PIONEERS OF HOPE: Doug Oliver's Interview with Dr. Kapil Bharti, Ph.D., Principal Investigator f
“We are not giving up, until the point that we are confident that I can take these cells and put them in my daughter’s eye or my grandma’s eye… We will not stop ’till that day.” ~ Kapil Bharti, Ph.D.
Doug Oliver: I’d like to welcome you, Dr. Kapil Bharti, to this, the third in an innovative new interview series that the Regenerative Outcomes Foundation is conducting. Its real reason for being is to provide a snapshot into your life - a more personal, intimate view of what kind of person you are and why you entered this field.
What drove you to pursue it? Do you have a story? How do you perceive the hope that patients are developing for the type of treatment that you are working on? Where do you see that intersect?
I want to welcome you as a Pioneer of Hope.
Kapil Bharti: Thank you.
Doug Oliver: That is the name of this interview series, and I selected you for a couple of reasons. One is because you're doing something that’s close to my heart, and close to my experience. As you know, I have an inherited retinal dystrophy that's a form of macular degeneration not technically treatable, but I had an experience with a bone marrow-derived stem cell transplant a couple of years ago with a positive response. I'm now doing what I can through the Regenerative Outcomes Foundation to get as many of these treatments into a safe, efficacious, science-driven environment as possible. That way, more patients can have the same outcome that I've had, and have it more guaranteed.
I’d also like to mention that recently, you graced us by going through quite a clearing process with the NIH ethics committee, a request that I made of you a few weeks ago to be a member of the Regenerative Outcomes Foundation Advisory Board.
You are a scientist who is here on a grant. Could you explain a little bit about who is sponsoring this research with NEI?
Kapil Bharti: So actually, I am part of what is called the intramural program of NIH. So, most people know the National Institutes of Health as a federal organization that funds research around the country. But there is also an intramural component of this which is this campus, and about 1,000 scientists on the campus across different institutes that are funded by a part of NIH called the intramural program.
So our money directly for our research and our salaries comes from that program. So we don't apply for the same RO1 grant money that the external world applies for. We stay within NIH, so we actually can’t even apply, we’re not allowed to apply to those grants.
We have a separate funding mechanism which sort of gives us equality to RO1 funding over a 4 year period.
Doug Oliver: Could you explain to us more about what “RO1” means?
Kapil Bharti: So RO1 is one of the quintessential funding mechanisms that NIH uses to fund research at most universities across the country.
Doug Oliver: Would it be basic research, or translational research, or both?
Kapil Bharti: Both, but RO1 is for mostly basic. There are specific mechanisms that form translational research, and those are usually larger grants because translational research tends to be more expensive, for the design of it.
But the advantage to the intramural model is that we have access to this immense resource of the clinic, a lot of core facilities for drug screening, imaging, and other things that are really valuable to move science forward collectively.
And collaborators - we think of a topic we wanna do in our research, and sure enough, there’s somebody on the campus who has experience in it, or is working on it. So you can just pick up the phone, call a colleague, and say, “Can I send my fellow to your lab for this one experiment?” “Sure!”
They're all happy to help. And that is this collective resource, which is the advantage of being in the intramural program.
Doug Oliver: Do you think that the intramural program model has fueled the progress that you've made in your research?
Kapil Bharti: No question about that. Absolutely. Because it’s allowing us to innovate on a completely different playing field. And this would just not have been possible, RO1 money or not, for our process, given the amount of money an RO1 gives.
So you know, this journey really has been going on for years, to bring this technology to patients, and we have manufactured these pigment epithelial cells - special cells that are located in the back of the eye and die off in macular degeneration patients.
Using patients’ own stem cells, just to give you an idea - the whole manufacturing process takes months. So just to optimize a process to make sure that it succeeds every time and the outcome is same for every patient, like you said -
Doug Oliver: So that you can scale it later.
Kapil Bharti: So that you can scale it out to every patient, and then to test those cells in animals to prove that they are safe and they have efficacy. This has been quite a journey. There have been aspects of this at every step, at every corner, which were really hard.
There were a lot of decisions we had to make, whether to go forward one way or the other. And there's one thing that we never compromised on, which was the quality of science.
There was a point in this whole project, and my team knows it well, that we just could not make the cells that we thought we could make under clinical settings. We could make them in the lab, but there was something different between the two processes.
I remember sitting at this table with five of my team members who were overseeing different parts of it. It was Friday late evening, and I said, what the hell is wrong here? We have to figure this out. We cannot let it go at this point. We can not say, this is good enough.
Doug Oliver: Okay. Let me focus in on this for a minute, because this camera is picking up the light in your eyes and it's picking up your passion. Your frustration has something to do with what you're about to say.
Kapil Bharti: Yeah. That is right. So we were really frustrated at that point and everyone said, maybe this is it. This is kind of the maximum quality of cells we can make. I said no, we're not giving up. We're not giving up to the point that we are confident that whether I will take the cells and put that in my daughter’s eye, or my grandma’s eye - we will not stop until that day. That was a Friday afternoon.
We were sitting here till 8:30 trying to find solutions.
Next morning, I wake up and I see all of them are working from home trying to find solutions - and they found solutions! And the emails were going back and forth -
Doug Oliver: The next day!
Kapil Bharti: And I said, “This is it. This is how, this is why we're gonna be hopeful - this will bring a right technology to the patients.”
Doug Oliver: What do you think made that happen?
Kapil Bharti: So, you know, there were small changes in the manufacturing process -
Doug Oliver: No, no, not with the cells. What made it happen?
Kapil Bharti: The passion of people. The collective passion.
There were two things. One, a certain level of pride that we can make the right kind of cells. And second, more importantly, not to give up on the science and the quality of the science.
We said, “We cannot compromise,” we can’t say, “This is good enough,” when we know we can achieve here, we can reach here, so we're not gonna stop there. So we will achieve all the way to the top. And that's what drove people.
Doug Oliver: Wow. Because they solved what they felt was the unsolvable, and they were very close to admitting that, and that must have been very inspirational for you - not just as a scientist, but as a human being, it must have been fulfilling to watch it happen like that.
Kapil Bharti: Yes.
Doug Oliver: That's an amazing professional story, especially since it touches on the reality that we all share the desire to excel in what we believe in.
We are going to explore some more of that non-scientific soft ground today. Not for the purpose of muddying the waters, but for the purpose of understanding some of the motivations that patients have in taking advantage of the science that you are so gracefully producing.
Do you consider yourself a “Pioneer Of Hope," now that I’ve labeled you that way?
Kapil Bharti: [laughing evasively]
Doug Oliver: This is why I like you. Internally I call you “the smiling scientist." You are so engaging and so empathetic, which sometimes isn't a common trait for scientists.
Kapil Bharti: So, we'll say I am a Pioneer of Hopeful.
Doug Oliver: Good!
Kapil Bharti: I’ll put it that way, because we are hopeful that the technology we are developing will actually be beneficial to the patients for whom we are developing this and for the society, and we'll move the science forward at the same time. So, hopeful.
Doug Oliver: Thanks for taking the wind right out of my sails. You’ve just renamed my whole series!
Kapil Bharti: No, just for myself! We are hopeful.
Doug Oliver: Well, that brings us to your experience of hope. When you say “hopeful,” you made the distinction.
You mentioned something about grandmothers... When I was in Washington, I discovered quickly that when people heard my story - now, granted this is on a non-scientific level - but when they heard my story and realized the gravity of it, one of their first responses was almost always, “Do you think this would work for my mother?” or “my grandmother?” Those same relationships.
Do you have a connection in your family? Maybe not yours, but why is it that you thought of daughter and grandmother?
Kapil Bharti: Well, those are the people closest to your heart, right? Those are the people you would not want any harm to come to. If I'm making a potential drug that I think will treat patients, I want it as good as I think I'm comfortable to give it to my mother or grandmother.
Doug Oliver: It sets the standard level of caring, and that's very human.
Kapil Bharti: We are human and patients are human.
Doug Oliver: You have a mother.
Kapil Bharti: Yes.
Doug Oliver: And you have a grandmother.
Kapil Bharti: Yes. And I have a daughter.
Doug Oliver: I bet you're thinking ahead for her in what you do.
Kapil Bharti: Yeah.
Doug Oliver: If you could, in a couple of paragraphs, as accurately as you can, describe in full scientific language what NIH, through you and your team, have discovered and hope to accomplish in your upcoming clinical trial for macular degeneration? Just give it to us straight.
Kapil Bharti: [laughing] So you know, macular degeneration - especially the age-related, non-mendelian form of macular degeneration - is thought to be caused by degeneration of a tissue called epithelium that is located in the back of the eye right underneath the photoreceptors. The photoreceptors are the light-sensing cells of the eye.
So what these epithelium cells do - for short we call them RPE cells - all throughout their life they maintain the health and integrity of photoreceptors.
Photoreceptors need nutrients and the RPE provides the mechanism that allows those nutrients to go back and forth with the cells. If these RPE cells die, which are transferring all the nutrients from the blood supply to the photoreceptors, the photoreceptors starve and die. They don’t get all the nutrient exchange and the health support. Hence, the patients go blind.
Doug Oliver: So in layman’s terms, what happens is that when the RPE becomes damaged or disintegrates and the photoreceptors fail to thrive, and then go to sleep, and then die, and then disappear, it causes the blindness that we call Macular Degeneration. Without the RPE…
Kapil Bharti: ...our photoreceptors are not getting enough oxygen, they’re not able to clear out the CO2 lactates - all the bad stuff is happening to the photoreceptors as RPE cells die off. That’s what happens in MD patients.
Doug Oliver: Tell us more about how your team is working on the RPE.
Kapil Bharti: What we have managed to do here at NIH is use a stem cell technology called induced pluripotent stem cells, in short IPS cells, which for practical purposes are related to the famous, controversial embryonic stem cells - ES cells - but instead of coming from embryos, can be made from patients’ own blood cells. So, I can draw a little bit of blood from you, and convert that into your own IPS cells, into your own stem cells.
Doug Oliver: You’re basically taking an adult cell and stripping away their education, in a sense, which makes them sort of mimic embryonic cells. You’re erasing their adult memory to the point where they know that they want to turn into another kind of cell, but you get to choose what kind of cell they’re turning into. You know how to coax them to differentiate the way you want into the kind of cell you want?
Kapil Bharti: Exactly. Yes. You got it.
Doug Oliver: That’s why they’re called “induced," because you’ve actively changed their makeup, and they’re “pluripotent” because they’ll turn into a number of different kinds of cells, and they’re stem cells because ...
Kapil Bharti: ...because they will now turn into, they can self-perpetuate and they can make other cell types of the body. That’s exactly it. But the challenge is now, pluripotent stem cells in an embryo make all of the body, all of the organs. Now you have to teach these induced pluripotent stem cells to only make RPE.
Doug Oliver: You need to keep them educated enough so that they won’t turn into untoward cells inside the eye.
Kapil Bharti: Yeah, into muscle, or bone, or kidney
Doug Oliver: You don’t want the cells to have no programming at all. Is that a genetic process?
Kapil Bharti: It’s called an epigenetic process. Switching off one gene, switching on another… But, you know, since we have 21,000 genes, switching the right combination on and off in every single case is what the whole story is about.
What we do is, in a dish, we mimic embryonic development from IPS cells to make them into one lineage, RPE cells. These cells will not make a heart, muscle, bone, cartilage, anything - they will only make RPE cells.
Doug Oliver: That’s an amazing technology.
Could you talk to us about a specific story in your personal life that drives you towards cellular medicine, towards innovative technology? Why didn't you become a doctor practicing medicine? What is driving you to do what you do? Why do you come to work every day, failure after failure, but learning after learning, and then success after success?
Kapil Bharti: I laughed at that when you said “doctor practicing medicine,” because... so this is coming from my older brother who is three years older than me. He said, as a child, when I was small, anyone who came to our house - uncles and aunts - they would ask me, “What do you wanna be?” And I would say, “I wanna be a doctor,” and they go, “Oh, great! So you can treat us when we get older, thank you.”
I thought, “I don't wanna be a doctor who treats you. I wanna be a doctor who makes medicine.” I wondered, “What kind of doctor is that?” I don't remember that - this is coming from my older brother...
Doug Oliver: At a very, very young age…
Kapil Bharti: Apparently, I always wanted to be a scientist. I didn't know that until I went to university, to actually learn how to become a scientist and what a scientist actually is. The rest is just kind of history, the rest is just the path to becoming a scientist.
Now the question is what drives us every day? I think part of it is what I already told you, the passion to do the right science and the passion of the team, people that are so enthusiastic about doing it right - getting it to the next level every day. Making a new discovery that we know or at least hope is going to be beneficial for society, for science, for patients.
Doug Oliver: Has anything ever kept you up at night because it was so exciting or so troubling?
Kapil Bharti: Oh, actually all the time. That is part of my life.
Doug Oliver: It's overwhelming sometimes.
Kapil Bharti: Yeah, the best part is that most of the good ideas actually come in right after a shower. When I’m in the shower, or when I've gone for a run - actually people who know me know the trend, that if they're getting emails from me, that means I either have come from a run or have been in shower. You are in science all the time. You are just fully immersed in it. That's the best part.
Sometimes I dream about these things, actually I often dream about these things.
Doug Oliver: Have the answers come to you in your dreams sometimes, or is it more when you wake up that something clicks for you?
Kapil Bharti: It’s more of when you wake up and you say, “This is it” - your head and your dreams have somehow cleared the clutter out and now you're able to think clearly. That happens a lot.
Doug Oliver: Let me go through a couple of other questions. Do you find your mind wandering while you're doing your work, pondering the gravity of the accomplishments that might result? Does the impact of your work stay with you, or does it come and go?
Kapil Bharti: So, I'm actually a very realistic person. I live in the moment. I don't live as much in the past or future, so I'm mostly busy solving everyday science problems that are gonna get us to the next step, rather than thinking “What is gonna happen if this or that becomes technology.”
It just keeps me grounded, because the actual reality is that everyday we are solving a lot of scientific problems to get to the next step.
Doug Oliver: So there's not a lot of dreaming.
Kapil Bharti: No.
Doug Oliver: I think that people who are engaged with patients a lot, or are patients themselves - they're very introspective or even prospective, and I'm wondering if that's part of the status of being a patient. I wonder if that's part of the difficulty in translating realistic hope.
Since this is a series about hope, it includes managing hope, and you've talked about that by just now saying, “We’re doing a lot of science to discover a lot of things every day.” Hope is action. Hope is a process. Hope is a theory.
Hope is everything. What happens when hope goes awry?
Kapil Bharti: Frustration, anger, a lot of running.
Doug Oliver: Yeah. Scientists anticipate as well, and because they're disappointed when something doesn't happen… Have you ever seen that disrupt a process in a very real way for a given time?
Kapil Bharti: In our case, that happened several times. There were a lot of problems that we could not solve to get to the next step that the team was really frustrated and disappointed about. For weeks, sometimes, people were not happy.
But what kept them going was the hope that yes, there is a potential solution somewhere, and if A didn’t work, B didn’t work, C didn’t work, let's try D - and suddenly D or E or F worked, and then I thought “Okay, all that hard work paid off.” We still go through that up and down all the time.
Doug Oliver: Even as far as the technology has come, to the point where you're saying “It's ready now, it's ready to test on patients” - the work's not done.
Kapil Bharti: The work’s not done until it's actually approved by the FDA for a phase one trial and actual work is not done until it's approved for commercial use in that setting.
Doug Oliver: Which means it works.
Kapil Bharti: Exactly, which really means it works. Right now, it’s a test phase, and that's a safety test phase. So it's a long journey.
Doug Oliver: Yeah, it's still a long road. I've been asked a couple of times, given all that I know, given my experience, and given what I know about the state of science at this point - both how far it’s come and with work that still needs to be done - what would be my advice to patients? My favorite answer is “Hang on, because the hope now is real.”
Kapil Bharti: Yes.
Doug Oliver: We can see it. We couldn't say that even five years ago, but now - "hang on, it's coming.” The truth of the matter is, though, it's not coming for everybody and there are going to be people left behind. I frame that in a disappointing way for some people, but from a scientific standpoint, it might look like we have so much more we can positively apply this to. You see that the potential moves on. This isn't the end game.
Kapil Bharti: No.
Doug Oliver: This is just the beginning.
Kapil Bharti: Yes.
Doug Oliver: Do you see - and you don't have to elaborate because I know that that might be uncomfortable to project, but - do you see this populated scaffold IPSC technology implanted on top of a retina that's damaged... is that applicable to other diseases?
Kapil Bharti: Do you mean other eye diseases, or other organs?
Doug Oliver: Both.
Kapil Bharti: Oh yeah, totally.
Doug Oliver: So this is a technology that's reconstructive of several organs.
Kapil Bharti: Yeah.
Doug Oliver: So you're producing a process, a protocol.
Kapil Bharti: So yes, absolutely, both for the eye and for other organs. The IPS cells can make other tissues, and there are hundreds of labs around the world who are trying to make muscle cells, heart cells, brain tissue, kidney tissue - you name it - from this.
We’re hoping that as our trial reaches phase one and gives people more confidence and hope that, yes, IPS cells can be brought to patients and they're safe. There will be more enthusiasm. There will be this trial, then hopefully we'll leverage other trials to go forward. So I think what you will see is really an outburst of multiple trials going forward.
Now, you combine this IPS cell approach with the famous CRISPR cast 9 gene editing… then you have treatment for a host of diseases.
Doug Oliver: Have you ever considered factors that might cause us to take pause at the enthusiasm you mentioned? The power of stem cell induction and gene therapy, especially when combined, is a disruptive technology. Is that something that scientists would benefit from by taking into consideration in planning a trial such as yours?
I can speak from experience that patients receiving these interventions may experience behavioural consequences that could maybe produce an adverse event. Not something under the microscope, but something is still going to affect the outcomes of your trial.
Kapil Bharti: You mean the behavior and outcomes of patients once they are treated.
Doug Oliver: Yes, any behavior that would affect their outcome.
Kapil Bharti: I think that that's a real possibility and we have to keep that in mind. We are actually setting up - a colleague of mine here is setting up a psychological study for patients starting before, why did they decide to enroll in the study? What are their expectations, and do they understand the potential real outcomes and distinguish it from what people call “magical treatment” -
Doug Oliver: The miracle factor.
Kapil Bharti: Yeah. Do they understand the difference, and do they know there is no miracle factor? This is a safety trial and likely the state where they are with their vision is, they may not benefit from it. And then go on, after they are treated - after three months, six months, up to a year and longer potentially - keep interviewing them to see what changes happen in their life and how they dealt with it. Hopefully no clinically observed adverse events happen. But then despite that, if we move that out of the discussion, how to build everyday life change, if we changed.
Doug Oliver: So this would be an observational study, would there be any treatment offered? Any interventions to try to manage that patient's behavioral journey in order to potentially maximize outcomes and help them thrive?
Kapil Bharti: That's a good point. We have not thought of any potential treatment… do you have anything in mind that you are thinking?
Doug Oliver: We’re not used to seeing a reversal of symptoms with these diseases and neither are patients. So neither the provider nor the patient really knows what might happen. But in chronicling my own experience and the experience of others, I noticed at least a correlation between the sequelae of a decline in a disease and its accompanying adaptations behaviorally matching the loss of functioning that had been grieved or dealt with.
Kapil Bharti: Wow.
Doug Oliver: The idea of a reverse sequelae, and specialized counseling to recognize its relationship to decline and the need to help a patient re-enter functioning from an emotional, spiritual, or other perspective, is a theoretical framework I’ve been working on.
Kapil Bharti: Yeah, no, that's definitely a great idea. And I think as we start the trial, if this is something we see in our first two patients, we’ll have to quickly adapt.
Doug Oliver: Are you going to be allowed to adapt, knowing that there might be an adverse adjustment? A complicated adjustment?
Kapil Bharti: Yes. I think so. We just have to go the IRB. There is no point for all of this effort up front if at the end, we are harming them in another way.