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COVID-19 Brings Health Disparities Research to the Forefront

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Zoom conversation between Francis Collins and Eliseo Perez-Stable

The coronavirus 2019 (COVD-19) pandemic has brought into sharp focus many of the troubling things that we already knew about health disparities in the United States but have failed to address. With the bright light now shining on this important issue, it is time to talk about the role research can play in reducing the disproportionate burden of COVID-19, as well as improving the health of all people in our great nation. 

In recent weeks, we’ve seen a growing list of disturbing statistics about how blacks, Hispanics, tribal communities, and some other racial, ethnic, and disadvantaged socioeconomic groups are bearing the brunt of COVID-19. One of the latest studies comes from a research team that analyzed county-by-county data gathered about a month ago. Their findings? The 22 percent of U.S. counties that are disproportionately black accounted for 52 percent of our nation’s COVID-19 cases and 58 percent of COVID-19 deaths. In a paper awaiting peer review, the team, led by Emory University, Atlanta, and amfAR, the Foundation for AIDS Research, Washington, DC., noted that neither the size of the county nor whether it was urban or rural mattered [1].

Recently, I had an opportunity to discuss the disparate burden of COVID-19 with Dr. Eliseo Pérez-Stable, Director of NIH’s National Institute on Minority Health and Health Disparities (NIMHD). Besides leading an institute, Dr. Pérez-Stable is a widely recognized researcher who studies various factors that contribute to health disparities. Our conversation took place via videoconferencing, with him linking in from his home in Washington, D.C., and me from my home in nearby Maryland. Here’s a condensed transcript of our chat:

Collins: Eliseo, you and I recently had a chance to have a pretty intense discussion with the Congressional Black Caucus about health disparities and the COVID-19 pandemic. So, could you start off with a little bit about what populations are being hit hardest?

Pérez-Stable: Collecting data about disease incidence and mortality on the basis of race and ethnicity and other important demographic factors, like socioeconomic status, had really been absent in this pandemic until recently.

Part of that I think is entirely understandable. Hospitals were pressed with a surge of very sick patients, and there was a certain amount of fear and panic in the community. So, people were not completing all these forms that usually get turned in to the health departments and then forwarded to the CDC. If you go back in history, similar things happened in the early 1980s with the HIV epidemic. We weren’t collecting data on race and other sociodemographic variables initially. But, with time, we did complete these data and a picture emerged.

With the COVID-19 pandemic, obviously, the outcomes are much faster, with over 60,000 deaths in just a matter of three months. And we started to see reports, initially out of Connecticut, Milwaukee, Chicago, and New Orleans, that African Americans were dying at a disproportionate rate.

Now, the initial—and I think still the most likely—explanation for this higher mortality relates to two factors. The first is a higher rate of co-morbidities. We know that if you have cardiovascular disease, more than mild obesity, or diabetes, you’re more likely to get severe COVID-19 and potentially die from it. So, we could have just said, “Aha! It’s obvious why this population, and others with higher rates of co-morbidities might be expected to have higher rates of severe disease and higher mortality.”

But there is a second factor that relates to getting infected, for which we have much-less clear data. There was recently a map in The Washington Post showing the distribution of the rate of COVID-19 infections in Washington, D.C., by ward. The highest rates are in the wards that are east of the Anacostia River, which are about 90 percent African American. So, there is an appearance of a correlation between the proportion of African Americans in the community and the rate of Covid-19 infection. Now why could that be?

Collins: Yes, what explains that?

Pérez-Stable: Well, I think crowding is part of it, certainly in this neighborhood. A second option would be multiple families living under one roof.

Collins: So, you can’t exactly practice physical distancing very well in that situation.

Pérez-Stable:  Absolutely. You and I can go into our respective rooms, probably have our respective bathrooms, and socially and physically isolate from the rest of the household if need be. Many people can’t do that. They have three generations in one small apartment, all using one bathroom, maybe two bedrooms for six or eight people.

So, we do face different conditions by which one casual infection can lead to much more community transmission. But much information still needs to be ascertained and there does seem to be some regional variance. For example, in Chicago, Milwaukee, and Atlanta, the reports, at least initially, are worse than they are in Connecticut or Florida. Also, New York City, which has been the epicenter of the U.S. for this pandemic, has an increased rate of infections and mortality among Latino-Hispanic populations as well. So, it isn’t isolated to an African-American issue.

Collins: What about access to healthcare?

Pérez-Stable: Again, we can postulate based on a little bit of anecdote and a little bit of data. I’m a general internist by background, and I can see the enormous impact this pandemic has had on healthcare settings.

First, elective ambulatory visits and elective admissions to the hospital have been postponed, delayed, or cancelled. About 90 percent of ambulatory care is occurring through telemedicine or telephone connections, so in-person visits are occurring only for really urgent matters or suspected COVID-19.

If you have health insurance and can use systems, you can probably, through telephone triage with a nurse, get either approval or nonapproval for being tested [for COVID-19], drive to a place, get tested by someone wearing protective equipment, and never actually have to visit with anyone. And you’ll get your result now back as soon as one day, depending on the system. Now, if you’re insured, but don’t really know how to use systems, navigating all these things can be a huge challenge. So, that could be a factor.

People are also afraid to come to clinic, they’re afraid to show up at the emergency room, because they’re afraid to get infected. So, they’re worried about going in, unless they get very sick.  And when they get very sick, they may be coming in with more advanced cases [of COVID-19].

So, telephone triage, advice from clinicians on the phone, is critical. We are seeing some doctors base their decisions on whether a person is able to breathe okay on the phone, able to say a whole sentence without catching their breath. These kinds of basic things that we learned in clinical medicine training are coming into play in a big way now, because we just cannot provide the kind of care, even in the best of circumstances, that people may need.

Of course, uninsured patients will have even more barriers, although everyone in the healthcare system is trying their best to help patients when they need to be helped, rather than depend on insurance triage.

Collins: A big part of trying to keep the disease from spreading has been access to testing so that people, even those with mild symptoms, can find out if they have this virus and, if so, quarantine and enable public health workers to check out their contacts. I’m guessing, from what you said, that testing has been happening a lot less in urban communities that are heavily populated by African Americans and that further propagates the spread of the disease. Am I right?

Pérez-Stable: So far, most testing has been conducted on the basis of symptoms. So, if you have enough symptoms that you may potentially need to be hospitalized, then you get tested. Also, if you’re a healthcare worker who had contact with a COVID-19 patient, you might be tested, or if there’s someone you’ve been very close to that was infected, you may be tested. So, I don’t think so much it’s a matter of disproportionate access to testing by one group or another, as much as that the overall triage and selection criteria for testing have been rather narrow. Up until now, it has not been a simple process to get tested for COVID-19. As we scale up and get better point-of-care tests and much easier access to getting tested, I think you’ll see dissemination across the board.

Collins: It’s interesting we’re talking about this, because this is an area that Congress recently came to NIH and said, “We want you to do something about the testing by encouraging more technology, particularly technology that can be distributed to the point-of-care, and that is out in the community.”

Everyone wants a test that gives you a quick turnaround, an answer within an hour, instead of maybe a day or two. A big part of what NIH is trying to do is to make sure that if we’re going to develop these new testing technologies, they get deployed in places that otherwise might not have much access to testing—maybe by working through the community health centers. So, we’re hoping we might be able to make a contribution there.

Pérez-Stable: The economic factors in this pandemic are also huge. A significant proportion of the population that we’re referring to—the disparity population, the minorities, the poor people—work in service jobs where they’re on the front line. They were the restaurant servers and people in the kitchen, they’re still the bus drivers and the Uber drivers, and those who are working in pharmacies and supermarkets.

On the one hand, they are at higher risk for getting infected because they’re in more contact with people. On the other hand, they’re really dependent on this income to maintain their household. So, if they test positive or get exposed to COVID-19, we really do have a challenge when we ask them to quarantine and not go to work. They’re not in a position where they have sick leave, and they may be putting themselves at risk for being laid off.

Collins: Eliseo, you’ve been studying health disparities pretty much your whole research career. You come from a community where health disparities are a reality, having been born in Cuba and being part of the Latino community. Did you expect that COVID-19 would be this dramatic in the ways in which it has so disproportionately affected certain groups?

Pérez-Stable: I can’t say that I did. My first thought as a physician was to ask: “Is there any reason to think that an infectious agent like COVID-19 would disproportionally infect or impact any population?” My gut answer was “No.” Infectious diseases usually seem to affect all people; sort of equal opportunity invaders. There are some data that would say that influenza and pneumonia are not any worse among African Americans or Latinos than among whites. There are some slight differences in some regions, but not much.

Yet I know this a question that NIH-funded scientists are interested in addressing. We need to make sure that there aren’t any particular susceptibility factors, possibly related to genetics or the lung epithelium, that lead to such different COVID-19 outcomes in different individuals. Clearly, something must be going on, but we don’t know what that is. Maybe one of those factors tracks through race or ethnicity because of what those social constructs represent.

I recently listened to a presentation by Rob Califf, former FDA Commissioner, who spoke about how the pandemic has created a spotlight on our disparities-creating system. I think much of the time this disparities-creating system is in the background; it doesn’t really affect most people’s daily lives. Now, we’re suddenly hit with a bucket of cold water called COVID-19, and we’re saying what is going on and what can we do about it to make a difference. I hope that, once we begin to emerge from this acute crisis, we take the opportunity to address these fundamental issues in our society.

Collins: Indeed. Let’s talk about what you’re doing at NIMHD to support research to try to dig into both the causes of health disparities and the interventions that might help.

Pérez-Stable: Prompted by your motivation, we started talking about how minority health and health disparities research could respond to this pandemic. In the short-term, we thought along the lines of how can we communicate mitigation interventions, such as physical distancing, in a more effective way to our communities? We also asked what we could do to enhance access to healthcare for our populations, both to manage chronic conditions and for diagnosis and treatment of acute COVID-19.

We also considered in the mid- and long-term effects of economic disruption—this surge of unemployment, loss of jobs, loss of insurance, loss of income—on people’s health. Worries include excess use of alcohol and other substances, and worsening of mental and emotional well-being, particularly due to severe depression and chronic mental disorders not being well controlled. Intimate partner violence has already been noted to increase in some countries, including France, Spain, and the United States, that have gone on physical distancing interventions. Similarly, child abuse can be exacerbated under these circumstances. Just think of 24/7 togetherness as a test of how people can hold it together all the time. I think that that can bring out some fragility. So, interventions to address these, that really activate our community networks and community-based organizations, are real strengths. They build on the resilience of the community to highlight how we can get through this difficult period of time.

I feel optimistic that science will bring answers, in the form of both therapies and vaccines. But in the meantime, we have a way to go and we a lot to do.  

Collins: You mentioned the promise of vaccines. The NIH is working intensively on this, particularly through a partnership called ACTIV, Accelerating Covid-19 Therapeutic Interventions and Vaccines. We hope that in several more months, we’ll be in a position to begin testing these vaccines on a large scale, after having some assurances about their safety and efficacy. From our conversation, it sounds like we should be trying to get early access to those vaccines to people at highest risk, including those in communities with the heaviest burden. But how will that be received? There hasn’t always been an easy relationship between researchers, particularly government researchers, and the African-American community.

Pérez-Stable: I think we have learned from our historical experiences that mistrust of the system is real. To try to pretend that it isn’t there is a big mistake. Address these concerns upfront, obtain support from thought leaders in the community, and really work hard to be inclusive. In addition to vaccines, we need participation in any clinical trials that are coming up for therapeutics.

We also need research on how optimally to communicate this with all the different segments of the population. This includes not just explaining what it means to be eligible for vaccine trials or therapeutic trials, but also discussing the consequences of, say, getting tested, whether it be a viral or antibody test. What does the information mean for them?  

Most people just want to know “Am I clear of the virus or not?” That certainly could be part of the answer, but many may require more nuanced responses. Then there’s behavior. If I’m infected and I recover, am I safe to go back out and do things that other people shouldn’t do? We’d love to be able to inform the population about that. But, as you know, we don’t really have the answers to that just yet.

Collins: Good points. How do we make sure, when we’re trying to reach out to populations that have shouldered such a heavy burden, that we’re actually providing information in a fashion that is readily understood?

Pérez-Stable:  One thing to keep in mind is the issue of language. About 5 to 10 percent of U.S. adults don’t speak English well. So, we really have to address the language barrier. I also want to highlight the challenge that some tribal nations are facing. Navajo country has had particular challenges with COVID-19 infections in a setting of minimal medical infrastructure. In fact, there are communities that have to go and get their water for the day at a distant site, so they don’t have modern plumbing. How can we recommend frequent hand washing to someone who doesn’t even have running water at home? These are just a few examples of the diversity of our country that need to be addressed as we deal with this pandemic.

Collins:  Eliseo, you’ve given us a lot to think about in an obviously very serious situation. Anything you’d like to add?

Pérez-Stable:  In analyzing health outcomes, researchers often think about responses related to a metabolic pathway or to a gene or to a response to a particular drug. But as we use the power of science to understand and contain the COVID-19 pandemic, I’d like to re-emphasize the importance of considering race, ethnicity, socioeconomic status, the built environment, the social environment, and systems. Much of the time these factors may only play secondary roles, but, as in all science related to humans, I think they have to be considered. This experience should be a lesson for us to learn more about that.

Collins: Thank you for those wonderful, inspiring words. It was good to have this conversation, Eliseo, because we are the National Institutes of Health, but that has to be health for everybody. With COVID-19, we have an example where that has not turned out to be the case. We need to do everything we can going forward to identify ways to change that.

Reference:

[1] Assessing Differential Impacts of COVID-19 on Black Communities. Millet GA et al. MedRxiv. Preprint posted on May 8, 2020.

Links:

Video: Francis Collins and Eliseo Pérez-Stable on COVID-19 Health Disparities (NIH)

Coronavirus (COVID-19) (NIH)

Director’s Corner (National Institute on Minority Health and Disparities/NIH)

COVID-19 and Racial/Ethnic Disparities. Webb Hooper M, Nápoles AM, Pérez-Stable EJ.JAMA. 2020 May 11.

amfAR Study Shows Disproportionate Impact of COVID-19 on Black Americans, amfAR News Release, May 5, 2020.



Dealing with Stress, Anxiety, and Grief during COVID-19

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Zoom conversation between Joshua Gordon and Francis Collins

If somebody had told you last year that that our country, along with the whole world, would soon be facing a major health challenge like the coronavirus disease 2019 (COVID-19) pandemic, you’d have thought it almost unimaginable. Yet here we are.

To help flatten the pandemic’s deadly curve, a great many of us have been asked to remain at home. I have been faithfully adhering to that recommendation—I haven’t been to my office or lab at NIH in almost three weeks, though I can’t remember a time where I have worked harder. While helping to protect ourselves and others, this physical distancing can affect our mental well-being.

Recently, I had an opportunity to discuss these aspects of COVID-19 with Dr. Joshua Gordon, Director of NIH’s National Institute of Mental Health. Our conversation took place via videoconferencing, with him linking in from his home in the New York area and me from my home in Maryland. Here’s a condensed transcript of our chat:

Collins: So, Josh, tell me how you’re doing there. How’s everybody coping?

Gordon: Right now, my family and I are doing fine. My daughter and I are ensconced here at home, both working from home. She’s finishing up high school online and my wife works for New York City. She’s an essential employee, so she’s still going into work but, fortunately, she’s able to make sure that her workspace is very sparse and she’s able to commute by herself.

Collins: I’m glad you’re okay. Exactly how do you name this kind of stress that everybody’s feeling right now? Is it fear? Is it anxiety about being put in such an area of uncertainty? Is it just grief, the sense that something really profound has happened here and we are losing things in terms of our ability to move around freely? Certainly, we also grieve deeply about the suffering and the death that we see.

Gordon: For different people, it’s different combinations. I know that I feel anxiety for myself and my family in terms of our health. But it’s not just anxiety about contracting the coronavirus, it’s also fear and anxiety about what’s happening to society, what’s happening to our economy, what’s happening to our friends and relatives.

And then there is tremendous grief. We’ve acknowledged that we’ve all lost something already. Right? We’ve lost our normal day-to-day interactions. We’ve lost our ability to physically connect with people and it makes it more challenging to socially connect with people. And we’ve lost that sense of certainty and self-power.

Collins: Talking to my wife Diane about this, I think the grief part of it was something we were both feeling, but hadn’t quite named. Somehow being able to talk about it, experience it, and not try to run away from it turned out to be helpful.

Gordon: Yes, it’s important to talk about it. For most people, it’s a matter of being able to talk about your feelings, get it out into the open, and hear from others that are going through the same thing. They’re your friends that you’re Zooming with, they’re your parents or grandparents that you’re talking to on the phone.

Collins: I hope everybody will feel a little more free to be honest about what they are going through. Maybe sometimes we try to just be tough and keep it all to ourselves and don’t want others around us to be influenced, if we’re talking about our own emotions. But we need to share those things. Besides that, what other things, can be helpful to people who are trying to cope with the current circumstances?

Gordon: One important thing is to focus on the facts. There’s a lot of rumor, there’s a lot of hyperbole out there, and there’s a lot of, frankly, uncertainty. But to the extent that you can, learn and share the facts about the virus. If you know what’s happening, it reduces the uncertainty.

At the same time, one can get so taken up with reading the daily news, listening to the various news conferences that are going on, checking the websites, etc., that it becomes all-consuming. So, it’s really important to set aside periods of each day where you turn off social media, you turn off the TV, turn off the news, and do something that you enjoy. It could be art, it could be exercise, it could be picking up the phone and talking to someone about something other than COVID.

The other thing that’s really important is to take care of your body in addition to your mind. Taking care of your body can help your mind do better. So, yoga, exercise, resting, naps, regular meals, all these things can be helpful. Alcohol is often used as an escape mechanism when you’re feeling stressed. That can be a little tricky or dangerous, so try to avoid drinking excessively.

Connecting with others is really important in this day of physical distancing. I like to call it physical distancing, rather than social distancing, because I think we can be socially intimate and physically distant. So, connect with others, reach out to people, use digital tools, use telephones, use email and text, write a letter.

Collins: A letter?

Gordon: Yes, why not? I haven’t gotten mail for three days. Just saying. So, write a letter, connect with people that you can unwind with, that you can get joy from.

Collins: My wife Diane just stepped in and I want to have her to come over for a minute and say something about this, because I think part of the grief we were feeling was this disconnection from face-to-face interactions with people. Diane’s a very sociable person and this is particularly hard when you’re so isolated in one place. But she came up with something yesterday that seemed to be a help.

Diane Baker: Yes. I’ve got to say, the shelter in place order here in Maryland just surprised me. It took me down a couple of notches and I can’t say it was warranted, I was like I can’t take this. Even though it’s what we’ve been doing, it just emotionally really got to me. And so a friend came up with this idea. She went for a walk in her neighborhood, I went for a walk in my neighborhood, we pulled our phones out and we had a conversation. Even though it was cold rainy day, we didn’t mind it because we were talking to each other. So, we’re going to try and do that on a regular basis.

Gordon: You’re right, your social connectedness really helps. Like I can reach out to my parents in North Carolina, I can reach out to my brother in Philadelphia. We’ve had almost nightly Zoom get-togethers and I actually feel like I’m seeing my relatives more these last couple of weeks than I have in months.

Collins: That’s interesting. We’ve done that too. Every Sunday now we have a Zoom meeting with my daughters and my grandkids.

Diane Baker: The other thing I think it’s done is forced us to be more intentional about our communication. I think that’s something we take for granted. For instance, I have this book club I’ve been a part of for a long time, but we always talk books and politics and topical issues. Now, I’m starting to reach out to them on email and say, “Hey, I’m having a real tough time,” and we’re supporting each other in a way that we haven’t before. It’s been very nice. I’ll let you guys go on..

Gordon: Nice to see you, Diane.

Collins: I think we all feel this urge to do something, to try to contribute in some way. In many ways, we feel a little paralyzed by the fact that we’re stuck indoors and all of the things you might like to do might be risky for yourself or other people. What can we do as far as actions to help other people?

Gordon: Those of you who are working directly on COVID can take a lot of pride in the fact that you’re contributing to that mission. But everyone is contributing to that mission by staying home. I would add a more practical bent to all this, which is that it is important to set goals and priorities for yourself. Finally, there are volunteer opportunities that can be done remotely. There are donations that are being accepted. So, I encourage you, if you feel so moved and have the means to do so, contribute in that way.

Collins: Parents are worried about their kids in terms of how this is affecting them. So, what kind of advice can you give to parents about how to interact with children in this very unusual situation?

Gordon: Kids are, I’m sure, feeling anxious. First, recognize what they’re going through. Talk to them about it, find out what’s concerning them.

Kids always surprise you. They’re not necessarily anxious or worried about the things that you’re anxious or worried about. They might be worried about getting COVID, but they might also just be worried that they’re going to miss their best friend’s birthday next week. So, if you find out what’s bothering them, then you can help them. You can have them Zoom a happy birthday song or connect in some other way.

Reassuring them can help. But, more importantly, it’s just answering their questions as honestly as you can. When you don’t know, admit that you don’t, but say that you’ll be there for them.

Collins: Everybody is facing a certain amount of stress, anxiety, and grief at this time, but it hits some people even harder. What would be the signs that this is getting into a circumstance that might require some additional help?

Gordon: Let’s talk about how we recognize when this might be a thing that we can’t deal with and that is sending us over the edge. I went out grocery shopping last Friday. I managed to find a mask to wear and gloves, but I actually couldn’t take it. I was so anxious. I bought a few things and I had to leave. I felt in me something I’ve really never felt before. My heart started racing, I started breathing fast. I was getting a panic attack. That was something pushing me over the edge in ways that I hadn’t been challenged before.

If that happens to you, recognize it and seek help. So, what are the signs? We’re all feeling anxious, but if you feel so anxious you can’t get your work done, you actually can’t do the thing that you set out to do, reach out for help either from a friend or from a professional. Other signs would be you’re starting to withdraw from people, having trouble sleeping, change in appetite, change in physical energy levels, or starting to become irritable or angry.

For those with pre-existing mental illnesses, it’s really important that they reach out to their providers and find ways of connecting. Every mental health provider that I know of right now is moving to telehealth sessions. Not everyone is used to teleconferences, not everyone knows how to use them. So, plan in advance with your provider how you’re going to contact with them so that you can get the help you need when you need it. Make sure that you have enough medication in-house and work out with your pharmacy how you can get it delivered rather than having to go pick it up, whether that’s from a mail order pharmacy or getting your local pharmacy to deliver to you.

Finally, there are hot lines. For those experiencing distress with the COVID epidemic, the Substance Abuse and Mental Health Service Administration has the Disaster Distress Helpline. That’s 800-985-5990 or text “TalkWithUs” to 66746. For those who are really struggling, and are thinking of hurting or killing themselves, there’s the National Suicide Prevention Lifeline at 800-273-8255 or you can text “HOME” to the Crisis Text Line at 741741.

Collins: Before we close, I’d like to talk about how, despite the stress, the anxiety, and the grief that we’re all feeling, we might somehow learn something pretty significant about ourselves during this pandemic. Can you say something about that?

Gordon: One thing we know is that resilience isn’t necessarily about something you already have. It’s something that you learn, that people who’ve been through challenging times and risen to the occasion, they learn from that. They become resilient. They learn how to get through challenging situations in the future.

For many of us, this is an opportunity to learn more about ourselves and how we can grow as people, as human beings, and as fathers and mothers and daughters and sons. This is an opportunity to prove that we can respond to an emergency like this in a way that is thoughtful, in a way that is caring, and in a way that contributes to improving the situation for all of us

Collins: It does call us, doesn’t it, to focus on things that in our daily rush of business as usual, we neglect to think about. What are we really here for? What’s the meaning of all of this? What is our responsibility to try to make the world a better place?

I’d predict that all of us who are living through this COVID-19 experience will look back on it as a time of special significance in terms of what we learned about ourselves and about the perspective of what really matters in this world. So, yes, it’s stressful, it’s full of grief and sorrow, but maybe it’s a way in which you can gain something to carry forward. Josh, thank you so much.

Resources:

The Disaster Distress Helpline, 1-800-985-5990 (Substance Abuse and Mental Health Services Administration)

National Suicide Prevention Lifeline, 1-800-273-8255

Crisis Text Line, 741741

Coping with Coronavirus: Managing Stress, Fear, and Anxiety, Director’s Messages (National Institute of Mental Health/NIH)

Stress and Coping, Coronavirus (Centers for Disease Control and Prevention)

Coronavirus (COVID-19) (NIH)


Replenishing the Liver’s Immune Protections

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Kupffer cells
Credit: Thomas Deerinck, National Center for Microscopy and Imaging Research, University of California, San Diego.

Most of our immune cells circulate throughout the bloodstream to serve as a roving security force against infection. But some immune cells don’t travel much at all and instead safeguard a specific organ or tissue. That’s what you are seeing in this electron micrograph of a type of scavenging macrophage, called a Kupffer cell (green), which resides exclusively in the liver (brown).

Normally, Kupffer cells appear in the liver during the early stages of mammalian development and stay put throughout life to protect liver cells, clean up old red blood cells, and regulate iron levels. But in their experimental system, Christopher Glass and his colleagues from University of California, San Diego, removed all original Kupffer cells from a young mouse to see if this would allow signals from the liver that encourage the development of new Kupffer cells.

The NIH-funded researchers succeeded in setting up the right conditions to spur a heavy influx of circulating precursor immune cells, called monocytes, into the liver, and then prompted those monocytes to turn into the replacement Kupffer cells. In a recent study in the journal Immunity, the team details the specific genomic changes required for the monocytes to differentiate into Kupffer cells [1]. This information will help advance the study of Kupffer cells and their role in many liver diseases, including nonalcoholic steatohepatitis (NASH), which affects an estimated 3 to 12 percent of U.S. adults [2].

The new work also has broad implications for immunology research because it provides additional evidence that circulating monocytes contain genomic instructions that, when activated in the right way by nearby cells or other factors, can prompt the monocytes to develop into various, specialized types of scavenging macrophages. For example, in the mouse system, Glass’s team found that the endothelial cells lining the liver’s blood vessels, which is where Kupffer cells hang out, emit biochemical distress signals when their immune neighbors disappear.

While more details need to be worked out, this study is another excellent example of how basic research, including the ability to query single cells about their gene expression programs, is generating fundamental knowledge about the nature and behavior of living systems. Such knowledge is opening new possibilities to more precise ways of treating and preventing diseases all throughout the body, including those involving Kupffer cells and the liver.

References:

[1] Liver-Derived Signals Sequentially Reprogram Myeloid Enhancers to Initiate and Maintain Kupffer Cell Identity. Sakai M, Troutman TD, Seidman JS, Ouyang Z, Spann NJ, Abe Y, Ego KM, Bruni CM, Deng Z, Schlachetzki JCM, Nott A, Bennett H, Chang J, Vu BT, Pasillas MP, Link VM, Texari L, Heinz S, Thompson BM, McDonald JG, Geissmann F3, Glass CK. Immunity. 2019 Oct 15;51(4):655-670.

[2] Recommendations for diagnosis, referral for liver biopsy, and treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Spengler EK, Loomba R. Mayo Clinic Proceedings. 2015;90(9):1233–1246.

Links:

Liver Disease (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Nonalcoholic Fatty Liver Disease & NASH (NIDDK)

Glass Laboratory (University of California, San Diego)

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences; National Cancer Institute


New Grants Explore Benefits of Music on Health

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It’s not every day you get to perform with one of the finest voices on the planet. What an honor it was to join renowned opera singer Renée Fleming back in May for a rendition of “How Can I Keep from Singing?” at the NIH’s J. Edward Rall Cultural Lecture. Yet our duet was so much more. Between the song’s timeless message and Renée’s matchless soprano, the music filled me with a profound sense of joy, like being briefly lifted outside myself into a place of beauty and well-being. How does that happen?

Indeed, the benefits of music for human health and well-being have long been recognized. But biomedical science still has a quite limited understanding of music’s mechanisms of action in the brain, as well as its potential to ease symptoms of an array of disorders including Parkinson’s disease, stroke, and post-traumatic stress disorder (PTSD). In a major step toward using rigorous science to realize music’s potential for improving human health, NIH has just awarded $20 million over five years to support the first research projects of the Sound Health initiative. Launched a couple of years ago, Sound Health is a partnership between NIH and the John F. Kennedy Center for the Performing Arts, in association with the National Endowment for the Arts.

With support from 10 NIH institutes and centers, the Sound Health awardees will, among other things, study how music might improve the motor skills of people with Parkinson’s disease. Previous research has shown that the beat of a metronome can steady the gait of someone with Parkinson’s disease, but more research is needed to determine exactly why that happens.

Other fascinating areas to be explored by the Sound Health awardees include:

• Assessing how active music interventions, often called music therapies, affect multiple biomarkers that correlate with improvement in health status. The aim is to provide a more holistic understanding of how such interventions serve to ease cancer-related stress and possibly even improve immune function.

• Investigating the effects of music on the developing brain of infants as they learn to talk. Such work may be especially helpful for youngsters at high risk for speech and language disorders.

• Studying synchronization of musical rhythm as part of social development. This research will look at how this process is disrupted in children with autism spectrum disorder, possibly suggesting ways of developing music-based interventions to improve communication.

• Examining the memory-related impacts of repeated exposures to a certain song or musical phrase, including those “earworms” that get “stuck” in our heads. This work might tell us more about how music sometimes serves as a cue for retrieving associated memories, even in people whose memory skills are impaired by Alzheimer’s disease or other cognitive disorders.

• Tracing the developmental timeline—from childhood to adulthood—of how music shapes the brain. This will include studying how musical training at different points on that timeline may influence attention span, executive function, social/emotional functioning, and language skills.

We are fortunate to live in an exceptional time of discovery in neuroscience, as well as an extraordinary era of creativity in music. These Sound Health grants represent just the beginning of what I hope will be a long and productive partnership that brings these creative fields together. I am convinced that the power of science holds tremendous promise for improving the effectiveness of music-based interventions, and expanding their reach to improve the health and well-being of people suffering from a wide variety of conditions.

Links:

The Soprano and the Scientist: A Conversation About Music and Medicine, (National Public Radio, June 2, 2017)

NIH Workshop on Music and Health, January 2017

Sound Health (NIH)

NIH Support: National Center for Complementary and Integrative Health; National Eye Institute; National Institute on Aging; National Institute on Alcohol Abuse and Alcoholism; National Institute on Deafness and Other Communication Disorders; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute of Nursing Research; Office of Behavioral and Social Sciences Research; Office of the Director


Can Organoids Yield Answers to Fatty Liver Disease?

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Liver Organoid
Confocal microscope image shows liver organoid made from iPS cells derived from children with Wolman disease. The hepatocyte cells (red) accumulate fat (blue). Credit: Cincinnati Children’s Hospital Medical Center

With advances in induced pluripotent stem cell (iPSC) technology, it’s now possible to reprogram adult skin or blood cells to form miniature human organs in a lab dish. While these “organoids” closely mimic the structures of the liver and other vital organs, it’s been tough to get them to represent inflammation, fibrosis, fat accumulation, and many other complex features of disease.

Fatty liver diseases are an increasingly serious health problem. So, I’m pleased to report that, for the first time, researchers have found a reliable way to make organoids that display the hallmarks of those conditions. This “liver in a dish” model will enable the identification and preclinical testing of promising drug targets, helping to accelerate discovery and development of effective new treatments.

Previous methods working with stem cells have yielded liver organoids consisting primarily of epithelial cells, or hepatocytes, which comprise most of the organ. Missing were other key cell types involved in the inflammatory response to fatty liver diseases.

To create a better organoid, the team led by Takanori Takebe, Cincinnati Children’s Hospital Medical Center, focused its effort on patient-derived iPSCs. Takebe and his colleagues devised a special biochemical “recipe” that allowed them to grow liver organoids with sufficient cellular complexity.

As published in Cell Metabolism, the recipe involves a three-step process to coax human iPSCs into forming multi-cellular liver organoids in as little as three weeks. With careful analysis, including of RNA sequencing data, they confirmed that those organoids contained hepatocytes and other supportive cell types. The latter included Kupffer cells, which play a role in inflammation, and stellate cells, the major cell type involved in fibrosis. Fibrosis is the scarring of the liver in response to tissue damage.

Now with a way to make multi-cellular liver organoids, the researchers put them to the test. When exposed to free fatty acids, the organoids gradually accumulated fat in a dose-dependent manner and grew inflamed, which is similar to what happens to people with fatty liver diseases.

The organoids also showed telltale biochemical signatures of fibrosis. Using a sophisticated imaging method called atomic force microscopy (AFM), the researchers found as the fibrosis worsened, they could measure a corresponding increase in an organoid’s stiffness.

Next, as highlighted in the confocal microscope image above, Takebe’s team produced organoids from iPSCs derived from children with a deadly inherited form of fatty liver disease known as Wolman disease. Babies born with this condition lack an enzyme called lysosomal acid lipase (LAL) that breaks down fats, causing them to accumulate dangerously in the liver. Similarly, the miniature liver shown here is loaded with accumulated fat lipids (blue).

That brought researchers to the next big test. Previous studies had shown that LAL deficiency in kids with Wolman disease overactivates another signaling pathway, which could be suppressed by targeting a receptor known as FXR. So, in the new study, the team applied an FXR-targeted compound called FGF19, and it prevented fat accumulation in the liver organoids derived from people with Wolman disease. The organoids treated with FGF19 not only were protected from accumulating fat, but they also survived longer and had reduced stiffening, indicating a reduction in fibrosis.

These findings suggest that FGF19 or perhaps another compound that acts similarly might hold promise for infants with Wolman disease, who often die at a very early age. That’s encouraging news because the only treatment currently available is a costly enzyme replacement therapy. The findings also demonstrate a promising approach to accelerating the search for new treatments for a variety of liver diseases.

Takebe’s team is now investigating this approach for non-alcoholic steatohepatitis (NASH), a common cause of liver failure and the need for a liver transplant. The hope is that studies in organoids will lead to promising new treatments for this liver condition, which affects millions of people around the world.

Ultimately, Takebe suggests it might prove useful to grow liver organoids from individual patients with fatty liver diseases, in order to identify the underlying biological causes and test the response of those patient-specific organoids to available treatments. Such evidence could one day help doctors to select the best available treatment option for each individual patient, and bring greater precision to treating liver disease.

Reference:

[1] Modeling steatohepatitis in humans with pluripotent stem cell-derived organoids. Ouchi R, Togo S, Kimura M, Shinozawa T, Koido M, Koike H, Thompson W, Karns RA, Mayhew CN, McGrath PS, McCauley HA, Zhang RR, Lewis K, Hakozaki S, Ferguson A, Saiki N, Yoneyama Y, Takeuchi I, Mabuchi Y, Akazawa C, Yoshikawa HY, Wells JM, Takebe T. Cell Metab. 2019 May 14. pii: S1550-4131(19)30247-5.

Links:

Wolman Disease (Genetic and Rare Diseases Information Center/NIH)

Nonalcoholic Fatty Liver Disease & NASH (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Stem Cell Information (NIH)

Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)

Takebe Lab (Cincinnati Children’s Hospital Medical Center)

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases


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