Dr. Paul Noble, MD, physician scientist, pulmonologist, and chair of the Department of Medicine at Cedars-Sinai Medical Center talks about Zinc being a new treatment for respiratory issues.
Interview conducted by Ivanhoe Broadcast News in August 2022.
What is IPF?
NOBLE: Idiopathic pulmonary fibrosis, or IPF, is a lung disease in which the lungs form scar tissue. The typical patient is male. It’s more common in men than women. It’s also much more common with age. Over the age of 60, it starts to accumulate more. But over the age of 80, it’s the leading cause of scar tissue in the lungs.
What causes it?
NOBLE: We don’t know, hence the term idiopathic. There are some genetic underpinnings. There are a few genetic mutations that have been shown to occur with idiopathic pulmonary fibrosis. It does run in families, but only about 20% of the time can we identify an underlying genetic underpinning. It’s a disease that is not only associated with age and male. Almost everyone has smoked in the past, as well.
Is it, like, a 20-year habit or is it, you know, I did it when I was a kid?
NOBLE: It’s usually some substantial smoking. But most people, by the time they present with idiopathic pulmonary fibrosis and are diagnosed, they don’t smoke anymore.
What are the symptoms?
NOBLE: This is the challenge. The symptoms are exactly what you would expect for getting older. You notice that you’re going up the stairs and you’re out of breath. It often is very insidious. You can get fatigued with exercise. The classic case is somebody who’s worked hard their whole life, then they retire. Maybe they’re 70 and they start doing more, and they just think, you know, I’m out of shape. I haven’t been exercising. But unfortunately, that is the insidious onset of idiopathic pulmonary fibrosis. That’s why the average time to diagnosis from the onset of symptoms is up to two years.
What are the traditional treatments?
NOBLE: Once we make the diagnosis, here’s what’s also extremely important. There are a few things that can look like idiopathic pulmonary fibrosis that are much more treatable. The biggest category are autoimmune diseases. The famous one, rheumatoid arthritis. Pulmonary fibrosis is the leading cause of mortality in patients who have rheumatoid arthritis. Scleroderma, which is a connective tissue disease that affects women more often than men, can be complicated by pulmonary fibrosis. Then, there are much less common autoimmune diseases that can also be associated with pulmonary fibrosis. They are generally much more treatable because you can treat the underlying etiology, which is a deranged immune system. So, it’s almost like your body is trying to reject your lungs. If you have an autoimmune disease, we use medications that target rejection. And sometimes we can get patients better. Rarely we can get them all better, but most of the time, we can prevent them from progressing. But about a third of the time, patients will progress anyway. The other huge category are things that you breathe in. The classic is if your home has had water damage and you have mold. Mold is a big cause of fibrotic lung disease. In addition, and we see this a lot, I’ve been out here at Cedars-Sinai for 10 years. I moved out here from North Carolina, where I was at Duke. Prior to that, I was at Yale for nine years. I’ve seen more cases of hypersensitivity pneumonitis. That’s an inhaled antigen that causes inflammation and ultimately scarring. I’ve seen more cases here in Los Angeles over the last 10 years than I ever saw back on the East Coast. I think there’s something about our ambient air. Not a lot of humidity for some reason. I think the spores are just more transmissible. And people love feathers in California. Telluride folks are a little peculiar, as well, but in a different way. But Los Angeles, a lot of people really like down feathers. And birds – cockatiels, finches, love birds. Indoor birds, not outdoor birds. That also can cause chronic hypersensitivity pneumonitis. Most of the time, if we can convince them to get rid of the birds or the down comforters or get the mold fixed, we can stop the disease from progressing and many times we can get it better. And then there are some medications. Some medications to try to treat heart disease like something called amiodarone for heart arrhythmias. There’s an antibiotic used many times in women who have recurrent urinary tract infections, particularly older women, called nitrofurantoin that can cause pulmonary fibrosis. If we can stop those drugs, we can usually get patients to improve. So, we do an exhaustive search. And if we can’t come up with a reason for the scarring, then we label it idiopathic. Sometimes we have to do a biopsy of the lung to look at the tissue because there are patterns that we recognize as being associated with idiopathic pulmonary fibrosis. But the high-resolution CAT scan has evolved to the point where it’s so sensitive and the imaging is so pristine that we can recognize the patterns. So, we much less commonly need to do open lung biopsies.
Is there some idea that this IPF could be genetic?
NOBLE: Absolutely. There’s a particular group of genes that encode proteins called telomerases. Telomerases keep our chromosomes from getting shorter, which is all about aging. IPF is a disease of aging of the stem cells in the distal alveolar space. The lung’s job is to take oxygen from the air and get it into the blood. That happens through the bronchioles getting smaller. They become these beautiful, lacy like alveolar structures. The lining of those alveoli are with these alveolar epithelial cells. There are two types – one and two. Type two is the stem cell. What happens is these prematurely age, and when they die off, IPF is a loss of these stem cells. What happens is that the surrounding cells that make scar tissue try to fill in the gap of this loss. The lung starts to form scar tissue. It ultimately obliterates the area where the lung extracts oxygen from the air. So, the symptom is breathlessness with exertion because your lungs need to take deep breaths to get your oxygen level up with exercise. But with IPF, it goes down. That’s the problem.
You have just published a study that involves zinc, can you tell me about that?
NOBLE: Absolutely. I can sit here and tell you honestly, I never imagined I would be thinking about zinc, NAD boosters, and sirtuins. So, the way we came upon this is when I can’t fix patients, when I fail at my job and they’re otherwise in reasonable condition, we do a lung transplant. If they’re under the age of 65, we put in two lungs. If they’re over the age of 65, generally, they get one lung. So, when my patient has a lung transplant, I get the tissue from the diseased lung, and with colleagues here in our Cedars-Sinai Women’s Guild Lung Institute, over the last decade, we’ve developed the ability to isolate these stem cells, it’s called the explanted lung. So, that’s the disease lung. And what’s happened, technology has evolved so amazingly that if there is a particular cell that you’re thinking you want to know what is it doing? What genes is it expressing? What proteins are making? If you can identify a marker on the cell surface, you can purify those single cells out and you can determine all the genes that they’re expressing. So, we published a few years ago that when we take these IPF stem cells out, they don’t work. Now, what does that mean? So, if we take normal, either from a mouse or from a patient who’s undergone, like, a lung resection for cancer in the surrounding lung, if we isolate those stem cells and we put them in a little dish with some matrix and feeder cells, they will form a little lung. It’s called an organoid. It’s beautiful. It’s trying to form this lung. We published a few years ago that the IPF stem cells don’t do it. They can’t form this lung. So, we’ve been trying to figure out why. So, to ask that question, we isolated these cells freshly, prepared their RNA and did this – what’s called single cell RNA sequencing. What we unexpectedly found was this zinc transporter is missing in IPF. Why? What would that be all about? Zinc is an essential mineral. It’s a nutrient that’s used for a lot of cellular processes. And then there are these great tools. It’s like big data. You can ask a question when this gene is down, what sort of downstream pathways might be affected? So, we ran this analysis of pathways and found that this pathway that encodes this nicotinamide deaminase, NAD plus and sirtuin one, these have been implicated in aging. About 20 years ago, there was the discovery of these sirtuins in worms called c elegans. They determined how long these worms would live. Now, there’s a whole industry that’s built up about this, and a lot of it is quite murky because a lot of these were supplements. And sirtuins are in red wine. You may have heard of resveratrol. You can go on the web, you can read about all this stuff, and even NAD boosters. NAD boosters are used to promote fertility in women, to potentially delay memory loss. What we then found was that this pathway was missing. When we go back and take our diseased alveolar stem cells in our dish and we put back these nutrients, the cells grow again in the dish, they can form a lung again. So, the idea that if we can replace this pathway, could we allow the lungs to be able to repair themselves? And then one of the other cool technologies that are available is that if you’re interested – like, I’m interested in this zinc transporter called ZnT8. So, in a mouse, you can genetically modify the mouse so those stem cells are only missing ZnT8. So, we generated this mouse model and lo and behold, over time, spontaneously, they develop fibrosis like IPF. When we isolate their stem cells, they can form a lung. So, we have this model that we’re working on to develop the right doses. All of these are supplements, meaning you can go on your computer, order them from Amazon. What we are hope now is to do some clinical trials with these. And they also appear to be safe. They’re not FDA-approved drugs, but there are a lot of regulations around these supplements. So here I am, a physician scientist, started my lab 30 years ago, on the web with these sites about supplements and tracking down these scientists who have been involved in this work. But now they have companies around this. Money gets involved. It gets a little dicey. So, we’re in the process of having unexpectedly made this discovery, trying to figure out the next step to see if we can demonstrate that if we restore the stem cells in the dish, that would that translate over time to people’s lung function getting better. The treatments that we have available for IPF don’t make patients better. It’s still a fatal disease. It slows down the loss of lung function, but everyone still dies from IPF. So, our hope is this new approach. And if we can identify ways to determine if we can restore this pathway in IPF patients, can we make them better?
Is it just zinc supplements?
NOBLE: Yes, Zinc supplement, NAD supplement, and a resveratrol supplement.
Have you come across anything like this in your life as a doctor where you are able to reverse damage like this?
NOBLE: Not in the lung. We have mouse models where we’ve been able to sort of prevent fibrosis. But reversing it hasn’t happened yet in this disease. The drugs that are currently being developed, what they target is remember how I told you when the stem cell dies, the cell that makes scar tissue starts to expand? What the therapies do is focused on making it harder to make new scar tissue. But that’s not going to cure the disease. In medicine, the way you cure a disease is you treat the underlying cause. We think we’ve identified a pathway that’s been implicated in other disease states as the primary cause in IPF. That’s what, for me as a physician who takes care of IPF patients every week and runs a laboratory, the idea of potentially improving lung function is something that really gets me out of bed in the morning.
And these are people who have worked their whole life, possibly done everything right – right?
NOBLE: Exactly, and on average, they either get a lung transplant or succumb to the disease within five years. The prognosis is worse than many cancers. It doesn’t have a bad – idiopathic pulmonary fibrosis. It takes patients a while to digest that. What does it even mean? But if you Google it, it says you’re going to live 3.8 years. So, it is like a cancer, and it behaves clinically like a cancer because it’s slowly progressive. It’s just the tumor is scar tissue.
Do you have hope that this is a cure? Is it a preventative? Is it something that everybody over 60 is going to start taking zinc?
NOBLE: Yeah. I mean, it’s not just the zinc. So, if the zinc transporter is missing, the zinc can’t get in. So, when we isolate all the stem cells in the dish and we add zinc back, we can get improvement. But we get much more improvement when we have the whole cocktail in there – zinc, NAD and the sirtuin one activator. So, this is my quest over the next several years. We have some other ideas that we’re also developing on the fibroblast scar tissue side. But my dream is that a combination of supplements or maybe a new drug that gets developed that restores the type two cell function in combination with a drug that makes it harder to form scar tissue allows patients to not only not progress, but if we get them early enough and there’s enough good lung left, that good lung can even get better. That’s our hope.
Is getting your research in clinical trials, next?
NOBLE: Yes. We’re beginning to explore avenues because it’s different for supplements. I’ve been involved in clinical trials for two decades. I was involved with both drugs that are FDA-approved, all developed by pharmaceutical companies. But pharmaceutical companies, as we know, are also motivated heavily by whether it’s going to be financially to their advantage. So, that’s where the challenge gets in because these aren’t patented. These are supplements. So, it’s a new world for me, thinking about how to do this. But I was talking with some of the leadership at the National Heart, Lung, and Blood Institute, and I think they might have some interest in this because these are also not, relatively speaking, not expensive therapies. The current therapies that are approved for FDA, they cost $100,000 a year. I mean, insurance generally covers it, but not always all of it. These are a fraction of a fraction of that. So, the other thing that would be remarkable is that if we could find supplements that work and they’re cheap, patients all the way around the world could get these things in underserved areas, and it would be remarkable. But this is why you do science. It may work. It may not work. The reason I’m a little more excited about this than other things is it’s all derived from patient tissue. It didn’t start with an idea of causing scar tissue in a mouse and studying. It started with the patients. So, it’s a long shot. But this is why we do what we do.
Whenever you talk about breathing problems, of course, everyone now goes back to long-haul COVID and everything. Would this also be a simple solution for those long haulers?
NOBLE: We think it might be. If you Google supplements NAD and COVID, people are going for all these rejuvenation things. So, there’s a whole murky side. And there are a lot of people that have been promoting these types of supplements for COVID. But the other thing that’s very exciting is that we have a world class lung transplant program at Cedars-Sinai. We’ve been one of the centers and have done among the most COVID fibrosis patients that have had lung transplants. We had an extraordinary story where a young woman came in, delivered her baby, COVID, was seriously sick, had a double lung transplant and is now home with her baby. So, we have the tissues from these COVID lung explants, and there are some common mechanisms between COVID and IPF. And we think this pathway might be one of them. So a lot more work to do, but it’s very exciting.
END OF INTERVIEW
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