Breathing is such an unconscious event – except when it isn’t. Then and only then do we get a suffocating sense of how dependent we are on our efficient and expertly packed lungs to keep us both alive and energized.
UCSF’s Thiennu Vu, MD, PhD, needs no firsthand reminders. Indeed, she chose to study lung biology in large part because of the suffering of others she’d witnessed on hospital wards.
And because therapies are in short supply, Vu decided to do something about it in the laboratory. But first, she needed to uncover the developmental clues behind the wondrously simple way in which air and blood are brought together.
Sure, everyone knows we inhale oxygen and exhale carbon dioxide. But the system that allows this exchange of gases takes physical shape under rules we have yet to learn.
And what if we do? Well, the unfolded surface of our lungs would fill a tennis court. That alone should make the lungs worthy of our interest. But imagine the possibilities if we could somehow stimulate the adult stem cells recently found in the lung to repair damaged tissue? Think asthma, emphysema, lung cancer.
This is the stuff of heroic science – just like that practiced by the men and women in white coats who saved the world in the Godzilla movies of Vu’s youth. She was inspired then to become a scientist. She hopes others will now follow her.
Jeff Miller: Hello, I’m Jeff Miller and welcome to Science Café, today I’m
with Thiennu Vu, an associate professor of medicine at UCSF, welcome Thiennu.
Thiennu Vu: Thank you very much.
Miller: Now, as anyone who regularly listens to Science café knows, I’m particularly fond of MVPhDs, so I need to ask you right off the bat, how long did it take you to get both degrees?
Vu: It took me 9 years.
Miller: 9 years? That seems a little shorter than some I’ve heard.
Vu: I think it’s about the average. Some take longer, some take shorter.
Miller: Is it true that MVPhDs have a special perspective on their world, primarily because they occupy two, both the clinical side and the research side, do you feel you have a little special perspective on problems?
Vu: I think that I do. I think my medical training helps me to see scientific problems in a different way. I tend to think of things that I can do that would help patients eventually, so I ask scientific questions not only for the intellectual curiosity, but also whether it is going to be good for patient care.
Miller: And that may not be true for someone who is really delving deep down into more basic scientific questions because they never see patients.
Vu: That could be true, but I also know PhDs who ask questions of relevance to medical care. But that may not be on their mind as much as it is mine.
Miller: In your case. We’re going to be talking about your work with lungs and lung biology and lung development in just a second, but I’m curious to know, is there anything in your training along the way, was there some pivotal moment that turned you toward your current research focus, maybe a patient problem, a problem of a relative, anything like that?
Vu: I think I got into pulmonary medicine first when I got into my clinical training, and I got interested in pulmonary medicine because I noticed the lack of really therapeutic treatment for a lot of the lung diseases, that was true when I was going through training and continues to be true now.
Miller: Let’s get a list of lung diseases so everyone is on the same page.
Vu: The common diseases are asthma, COPD or emphysema, interstitial lung diseases, lung cancer, and some of the infectious diseases such as pneumonia.
Miller: So when you’ve seen patients with lung diseases, did that trigger your interest?
Vu: Yes. Patients with lung diseases suffer a lot, it is a very uncomfortable and scary feeling when you cannot breathe. And because the lack of effective treatment, it really motivated me to try to do research, to learn more about lung diseases so that we can come up with better treatment for these patients.
And the other factor that motivated me to go into pulmonary medicine was patients in intensive care units. The patients are very ill, critically ill, and they’re at moments of their lives when basically they cannot do anything but entrust themselves into the care of physicians, and the families also are very concerned and worried about the patients. And a lot of the patients in critical care units are there because of lung problems also, so that also motivated me to go into pulmonary medicine.
Miller: So how much time do you spend seeing patients and working in the lab at this point in your career?
Vu: Currently I spend about twenty percent doing clinical medicine and the rest in the lab.
Miller: I know you came to the U.S. from Vietnam when you were 16, were there any members of your family who had a medical background, and what prompted you to even consider a career in medicine or science?
Vu: There’s no one in my family who was in medicine or science, and actually when I was growing up I never thought about going into medicine – but I always wanted to be a scientist, even when I was a child.
Miller: And How did you know that as a child, was there something in particular you were interested in, were you very curious about why things worked? How did that manifest itself?
Vu: This is actually a very funny reason, because when I was growing up – I don’t know if you have seen or heard of a series of movies about Godzilla?
Miller: Sure, of course!
Vu: (laughter) They were very popular when I was growing up, my dad used to take us to see Godzilla movies a lot, and in these movies, the heroes are always these scientist, in white coats trying to save the world--
Miller: And you wanted to be one of those people-
Vu: I wanted to be one of those people trying to save the world from Godzilla!
Miller: And now you’re tackling lung disease. So I think everyone understands on the most basic level that we breathe in oxygen and exhale carbon dioxide, but how do the lungs actually make that happen?
Vu: I’m glad you asked that question because the lungs are very complex but beautiful organs. I guess you know the function of the lung is to bring oxygen and blood together so that we can exchange gas. Oxygen into the blood and carbon dioxide waste products into the air. And it has to do that very efficiently so it has to move air in and out of the lungs very efficient and quick-pace, so when we’re sitting, talking, we’re moving maybe 4 or 5 liters of air per minute.
Miller: Just now as we’re sitting and talking we’re moving that much?
Vu: Yes. And you need to move air in order to speak. When you exercise you increase that capacity as well, up to maybe twenty or thirty liters per minute.
And then you have to bring the air into contact with the blood over a very large surface area so gas can diffuse between the two compartments very quickly as well.
Miller: How big a surface area? I forget the actual measurements of the lung when you lay it out flat.
Vu: About the size of a tennis court. About 80 meters square is the total surface of the gas exchange area of the lungs. It has a series of conduits, which is the airways, to bring air in and out of the lungs very quickly. And then it has this total surface area which is very large, but the problem is it has to fit all of that into the small chest cavity as well, so how do you fold up this large surface area with systems of conduits inside the chest cavity? That is a very complex problem.
Miller: And this is a problem of development, how the organ actually develops, how it takes shape as well as the structural integrity of it.
Miller: Is there anything special about the human lungs? Are they fundamentally different in some way?
Vu: It’s not different from other mammalian lungs, so it’s very similar to primate lungs or rogan lungs, but it’s different from avian lungs for example, from the lungs of the birds.
Miller: Are human lungs among mammals the largest, the strongest, somewhere in between?
Vu: I think it’s not the largest, it’s certainly not the smallest, it’s somewhere in between.
Miller: The exchange that goes on at the alveoli level – is that something that is particularly complicated? I know it’s obviously essential, and is it tied into some fashion in the way the lungs actually develop?
Vu: The gas exchange?
Vu: It’s simple, you just have to bring air and blood together very closely separated by very thin membrane, so that the gas can diffuse freely very quickly. So the development of the lungs, how to make that happen is the complicated part.
Miller: Now are you studying at this point in your research the actual development of the lung itself?
Vu: Yes, I have been studying lung development, especially the development of the gas exchange surface or the alveoli.
Miller: And what have you learned so far?
Vu: What I have focused on is how the development of the vasculature is regulated. How it develops and how it contributes to the development of the airways, And the reason I focus on that area is because in the lung, particularly because of the function of the lung, that it needs to bring air and blood close together, you really need to bring the blood vessels, very close together with the airways. And so there has to be cross-talk. The two systems, when they develop, they have to talk to each other, so that they develop at the same rate, the same time, in the same spatial relationship.
Miller: In a normal situation are the blood vessels very densely packed in the tissue or is it kind of a thin network.
Vu: It depends on each different organ, so in each organ the vasculature has a very particular relationship with the tissue, so in some tissues it could be very dense, in some tissues, more sparse.
Miller: So now you’re studying how this develops, clearly in doing so you’re learning how things go wrong, so what does that tell you? Are these genetic influences? Is it the way the genes are not responding correctly in the course of development that underlines some of these lung problems – which I’m sure if that’s the case, develop early in a person’s life?
Vu: There are definitely genetic influences in the lung development, because if you alter the expression of several of the genes we’ve been studying, you definitely see abnormalities in the development of the lungs. So what we’ve been focusing on is what regulates the vascular development, and we have identified one of the genes that are critical for that, it is called vascular endothelial growth factor (VEGF), which is a very essential factor regulating blood vessel development in many different organs.
And that regulates how the vasculature develops. And if we alter the expression of that factor, we inhibit the development of the vessels, and then you also alter or impair the development of the airways.
Miller: Is the mutation in that gene fairly common, and if so would it show up as something dramatic in a newborn, of would it be something more progressive.
Miller: And before you answer, could defects in that system contribute to the development of asthma and other things?
Vu: The mutations of these genes have not been reported, I think because it is such an important factor for blood vessel development, that any mutations that cause alteration in its expression probably are not viable.
Miller: So the fetus would not be viable.
Vu: Exactly. But there could be alteration in expression, not because of mutation but because of environmental factors. For example in babies who are born very prematurely, and they have to be placed on supplemental oxygen or mechanical ventilation, and this could alter the expression of this growth factor because they are exposed to higher level of oxygen prematurely.
When the fetus is in the womb the oxygen level is not as high as if you place them on supplemental oxygen.
Miller: And have there been studies of premature infants, as they grow up, showing greater signs of lung problems?
Vu: Yes. So these premature babies placed on supplemental oxygen or mechanical ventilation, sometimes do not survive. And when they survive, they develop a disease we call chronic lung disease of prematurity. And that causes them to have a lot of lung problems as a child and when they grow older as well.
Miller: Does the percentage of impairment vary from person to person? Are we talking 50% loss of function or greater, or what?
Vu: It varies for individuals depending on how severe the damage is when they are born.
Miller: And that would mean since the really tiny preemies would be in the oxygen longer, if they survive, then their lung impairment later in life would be greater.
Miller: I know you are studying too, the possibility of using adult stem cells to somehow repair lung tissues, is that correct?
Vu: Yes. I’m interested in seeing whether there are resident or stem cells that reside in the lungs themselves, that can repair lungs after damage. And right now, this is not our work, but other people have identified a population of what seem to be stem cells in the lungs. And they reside at the very end of the airways, before the airways branch out into alveoli.
Miller: Was that a surprise to find stem cells at that location?
Vu: In retrospect it’s not surprising because if you think about the analogy of a tree, right now is cherry blossom season, so when you look at a cherry tree in blossom, you can think of the airways as the tree and the branches of the tree, and the blossoms as the alveoli. And when the blossoms are gone, you just have the braches of the tree left, but there’s still something there at the tips of the branches, so that the next season the leaves will come out the blossoms will arise again.
So it could be like that with the lungs. At the end of the airways there’s something there that can be redeveloped into alveoli. So that makes me think that the location is not surprising. But whether these few cells that we have found that have stem cell properties at this location can really redevelop and reform the whole sets of alveoli again – you know like whatever buds are left at the tip of the tree can form the blossoms again, is not clear.
Miller: But wouldn’t these “buds” perhaps be damaged by the disease itself?
Vu: Possibly. Possibly. Right now we actually have not been able to identify instances where the lungs actually regenerate following disease or damage-
Miller: Is this something you’re exploring though in your research?
Vu: Exactly. Yes.
Miller: Are you very early into to it? Are we many years away from having any kind of answer? Are there lots of people working on this or is this a specialty of yours?
Vu: There are a few people, a few groups working on this, I think there will be more, because I think we’re still far from being able to induce the lungs to regenerate. Probably not in the near future.
Miller: I’m not going to put you on the spot and say how many years before a cure
Miller: Now I’m going to ask you to put your clinical hat on for a second, we’re near the end of our science café interview for today… Is there anything people can do, apart from not smoking, obviously, to protect their lungs and health? Is there a way to increase capacity, obviously there’s exercise, what would be some dos and don’ts?
Vu: I’m not sure if there’s anything you can really do to improve your lung health, besides trying not to cause damage to the lungs by smoking or by exposing your lungs to toxic chemicals or fumes or pollutions.
Miller: So if you paint at home, wear a mask, these kinds of things?
Vu: Yes. Try to avoid breathing in fumes, smokes, chemicals that nay cause damage to the lungs.
Miller: Just a question that occurred to me, are you ever approached by groups on the outside that may be complaining that they’ve been exposed to something in the air, and you’re asked to offer your professional advice? Just curious.
Vu: I haven’t been, so far.
Miller: Thank you very much for joining me on Science café – still stuck in my head is that image of my lungs splayed across a tennis court, I’ll never think of them in quite the same way. Thank you for that and good luck in your research.
Vu: Thank you very much.