How gene editing a person’s brain cells could be used to curb the opioid epidemic
Is CRISPR the solution?
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.
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.
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.
- 5 ways CRISPR will reshape humanity and the world - Big Think ›
- Opioids: Things your doctor should tell you before prescribing - Big ... ›
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Hungarian cartographer travels the world while mapping its treasures.
- Simple idea, stunning result: the world's watersheds in glorious colors.
- The maps are the work of Hungarian cartographer Robert Szucs.
- His job: to travel and map the world, one good cause at a time.
The world<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8xOTE0MjUyNS9vcmlnaW4ucG5nIiwiZXhwaXJlc19hdCI6MTYzMzU3Njk1M30.rRdZpcl0bfVi4oBsljHdZSbcX0New9rdLcx6fr2mD7Y/img.png?width=980" id="f982a" class="rm-shortcode" data-rm-shortcode-id="fa67421340f881d5ab91463514cf9a6d" data-rm-shortcode-name="rebelmouse-image" />
Can you spot the world's ten largest drainage basins? In order of magnitude: Amazon, Congo, Nile, Mississippi, Ob, Parana, Yenisei, Lena, Niger, Amur. Image source: Grasshopper Geography
Africa<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8xOTE0MjUyNi9vcmlnaW4ucG5nIiwiZXhwaXJlc19hdCI6MTYzOTI2MzI0MX0.OeTS-scZwBES4AlZAan7fBlaBkznkig5hPjgcd1j6hw/img.png?width=980" id="e987c" class="rm-shortcode" data-rm-shortcode-id="2d3a8999ed4071a123b30efc5652fee9" data-rm-shortcode-name="rebelmouse-image" />
Africa is home to the rivers with the world's second- and third-largest catchment areas: the Congo (in blue), with a basin of 1.44 million square miles (3.73 million km2), and the Nile (in red), with basin area of 1.26 million square miles (3.25 million km2). The Nile is the longest river in Africa, though (4,130 miles; 6,650 km), followed by the Congo: 2,900 miles (4,700 km). The Congo River's alternative name, Zaire, comes from the Kikongo nzadi o nzere ('river swallowing rivers'). Image source: Grasshopper Geography
Europe<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8xOTE0MjUyOS9vcmlnaW4ucG5nIiwiZXhwaXJlc19hdCI6MTY0NTkzOTMyMH0.tq5fjnq8wvLqXY0C9gzfoUd0ahOAQ7IZQxbpVnC1FdY/img.png?width=980" id="a8ec4" class="rm-shortcode" data-rm-shortcode-id="1ce5f59691501103343e080905ce74a3" data-rm-shortcode-name="rebelmouse-image" />
The Volga (in yellow) is the river with the biggest catchment area in Europe (just under 545,000 square miles; 1.41 million km2). It flows exclusively through Russia, and the catchment area is entirely within Russia as well. Europe's number two is the Danube (in orange), which flows through 10 countries — more than any other river in the world. Its drainage basin (just over 307,000 square miles; almost 796,000 km2) includes nine more countries. Image: Grasshopper Geography
Germany<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8xOTE0MjUzMC9vcmlnaW4ucG5nIiwiZXhwaXJlc19hdCI6MTY0Mzk4ODA3Nn0.qX1sOfJWAI7TUbTQCiIob-R5p4_wj299wEtrYAUREmg/img.png?width=980" id="d5efa" class="rm-shortcode" data-rm-shortcode-id="8e73c53d75840f21b4f2ca4b8a1e7f51" data-rm-shortcode-name="rebelmouse-image" />
The hydrographic map of Germany is dominated by just four major drainage systems: the Danube (in orange) in the south, the Rhine (in blue) in the west, the Elbe (in purple) in the east and the Weser (in green) between the latter two. In Antiquity, the Rhine was the border between the Roman Empire and the Germans. Rome once attempted to shift the border to the Elbe, which would have radically altered the course of history, but it suffered a massive defeat in 9 CE at the Teutoburger Wald (roughly between both rivers). Image: Grasshopper Geography
Great Britain and Ireland<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8xOTE0MjUzMS9vcmlnaW4ucG5nIiwiZXhwaXJlc19hdCI6MTY1OTk2MjM3MX0.nDy__OLIyC1arty4_2xd54fjTzmfsIZo-2pe5QRjjA4/img.png?width=980" id="31a6f" class="rm-shortcode" data-rm-shortcode-id="d089f66097f37a10ab854eaccdac3581" data-rm-shortcode-name="rebelmouse-image" />
Both Ireland and Great Britain are islands, as a result of which neither boasts a continental-class river. Twenty of the 30 longest British rivers are less than 100 miles (160 km) long. The longest river in Britain is the Severn (220 miles, 354 km), its catchment area shown in blue in the southwest. Ireland's longest river is the Shannon (224 miles, 360 km). Even combined they're not as long as France's Seine (483 miles, 777 km). Image: Grasshopper Geography
United States<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8xOTE0MjUzNC9vcmlnaW4ucG5nIiwiZXhwaXJlc19hdCI6MTY2MDYyMzEyM30.7S_83dA6bcLyID_7BhH1R_OTy61tpgDZrBMQ_iPwnjM/img.png?width=980" id="a879d" class="rm-shortcode" data-rm-shortcode-id="a7c74a7b5a7887fb2d13b40d5d96223c" data-rm-shortcode-name="rebelmouse-image" />
Spread-eagled across the central part of the United States, the Mississippi's drainage basin covers all or parts of 32 U.S. states (and two Canadian provinces). The easternmost point of Ol' Man River's catchment area is really far east: Cobb Hill in northern Pennsylvania. Here rises the Allegheny, tributary of the Ohio, which in turn flows into the Mississippi at Cairo, Illinois. Image: Grasshopper Geography
Washington State<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8xOTE0MjUzNS9vcmlnaW4ucG5nIiwiZXhwaXJlc19hdCI6MTY0MzU2MzM4OH0.mniqbkEQq84rNaWOQIl4fB4mOhNdJf5WactNyE_VsyM/img.png?width=980" id="adc4d" class="rm-shortcode" data-rm-shortcode-id="97eb5a5add49c06ef00ff0bca812b380" data-rm-shortcode-name="rebelmouse-image" />
Even leaving out the Mississippi, there's enough going on in the rest of North America to keep the eye occupied. Here's a drainage map of Washington State. The big fish in this much smaller pond is the Columbia River (drainage area in blue), the largest river in the Pacific Northwest. Only in the western third of the state is there a colourful counterpoint, in the multitude of smaller river basins that are draining into the Pacific or into Puget Sound. Image: Grasshopper Geography
Australia<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8xOTE0MjUzNi9vcmlnaW4ucG5nIiwiZXhwaXJlc19hdCI6MTYzOTM0ODM2NH0.U7vckwnoNoxf-bk8SuYO246hNMpR2zXILILsd4pas9o/img.png?width=980" id="38c2b" class="rm-shortcode" data-rm-shortcode-id="0c44d30d61c6cb94b8d5c7205cbabd58" data-rm-shortcode-name="rebelmouse-image" />
At 1,558 miles (2,508 km), the Murray is Australia's longest river. It is often considered in conjunction with the Darling (915 miles, 1,472 km), the country's third-longest river, which flows into the Murray. The Murray-Darling basin (in blue, in the southeast) covers just under 410,000 square miles (1.06 million km2), or 14 percent of Australia's total territory. Don't let that spidery network of river courses in the interior fool you: Australia is the world's driest inhabited continent (Antarctica, bizarrely, is drier). Image: Grasshopper Geography
Russia<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8xOTE0MjUzNy9vcmlnaW4ucG5nIiwiZXhwaXJlc19hdCI6MTYwNzg5MzIxOX0.WhShHLjjWdEh4FF_OZsY1oTN3Vc77X29TbMYbVHrHqA/img.png?width=980" id="f5cee" class="rm-shortcode" data-rm-shortcode-id="53acd93f1ab67be979e6ab128c144ce6" data-rm-shortcode-name="rebelmouse-image" />
Four of the world's largest drainage basins are in Russia: the Ob, Yenisei and Lena (origin of Vladimir I. Ulyanov's nom de guerre, Lenin) entirely and the Amur, shared with China. The Volga may be Europe's longest river, but 84 percent or Russia's surface water is east of the Urals, in Siberia. The sparsely-populated region is traversed by 40 rivers longer than 1,000 km. Combined, the Ob, Yenisey and Lena rivers cover a drainage area of about 8 million km2, discharging nearly 50,000 m3 of water per second in the Arctic. Image: Grasshopper Geography
The images and our best computer models don't agree.
A trio of intriguing galaxy clusters<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yNDQzNDA0OS9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTYxNTkzNzUyOH0.0IRzkzvKsmPEHV-v1dqM1JIPhgE2W-UHx0COuB0qQnA/img.jpg?width=980" id="d69be" class="rm-shortcode" data-rm-shortcode-id="2d2664d9174369e0a06540cb3a3a9079" data-rm-shortcode-name="rebelmouse-image" />
The three galaxy clusters imaged for the study
Mapping dark matter<span style="display:block;position:relative;padding-top:56.25%;" class="rm-shortcode" data-rm-shortcode-id="d904b585c806752f261e1215014691a6"><iframe type="lazy-iframe" data-runner-src="https://www.youtube.com/embed/fO0jO_a9uLA?rel=0" width="100%" height="auto" frameborder="0" scrolling="no" style="position:absolute;top:0;left:0;width:100%;height:100%;"></iframe></span><p>The assumption has been that the greater the lensing effect, the higher the concentration of dark matter.</p><p>As scientists analyzed the clusters' large-scale lensing — the massive arc and elongation visual effects produced by dark matter — they noticed areas of smaller-scale lensing within that larger distortion. The scientists interpret these as concentrations of dark matter within individual galaxies inside the clusters.</p><p>The researchers used spectrographic data from the VLT to determine the mass of these smaller lenses. <a href="https://www.oas.inaf.it/en/user/pietro.bergamini/" target="_blank" rel="noopener noreferrer">Pietro Bergamini</a> of the INAF-Observatory of Astrophysics and Space Science in Bologna, Italy explains, "The speed of the stars gave us an estimate of each individual galaxy's mass, including the amount of dark matter." The leader of the spectrographic aspect of the study was <a href="http://docente.unife.it/docenti-en/piero.rosati1/curriculum?set_language=en" target="_blank">Piero Rosati</a> of the Università degli Studi di Ferrara, Italy who recalls, "the data from Hubble and the VLT provided excellent synergy. We were able to associate the galaxies with each cluster and estimate their distances." </p><p>This work allowed the team to develop a thoroughly calibrated, high-resolution map of dark matter concentrations throughout the three clusters.</p>
But the models say...<p>However, when the researchers compared their map to the concentrations of dark matter computer models predicted for galaxies bearing the same general characteristics, something was <em>way</em> off. Some small-scale areas of the map had 10 times the amount of lensing — and presumably 10 times the amount of dark matter — than the model predicted.</p><p>"The results of these analyses further demonstrate how observations and numerical simulations go hand in hand," notes one team member, <a href="https://nena12276.wixsite.com/elenarasia" target="_blank">Elena Rasia</a> of the INAF-Astronomical Observatory of Trieste, Italy. Another, <a href="http://adlibitum.oats.inaf.it/borgani/" target="_blank" rel="noopener noreferrer">Stefano Borgani</a> of the Università degli Studi di Trieste, Italy, adds that "with advanced cosmological simulations, we can match the quality of observations analyzed in our paper, permitting detailed comparisons like never before."</p><p>"We have done a lot of testing of the data in this study," Meneghetti says, "and we are sure that this mismatch indicates that some physical ingredient is missing either from the simulations or from our understanding of the nature of dark matter." <a href="https://physics.yale.edu/people/priyamvada-natarajan" target="_blank">Priyamvada Natarajan</a> of Yale University in Connecticut agrees: "There's a feature of the real Universe that we are simply not capturing in our current theoretical models."</p><p>Given that any theory in science lasts only until a better one comes along, Natarajan views the discrepancy as an opportunity, saying, "this could signal a gap in our current understanding of the nature of dark matter and its properties, as these exquisite data have permitted us to probe the detailed distribution of dark matter on the smallest scales."</p><p>At this point, it's unclear exactly what the conflict signifies. Do these smaller areas have unexpectedly high concentrations of dark matter? Or can dark matter, under certain currently unknown conditions, produce a tenfold increase in lensing beyond what we've been expecting, breaking the assumption that more lensing means more dark matter?</p><p>Obviously, the scientific community has barely begun to understand this mystery.</p>
Scientists have found evidence of hot springs near sites where ancient hominids settled, long before the control of fire.