Interview 6 – Daniel Weiss, doctor

In this series of interviews. I ask scientists, engineers, and ethicists how technology might change our future. We had these conversations during the research for my book, Welcome to the Future (Quarto, 2021).

Interview 6 – Daniel Weiss, doctor

Dr. Daniel Weiss is a pulmonologist, meaning he specializes in treating lung diseases, at the University of Vermont Medical Center in Burlington. He is also a professor of medicine at the University of Vermont’s Larner College of Medicine. In addition to seeing patients and teaching courses, he has conducted research into growing human lungs in the lab. The eventual goal is to be able to transplant lab-grown lungs into patients. We spoke in September 2019. (In the wake of the COVID-19 pandemic, his lab has switched over to studying the impact of the coronavirus on the lungs in the hopes of finding new ways to treat COVID-19 and related diseases.)

In my book, I have a chapter on the idea of living forever, or at least living for an extremely long time. Do you think this future is possible?

I can’t speak to the entire spectrum of the idea of living forever, but advancements in science make this potentially a real possibility. The way to think about it is that your body normally ages and if you’re fortunate enough not to have any diseases, at some point your body is going to run out of its own regenerative capacity. A lot of things go into that. It’s really interesting science. In no particular order, let’s talk about a couple things. You’ve probably heard of stem cells. Every organ has its own resident stem cells. These are generally very few in number. If there is some sort of injury to that organ, these stem cells that live in the organ will have the ability to proliferate and differentiate and try to replace the damaged cells from the injury.

This is a very exciting concept. Part of the challenge is to identify exactly what these stem cells are in each organ. A stem cell in a brain is different from a stem cell in a lung, for example. So once you identify that you have to figure out what makes them work. And what triggers them to proliferate and differentiate and do their function. That’s a very exciting field.

Part of the problem is that these resident stem cells run out of juice. We don’t know why, but eventually they will peter out. That’s part of what happens during aging. You don’t have constant replenishment of wear and tear. If we can figure out how to keep these resident stem cells going, then theoretically they will be able to continue to replenish age-related damage beyond the normal lifespan.

That’s the first arm of regenerative medicine. The second arm is to try to grow new body parts outside of the body to implant or transplant to replace an affected organ. This is a fun one. This is something I always talk to my students about. Who was the first regenerative medicine scientist? She wrote a very famous book in late 1800s, that is a classic in every way.

Was it Mary Shelley, the author of Frankenstein?

Exactly. If you think about it, we’re just trying to catch up. As a pulmonary care physician, one of my research areas is to try to grow lungs outside the body to then implant into a patient.There area lot of cool techniques that have evolved over the past five to ten years. There arethings like 3D bioprinting, where you can program a computer and a printer and feed in the right types of materials and cells, and you’ve printed out an organ. That actually works for things like bone or muscle or cartilage since they are simpler than a brain or a heart or a lung or a liver. There’s still a long way to go for complex organs. The resolution of the 3D printers isn’t fine enough yet to get down to the microscopic cell structure that would create a lung.

In addition to that, there are organ-on-a-chip technologies. If you take cells from an organ and put them on a wafer and put that into a chamber, you can mimic the cell biology of that organ. That’s a great tool for the pharmaceutical industry because they can screen new drugs on this organ-on-a-chip.

Then there’s something called organoid culture. If you take different types of stem cells and put them into a supporting matrix, they have the ability to talk to each other and can form miniature versions of the organ in question. That’s very exciting.  But these are microscopic, little cell cultures. To scale up to a full-fledged organ is something down the road.

How would you grow an entire organ outside the body?

First, you need some sort of scaffold. All of your organs are made up of an underlying structural matrix. Most of it is collagen. That’s the underlying structural protein. You can try to mimic the growth structure and microscopic anatomy of an organ using a variety of biosynthetic materials. And then you can take the cells and put them into that scaffold to see if you can get something functional that mimics the actual organ itself.

One of the things has been a spin-off of that is the concept of decellularization and recellularization. The idea here is that an organ is going to be its own best scaffold. So if you take a lung or a heart or a liver and you treat it with enzymes or detergents with the goal of breaking up the cells and washing them out, then what you’re left with is that underlying 3D structure or scaffold. The extracellular matrix is the formal term for it. Then the challenge is to try to put cells back into it in a way that is going to make it function.

Think about organ transplantation right now. Patients are getting completely foreign organs, so they have to be on immunosuppressant medications. [Or else the immune system will reject the organ.] Those have a lot of side effects and it’s problematic. The extracellular matrix shouldn’t cause an immune response if you transplant it into somebody. If you could seed it with cells obtained from the eventual transplant recipient — you’d have to harvest some of those organ-specific stem cells and figure out how to get them to differentiate into the cells you want them to be and get them to grow – then you’ve got a tailor-made organ for that individual. That’s the ultimate in personalized medicine. At some point we’ll actually be able to make a functional heart or lung or whatever using that approach.

Getting back to your longevity question, if your heart runs out of steam, well we’ll grow you a new heart using your own cells, then put that into your body.

This brings up even more interesting stuff. Let’s say we can figure out how to do this with lungs. Unfortunately most lung diseases don’t have any cure. There’s no cure for emphysema or cystic fibrosis. At the end of the day, lung transplantation is the only option. But there are just not that many lungs to go around that are good for transplantation.  Even if we figure out how to take those lungs that aren’t usable as is, and we decellularize and recellularize them with new cells, there are still not going to be enough to go around. One of the hot areas of pursuit right now is to use animal lungs. Pigs are the primary target because pig’s lungs are reasonably similar to human lungs in size and shape. The idea is if you can decellularize the pig lung, and then put human lung cells into that lung, then you’ve created a functioning lung.

Those are two of the three arms of regenerative medicine. The third arm is if you can’t figure out how to get body to repair itself and you can’t figure out how to grow an organ or tissue outside of the patient, then you can make some sort of device to take the place of that failing organ. Think about dialysis for kidney disease. That’s the paradigm. They go in, get hooked up to a dialysis machine, and that is their kidney. Imagine if you could do that with all the other organs. Even better still, you could make these small and portable. If you had your lung in a backpack hooked up to your blood supply, you could walk around with it and lead a fairly satisfying life.

What has your team accomplished when it comes to growing a lung outside the body?

We’ve done a lot of work on that. We can certainly decellularize. We’ve spent a lot of time to figure out the nature of that scaffold that’s left over. We want to maximize the potential of being able to put cells into it and get them to grow and do what we want to do. We do a lot of work with human lungs. We get lungs from autopsy and we are able to decellularize them. We can get a lot of cells into them. And we are understanding how to get them to grow properly and be in the right place. You don’t want a cell that should be in one part of the lung to end up in a different part. We’ve also done a lot of work with pig lungs. We’ve been able to decellularize pig lungs and put in human cells and get them to grow. We’re studying the immunology of that pig lung, to see if it will provoke immune responses.

Are you decellularizing the entire lung, or taking a piece of it and working on that piece?

It depends on the animal source. For things like mice and rats, we can take the whole lung. With pig lungs and human lungs, they’re really big. So generally we’ll only work with one lobe at a time. A lobe of a human lung is the size of a soccer ball or football. We can take a decellularized pig or human lung and carve out little chunks if you will, and make lots of little baby lungs, about the size of your thumb. Then you get a higher throughput to be able to study everything.

What does a decellularized lung look like?

It looks exactly like a lung [only completely pale and translucent]. That’s the importance of being able to maintain that scaffold. You have the 3D structures maintained. All of the anatomy is maintained. It just doesn’t have any cells in it.

How many cells do you have to put back into that scaffold?

There are billions of cells in a lung. And there aremany different types of cells. To try to recapitulate all that in a laboratory is pretty daunting, actually.

What are some of the different types of cells that you have to put back in and where do they go?

Blood vessels have to be lined with a particular type of cell. You want to get the cells that live in the airways to go in and do the right thing. But blood vessels are the biggest challenge right now. If you don’t completely recellularize the blood vessels – let’s say there are some patches where the cells haven’t grown – once blood starts flowing through, blood clots will form there. Unless you have 100% coverage of the surface of the blood vessels then there’s a strong likelihood that you’re going to get clots and the lung is useless.

How do you keep these cells alive while they’re growing?

That’s a big challenge. We have large plexiglass chambers we can put the lungs in. We hook them up to something to supply fluid and eventually blood. We can hook them up to ventilators to pump gas in and out. But the problem there is just as you say, how do you keep the cells alive long enough? It could take weeks to months to grow enough cells to get the full surface area covered.

To put this in context, if you’re doing a lung transplantation and you have a viable, perfectly healthy donor lung and you want to get that over into a recipient, you have maybe 12 hours. There are some advances in technology where you can hook up those donor lungs to sophisticated pumping systems and pump nutrients through, but you maybe buy a couple more hours.  We don’t even know how to keep a fully mature organ alive outside the body for more than a day. So how are we going to keep something that we’re trying to grow into a new functioning lung alive for weeks or potentially months? It’s a big challenge.

How long do you think it will take until you can grow a lung this way?

There has been a lot of progress from us. And a handful of other labs are doing this. We’ve gotten to a point where we can get a whole lot of cells in there. And we think we’re beginning to see the right kind of function. But we haven’t got a completely, fully, recellularized lung yet. Until we figure out how to do that, then it’s still not ready for implantation. I’m always an optimist and I want to say 5 years down the road we may have something that’s going to work.That may be completely unrealistic. We’ve been doing this now almost 10 years. And there’s been a whole lot of progress, but we still haven’t solved the problem.

Are you confident that your method of decellularization and recellularization is going to be what works? Or do you think other methods might get there first?

It depends on the organ. Let’s shift gears to look at the liver. You can lose most of your liver, and as long as you have some minimal amount, you can still get function. So it’s conceivable to take a home grown piece of liver and then implant it next to the remnant of a liver, and hopefully it will take and grow. It’s hard to conceive of something like that for the heart or lung. If you’re able to just grow one lobe of the lung and implant that next to the resident lung, that new lung may mature in the body farther than we could get it to mature in laboratory, and then start functioning.

There is a lot of pseudoscience out there about stem cells, and I want to make sure I’m very clear about what is NOT possible in that area. Could you talk about that?

It’s called stem cell medical tourism. Unfortunately, you can go on internet and type in “stem cells,” and you get large numbers of “clinics” out there offering to inject you with stem cells to “cure” everything from Parkinson’s disease to baldness. It’s all snake oil. These are unproven therapies. [And they could be dangerous]. There is no approved cell-based therapy in the United States, apart from things like bone marrow transplantation for leukemias and lymphomas. It’s something you find on the internet, and it’s taking advantage of desperate people. The FDA has begun to crack down on this and enforce action against clinics offering this bogus therapy. The Justice Department has also been getting involved. This is all a drop in the bucket because a lot of these stem cell clinics have a lot of money and legal fire power behind them. To take them on is a daunting task. It’s like a hydra. You cut off one head and seven more heads grow back in. It’s been a difficult task.

Where can people find fact-based information on stem cell therapies?

The International Society for Stem Cell Research (ISSCR) and the International Society for Cell and Gene Therapies (ISCT). I’m the key scientific officer for the ISCT. We have a task force that is trying to combat stem cell medical tourism. Recently, Google announced that they’re no longer going to allow advertisements from the stem cell medical tourism industry.  

But it is possible that someday, you could use these cells to allow organs to repair themselves or to grow new pieces of organs?

We all hope so! Right now, it’s still heavily in the research phase.

Would you want to live in a future where people endlessly repair their bodies?

That gets into a philosophical question that I can’t really give you any profound insight into. The target for us is not longevity. It’s to cure disease and give people a better quality of life.