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How gene editing a person’s brain cells could be used to curb the opioid epidemic

How gene editing a person’s brain cells could be used to curb the opioid epidemic

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CRISPR/Cas is a tool for editing genes. STEVEN MCDOWELL/SCIENCE PHOTO LIBRARY / Getty Images

Even as the COVID-19 pandemic cripples the economy and kills hundreds of people each day, there is another epidemic that continues to kill tens of thousands of people each year through opioid drug overdose.

Opioid analgesic drugs, like morphine and oxycodone, are the classic double-edged swords. They are the very best drugs to stop severe pain but also the class of drugs most likely to kill the person taking them. In a recent journal article, I outlined how a combination of state-of-the-art molecular techniques, such as CRISPR gene editing and brain microinjection methods, could be used to blunt one edge of the sword and make opioid drugs safer.

I am a pharmacologist interested in the way opioid drugs such as morphine and fentanyl can blunt pain. I became fascinated in biology at the time when endorphins – natural opioids made by our bodies – were discovered. I have been intrigued by the way opioid drugs work and their targets in the brain, the opioid receptors, for the last 30 years. In my paper, I propose a way to prevent opioid overdoses by modifying an opioid user’s brain cells using advanced technology.

Opioid receptors stop breathing

Opioids kill by stopping a person from breathing (respiratory depression). They do so by acting on a specific set of respiratory nerves, or neurons, found in the lower part of the brain that contain opioid receptors. Opioid receptors are proteins that bind morphine, heroin and other opioid drugs. The binding of an opioid to its receptor triggers a reaction in neurons that reduces their activity. Opioid receptors on pain neurons mediate the pain-killing, or analgesic, effects of opioids. When opioids bind to opioid receptors on respiratory neurons, they slow breathing or, in the case of an opioid overdose, stop it entirely.

Respiratory neurons are located in the brainstem, the tail-end part of the brain that continues into the spine as the spinal cord. Animal studies show that opioid receptors on respiratory neurons are responsible for opioid-induced respiratory depression – the cause of opioid overdose. Genetically altered mice born without opioid receptors do not die from large doses of morphine unlike mice with these receptors present.

The brainstem is the the red part protruding from the bottom of the brain. MedicalRF.com / Getty Images

Unlike laboratory mice, humans cannot be altered when embryos to remove all opioid receptors from the brain and elsewhere. Nor would it be a good idea. Humans need opioid receptors to serve as the targets for our natural opioid substances, the endorphins, which are released into the brain during times of high stress and pain.

Also, a total opioid receptor knockout in humans would leave that person unresponsive to the beneficial pain-killing effects of opioids. In my journal article, I argue that what is needed is a selective receptor removal of the opioid receptors on respiratory neurons. Having reviewed the available technology, I believe this can be done by combining CRISPR gene editing and a new neurosurgical microinjection technique.

CRISPR to the rescue: Destroying opioid receptors

CRISPR, which is an acronym for clustered regularly interspaced short palindromic repeats, is a gene editing method that was discovered in the genome of bacteria. Bacteria get infected by viruses too and CRISPR is a strategy that bacteria evolved to cut-up the viral genes and kill invading pathogens.

The CRISPR method allows researchers to target specific genes expressed in cell lines, tissues, or whole organisms, to be cut-up and removed – knocked out – or otherwise altered. There is a commercially available CRISPR kit which knocks out human opioid receptors produced in cells that are grown in cell cultures in the lab. While this CRISPR kit is formulated for in vitro use, similar conditional opioid receptor knock-out techniques have been demonstrated in live mice.

To knockout opioid receptors in human respiratory neurons, a sterile solution containing CRISPR gene-editing molecules would be prepared in the laboratory. Besides the gene-editing components, the solution contains chemical reagents that allow the gene-editing machinery to enter the respiratory neurons and make their way into the nucleus and into the neuron’s genome.

How does one get the CRISPR opioid receptor knockout solution into a person’s respiratory neurons?

Enter the intracranial microinjection instrument (IMI) developed by Miles Cunningham and his colleagues at Harvard. The IMI allows for computer-controlled delivery of small volumes of solution at specific places in the brain by using an extremely thin tube – about twice the diameter of a human hair – that can enter the brain at the base of the skull and thread through brain tissue without damage.

The computer can direct the robotic placement of the tube as it is fed images of the brain taken before the procedure using MRI. But even better, the IMI also has a recording wire embedded in the tube that allows measurement of neuronal activity to identify the right group of nerve cells.

Because the brain itself feels no pain, the procedure could be done in a conscious patient using only local anesthetics to numb the skin. Respiratory neurons drive the breathing muscles by firing action potentials which are measured by the recording wire in the tube. When the activity of the respiratory neurons matches the breathing movements by the patients, the proper location of the tube is confirmed and the CRISPR solution injected.

The call for drastic action

Opioid receptors on neurons in the brain have a half-life of about 45 minutes. Over a period of several hours, the opioid receptors on respiratory neurons would degrade and the CRISPR gene-editing machinery embedded in the genome would prevent new opioid receptors from appearing. If this works, the patient would be protected from opioid overdose within 24 hours. Because the respiratory neurons do not replenish, the CRISPR opioid receptor knockout should last for life.

With no opioid receptors on respiratory neurons, the opioid user cannot die from opioid overdose. After proper backing from National Institute on Drug Abuse and leading research and health care institutions, I believe CRISPR treatment could enter clinical trials in between five to 10 years. The total cost of opioid-involved overdose deaths is about US$430 billion per year. CRISPR treatment of only 10% of high-risk opioid users in one year would save thousands of lives and $43 billion.

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Intracranial microinjection of CRISPR solutions might seem drastic. But drastic actions that are needed to save human lives from opioid overdoses. A large segment of the opioid overdose victims are chronic pain patients. It may be possible that chronic pain patients in a terminal phase of their lives and in hospice care would volunteer in phase I clinical trials for the CRISPR opioid receptor knockout treatment I propose here.

Making the opioid user impervious to death by opioids is a permanent solution to a horrendous problem that has resisted efforts by prevention, treatment and pharmacological means. Steady and well-funded work to prove the CRISPR method, first with preclinical animal models then in clinical trials, is a moonshot for the present generation of biomedical scientists.

Craig W. Stevens does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

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The next pandemic? It’s already here for Earth’s wildlife

Bird flu is decimating species already threatened by climate change and habitat loss.

I am a conservation biologist who studies emerging infectious diseases. When people ask me what I think the next pandemic will be I often say that we are in the midst of one – it’s just afflicting a great many species more than ours.

I am referring to the highly pathogenic strain of avian influenza H5N1 (HPAI H5N1), otherwise known as bird flu, which has killed millions of birds and unknown numbers of mammals, particularly during the past three years.

This is the strain that emerged in domestic geese in China in 1997 and quickly jumped to humans in south-east Asia with a mortality rate of around 40-50%. My research group encountered the virus when it killed a mammal, an endangered Owston’s palm civet, in a captive breeding programme in Cuc Phuong National Park Vietnam in 2005.

How these animals caught bird flu was never confirmed. Their diet is mainly earthworms, so they had not been infected by eating diseased poultry like many captive tigers in the region.

This discovery prompted us to collate all confirmed reports of fatal infection with bird flu to assess just how broad a threat to wildlife this virus might pose.

This is how a newly discovered virus in Chinese poultry came to threaten so much of the world’s biodiversity.

H5N1 originated on a Chinese poultry farm in 1997. ChameleonsEye/Shutterstock

The first signs

Until December 2005, most confirmed infections had been found in a few zoos and rescue centres in Thailand and Cambodia. Our analysis in 2006 showed that nearly half (48%) of all the different groups of birds (known to taxonomists as “orders”) contained a species in which a fatal infection of bird flu had been reported. These 13 orders comprised 84% of all bird species.

We reasoned 20 years ago that the strains of H5N1 circulating were probably highly pathogenic to all bird orders. We also showed that the list of confirmed infected species included those that were globally threatened and that important habitats, such as Vietnam’s Mekong delta, lay close to reported poultry outbreaks.

Mammals known to be susceptible to bird flu during the early 2000s included primates, rodents, pigs and rabbits. Large carnivores such as Bengal tigers and clouded leopards were reported to have been killed, as well as domestic cats.

Our 2006 paper showed the ease with which this virus crossed species barriers and suggested it might one day produce a pandemic-scale threat to global biodiversity.

Unfortunately, our warnings were correct.

A roving sickness

Two decades on, bird flu is killing species from the high Arctic to mainland Antarctica.

In the past couple of years, bird flu has spread rapidly across Europe and infiltrated North and South America, killing millions of poultry and a variety of bird and mammal species. A recent paper found that 26 countries have reported at least 48 mammal species that have died from the virus since 2020, when the latest increase in reported infections started.

Not even the ocean is safe. Since 2020, 13 species of aquatic mammal have succumbed, including American sea lions, porpoises and dolphins, often dying in their thousands in South America. A wide range of scavenging and predatory mammals that live on land are now also confirmed to be susceptible, including mountain lions, lynx, brown, black and polar bears.

The UK alone has lost over 75% of its great skuas and seen a 25% decline in northern gannets. Recent declines in sandwich terns (35%) and common terns (42%) were also largely driven by the virus.

Scientists haven’t managed to completely sequence the virus in all affected species. Research and continuous surveillance could tell us how adaptable it ultimately becomes, and whether it can jump to even more species. We know it can already infect humans – one or more genetic mutations may make it more infectious.

At the crossroads

Between January 1 2003 and December 21 2023, 882 cases of human infection with the H5N1 virus were reported from 23 countries, of which 461 (52%) were fatal.

Of these fatal cases, more than half were in Vietnam, China, Cambodia and Laos. Poultry-to-human infections were first recorded in Cambodia in December 2003. Intermittent cases were reported until 2014, followed by a gap until 2023, yielding 41 deaths from 64 cases. The subtype of H5N1 virus responsible has been detected in poultry in Cambodia since 2014. In the early 2000s, the H5N1 virus circulating had a high human mortality rate, so it is worrying that we are now starting to see people dying after contact with poultry again.

It’s not just H5 subtypes of bird flu that concern humans. The H10N1 virus was originally isolated from wild birds in South Korea, but has also been reported in samples from China and Mongolia.

Recent research found that these particular virus subtypes may be able to jump to humans after they were found to be pathogenic in laboratory mice and ferrets. The first person who was confirmed to be infected with H10N5 died in China on January 27 2024, but this patient was also suffering from seasonal flu (H3N2). They had been exposed to live poultry which also tested positive for H10N5.

Species already threatened with extinction are among those which have died due to bird flu in the past three years. The first deaths from the virus in mainland Antarctica have just been confirmed in skuas, highlighting a looming threat to penguin colonies whose eggs and chicks skuas prey on. Humboldt penguins have already been killed by the virus in Chile.

A colony of king penguins.
Remote penguin colonies are already threatened by climate change. AndreAnita/Shutterstock

How can we stem this tsunami of H5N1 and other avian influenzas? Completely overhaul poultry production on a global scale. Make farms self-sufficient in rearing eggs and chicks instead of exporting them internationally. The trend towards megafarms containing over a million birds must be stopped in its tracks.

To prevent the worst outcomes for this virus, we must revisit its primary source: the incubator of intensive poultry farms.

Diana Bell does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

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A major cruise line is testing a monthly subscription service

The Cruise Scarlet Summer Season Pass was designed with remote workers in mind.

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While going on a cruise once meant disconnecting from the world when between ports because any WiFi available aboard was glitchy and expensive, advances in technology over the last decade have enabled millions to not only stay in touch with home but even work remotely.

With such remote workers and digital nomads in mind, Virgin Voyages has designed a monthly pass that gives those who want to work from the seas a WFH setup on its Scarlet Lady ship — while the latter acronym usually means "work from home," the cruise line is advertising as "work from the helm.”

Related: Royal Caribbean shares a warning with passengers

"Inspired by Richard Branson's belief and track record that brilliant work is best paired with a hearty dose of fun, we're welcoming Sailors on board Scarlet Lady for a full month to help them achieve that perfect work-life balance," Virgin Voyages said in announcing its new promotion. "Take a vacation away from your monotonous work-from-home set up (sorry, but…not sorry) and start taking calls from your private balcony overlooking the Mediterranean sea."

A man looks through his phone while sitting in a hot tub on a cruise ship.

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This is how much it'll cost you to work from a cruise ship for a month

While the single most important feature for successful work at sea — WiFi — is already available for free on Virgin cruises, the new Scarlet Summer Season Pass includes a faster connection, a $10 daily coffee credit, access to a private rooftop, and other member-only areas as well as wash and fold laundry service that Virgin advertises as a perk that will allow one to concentrate on work

More Travel:

The pass starts at $9,990 for a two-guest cabin and is available for four monthlong cruises departing in June, July, August, and September — each departs from ports such as Barcelona, Marseille, and Palma de Mallorca and spends four weeks touring around the Mediterranean.

Longer cruises are becoming more common, here's why

The new pass is essentially a version of an upgraded cruise package with additional perks but is specifically tailored to those who plan on working from the ship as an opportunity to market to them.

"Stay connected to your work with the fastest at-sea internet in the biz when you want and log-off to let the exquisite landscape of the Mediterranean inspire you when you need," reads the promotional material for the pass.

Amid the rise of remote work post-pandemic, cruise lines have been seeing growing interest in longer journeys in which many of the passengers not just vacation in the traditional sense but work from a mobile office.

In 2023, Turkish cruise line operator Miray even started selling cabins on a three-year tour around the world but the endeavor hit the rocks after one of the engineers declared the MV Gemini ship the company planned to use for the journey "unseaworthy" and the cruise ship line dealt with a PR scandal that ultimately sank the project before it could take off.

While three years at sea would have set a record as the longest cruise journey on the market, companies such as Royal Caribbean  (RCL) (both with its namesake brand and its Celebrity Cruises line) have been offering increasingly long cruises that serve as many people’s temporary homes and cross through multiple continents.

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As the pandemic turns four, here’s what we need to do for a healthier future

On the fourth anniversary of the pandemic, a public health researcher offers four principles for a healthier future.

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John Gomez/Shutterstock

Anniversaries are usually festive occasions, marked by celebration and joy. But there’ll be no popping of corks for this one.

March 11 2024 marks four years since the World Health Organization (WHO) declared COVID-19 a pandemic.

Although no longer officially a public health emergency of international concern, the pandemic is still with us, and the virus is still causing serious harm.

Here are three priorities – three Cs – for a healthier future.

Clear guidance

Over the past four years, one of the biggest challenges people faced when trying to follow COVID rules was understanding them.

From a behavioural science perspective, one of the major themes of the last four years has been whether guidance was clear enough or whether people were receiving too many different and confusing messages – something colleagues and I called “alert fatigue”.

With colleagues, I conducted an evidence review of communication during COVID and found that the lack of clarity, as well as a lack of trust in those setting rules, were key barriers to adherence to measures like social distancing.

In future, whether it’s another COVID wave, or another virus or public health emergency, clear communication by trustworthy messengers is going to be key.

Combat complacency

As Maria van Kerkove, COVID technical lead for WHO, puts it there is no acceptable level of death from COVID. COVID complacency is setting in as we have moved out of the emergency phase of the pandemic. But is still much work to be done.

First, we still need to understand this virus better. Four years is not a long time to understand the longer-term effects of COVID. For example, evidence on how the virus affects the brain and cognitive functioning is in its infancy.

The extent, severity and possible treatment of long COVID is another priority that must not be forgotten – not least because it is still causing a lot of long-term sickness and absence.

Culture change

During the pandemic’s first few years, there was a question over how many of our new habits, from elbow bumping (remember that?) to remote working, were here to stay.

Turns out old habits die hard – and in most cases that’s not a bad thing – after all handshaking and hugging can be good for our health.

But there is some pandemic behaviour we could have kept, under certain conditions. I’m pretty sure most people don’t wear masks when they have respiratory symptoms, even though some health authorities, such as the NHS, recommend it.

Masks could still be thought of like umbrellas: we keep one handy for when we need it, for example, when visiting vulnerable people, especially during times when there’s a spike in COVID.

If masks hadn’t been so politicised as a symbol of conformity and oppression so early in the pandemic, then we might arguably have seen people in more countries adopting the behaviour in parts of east Asia, where people continue to wear masks or face coverings when they are sick to avoid spreading it to others.

Although the pandemic led to the growth of remote or hybrid working, presenteeism – going to work when sick – is still a major issue.

Encouraging parents to send children to school when they are unwell is unlikely to help public health, or attendance for that matter. For instance, although one child might recover quickly from a given virus, other children who might catch it from them might be ill for days.

Similarly, a culture of presenteeism that pressures workers to come in when ill is likely to backfire later on, helping infectious disease spread in workplaces.

At the most fundamental level, we need to do more to create a culture of equality. Some groups, especially the most economically deprived, fared much worse than others during the pandemic. Health inequalities have widened as a result. With ongoing pandemic impacts, for example, long COVID rates, also disproportionately affecting those from disadvantaged groups, health inequalities are likely to persist without significant action to address them.

Vaccine inequity is still a problem globally. At a national level, in some wealthier countries like the UK, those from more deprived backgrounds are going to be less able to afford private vaccines.

We may be out of the emergency phase of COVID, but the pandemic is not yet over. As we reflect on the past four years, working to provide clearer public health communication, avoiding COVID complacency and reducing health inequalities are all things that can help prepare for any future waves or, indeed, pandemics.

Simon Nicholas Williams has received funding from Senedd Cymru, Public Health Wales and the Wales Covid Evidence Centre for research on COVID-19, and has consulted for the World Health Organization. However, this article reflects the views of the author only, in his academic capacity at Swansea University, and no funding or organizational bodies were involved in the writing or content of this article.

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