoppable.
Dr. Bobby Robbins is the kind of guy that can lead us. He did not come from one of our institutions and he has the ability to bring this outside perspective. We really have to build a cooperative environment here. As funding goes down for research, it is critical that we have clinicians and scientists and clinician scientists interacting in a way that lets us advocate for each other. In my world view, when you look at individuals and institutions that are successful, they have the ability to go from the new ideas in basic science, through the preclinical filter, to first in human studies, and then commercialization.
We have all of those components here and now we are developing a plan to make this a reality.
What are some of your closing thoughts as you look ahead?
Dr. Taylor: I really have a couple of mantras in my group. One of them is “Trust your crazy ideas.” I used to have that on a postcard that was on my office wall but I gave it away to a woman named Katie Piper, who was a model in the UK. She came to the University of Minnesota to visit me because she was about to have stem cell therapy. And the reason she was about to have stem cell therapy was the man she had been dating hired someone to throw acid in her face.
So she had acid destroy her face, destroy her upper body, and two things really struck me about her. She didn’t give up. She has tried every innovative therapy there is. Just think about going from being someone whose whole world view is based on what you look like, to having to reconstruct your view of the world. And all the people around you, who have changed their opinion of you, because their opinion was based on what you look like. She created this website called “The Katie Piper Foundation” and it is designed to teach people what beauty is in a different way, and it’s phenomenal. So I gave her the post card. Trust your crazy ideas.
We do this every day. We all get up and we change the world every day. And I’d like to believe that here in the Texas Medical Center we all come to work every day thinking we can and we will. I came to the Texas Heart Institute because people like Dr. Jim Willerson have a vision and I am proud to be part of it.
Perhaps I am also driven by my past of losing my father so early, growing up with a brother who was different, in a state where things were happening and being a woman in that environment.
My other mantra is “Give nature the tools and get out of the way.” Many scientists think we have to understand every detail of something. We are never going to understand every detail of anything. I could spend the next twenty years trying to understand a stem cell, and I wouldn’t.
So I believe in making things simple. Give nature the tools, and get out of the way. Give it the scaffold, give it the cells, and let nature figure part of it out. That’s my approach to the world.
Another example is how many women have heart failure because they have received Adriamycin. A lot. If you get above a certain dose, you will develop heart failure. Adriamycin is the drug of choice for breast cancer treatment. If you get above a certain dose, you will get heart failure. MD Anderson has a huge population of women who no longer have breast cancer, but now have to deal with the consequences of that. They are grateful to be alive, but my colleagues here at THI are now beginning to take some of the things we know about cell therapy and thinking about applying that to women with heart failure from breast cancer treatment. That’s a perfect synergy that wouldn’t exist other places. It can only exist in a place like the Texas Medical Center.