Building Organs, On One Microchip At A Time

Bioengineers are developing microchips, about the size of a thumb, that can behave like human organs. Donald Ingber, director of the Wyss Institute for Biologically Inspired Engineering, discusses how the "organ-on-a-chip" works and why the technology could replace the animal model for drug testing.

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IRA FLATOW, HOST:

You're listening to SCIENCE FRIDAY. I'm Ira Flatow. When you think of a human organ, like maybe your heart or your stomach, you probably think of something slippery and meaty and seeping with bodily fluids and lined with intricate networks of arteries and veins. What probably does not come to mind is a crystal clear microchip as small as your thumb with a tiny network of chambers and membranes placed inside. But scientists at the Wyss Institute at Harvard University are engineering microchips to do just that - behave like human organs. And they've had some success with what they call the lung-on-a-chip, and they have now designed a human gut-on-a-chip. And they're looking into mimic even more organs with the hope of linking them all together one day and creating a human-on-a-chip.

So exactly - what exactly does a organ-on-a-chip do? How does it work? What can we learn about the human body from these chips? And will this new technology make testing drugs on lab rats obsolete? Very interesting question. Dr. Donald Ingber is a director of the Wyss Institute for Biological Inspired Engineering and a professor at the Medical Engineering School at Harvard University. He joins us from Boston. Welcome back to SCIENCE FRIDAY.

DONALD INGBER: Oh, it's my pleasure to be back.

FLATOW: I think the last time we talked here, you had gotten one organ out of the way. Now you're working on more.

INGBER: Yeah, many more.

FLATOW: Tell us about those. Which - how many more?

INGBER: Well, when we spoke, we - it was, I think, two years ago when we had published the lung-on-a-chip, the human breathing lung-on-a-chip. We just published the gut. We have a bone marrow-on-a-chip that we've been developing, kidney-on-a-chip. Kit Parker, who's at the Wyss Institute, has developed beating heart-on-a-chip. And we just received a major funding from DARPA, the Defense Advanced Research Projects Agency, to develop 10 different human organs, link them together, and develop an instrument that would automate analysis to effectively have a human body-on-a-chip, an instrumented human body-on-a-chip to hopefully replace animal testing over time.

FLATOW: So you can use these organs-on-chips and experiment on the effect of pharmaceuticals on them instead of lab rats?

INGBER: Yes, and there are ways we've been making, you know, headway looking at both toxicity and efficacy, which are the two - the FDA, who is a partner with DARPA in this effort, as is the NIH, the new NCATS, the new institute that's into translational finds at NIH. The FDA is very interested in toxicity of drugs, knowing, you know, before it gets to the clinic that there's a problem. But the drug companies want to know that, but they also want to know if the drug is going to be effective. And so we have partnerships beyond government funding agencies with pharmaceutical companies. And so we're exploring all of that.

I think the important point for the audience is that there's a real major problem right now in the pharmaceutical industry, which is that the animal models really don't work. We know it's an ethical issue and that many animal lives are lost. And they, you know, they work to some degree, but there's still many, many cases, a surprisingly large number of cases where, you know, millions of dollars, hundreds of millions of dollars and years of development have gone through validating in animal models, and then it gets into the clinic and fails. And so the FDA recognizes this as a problem. Pharmaceutical companies recognize it.

DARPA has identified the need to accelerate drug development because of, you know, infectious disease threats, bio threats. When influenza epidemic happened, you know, in the last few years, it was very clear that we couldn't come up with a response as fast as we would like to. So this becomes an issue for the defense of the United States, both economically because of the pharmaceutical industry and in terms of true defense, in terms of threats. And so that's one reason that you're seeing all these agencies putting out funding opportunities in this area right now.

FLATOW: Mm-hmm. Sometimes a drug will fail because it affects negatively a part of the body that it's not supposed to. Well, if you have just individual organs like a lung or a kidney, and you test it out, how would you know how it might affect the rest of the body, let's say, on a whole animal?

INGBER: Well, that's the explicit reason we've moved to multiple organs, and the concept of this new funding opportunity is to have an instrument that would have 10 different organs representing the major systems. So, for example, you might deliver an oral drug to the gut, see it absorbed, watch it metabolize by the liver. It's being peed out by the kidney, and you're looking for its toxicity on the heart. Or you might deliver something by aerosol to the lung and do similar sorts of things. The important point is, in the body, as opposed to the way people usually test drugs with cells in dishes is, much like you said, they're multiple different organs, but more importantly, the level of drug is dictated by the drug being broken down by organs like the liver and being peed out by organs like the kidney while you're infusing it or absorbing it from your gut. And that really can't be tested in a regular old dish.

What we can do in these little microorganism - these organs on chips are - have little hollow channels with fluids flowing through like - that are effectively a blood substitute. They also, if it's a organ like the lung, has air over the air - in the airspace, and the gut similarly, it can have literally microbiome. The bugs that live in your gut, we can put in this human gut that also undergoes peristaltic-like motions in the lungs goes - undergoes breathing-like motions and the heart beats and contracts. And so we could actually study what you're asking, this interplay between the different organs, and we also are doing it - the goal is to do it all with human cells.

And the important point there is that a lot of toxicities in humans are not seen in animals because the specific molecules that, for example, degrade the drug or transport the drug from the blood to the urine don't exist in animals, only in humans. So this is something that we could begin to mimic in these integrated chip systems that you can't do in animals.

FLATOW: Mm-hmm. Sometimes I understand that the microchips behave in ways that you didn't expect.

INGBER: Well, you know, I mean, I have to say some of them are behaving better than we have ever expected.

(LAUGHTER)

FLATOW: Give us - give me an example. Give me...

INGBER: One example was that we put human intestinal cells that have been studied and cultured for years, and the pharmaceutical companies actually use them for looking at absorption in dishes, but everybody knows they're not very good. They don't really mimic gut function. When we put them in our chip and when we give them peristaltic-like undulating stretching rhythmically and we trickle flow over them like in your gut, they start forming villi, which are like the finger-like projections that increase surface area for absorption in your intestine.

And what really surprised me is that the proliferative cells, the cells that are dividing rapidly, are in the crypt, the bottom - like between your fingers, at the bottom of these fingers, which is exactly like in your intestine. Plus, they put out mucus on the top of it, which protects it, and now we can put microbes on top. If you put microbes - if you put bacteria on cells in a dish, we call it contamination, and you have to throw it out and sterilize it. But we put microbes on the top and they're perfectly happy. They're symbiotic. And this is important because - and I don't know if your show highlighted it, but over the last few months there's been a lot of news that the microbiome - the microorganisms that live in our body can be very important for various diseases. And so we now have ways to study that. And the microbiome in the human is different than the mouse. And so this is very exciting for new opportunities.

FLATOW: So you came up - you sort of serendipitously discovered something...

INGBER: Well, you know...

FLATOW: ...that you couldn't make before.

INGBER: We, you know, we actually - I've worked for 35 years in a strange - from a strange perspective in biology in that I've been - I was convinced that mechanical forces, that the forces due to breathing-like motions and stretching, you know, your muscles and the pulsations of blood through your vessels, that the stretching and the relaxing, the mechanical stresses are as important for regulating cell and tissue function as chemicals in genes. This is now getting more accepted in biology, but because of that, I felt that we had to create microenvironments that could mimic that - we had to develop microchips that can mimic that microenvironment. And what we 're finding consistently is that cells that people used before that they didn't think were very good are now recapitulating organ-like functions.

And as I said at a meeting yesterday, you know, there are no bad cells, just like there are no bad kids. There are bad families. There are bad neighborhoods and so forth. But - and so you have to give it the right microenvironment. We've also - I guess another surprising thing in the lung - and this was surprising - is that not only did we mimic complex functions such as the entire inflammatory response if we put a bacteria in the airspace in our little breathing lung on a chip, we saw in human, white blood cells stick to the vessel migrate across and engulf them. And that is something we hope for.

But when we started to do things like we looked at toxicities of airborne particulates like in smog, we found that they were absorbed across the airspace to the vessel, which was great, but we found that breathing motions, physiological breathing motions increase the efficiency of that by tenfold. Now that no one's even thought of before, nor have I. And so that was a prediction. And then we went back to animal models where we could control ventilation and we found exactly the same thing.

FLATOW: OK. So you've discovered that you do need these mechanical processes moving around to actually create more normal circumstances, more normal environment in action.

INGBER: Yes. And, you know, I was trained in medicine as well as, you know, basic biology. And so, I mean, in the clinic, respiratory, you know, physiologists know this is true. Clinicians know this is true. Surgeons know this is true. Surgeons often take advantage of mechanical forces to enhance wound healing that's why they put pegs in bone and put forces on bone or they - if you have an injury where there's a large hunk of skin lost in a car accident and they want to transplant skin from one spot to the other, they'll put a silicone bag under the skin, almost like a breast implant, and fill it with saline until the skin under normal sight hurts, and then they'll fill it again each week until - because that makes the skin grow. And then they move that piece of skin, and now they've covered the injury, and you don't have a defect at the surgery.

So it's a - so clinicians know about mechanics. Biologists, you know, because of the genome revolution, they were very focused on the parts and the genes and the molecules, but it's coming back together again now that the physical forces are really exceedingly important.

FLATOW: Talking with Donald Ingber about microchips and how to use them on SCIENCE FRIDAY from NPR. And can the chips be used to study how a disease behaves in the body, like cancer or something else?

INGBER: You know, there are many labs now that are moving in the direction of these sort of microfluidic chips, or other sort of engineered organs, on chips. And I should say that this - we recently got funded; two groups - one at MIT led by Linda Cima [POST-BROADCAST CORRECTION: Linda Griffith is the name of the MIT professor] and mine at Harvard - for this 10-organ automated instrument type of thing. But NIH had a big opportunity. I think they funded 15 or 16 different organs, and various groups are trying to study disease processes.

We have - we've been studying pulmonary edema with a lung chip where you have fluid on the lungs, and we're able to actually get some - you know, we're getting exciting results there where we can model - we could see fluid shifting from the blood channel into the lung, as well as blood clot formation in the lung which happens in patients.

And I think other groups are looking at, you know, viral infections, for example. With our gut-on-a-chip, we're hoping to study Crohn's disease. Where it's known in Crohn's disease, there are three major contributors. One is inflammation, and we could add white blood cells, for example. The other is the microbiome, the microbes living in the gut. The other is peristaltic-like motions - again, mechanics. And so we can control all three of those.

And the great thing about the chips is that we can start with the simplest model, and we can add that complexity if we don't get physiological relevance, where in animals, there's so much going on.

FLATOW: Yeah.

INGBER: And you have - and you basically only get to look at the tissue after the animal is sacrificed or dies, whereas we can watch it in real time at very high resolution.

FLATOW: Let's go to Sally(ph) in - is it Shawnee, Kansas?

SALLY: Yes.

FLATOW: Hi there. Welcome to SCIENCE FRIDAY.

SALLY: Thank you. I'm wondering if you could put a chip at the back of the eyeball where the retina is placed. I'm particularly interested in this because I have glaucoma,a cataracts and detaching vitreouses. My father had two detached retinas, and I'm at bigger risk for that. And I'm wondering what you could do with the eye.

FLATOW: Good question. What could you do with the eye? Have you thought about that?

INGBER: Actually, we haven't started working on that, but we saw it both in the front of the eye and the back of the eye. The front of the eye should be relatively straightforward in that you're basically building layers of different tissue. So that would be good for drug delivery across the eye, which could help everyone with eye disease.

The back of the eye is also layers of - there's blood vessels and nerves and specialized cells. Now we're not, right now, building chips to be placed into the eye. There are other groups - groups, I think, at USC - that are building artificial retinas, for example, with microchips, and those are real microelectronic chips that are placed - implanted. And so that's to help people see again.

You know, we're really trying to model right now to help drug development or to study disease processes. Glaucoma is actually a mechanical disease in some way in that there's a constriction of a canal that's a small, hollow tube in the eye that lets the fluid flow from one chamber to the other. When that gets obstructed, you get pressure buildup. That's something that potentially could be modeled.

I mean, what you - what we're trying to do is mimic the critical - the minimal critical elements of the architecture of the organ that are relevant for the functions that you want to study. We're not mimicking the whole organ.

FLATOW: Yeah. You're trying to build like a little lab bench.

INGBER: Yeah. It's like a little 3-D living cross section of a tissue, but it's human and it's alive.

FLATOW: And so you can fool around with that little cross section and try little different things to make it work better.

INGBER: Yeah. And we could do it in replicas, and we can do it with real-time, high-resolution analysis, which sounds technical. But what it means for the pharmaceutical companies is that if they have a drug and it actually - you know, they're moving it through their billion-dollar investment through animals to humans and they see some toxicity in an animal, they don't know what that means.

FLATOW: Yeah.

INGBER: Where here they can go back and say, why is it toxic? And I have five other drugs in my library that I could bring in. Are any of those better? And so things like that could have huge value, I think, for the pharmaceutical industry.

FLATOW: Dr. Ingber, thank you very much for taking time to be with us today. Good luck to you.

INGBER: My pleasure. Thank you.

FLATOW: Dr. Donald Ingber, director of the Wyss Institute for Biologically Inspired Engineering and professor at the medical and engineering schools at Harvard University. That's about all the time we have for today. We want to give a shout-out to WWNO in New Orleans, who's - the station and their listeners are joining us first time this week on SCIENCE FRIDAY. We welcome them into our SCIENCE FRIDAY family. Welcome aboard.

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