Darrell Kotton is one of those rare physicians who successfully straddles the worlds of medicine and research. Trained as a pulmonary doctor, Kotton is the codirector of the Center for Regenerative Medicine (CReM), which he founded with George Murphy and Gustavo Mostoslavsky in a collaborative effort among scientists at Boston University and Boston Medical Center. He also works as a physician in pulmonary, allergy, and sleep medicine at Boston Medical Center.
CReM’s motto is “advancing science to heal the world.” “As corny as that sounds,” said codirector Murphy, “we really want to push science forward to effect change.” CReM encompasses six labs, studying how stem cells may be used to treat diseases of the lungs, liver, blood, and gut. Within CReM, Kotton’s lab focuses specifically on inherited lung disease. One of his lab’s cornerstone achievements has been the creation of a lung disease “bank” with more than 100 lung-disease-specific stem cell lines. They also developed a method to grow lung tissue from induced pluripotent stem cells, giving researchers a critical tool to investigate the diseases in CReM’s bank. Rather than sell the disease bank, Kotton decided to make it freely available to other researchers in the hope of advancing the field more quickly. This type of “open source biology”—openly sharing reagents, protocols, and data—is fundamental to Kotton’s research and his philosophy of science.
Did you always know that you wanted to go into research?
KOTTON: No, I didn’t. I was always interested in science and research, but I didn’t think I wanted to do it for my life. It was only when I was a pulmonary fellow and developed a project with my BU mentor, Alan Fine, that had a stem cell bent to it—that work sparked a complete love and obsession with basic science research. It was quite unexpected. I was meant to be a friendly neighborhood pulmonologist, a full-time clinician, and I guess I had no choice; it was just to surrender to my obsession.
How did you think stem cell research might help solve lung disease?
KOTTON: Pulmonary medicine had made great strides in developing drugs and treatments for inflammatory diseases like asthma. You could take patients who were short of breath, diagnose them with asthma—if that’s what they had—prescribe an inhaler, and they’d come back essentially cured the next visit. It was remarkable. And yet there were these other patients who had diseases of the lung epithelium—wound responses in the lungs that end up scarring—and for those patients we had nothing to offer. It was like we just served as priests or rabbis. We would counsel them and diagnose them and then prescribe drugs that we freely admitted didn’t work. And I think it was logical to most of us that some kind of stem cell might solve the hurdles of lung epithelium not repairing.
Because it could actually regenerate?
KOTTON: Yeah, the buzzwords regeneration and repopulation were all the rage and we thought the native lung wasn’t doing a great job in these patients, and so artificially engineering an exogenous cell therapy like a stem cell would be the answer. There was no question that pluripotent stem cells could turn into lung epithelium—at least nature could do it in an embryo—and how to mimic that in a culture dish was really the question. We had no idea how to do it. What I then found through a lot of reading and discussion was that so little was known about how the lung develops early on, that it was going to be very difficult to do it without doing basic developmental studies first.
This all seems obvious. I mean, of course that’s how you do it.
KOTTON: It seems obvious in retrospect, but at the time we thought of it—most of us in the field behaved like alchemists. I mean, it’s almost embarrassing to look back on how we oversimplified the field and how naïve we were. We thought you could take hematopoietic stem cells that can become anything, sprinkle salt and pepper on them, and out comes your desired lineage. And now we know that’s so simplistic.
“That was the best way to try to reach truth, which is in the end what we’re all after.”
So how did you meet George Murphy and Gustavo Mostoslavsky, and how did CReM come into being?
KOTTON: While I was in Richard Mulligan’s lab at Harvard for my postdoctoral fellowship, I quickly found my scientific soul mates, who were Gustavo, George, and another student at that time named Alex Balazs, and the four of us talked science endlessly, debated, argued, criticized each other, and basically were each other’s best fans and best critics. We realized that we had a common way of approaching science, which was to surround oneself with very vocal critics to continually have your results scrutinized. That was the best way to try to reach truth, which is in the end what we’re all after.
I knew I wanted to come back to Boston University at the end of my postdoc to open my own lab because I felt that BU was a very special place, a very collaborative place. It was almost like an artists’ colony of pulmonary medicine and research. I also began to encourage George and Gustavo to consider Boston University, since if they joined me we could do science the way we wanted to, in the most collaborative, communal way possible.
Did you see science being done in a way that was not what you wanted to do?
KOTTON: I think when a student or a postdoc first decides to pursue a life in science, it’s done from a deep-seated love for the scientific method, for the search for truth, the advancement of new knowledge, and it’s done for the most pure, altruistic reasons. And then, as you form your own lab, you become a principal investigator and then later, if you’re successful, you start to get exposed to tremendous pressures. And I think career advancement in science often brings out the worst in us, which is the urge to be . . .
KOTTON: Elitist, exclusive, competitive, a need to feed one’s ego, perhaps—a desire for credit, and it sometimes can cause people to behave selfishly, which is completely removed from the ideals and the reasons they went into science in the first place. Personally, the times in my life when I’ve been most fulfilled and most happy are when I’ve been the most altruistic. So, for a long time I was a busker on the streets, playing guitar and singing to people, which is a very fulfilling job, I must say, and you’re basically giving it out for free. The other time in my life is when I was with my wife volunteering abroad in India and Africa for no pay, serving as a volunteer in medical schools there. It was an incredibly fulfilling experience.
Did you think that joining forces with two like-minded people would help keep you on the right track?
KOTTON: Yes. I think there’s so much pressure to be knocked off the path of your ideals that having your best friends, really, there to smack you in the face and say, “Hey, remember who you are,” and, “Remember the goal” has been very valuable for the three of us.
And theoretically your science will actually progress faster—that’s your hope?
KOTTON: There’s no question that the amount of creative thinking and data and interpretation that we have access to, from collaborators, is much more, having this open source approach. People are very trusting; people know they can share things with us because it’s always going to be a two-way arrow. And that makes the science move much faster.
After we published the cell bank, a lot of companies and venture capitalists sought us out. Their goal was to gain control of our bank and they were willing to pay a lot of money for it. And so that was a moment of reckoning: were we going to give up control for the money, or were we going to maintain control of our bank and promote it in the way we had envisioned, as a freely available resource for all mankind? In the end, we didn’t give up control and that was an important moment in our evolution.
That’s interesting because one could argue if you sold the bank, or whatever—leased the bank—you could have made enough money to hire more researchers and promote your science that way.
KOTTON: Well, this is exactly the conversation we had: should we do that? But then it really forced us to think about the end goal. And we thought if the outcome was that the bank became exclusive or restricted in any way to the research community—that this was against our ideals and our goals and that we couldn’t do that.
And do you feel good about that?
KOTTON: I think it’s the best decision we ever made.
In the annals of cruel diseases, Alpha-1 antitrypsin deficiency surely ranks high on the list. Caused by a defect in a single gene, the disease, called “Alpha-1” for short, causes wheezing, shortness of breath, and recurring lung infections, and often leads patients to develop emphysema in their 30s. “These people are suffering on so many levels,” says Darrell Kotton. “They are literally suffocating to death.”
Kotton’s clinical experience has led him to an ambitious research goal: to develop cures for inherited lung diseases like Alpha-1 and cystic fibrosis using gene therapy and stem cells. And he has a firm vision of how it can be done: scratch a few skin cells off a patient, turn them into stem cells, knock out the damaged gene, replace it with a normal gene, grow the stem cells into healthy lungs, and put them back into the patient. Though the path is clear, each step will take years of painstaking science, and his vision will likely take decades to realize. “It’s so frustrating because we know the mutation responsible for the disease and we’re powerless to do anything about it,” says Kotton. “On paper you can actually write down all the steps it would take to cure the disease. Not to treat it, but to cure it.”
Yet progress has begun and is accelerating. “This is a field that literally changes by the week,” says George Murphy, who codirects CReM with Kotton. And though a cure is probably decades away, the first fruits of Kotton’s work will likely go from bench to bedside in the next five years.
Kotton’s lab works with induced pluripotent stem (iPS) cells. These are adult skin cells that scientists reprogram to pluripotency, after which the cells can differentiate into almost any type of tissue. But iPS cells are finicky, and getting them to follow directions is not easy. For instance, it took Kotton’s team seven years to develop a technique for growing iPS cells into lung cells. To do it, they created a knock-in reporter gene that glowed green when the stem cells expressed a gene called Nkx2-1, marking a step toward becoming lung cells. This allowed the team to track the cells as they developed into lung tissue. This work, published in Cell Stem Cell in 2012, marked a huge advance in the field and will likely have a far-reaching impact on the study of inherited lung disease. But the homegrown lung cells are far too delicate and immature to help patients yet.
“The main hurdle in the field is that the cells we’re making aren’t good enough,” says Kotton. “The lung cells we reach might be analogous to a baby in the third trimester, and we really need to go much further.” Creating more mature cells requires a deeper knowledge of how progenitor cells grow into lung cells. How, exactly, does a stem cell decide to become a lung cell? And once it decides, how does it remember that it’s a lung cell and not a liver cell?
In Kotton’s lab, many of these basic questions fall to Assistant Professor of Medicine Laertis Ikonomou, who studies the “primordial progenitors,” the 100 or so undifferentiated cells that lead to all lung cells. “It’s very fast,” says Ikonomou, describing the process. “It starts as a spot of 100 cells and within 24 hours the beautiful branching of lung tissue appears. When I see this I’m still amazed.” Ikonomou is now performing “deep sequencing,” on the primordial progenitors, a detailed gene sequence that will note exactly which biomarkers are expressed at each step, and lead to a more nuanced understanding of the differentiation process.
In addition to these basic biology questions, Kotton’s lab is also addressing some critical questions of stem cell safety and engineering. “There are major safety issues with pluripotent cells,” notes Murphy. Because the cells can become any type of tissue, without proper safeguards they could potentially grow out of control, forming tumors.
Then there’s the engineering challenge: once the safety issues are overcome, how do you deliver iPS-derived lung cells into patients? Delivering genes to damaged lung tissue is tricky because of the lungs’ architecture and physiology—they don’t regenerate much and have a complicated air exchange system, so it’s difficult for cells to graft there. Similarly, a dish of lung cells doesn’t automatically form itself into a lung, even when seeded onto a lung-shaped scaffold. Kotton’s group is collaborating with scientists in Boston University’s biomedical engineering department to deal with some of these challenges, creating better scaffolds and understanding the mechanical forces at work.
Despite these long-term challenges, it’s likely that some of Kotton’s research will be helping patients within the next few years. One near-term application is in the burgeoning field of personalized medicine, or what Kotton likes to call “a clinical trial in a test tube.” Kotton is partnering with an existing clinical trial that is using a new drug to treat liver disease. Kotton plans to make iPS cells from people currently undergoing the trial, and test if the iPS cells can predict which drugs will be toxic or beneficial in which patients. If this approach works, it could streamline drug testing with less risk to patients.
Kotton’s team is also investigating another aspect of personalized medicine: taking a patient who is not responding to conventional drug therapy, and using their iPS cells to design a drug regimen that is more likely to work. This technique would allow doctors to simultaneously test different therapies on a patient’s actual cells with no risk to the patient.
Kotton and his team speak regularly to Alpha-1 antitrypsin deficiency support groups, and also host groups of patients in their lab, who “really push us to come up with a cure,” says Kotton. “That’s the hardest thing,” says Gustavo Mostoslavsky, who codirects CReM with Kotton and Murphy. “But now we are able to tell them that the treatments are going to come in our lifetime.”
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