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Coping with the Collision of Public Health Crises: COVID-19 and Substance Use Disorders

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For the past half-dozen years, I’ve had the privilege of attending the Rx Drug and Heroin Abuse Summit. And I was counting on learning more about this national crisis this April in Nashville, where I was scheduled to take part in a session with Dr. Nora Volkow, Director of NIH’s National Institute on Drug Abuse. But because of the physical distancing needed to help flatten the deadly curve of the coronavirus-19 (COVID-19) pandemic, it proved to be impossible for anyone to attend in person. Still, the summit did go on for almost three days—virtually!

Dr. Volkow and I took part by sharing a video of a recent conversation we had via videoconference. Since we couldn’t take live questions, we solicited some in advance. Here’s a condensed transcript highlighting portions of our dialogue that focused on the impact of the COVID-19 pandemic on individuals struggling with substance abuse disorders, along with all those who are trying to help them.

VOLKOW: Hello, Francis. Nice to see you, virtually!

COLLINS: Nice to see you too. I’m in my home office here, where I’ve been pretty much for the last three weeks. I’ve been stepping outdoors to occasionally get a breath of fresh air, but trying to live up to all those recommendations about social distancing—or at least physical distancing. I’m trying to keep my social connections going, even if they’re electronic.

I think we’re all feeling this is a time of some stress for us at NIH. We are trying to do everything we can to address this COVID crisis and speed up the process of developing vaccines and therapeutics and all kinds of other things. How are you doing? What’s it like being sequestered back in your home space when you are somebody with so much energy?

VOLKOW: Francis, it’s not easy. I actually am very, very restless. We probably are all experiencing that anxiety of uncertainty, looking at the news and how devastating it is. But I think what makes it easier is if we can do something. Working with everything that we have to try to help others, I think, provides some relief.

COLLINS: Yes, we’re going to talk about that right now. In fact, let’s talk about the way in which this crisis, the global pandemic called COVID-19, is colliding with another public health crisis, which is that of substance use disorder. You recently wrote about this collision in an article in the Annals of Internal Medicine. What does this mean? What are some of the unique challenges that COVID-19 brings to people suffering from addiction?

VOLKOW: I’m glad you are bringing up this point because it’s one of the issues of greatest concern for all of us who are working in the field of substance use disorders. We had not yet been able to contain the epidemic of opioid fatalities, and then we were hit by this tsunami of COVID.

We immediately can recognize the unique challenges of COVID-19 for people having an addiction. Some of these are structural; the healthcare system is not prepared to take care of them. They relate also to stigma and social issues. The concept of social distancing makes such people even more vulnerable because it interferes with many of the support systems that can help them to reach recovery. And, on top of that, drugs themselves negatively influence human physiology, making one more vulnerable to getting infected and more vulnerable to worse outcomes. So that’s why there is tremendous concern about these two epidemics colliding with one another.

COLLINS: How has this influenced treatment delivery for people with substance use disorders, who are counting on that to be able to keep themselves from slipping backward?

VOLKOW: Well, that has been very challenging. We’re hearing from multiple sources that it’s become harder for patients to be able to access treatment. And that relates, for example, to access of medications for opioid use disorders, which are the main strategy—and the most effective one—that we have to prevent people from dying from overdoses.

Some clinics are decreasing the number of patients that they can take care of. The healthcare system is also much less able to initiate persons on buprenorphine. And because of social isolation, if you overdose, the likelihood that someone can rescue you with naloxone is much lower. We don’t yet have statistics on about how that’s influencing fatalities, but we are very concerned.

COLLINS: Nora, you are one of the lead persons for NIH’s Helping to End Addiction Long-term (HEAL) initiative. How has the COVID-19 pandemic affected all the grand research plans that we had put in place as part of our big vision of how NIH could help with the substance use disorder crisis?

VOLKOW: Well, $900 million had recently been deployed on research. That is incredibly meritorious, and some of that research had already started. Unfortunately, it has had to stop almost completely. Why? Because the research that’s relying on the healthcare system, for example, is no longer able to focus on research when they have other clinical needs to meet.

Also, research to bring medication-assisted treatments to prison inmates has stopped. Prisons are not allowing the researchers to go on site because they are closing the doors to outsiders, since they are places at high risk for the spread of COVID-19. Furthermore, some institutional review boards (IRBs) are actually closing, making it impossible to recruit patients for the clinical trials. So, most studies have come to a halt. The issue now is how can we become creative and use virtual technologies to advance some of the goals that we aim to achieve with the HEAL initiative.

COLLINS: Of course, this applies to many other areas of NIH-supported research. Most clinical trials, unless they’re for life-threating conditions, are pretty much in a state of hibernation. We can’t justify having people get out there in ways that might put them at risk of COVID-19. So, yes, it’s a tough time for clinical research all over. And that’s certainly what’s happened with the opioid use disorder problems. Still, I think our teams are really devoted to making sure they make the best of this time, doing things that they can do in terms of planning and setting up data systems.

Meanwhile, bring us up to date on what’s happened as far as the state of the opioid crisis. Are there trends there that we ought to look at for a minute?

VOLKOW: Yes, it’s important to actually keep our eyes on the epidemic, because it’s changing so very rapidly. It’s gone from prescription opioids to heroin to synthetic opioids like fentanyl. And what we have observed ramping up over the past two or three years is an increase in fatalities from the use of psychostimulant drugs.

For example, the number of deaths from methamphetamine has increased five-fold over a period of six years. Similarly, deaths from cocaine are going up. The reality is that people are now dying not just from opioids, but from mixtures of drugs and stimulant drugs, most notably methamphetamine.

COLLINS: So, what can we learn from what we’ve been doing about opioid addiction, and try to apply that to this emerging methamphetamine crisis?

VOLKOW: Unfortunately, we do not have effective medications to treat methamphetamine addiction like we do for opioid use disorders. We also do not have an overdose reversal like we have with naloxone. So, in that respect, it is more challenging.

COLLINS: People sometimes think we’re only focused on trying to treat the problems that we have now. What about prevention? One of the questions we received in our HEAL mailbox was: How can small town communities create an environment where addiction does not take root in the next generation of young people? I’m sure you want to talk about the rewarding power of social interactions, even though right now we’re being somewhat deprived of those, at least face-to-face.

VOLKOW: I’m glad you’re bringing up that question, Francis. Because when you asked at the start of our conversation about how I am doing, I sort of said, “Well, it’s not easy.” But the positive component was that sense that we have a shared mission: we can help others. And the lack of a sense of mission, the lack of a purpose in life, has been identified as one of the factors that make people more vulnerable to take drugs.

Feeling irrelevant, feeling that no one cares for you, is probably one of the most devastating feelings a human being can have. Epidemiological studies show that social isolation and neglect increase dramatically the risk of taking drugs, and, if you are trying to stop taking drugs, it increases that risk of relapse. And so that’s an issue right now of great concern. The challenge is “How do we provide social support for people at risk of substance abuse during the COVID-19 pandemic?”

Also, independent of COVID-19, I think that we as a nation have to face the concept that we have made America vulnerable to drugs because we have eroded that social sense of community. If we are to prevent future generations from getting addicted to drugs, we should build meaningful interactions between people. We should give each individual an opportunity to be part of a society that appreciates them. We do need each other in very, very fundamental ways. We need others for our well-being. If we don’t have that then we become very vulnerable.

COLLINS: Well, here’s one last question from the mailbox. Somebody notes that the “L” in HEAL stands for “long-term.” That is, Helping End Addiction Long-term. The questioner asks: “What’s our vision of a long-term goal and how do we imagine getting there?”

Mine very simply is that we would have an environment that would support people in productive ways, so that the distractions of things that turn out to be destructive are not so tempting, and that the possibility of having meaning in everyone’s life becomes greater.

Ironically, because of COVID-19, we are in the midst of a circumstance where economic distress is pressing on people and social distancing is being required. Seems like we’re going the wrong way. But if you look back in history, often these times of national crisis have been times when people did have the chance to survey what really matters around them, and perhaps to regain a sense of meaning and significance. That’s my maybe slightly over-optimistic view of the current era that we’re in.

Nora, what do you think?

VOLKOW: Francis, I will agree with you. I think that we need to create a society that provides social support and allows people to participate in a meaningful way. If we want to achieve integration of people into society, one of the things that we need to do urgently is remove the stigma of addiction because when you stigmatise someone, you are socially isolating them.

No one likes to be mistreated or discriminated against. So, if you are a person who is addicted and you are afraid of discrimination, you will not seek help. You will continue to isolate. So I think as we’re dealing with the opioid crisis, as we’re dealing with COVID-19, we cannot tolerate discrimination. We cannot tolerate stigma. And we need to be very creative to identify it and to create models that will actually eliminate it.

COLLINS: That’s a wonderful view of where we need to get to. All of these developments give me hope for our capacity to deal with this crisis by working together.

I want to say to all of you who’re listening to this in your own virtual spaces, how much I admire the work that you all are doing, in a selfless way, to try to help our nation deal with what has clearly been a terrible tragedy in far too many lives. I wish you all the best in continuing those creative and energetic efforts, even in the midst of the COVID-19 pandemic. NIH wants to be your ally. We want to be your source of information. We want to be your source of evidence for what works. We want to be your friends.

So, thank you for listening, and thank you, Nora Volkow, for joining me in this discussion today with all of the talent and leadership that you represent. I wish the best health to all of you. Stay safe and keep the progress going!

Links:

Video: Fireside Chat Between NIH, NIDA Heads Addresses COVID-19, the HEAL Initiative, and the Opioids Crisis (National Institute on Drug Abuse/NIH)

COVID-19 Resources (NIDA)

COVID-19: Potential Implications for Individuals with Substance Use Disorders, Nora’s Blog (NIDA)

NIDA Director outlines potential risks to people who smoke and use drugs during COVID-19 pandemic (NIDA)

Collision of the COVID-19 and Addiction Epidemics. Volkow ND. Ann Intern Med. 2 April 2020. [Epub ahead of print]

Helping to End Addiction Long-term (HEAL) Initiative (NIH)

Rx Drug Abuse & Heroin Summit, A 2020 Virtual Experience


Study Suggests Repurposed Drugs Might Treat Aggressive Lung Cancer

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Small cell lung cancer cells
Caption: Small cell lung cancer cells (red) spreading via blood vessels (white) from the lung to the liver of a genetically-engineered mouse model.
Credit: Leanne Li, Koch Institute at MIT

Despite continued progress in treatment and prevention, lung cancer remains our nation’s leading cause of cancer death. In fact, more Americans die of lung cancer each year than of breast, colon, and prostate cancers combined [1,2]. While cigarette smoking is a major cause, lung cancer also occurs in non-smokers. I’m pleased to report discovery of what we hope will be a much-needed drug target for a highly aggressive, difficult-to-treat form of the disease, called small cell lung cancer (SCLC).

Using gene-editing technology to conduct a systematic, large-scale search for druggable vulnerabilities in certain types of cancer cells grown in lab dishes, NIH-funded researchers recently identified a metabolic pathway that appears to play a key role in SCLC. What makes this news even more encouraging is drugs that block this pathway already exist. That includes one in clinical testing for other types of cancer, and another that’s FDA-approved and has been safely used for more than 20 years to treat people with rheumatoid arthritis.

The new work comes from the lab of Tyler Jacks, Massachusetts Institute of Technology (MIT), Cambridge. The Jacks lab, which is dedicated to understanding the genetic events that lead to cancer, develops mouse models engineered to carry the same genetic mutations that turn up in human cancers.

In work described in Science Translational Medicine, the team, co-led by Leanne Li and Sheng Rong Ng, applied CRISPR gene-editing tools to cells grown from some of their mouse models. Aiming high in terms of scale, researchers used CRISPR to knock out systematically, one by one, each of about 5,000 genes in cells from the SCLC mouse model, as well in cells from mouse models of other types of lung and pancreatic cancers. They looked to see what gene knockouts would slow down or kill the cancer cells, because that would be a good indication that the protein products of these genes, or the pathways they mediated, would be potential drug targets.

Out of those thousands of genes, one rose to the top of the list. It encodes an enzyme called DHODH (dihydroorotate dehydrogenase). This enzyme plays an important role in synthesizing pyrimidine, which is a major building block in DNA and RNA. Cytosine and thymine, the C and T in the four-letter DNA code, are pyrimidines; so is uracil, the U in RNA that takes the place of T in DNA. Because cancer cells are constantly dividing, there is a continual need to synthesize new DNA and RNA molecules to support the production of new daughter cells. And that means, unlike healthy cells, cancer cells require a steady supply of pyrimidine.

It turns out that the SCLC cells have an unexpected weakness relative to other cancer cells: they don’t produce as much pyrimidine. As a result, the researchers found blocking DHODH left the cells short on pyrimidine, leading to reduced growth and survival of the cancer.

This was especially good news because DHODH-blocking drugs, including one called brequinar, have already been tested in clinical trials for other cancers. In fact, brequinar is now being explored as a potential treatment for acute myeloid leukemia.

Might brequinar also hold promise for treating SCLC? To explore further, the researchers looked again to their genetic mouse model of SCLC. Their studies showed that mice treated with brequinar lived about 40 days longer than control animals. That’s a significant survival benefit in this system.

Brequinar treatment appeared to work even better when combined with other approved cancer drugs in mice that had SCLC cells transplanted into them. Further study in mice carrying SCLC tumors derived from four human patients added to this evidence. Two of the four human tumors shrunk in mice treated with brequinar.

Of course, mice are not people. But the findings suggest that brequinar or another DHODH blocker might hold promise as a new way to treat SCLC. While more study is needed to understand even better how brequinar works and explore potentially promising drug combinations, the fact that this drug is already in human testing for another indication suggests that a clinical trial to explore its use for SCLC might happen more quickly.

More broadly, the new findings show the promise of gene-editing technology as a research tool for uncovering elusive cancer targets. Such hard-fought discoveries will help to advance precise approaches to the treatment of even the most aggressive cancer types. And that should come as encouraging news to all those who are hoping to find new answers for hard-to-treat cancers.

References:

[1] Cancer Stat Facts: Lung and Bronchus Cancer (National Cancer Institute/NIH)

[2] Key Statistics for Lung Cancer (American Cancer Society)

[3] Identification of DHODH as a therapeutic target in small cell lung cancer. Li L, Ng SR, Colón CI, Drapkin BJ, Hsu PP, Li Z, Nabel CS, Lewis CA, Romero R, Mercer KL, Bhutkar A, Phat S, Myers DT, Muzumdar MD, Westcott PMK, Beytagh MC, Farago AF, Vander Heiden MG, Dyson NJ, Jacks T. Sci Transl Med. 2019 Nov 6;11(517).

Links:

Small Cell Lung Cancer Treatment (NCI/NIH)

Video: Introduction to Genome Editing Using CRISPR Cas9 (NIH)

Tyler Jacks (Massachusetts Institute of Technology, Cambridge)

NIH Support: National Cancer Institute


Tagging Essential Malaria Genes to Advance Drug Development

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Red blood cell infected with malaria-causing parasites

Caption: Colorized scanning electron micrograph of a blood cell infected with malaria parasites (blue with dots) surrounded by uninfected cells (red).
Credit: National Institute of Allergy and Infectious Diseases, NIH

As a volunteer physician in a small hospital in Nigeria 30 years ago, I was bitten by lots of mosquitoes and soon came down with headache, chills, fever, and muscle aches. It was malaria. Fortunately, the drug available to me then was effective, but I was pretty sick for a few days. Since that time, malarial drug resistance has become steadily more widespread. In fact, the treatment that cured me would be of little use today. Combination drug therapies including artemisinin have been introduced to take the place of the older drugs [1], but experts are concerned the mosquito-borne parasites that cause malaria are showing signs of drug resistance again.

So, researchers have been searching the genome of Plasmodium falciparum, the most-lethal species of the malaria parasite, for potentially better targets for drug or vaccine development. You wouldn’t think such work would be too tough because the genome of P. falciparum was sequenced more than 15 years ago [2]. Yet it’s proven to be a major challenge because the genetic blueprint of this protozoan parasite has an unusual bias towards two nucleotides (adenine and thymine), which makes it difficult to use standard research tools to study the functions of its genes.

Now, using a creative new spin on an old technique, an NIH-funded research team has solved this difficult problem and, for the first time, completely characterized the genes in the P. falciparum genome [3]. Their work identified 2,680 genes essential to P. falciparum’s growth and survival in red blood cells, where it does the most damage in humans. This gene list will serve as an important guide in the years ahead as researchers seek to identify the equivalent of a malarial Achilles heel, and use that to develop new and better ways to fight this deadly tropical disease.


Treating Zika Infection: Repurposed Drugs Show Promise

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Zika researcher

Caption: An NCATS researcher dispenses Zika virus into trays for compound screening in a lab using procedures that follow strict biosafety standards.
Credit: National Center for Advancing Translational Sciences, NIH

In response to the health threat posed by the recent outbreak of Zika virus in Latin America and its recent spread to Puerto Rico and Florida, researchers have been working at a furious pace to learn more about the mosquito-borne virus. Considerable progress has been made in understanding how Zika might cause babies to be born with unusually small heads and other abnormalities and in developing vaccines that may guard against Zika infection.

Still, there remains an urgent need to find drugs that can be used to treat people already infected with the Zika virus. A team that includes scientists at NIH’s National Center for Advancing Translational Sciences (NCATS) now has some encouraging news on this front. By testing 6,000 FDA-approved drugs and experimental chemical compounds on Zika-infected human cells in the lab, they’ve shown that some existing drugs might be repurposed to fight Zika infection and prevent the virus from harming the developing brain [1]. While additional research is needed, the new findings suggest it may be possible to speed development and approval of new treatments for Zika infection.


Gene Expression Test Aims to Reduce Antibiotic Overuse

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Doctor with ER patient

Caption: Duke physician-scientist Ephraim Tsalik assesses a patient for a respiratory infection.
Credit: Shawn Rocco/Duke Health

Without doubt, antibiotic drugs have saved hundreds of millions of lives from bacterial infections that would have otherwise been fatal. But their inappropriate use has led to the rise of antibiotic-resistant superbugs, which now infect at least 2 million Americans every year and are responsible for thousands of deaths [1]. I’ve just come from the World Economic Forum in Davos, Switzerland, where concerns about antibiotic resistance and overuse was a topic of conversation. In fact, some of the world’s biggest pharmaceutical companies issued a joint declaration at the forum, calling on governments and industry to work together to combat this growing public health threat [2].

Many people who go to the doctor suffering from respiratory symptoms expect to be given a prescription for antibiotics. Not only do such antibiotics often fail to help, they serve to fuel the development of antibiotic-resistant superbugs [3]. That’s because antibiotics are only useful in treating respiratory illnesses caused by bacteria, and have no impact on those caused by viruses (which are frequent in the wintertime). So, I’m pleased to report that a research team, partially supported by NIH, recently made progress toward a simple blood test that analyzes patterns of gene expression to determine if a patient’s respiratory symptoms likely stem from a bacterial infection, viral infection, or no infection at all.

In contrast to standard tests that look for signs of a specific infectious agent—respiratory syncytial virus (RSV) or the influenza virus, for instance—the new strategy casts a wide net that takes into account changes in the patterns of gene expression in the bloodstream, which differ depending on whether a person is fighting off a bacterial or a viral infection. As reported in Science Translational Medicine [4], Geoffrey Ginsburg, Christopher Woods, and Ephraim Tsalik of Duke University’s Center for Applied Genomics and Precision Medicine, Durham, NC, and their colleagues collected blood samples from 273 people who came to the emergency room (ER) with signs of acute respiratory illness. Standard diagnostic tests showed that 70 patients arrived in the ER with bacterial infections and 115 were battling viruses. Another 88 patients had no signs of infection, with symptoms traced instead to other health conditions.


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