📷 UCLA Broad STEM Cell Research Centre
Journalist: Luke Peterson
Luke: Welcome to SciSection! My name is Luke Peterson and I am a journalist for the SciSection Radio Show broadcasted on the CFMU 93.3 FM radio station, and we are here today with Doctor Bridgette Gomperts. Thanks for taking the time to meet with me Dr. Gomperts.
Gomperts: Thank you for having me.
Luke: Would you mind if we started with you explaining to our audience what research interests are and what you do at UCLA?
Gomperts: I am a physician scientist at UCLA in the David Geffen School of Medicine and the Children’s Discovery and Innovation Institute. As a phy-sci, I see patients in the clinic and I also run a research lab. I also spend a large amount of my time training and mentoring the next generation of scientists and physician scientists.
Luke: Alright. I understand that your work or your interests have shifted bc of the pandemic but maybe you could spend a bit of time explaining what your priorities were before the pandemic. Maybe how those have changed bc of the pandemic.
Gomperts: My lab studies lung-repair and regeneration from stem cells and how these processes can go awry and lead to lung diseases, and we spent the last decade or so developing lung models to study lung stem cells and how they are effective in lung diseases. So when the COVID 19 pandemic struck in March and we realized the biggest impact of the disease was on the airway in the lungs, several colleagues approached me to ask if we could collaborate to study the effects of the virus on the airways, and this has led to multiple very exciting collaborations all across the country, and we;re working with the very talented ucla virologist, maitee arosami, who’s actually infecting our little lung organoids with live SARS-COVID virus, which is the virus that causes COVID-19, and we were just really lucky that we already had our human-airway cell models already growing in the lab, so we were able to get started very quickly with these viral infections and studying COVID-19 in the labs.
Luke: I read online on one of your profiles that you used, prior to the pandemic, you were primarily studying pulmonary fibrosis, and correct me if I’m wrong, that can result in types of lung scarring, so do you think that work prepared you for what you’re doing right now?
Gomperts: Definitely. A lot of the models that we had up and running are now applicable and we’re thinking a lot about scarring in the lungs after SARS-COVID infection. It’s something that we’re seeing clinically in patients, and we’re trying to investigate how the virus might be inducing this kind of scarring fibrosis.
Luke: Are there any other diseases that you studied prior to the pandemic?
Gomperts: We’re really interested in cystic fibrosis and trying to better understand the different cell types in the lungs that could potentially be used for gene therapeutic approaches for cystic fibrosis. For many years my lab has been really interested in studying the response of the airways to different kinds of injury and how those responses could go wrong and how they could lead to precancerous areas in the lung, and those are the major areas that we’ve been investigating in the lab.
Luke: And I suppose those studies are related to what you’ve done before the pandemic. And from what I understand also, you’ve been testing various therapeutics and drugs to see whether those are applicable to COVID. Are you using the same methodologies there to test what could result from those?
Gomperts: We’re using these stem cell derived lung models and all we do is we take primary human cells and we put them on the scaffolds and we try to recreate all of the different cell types and the architecture of the lung and tissues as much as we can. Although no model is really perfect, we do think that it quite closely represents lung tissue, and this is what we’re using now for the live viral infections. And what we believe is that because these primary human cells are placed in an environment that is very similar to the experience of the body, that it is more likely that we will find different drugs that will be more likely to work in patients. These complicated 3D models are difficult to grow, and they’re expensive and take a lot of time, we think they’re more closely aligned to what is happening in the body, and we believe that any drugs we find that respond or work in our models are more likely to work in patients.
Luke: How long ago were 3D models or lung organoids; were those well developed before you started to get involved with that work or was that more of a novel science?
Gomperts: There’s been a real push for lung organoids and to differentiate lung cells from pluripotent stem cells for the last decade or so; there’s been a lot of work in this area so there are a lot of different lung models out there, and i know that many of my colleagues in this area have been busy working on COVID-19 bc these lung model each have their strengths and weaknesses, but they’re all useful in studying COVID-19.
Luke: How close do u think you’re current models resemble the actual structures in our lungs? What do u think about that?
Gomperts: Some are better than others, but the lung is actually structurally and functionally quite complex; there are different regions of the lung that have different structures, cells that have different functions and they look pretty different. For example, our upper airways which includes the nasal cavity and sinuses and throat and the windpipe, the trachea and the bronchi. This is actually part of the airway of the lung; the airways are directly in contact with the environment, so they have a really important function for host defence, which means they protect the body, and they do this by generating mucus which traps the viruses and the bacteria and the pollution and bad things we breathe in; and there are these ciliated cells which are cells with hair-like projections, and these hairs beat in one direction which move the mucus out of the body where it can be coughed out or swallowed, which is a good way of protecting the body. Those cells are highly specialized for that region; and there are these cells that are found in the lower regions of the lungs and these are completely different cells. Their main function is the gas exchange so these cells are very very spread out and they form a very large surface area, across which oxygen can diffuse into the body and carbon dioxide can diffuse out. And so all groups are modelling these different regions in different ways with these highly specialized cells. I would say that we’re fairly successful, but not completely successful; there are many parts where the models are really not equivalent to be in actual patients. For example, in the situation where we’re in the lower airways and where there’s gas exchange, what happens there is that the oxygen moves into capillaries and from there throughout the blood system in the body, but it’s been incredibly difficult to model that gas exchange into capillaries bc it’s very hard to make those capillaries, so that’s one area that is lacking. And there’s also been very difficult to get inflammatory cells into our models. That’s another area which is obviously room for improvement.
Luke: Do you anticipate your models will become more complex in the foreseeable future?
Gompert: Yes; we definitely have plans to make our models more complex and to identify ways in which we can introduce inflammatory cells into the airways and where we can actually more closely mimic the respiratory membrane where we can have functional capillaries in contact with the lining with the epithelial cells.
Luke: I think earlier you said that the approach your lab is taking, or that the methods for what you’re using your 3D organoids, that they’re expensive and really difficult to establish, so do you think that the benefits that you are seeing with these 3D models are worth that cost?
Gomperts: 2D models are very easy to do; it’s very easy to grow them in the dish. And they’re not very expensive, but they don’t very closely mimic what happens in the body, and often people perform drug screens with cells in 2D and they find drugs that work just fine in the dish in 2D but when those drugs get to patients, those clinical trials fail. So I believe that the 3D tissue-like structures that we are growing much more closely replicate what’s happening in the body, that if we find drugs which work in these 3D models, then it’s much more likely that they’ll be effective in patients. In the long run, it might be more cost-effective to screen in these 3D models, because the cost of failing in drug discovery is obviously a huge cost.
Luke: So that’s also a part of your work, right? You’re lab is screening drugs, potential treatments for COVID?
Gomperts: Yes, we are right now trying to set up models with high put systems where we can hopefully screen a few thousand drugs. Like you said, it’s very expensive and difficult to get these models going, so we might not be able to test hundreds of thousands of drugs, but we hope we can test a few thousand drugs for COVID-19, and our goal there is to test drugs that have already seen out into the clinic or have been through early clinical trials so that drugs that can be repurposed for a treatment. This may work bc COVID-19 hijacks the body’s functions; the cells’ functions, and so what we think is that some drugs that are already effective for example in cancer could be helpful here and so our plan is to try and repurpose drugs that have already been through some safety testing and have been found to be safe bc we think this is a much better way to get to the clinic.
Luke: Have you been screening them for potential long-term results? Would you have to be patient about the process, or how much pressure do you think you or the scientific community facing in general to get results out?
Gomperts: Obviously we’d like to find therapies in a rapid manner, but like i said before, we have to make sure that the screens are done appropriately; it would be worse if we didn’t run really rigorous tests to make sure that any drugs that we think would be effective in a clinic are really soundly screened for, and so we can have to weigh those up against each other. There are certainly many groups around the globe that are rushing to find new therapies and vaccines, so there is a very large push right now in this area.
Luke: Can you describe the general methods that you use to screen them, or what you look for or what the indicators are that there might be a drug that shouldn’t be used as a therapy?
Gomperts: So we’ve developed several weed-outs to detect whether a drug in a screen is likely to be effective at treating SARS-COVID viral infections, and we’ve measured things like the number of dead cells and the number of infected cells afterlife virus infection, and then we call that the primary screen, and once we’ve found some compounds that seem to work well in the 3D screen, then we go on and do a secondary screen and here we test things like whether the compound is effective at a low dose, and whether it’s effective across multiple different lung organoids and especially whether it’s effective on cells that have developed on different people from multiple races and ethnicities, and we really want to give a sense on how reproducible a drug effect is on these 3D models, and our priority is to test drugs that are really known for other indications, and we have been through these early clinical testing to make sure that they have no bad side effects and that they can be well tolerated.
Luke: As it relates to the virus itself, have you found that there are elements of it that are remarkable or that compare to other diseases that you have worked with before?
Gomperts: What we’ve found is that the virus, when it tries to infect our 3D organoids, it actually has; it’s not a really simple infection; it seems that our 3D tissues have a pretty good immune response to the virus, and most of the time we see very little viral infection, sometimes in the order of about 5 to 10 percent of infection; we’ve done things like expose our little lung 3D organoid models to cigarette smoke, and in that situation we actually induce the immune response and then we see a lot more cells being infected by the virus. That’s been a really interesting twist that i wasn’t expecting; you said that the virus really responds very well to the host immune system just within those epithelial cells lining the airways.
Luke: Is there anything else that you think would be good for people my age - or students - or science minded students to know about what your work entails; do you have anything to add or anything we should prioritize when considering the virus?
Gomperts: The most important thing is that these 3D lung organoid models are actually really useful for studying the live viral infection and it’s quite a lot that we can learn from these models. Obviously a big priority is to try and use them for drug-discovery, but these models can also be used to test for specific questions; for example, how cigarette smoke environmental exposure question, or any other kinds of things that might be impacting the virus, and it seems like these models could also be useful for testing across multiple different people, even thinking about high-risk groups like older-aged or diabetics or obese groups. We were certainly able to get primary lung cells from these patient demographics for testing. I think these models are very useful for studying the SARS-COVID virus and how it is infecting the lungs and the responses that are happening in the lungs. Of course there are some downsides to the model, most specifically I think the fact that we don’t have inflammatory cells in the model right now, and the inflammatory component is obviously very important in SARS-COVID infection. I think something we need to work towards is figuring out how to include that component. But I am hopeful that these 3D models can be improved over the future and can be used not only for studying COVID and viral infections but for other lung diseases as well.
Luke: Is there anything else that you’d like to say or add?
Gomperts: I can’t think of anything else.
Luke: That’s it for this week of SciSection! Make sure to check out our podcast available on global platforms for our latest interviews, and I’ll talk to you later!