Building Living, Breathing Lungs In The Lab

Laura Niklason engineered working lungs in the lab by stripping the cells from rat lungs and repopulating the remaining structure with fresh cells. Don Ingber created a "lung on a chip," which mimics the chemistry and mechanics of a working lung and could be used for drug testing.

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You're listening to SCIENCE FRIDAY, from NPR. I'm Ira Flatow.

Organ transplant patients spend months, if not years, waiting for the right organ from the right donor. According to the U.S. Organ Procurement and Transplantation Network, over 108,000 people are waiting for organs right now: kidneys, livers, hearts, lungs. All of those patients, of all - and all of them, 14,000, have been waiting for more than five years.

But what if instead of waiting for someone else's organ to free up, you could make a fresh, new one in the laboratory using your own patient's cells? That, of course, is impossible right now, but my next guest has taken a significant step towards it by building working lungs, building working lungs in a laboratory. And how she did it is quite a story, and that research appears in the journal Science this week.

Laura Niklason is professor of anesthesiology and biomedical engineering at Yale University in New Haven, Connecticut. She joins us by phone. Welcome to SCIENCE FRIDAY, Dr. Niklason.

Dr. LAURA NIKLASON (Professor, Anesthesiology & Biomedical Engineering, Yale University): It's great to be here. Thank you very much.

FLATOW: We have a little video of - you're building the lung. You actually built the lung in the laboratory. Give us the steps of what you did.

Dr. NIKLASON: Well, we started off by taking a lung from adult rats and taking them out and carefully washing away the cells that were in the lungs so that what was left behind was really the scaffolding or the skeleton of the lung that's made up of proteins, extracellular matrix, like collagen and elastin.

We then put cells back into the scaffolding, back into the skeleton, and cultured the lungs in a bioreactor that really mimics some of the environment of the fetus while the fetus is growing. After about a week of culture, we put some of these lungs back into different rats, and we saw that they functioned, at least for a couple hours.

FLATOW: So you basically washed away all the cells and the lungs, left the structure, and you put your sort of recreated the womb, in effect, again, where the lungs originated.

Dr. NIKLASON: Yeah, we did. We worked for several years to create a bioreactor that would mimic some of the aspects of the womb, including perfusion of nutrient medium through the lungs. And we also fitted out the bioreactors so that it could coax the lungs to breathe, to inhale and exhale nutrient medium, much like the fetal lungs do during development.

FLATOW: Now, how did the cells and there are a lot of different kinds of cells in a lung, correct?

Dr. NIKLASON: Correct.

FLATOW: How did they know where to go and what to do?

Dr. NIKLASON: Well, that's one of the surprising and remarkable findings of some of this work, is that we didn't expect to find, but we did find, that when we took cells away from an intact lung, that the skeleton left behind actually had a lot of zip codes in it. It actually had a lot of information about which cell types are supposed to land where.

And we discovered this only when we put mixtures of different kinds of cells onto the matrix and then looked about a week later. What we found was that most of the cells had gone to their correct spots, as if they had little homing signals.

FLATOW: Wow. 1-800-989-8255 is our number. We're talking about creating lungs in a laboratory. You can also tweet us @scifri, @-S-C-I-F-R-I, and join the discussion on our website at sciencefriday.com, where we have a little video that we got from Dr. Niklason about these lungs.

Now, the lungs only lasted, you say, for a short time when you put them back in the rats. Do you know why what happened there?

Dr. NIKLASON: Well, they when we first sewed them in, they profused with blood and they filled with air and they exchanged oxygen and carbon dioxide very much like the native lungs. And so we were thrilled at that.

But after a couple hours, what started to happen is small blood clots started to form in the blood vessels of the lung, and we think that's because our cell coating on the lung blood vessels, while it was pretty good, wasn't perfect. And so it left some bald spots in the blood vessels, which then stimulated some clotting after a few hours.

FLATOW: So if you think you had given it more time...

Dr. NIKLASON: Yeah, I think more time in culture, but I also think just doing some technological improvements in how we cultured the cells and the growth factors, and there's a lot of things that we can improve.

FLATOW: And so what are the key breakthroughs you need to make before this is ready for primetime with humans?

Dr. NIKLASON: Well, I think that there's a couple of things we have to do. One is, as you point out, we have to sort of improve our techniques for making the cells in the lung very, very uniform and for making sure that the skeleton of the lung that we produce in the first place is really very high quality and doesn't have any little defects in it.

You know, some of our lung skeletons did have some small defects. So we need to work on that, but those are sort of technology improvements.

FLATOW: Mm-hmm. And it's not just lungs. Aren't people working along the same lines with this matrix with livers and hearts and things like that?

Dr. NIKLASON: Absolutely. I mean, this is sort of an echo of an approach that started to be reported a couple years ago, and I think it's a really it's a fascinating and powerful approach, particularly for complicated organs, as you say, like heart and lung. It's probably not as useful or important for simpler tissues like skin or cartilage.

FLATOW: Mm-hmm. Could you rehabilitate, let's say, a smoker's lung, you know, suffering from emphysema?

Dr. NIKLASON: You know, lung structure doesn't regrow terribly well. One of the problems with emphysematous lungs is that a lot of that skeletal structure that we talked about actually gets broken down. And right now, I'm frankly not sure we could rebuild that in the lab.

FLATOW: Mm-hmm. So you have to have a good matrix to begin with on all of these organs.

Dr. NIKLASON: Yeah, I think that's probably true. It probably doesn't have to be the most perfect, healthy matrix in the world, but it probably can't be terribly sick, either.

FLATOW: I'd like to bring on another guest now who's doing some similar research. He's not building an actual lung in the lab, but a little virtual lung on a clear chip the size of your thumb with lung cells inside, Don Ingber, the director of the Wyss Institute For Biologically Inspired Engineering at Harvard University. Welcome to SCIENCE FRIDAY.

Dr. DON INGBER (Director, Wyss Institute For Biologically Inspired Engineering Harvard University): Thank you.

FLATOW: Tell us about this lung on a chip. What is it? How does it work?

Dr. INGBER: Well, we're targeting a much more near-term challenge, which hopefully will have impact in the next few years, which is essentially shortcutting the time it takes to get drugs through the development process to the patient, because as we all know, it's incredibly expensive, and a big part is that has to go through animal studies. And not only are they costly and time-consuming, they often don't predict what happens in humans.

So we set out to develop a small device that could be mass-produced in the future at low cost, lined by human cells that would mimic the breathing, functional unit of the lung, the breathing air sac.

So in the device, it basically is a little, clear, rubbery device that has two channels that are hollow, that are directly placed against each other and separated by a flexible membrane, coated with the same matrix that Laura was talking about, and we have airway cell air sac cells from the human lung on one side, capillary blood vessel cells from the lung on the other. And then a little trick is we have side chambers, where we apply cyclic suction that pulls the flexible material and relaxes it so that it actually breathes.

And by putting air on one side and flowing medium sometimes with human white blood cells on the other, we can mimic the effect of putting, for example, environmental pollutants, nanoparticles on one side, on the air side, and measuring what they do to the lung and whether they're absorbed. Or we put a living bacterium, a microbe, on the airway side, human white blood cells in the flowing medium, and we could watch the entire inflammatory response.

FLATOW: Wow. So you could screen, then, chemicals or other even nanoparticles, I understand you're working with.

Dr. INGBER: Yeah, yeah. I mean, one of the interesting things that we found is I'm sure you've probably had other shows on the potential concerns about nanoparticles or nanotoxicology in the environment. And I think one thing that's been surprising to many biologists, including me, is how do these particles get into our body and all over our bodies?

And so we added particles that are often used to study environmental pollutants, and we put them on the airway side. And one thing that we found is they went across to the capillary channel with a low level of efficiency. But when we had physiological breathing, the same way our lung expands every time we take a breath, we had an eight-fold higher increase in how many particles got across, and we saw some sort of toxic reactions and inflammatory reactions.

So we see and the most important thing is that this has not ever been noticed before, and we actually confirmed this by going back into a whole animal model. So this little, rubbery device that was made with a manufacturing strategy originally developed for the microchip industry was able to predict whole animal results at the whole organ level.

FLATOW: And can you do it for other organisms, besides lungs?

Dr. INGBER: Well, we are - we at the Wyss Institute, you know, our goal is, essentially, to develop new engineering solutions by leveraging new biological principles that have been uncovered the last few years.

So we are, in fact, trying to make organs on chips. We have one project with the peristalsing gut on a chip. Someone is working on a kidney, bone marrows, livers, cancers. And, you know, with the long range - you know, now we're talking 10 years out, 15 years out - of linking them together by engineered channels, carrying fluid, so that we kind of have a synthetic human on a chip, if you like.

FLATOW: Wow.

(Soundbite of laughter)

FLATOW: Human on a chip. But, you know, we always hear that scientists are hearing from the public that they'd like to replace laboratory animals with chips or other kinds of screeners. Do you think that these chips could replace using lab animals on experiments?

Dr. INGBER: Well, I don't they're going to replace - fully replace animals in any near term. However, I think that they can definitely cut out a lot of animals, accelerate the process, and make sure that whatever animal testing we do is really well designed and narrowed down to critical experiments, just like we try to do at the human clinical trials.

FLATOW: Dr. Niklason, where do you go from here with your recreating the lungs in the matrix? What's your next step?

Dr. NIKLASON: Well, we're going to make some of those improvements that we mentioned in terms of how we culture the lungs. But we're also going to pursue pretty actively, adult stem cell work, because if this is really ever going to make it to a clinical application in a few decades, we're really going to need adult stem cells from patients that we can coax to differentiate in to all of these different cells that are needed to grow a whole lung.

FLATOW: So instead of infusing all the different cells, you would put stem cells and let them differentiate themselves?

Dr. NIKLASON: That might be part of it or we might grow some stem cells in a dish and coax them in eight different directions and then put those cells back into the matrix.

FLATOW: And I guess, to avoid rejection, you'd want to have stem cells from the patient him or herself?

Dr. NIKLASON: Absolutely. Absolutely. But what's been wonderful about the stem cell revolution, especially in the past few years, is that it's looking like those stems - those cell sources that are now at hand.

FLATOW: Uh-huh. And you work on other blood vessels, don't you, trying to get the same thing to happen?

Dr. NIKLASON: Yes. We've been tissue engineering blood vessels probably for 15 years now. It's been a long development cycle, but pretty standard, I think, for new therapeutics in the industry. And we're hoping, actually, to be in humans in the next year or two.

FLATOW: So these are made-to-order blood vessels.

Dr. NIKLASON: Yes, they are, tissue engineered in a jar, just a different jar from the lung engineering jar.

FLATOW: So there's like an - there's an aorta in a jar somewhere?

Dr. NIKLASON: No aorta, we don't grow them quite that big, but blood vessels that are three to six millimeters in diameter, so like arteries in your leg or arm, for example.

FLATOW: Wow. We're talking about growing all kinds of stuff on chips and in jars this hour on SCIENCE FRIDAY from NPR. I'm Ira Flatow. And Don, where would you go next?

Dr. INGBER: Well, interestingly, the idea of being able to make chips that have cells from individuals is - would - could follow up at a similar path at the Wyss Institute. We have other faculties such as George Church who is a leader in the personalized genome project, where they're actually collecting thousands of biopsies of skin. And that's how people now use as a source to do what they call an inducible pluripotent stem cells to add four genes or chemicals and make them embryonic stem cell mimics, if you like.

And so the idea of taking a patient's cell and making little chips that have their cells or their cancer by collecting tumor cells in the circulation is plausible.

I think what might even be more interesting for drug development is to pursue what they all pharmacogenomics in the clinical trials world, where they know that certain subpopulations of humans, genetically, respond differently to drugs, and it may be possible to make chips that effectively represent whole populations and thus you could be doing that kind of pharmacogenomics, if you like, but doing it on, you know, thousands of little micro channels on a chip the size of your hand, and multiplexing and doing (unintelligible).

FLATOW: Wow. And how far away are you from that?

Dr. INGBER: I think this - all of us are looking at it by the stem cell field, which is incredibly exciting but still have many challenges in terms of being able to efficiently make those cells go down, you know, the particular paths you want. I think what we were excited about, one we think we're a little closer here, is that just using the cell lines, the human cell lines that we did, we were able to predict, very effectively, results in whole animal studies.

And we - you know, and there are other ways of getting primary cells from surgical, you know, specimens that are discarded. So those are sort of directions we're going there.

The other direction is really to reach out to industry and find out where is the need, you know? Where have you had problems where you went all the way to an animal and then failed in humans, or there's no animal model to test it, or the cells don't do what they do in the body.

And I think one thing that probably Laura would agree with us is that the mechanical motions of organs are critical for their development and function, certainly for the blood vessel in the lung, and so that's been ignored a lot, almost exclusively in cell-based screens.

FLATOW: Yeah. And so what your chip does is it actually moves and breaths like...

Dr. INGBER: It's moves as, you know...

FLATOW: Yeah.

Dr. INGBER: ...physiological breathing motions of the level of the cells.

FLATOW: Right. Laura, you agree that this - that's what's lacking in some of the model?

Dr. NIKLASON: Absolutely. I think that both the substrate and the physical motion is only now becoming, you know, as appreciated as it should be. I agree, for years or decades, it's been sort of unappreciated.

FLATOW: Well, as I hear from both of you there, well, the medical field now is becoming more engineering than biology.

Dr. INGBER: Absolutely. And I think you're seeing on both of our parts the merged - I call it the unification of the sciences with engineering, you know, biology and medicine. The boundaries between fields are merging, and all of us are doing a little of everything.

FLATOW: Laura, you agree?

Dr. NIKLASON: I do, and I actually think that's good for patients and good for taxpayers in the long run because, frankly, I think by fusing engineering and science, we're going to make progress a lot more rapidly toward therapies that help people.

FLATOW: All right. I want to thank both of you for taking time to be with us and talk about how engineering and science is fusing and how these new techniques are working. So I wanted to thank my guests, Don Ingber who is director of the Wyss Institute for Biologically Inspired Engineering at Harvard, and Laura Niklason, who is professor of anesthesiology and biomedical engineering at Yale. Oh, we have Harvard and Yale on together, speaking peacefully.

(Soundbite of laughter)

Dr. NIKLASON: We're being nice to each other. It's amazing.

(Soundbite of laughter)

Dr. INGBER: I went to both, so - I was involved in both, I would say, so I could - I have - I try to keep fair both ways.

FLATOW: There you go. We keep peace here on SCIENCE FRIDAY. Thank you for both of you for taking time to be with us.

Dr. INGBER: Okay. Bye-bye. Thank you.

Dr. NIKLASON: Thank you.

FLATOW: Have a good weekend.

We're going to take a break. And after the break, do you know how easily your mind is influenced by things around you? That cup of coffee you're holding or the chair you're sitting on could affect your decision-making. Yeah, we'll tell you how that works all out, and we'll find out how you can take advantage of that. So stay with us. We'll be right back after this break.

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