What Is Naloxone? Where To Get Narcan And How To Reverse Overdoses

The overdose crisis continues to worsen in the U.S., and overdose deaths reached an all-time high in 2021. Experts say that a simple drug — naloxone — is a key tool in preventing more deaths. But not enough people know about it, have access to it or actually carry it with them.

“Naloxone is a miracle drug,” Dr. Kimberly Sue, medical director for the National Harm Reduction Coalition and associate professor of medicine at Yale School of Medicine, told TODAY. “It’s literally a Lazarus drug that prevents people from dying of an opioid overdose.”

And in the midst of the overdose crisis, which claimed nearly 108,000 lives just last year, getting naloxone to those who need it is vitally important. Here, experts discuss what naloxone is, how to get it and how it can save lives.

How does naloxone work?

Naloxone, also referred to by the brand name Narcan, is what experts call an opioid antagonist, Dr. Sarah Wakeman, medical director for the Massachusetts General Hospital Substance Use Disorder Initiative, told TODAY. Narcan is not the only branded naloxone product; a high-dose nasal spray called Kloxxado works similarly, according to the FDA.

That means it “binds to the opioid receptors in the brain — the same receptors that opioid drugs or medications like oxycodone or heroin or fentanyl bind to — and then blocks those receptors,” Wakeman explained. In the event of an opioid overdose, naloxone “can actually kick off the opioid from the receptor, reverse the acute effects of an opioid overdose and save someone’s life.”

A standard dose of naloxone is effective against even fentanyl, Wakeman said. If they’ve taken an opioid and something else, or if they took something like cocaine that was tainted with illicit fentanyl, naloxone will still work against the opioid in their system.

“And naloxone won’t be harmful to someone who doesn’t have an opioid in their body,” Wakeman said. “So if there’s a possibility that you think someone is having an overdose … then it is always a good idea to give naloxone.”

When should naloxone be given?

Before using naloxone, check to see if someone has the telltale signs of an overdose, Dr. Ayana Jordan, an addiction expert and associate professor of psychiatry at NYU Grossman School of Medicine, told TODAY. She pointed to the Center for Disease Control and Prevention‘s tips to learn about the signs of an overdose.

According to the CDC, someone having an overdose may have:

  • Loss of consciousness.
  • Weak, slow or no breathing.
  • Small or constricted pupils.
  • Choking or gurgling sounds.
  • Limp body.
  • Clammy or cold skin.
  • Blue or discolored skin, especially around the lips. (However, Jordan notes that this may not apply to people with darker skin.)

In general, someone who is in the midst of an overdose will “have slowed and very shallow breathing to the point that, ultimately, they’ll stop breathing,” Wakeman said. “So they may look blue or cold and not be responsive.”

Giving someone naloxone

Once you’ve identified that someone might be having an overdose, you should call 911, the CDC says. Even if you’re able to reverse the overdose, they will likely still need emergency services. (Some states, but not all, have Good Samaritan laws, which protect people calling for medical help from some drug-related charges, Sue explained.)

From there, the right way to use naloxone depends on the specific formulation you’re using. For most people, that will likely be the nasal spray called Narcan, Wakeman said. In the hospital, naloxone may be given through an IV or as an injection into the muscle, she added.

After administering naloxone, the person should wake up within seconds to minutes, Wakeman said. And you should always start with as low a dose as possible. If someone is a regular opioid user and you give them a massive dose of naloxone all at once, “they’re going to immediately go into withdrawal,” Wakeman explained. While that isn’t necessarily harmful, it is pretty unpleasant and uncomfortable.

After giving someone naloxone, you should stay with them if you can until emergency medical help arrives. “Naloxone works very quickly, but it also wears off very quickly,” Wakeman said. In fact, the effects of naloxone can wear off within 30 minutes. And if someone still has the other opioid in their system, they may fall back into an overdose after the naloxone has worn off.

Where to get naloxone

If you use drugs, your doctor may give you a naloxone prescription as a regular part of their practice. “I make sure that everyone that sees me gets prescribed naloxone and that they understand how to use it,” Jordan said.

Depending on the state, you may be able to get naloxone at a local pharmacy without a prescription through the use of a standing order, Wakeman noted. (Standing orders allow pharmacies to give out prescription medications, like the annual flu vaccine, without requiring each individual person to have their own prescription.)

Another option is to connect with local harm reduction groups in your area, which frequently hand out naloxone kits, Wakeman said. These community-based organizations may also offer in-person or virtual trainings on how to use naloxone. Jordan noted that her research group also does large virtual naloxone training sessions for people who participate in their studies looking at drug use.

If you live in a state without a standing order and want to get naloxone to use on someone else, you can likely get a third-party prescription through a doctor, Sue said. She recommended looking at the local health department’s website for more information about where to get naloxone in your area.

It’s most important for people who use drugs to have access to naloxone. But if you know someone who uses drugs, you should consider carrying naloxone, too, the experts said. “Carrying naloxone is no different than carrying an epi-pen,” Jordan said.

And even though there are several ways to get naloxone now, there are still barriers to actually accessing and using it, Sue explained. She recalled a story of pharmacy staff being simply unaware of the standing order for naloxone, for instance, and noted that harm reduction groups are experiencing an ongoing naloxone shortage.

Additionally, naloxone is something that, by definition, people can’t use on themselves in the event of an overdose, Sue said. (If you are going to use by yourself, Sue recommended calling the Never Use Alone hotline so there is someone who can notify emergency services if you lose consciousness.)

Naloxone is a crucial tool in reducing overdose deaths, experts say

“Really, no one should die from an opioid overdose,” Wakeman said. “Not only do we know how to prevent overdoses and how to treat people who have an opioid use disorder, but we also have this life-saving, immediately-acting medication that will quickly reverse the effects of an opioid overdose.” 

The challenge for experts now is to make naloxone more accessible to those who need it. “There’s no moral or medical reason to keep this life-saving medication behind the counter,” Dr. Bobby Mikkamula, chair of the American Medicine Association’s Substance Use and Pain Care Task Force, told TODAY.

Earlier this year, AMA urged the Biden administration to remove naloxone’s prescription status, which would make it available over-the-counter. “It’s not the kind of thing that needs to be protected or that people need to be protected from,” Mikkamula said. “This saves their lives, and the fewer barriers we have to getting this into their hands and into their medicine cabinets, the better.”

For Jordan, the importance of naloxone comes down to one simple truth: “I can’t help people who are dead,” she said.

By

Source: What Is Naloxone? Where To Get Narcan And How To Reverse Overdoses

Related links:

Overdose Deaths Behind Bars Rise as Drug Crisis Swells The Good Men Project

Report details Alaska demographics hurt most by 2021 spike in drugoverdose deaths Alaska Public Media

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13:02 Fri, 29 JulOpioid Crisis Fentanyl
15:34 Mon, 25 JulNative Americans Pandemic Racism
01:14 Thu, 21 JulNative Americans CDC Alaska
17:49 Thu, 28 JulDundee Scotland
Fentanyl, death by the dose The Washington Times
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How Do Painkillers Kill Pain? It’s About Meeting The pain Where It’s At

Without the ability to feel pain, life is more dangerous. To avoid injury, pain tells us to use a hammer more gently, wait for the soup to cool or put on gloves in a snowball fight. Those with rare inherited disorders that leave them without the ability to feel pain are unable to protect themselves from environmental threats, leading to broken bones, damaged skin, infections, and ultimately a shorter life span.

In these contexts, pain is much more than a sensation: It is a protective call to action. But pain that is too intense or long-lasting can be debilitating. So how does modern medicine soften the call?

As a neurobiologist and an anesthesiologist who study pain, this is a question we and other researchers have tried to answer. Science’s understanding of how the body senses tissue damage and perceives it as pain has progressed tremendously over the past several years. It has become clear that there are multiple pathways that signal tissue damage to the brain and sound the pain alarm bell.

Interestingly, while the brain uses different pain signaling pathways depending on the type of damage, there is also redundancy to these pathways. Even more intriguing, these neural pathways morph and amplify signals in the case of chronic pain and pain caused by conditions affecting nerves themselves, even though the protective function of pain is no longer needed.

Painkillers work by tackling different parts of these pathways. Not every painkiller works for every type of pain, however. Because of the multitude and redundancy of pain pathways, a perfect painkiller is elusive. But in the meantime, understanding how existing painkillers work helps medical providers and patients use them for the best results.

Anti-inflammatory painkillers

A bruise, sprain, or broken bone from an injury all lead to tissue inflammation, an immune response that can lead to swelling and redness as the body tries to heal. Specialized nerve cells in the area of the injury called nociceptors sense the inflammatory chemicals the body produces and send pain signals to the brain.

Common over-the-counter anti-inflammatory painkillers work by decreasing inflammation in the injured area. These are particularly useful for musculoskeletal injuries or other pain problems caused by inflammation such as arthritis.

Nonsteroidal anti-inflammatories like ibuprofen (Advil, Motrin), naproxen (Aleve), and aspirin do this by blocking an enzyme called COX that plays a key role in a biochemical cascade that produces inflammatory chemicals. Blocking the cascade decreases the amount of inflammatory chemicals, and thereby reduces the pain signals sent to the brain. While acetaminophen (Tylenol), also known as paracetamol, doesn’t reduce inflammation as NSAIDs do, it also inhibits COX enzymes and has similar pain-reducing effects.

Prescription anti-inflammatory painkillers include other COX inhibitors, corticosteroids, and, more recently, drugs that target and inactivate the inflammatory chemicals themselves.

Because inflammatory chemicals are involved in other important physiological functions beyond just sounding the pain alarm, medications that block them will have side effects and potential health risks, including irritating the stomach lining and affecting kidney function. Over-the-counter medications are generally safe if the directions on the bottle are followed strictly.

Corticosteroids like prednisone block the inflammatory cascade early on in the process, which is probably why they are so potent in reducing inflammation. However, because all the chemicals in the cascade are present in nearly every organ system, long-term use of steroids can pose many health risks that need to be discussed with a physician before starting a treatment plan.

Topical medications

Many topical medications target nociceptors, the specialized nerves that detect tissue damage. Local anesthetics, like lidocaine, prevent these nerves from sending electrical signals to the brain.

The protein sensors on the tips of other sensory neurons in the skin are also targets for topical painkillers. Activating these proteins can elicit particular sensations that can lessen the pain by reducing the activity of the damage-sensing nerves, like the cooling sensation of menthol or the burning sensation of capsaicin.

Because these topical medications work on the tiny nerves in the skin, they are best used for pain directly affecting the skin. For example, a shingles infection can damage the nerves in the skin, causing them to become overactive and send persistent pain signals to the brain. Silencing those nerves with topical lidocaine or an overwhelming dose of capsaicin can reduce these pain signals.

Nerve injury medications

Nerve injuries, most commonly from arthritis and diabetes, can cause the pain-sensing part of the nervous system to become overactive. These injuries sound the pain alarm even in the absence of tissue damage. The best painkillers in these conditions are those that dampen that alarm.

Antiepileptic drugs, such as gabapentin (Neurontin), suppress the pain-sensing system by blocking electrical signaling in the nerves. However, gabapentin can also reduce nerve activity in other parts of the nervous system, potentially leading to sleepiness and confusion.

Antidepressants, such as duloxetine and nortriptyline, are thought to work by increasing certain neurotransmitters in the spinal cord and brain involved in regulating pain pathways. But they may also alter chemical signaling in the gastrointestinal tract, leading to an upset stomach.

All these medications are prescribed by doctors.

Opioids

Opioids are chemicals found or derived from the opium poppy. One of the earliest opioids, morphine, was purified in the 1800s. Since then, medical use of opioids has expanded to include many natural and synthetic derivatives of morphine with varying potency and duration. Some common examples include codeine, tramadol, hydrocodone, oxycodone, buprenorphine and fentanyl.

Opioids decrease pain by activating the body’s endorphin system. Endorphins are a type of opioid your body naturally produces that decreases incoming signals of injury and produces feelings of euphoria—the so-called “runner’s high.” Opioids simulate the effects of endorphins by acting on similar targets in the body. Although opioids can decrease some types of acute pain, such as after surgery, musculoskeletal injuries like a broken leg, or cancer pain, they are often ineffective for neuropathic injuries and chronic pain.

Because the body uses opioid receptors in other organ systems like the gastrointestinal tract and the lungs, side effects and risks include constipation and potentially fatal suppression of breathing. Prolonged use of opioids may also lead to tolerance, where more drug is required to get the same painkilling effect. This is why opioids can be addictive and are not intended for long-term use. All opioids are controlled substances and are carefully prescribed by doctors because of these side effects and risks.

Cannabinoids

Although cannabis has received a lot of attention for its potential medical uses, there isn’t sufficient evidence available to conclude that it can effectively treat pain. Since the use of cannabis is illegal at the federal level in the US, high-quality clinical research funded by the federal government has been lacking.

Researchers do know that the body naturally produces endocannabinoids, a form of the chemicals in cannabis, to decrease pain perception. Cannabinoids may also reduce inflammation. Given the lack of strong clinical evidence, physicians typically don’t recommend them over FDA-approved medications.

Matching pain to drug

While sounding the pain alarm is important for survival, dampening the klaxon when it’s too loud or unhelpful is sometimes necessary.

No existing medication can perfectly treat pain. Matching specific types of pain to drugs that target specific pathways can improve pain relief, but even then, medications can fail to work even for people with the same condition. More research that deepens the medical field’s understanding of the pain pathways and targets in the body can help lead to more effective treatments and improved pain management.

Source: How do painkillers kill pain? It’s about meeting the pain where it’s at | Ars Technica

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Moderna Data Shows mRNA Isn’t a Quick Fix For The Flu Vaccine

The first data from clinical trials of Moderna’s mRNA-based seasonal flu vaccine, released by the company Friday morning, were underwhelming — a finding that shows gene-based vaccines might not be a fix for all the problems with vaccine development.

The overwhelming success of the mRNA COVID-19 vaccines, made by Moderna and Pfizer / BioNTech, supercharged interest in that strategy for developing shots. The shots inject people with tiny snippets of the gene for a virus, which the body builds and then uses to learn how to fight the virus.

Current flu shots contain inactivated copies of the influenza virus. mRNA vaccines are faster to design and produce because manufacturers don’t have to grow copies of the virus, which is why experts have for years seen them as the future of vaccines.

Moderna launched a clinical trial of an mRNA seasonal flu vaccine this summer, hoping to capture the same success as it did with its COVID-19 vaccine. Typically, seasonal flu shots are around 40 to 60 percent effective, and pharmaceutical companies want to make that better. Three other companies are also working on mRNA flu shots.

Moderna released its first results during an investor phone call and presented slides showing that the mRNA flu shots did generate antibodies — but the levels of those antibodies weren’t higher than those for other flu shots already on the market. They also had more side effects than existing shots.

The findings don’t necessarily mean that mRNA flu shots aren’t any better than what we have now. Because mRNA vaccines are faster to design and make, the shots don’t have to be developed as far in advance. Companies may not have to do as much guesswork around what strain of the flu to target them against each year because they can wait to make the shots until they see what strains are circulating.

And as far as efficacy goes, there’s still a lot more data to collect: Moderna is preparing to conduct larger trials that would test how well the shots actually keep people from getting sick in the real world (not just testing antibody levels)..

Still, this early data shows that the immune system is tricky and that mRNA vaccines probably aren’t an easy shortcut for stopping a virus as persistent as the flu. More studies will be needed to figure out if there is a specific benefit to using mRNA vaccines to fight the flu, wrote chemist and writer Derek Lowe in Science. But it’s not a sure thing.

Nicole Wetsman

Source: Moderna data shows mRNA isn’t a quick fix for the flu vaccine – The Verge

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The Symptoms of The Delta Variant Appear To Differ From Traditional COVID Symptoms. Here’s What To Look Out For

We’ve been living in a COVID world for more than 18 months now. At the outset of the pandemic, government agencies and health authorities scrambled to inform people on how to identify symptoms of the virus.

But as the virus has evolved, it seems the most common symptoms have changed too.

Emerging data suggest people infected with the Delta variant — the variant behind most of Australia’s current cases and highly prevalent around the world — are experiencing symptoms different to those we commonly associated with COVID earlier in the pandemic.


Read more: What’s the Delta COVID variant found in Melbourne? Is it more infectious and does it spread more in kids? A virologist explains

Clear explanations about the pandemic from a network of research experts

We’re all different

Humans are dynamic. With our differences come different immune systems. This means the same virus can produce different signs and symptoms in different ways.

A sign is something that’s seen, such as a rash. A symptom is something that’s felt, like a sore throat.

The way a virus causes illness is dependent on two key factors:

  • viral factors include things like speed of replication, modes of transmission, and so on. Viral factors change as the virus evolves.
  • host factors are specific to the individual. Age, gender, medications, diet, exercise, health and stress can all affect host factors.

So when we talk about the signs and symptoms of a virus, we’re referring to what is most common. To ascertain this, we have to collect information from individual cases.

It’s important to note this data is not always easy to collect or analyse to ensure there’s no bias. For example, older people may have different symptoms to younger people, and collecting data from patients in a hospital may be different to patients at a GP clinic.

So what are the common signs and symptoms of the Delta variant?

Using a self-reporting system through a mobile app, data from the United Kingdom suggest the most common COVID symptoms may have changed from those we traditionally associated with the virus.

The reports don’t take into account which COVID variant participants are infected with. But given Delta is predominating in the UK at present, it’s a safe bet the symptoms we see here reflect the Delta variant.


The Conversation, CC BY-ND

While fever and cough have always been common COVID symptoms, and headache and sore throat have traditionally presented for some people, a runny nose was rarely reported in earlier data. Meanwhile, loss of smell, which was originally quite common, now ranks ninth.

There are a few reasons we could be seeing the symptoms evolving in this way. It may be because data were originally coming mainly from patients presenting to hospital who were therefore likely to be sicker. And given the higher rates of vaccination coverage in older age groups, younger people are now accounting for a greater proportion of COVID cases, and they tend to experience milder symptoms.

It could also be because of the evolution of the virus, and the different characteristics (viral factors) of the Delta variant. But why exactly symptoms could be changing remains uncertain.


Read more: Coronavirus: how long does it take to get sick? How infectious is it? Will you always have a fever? COVID-19 basics explained


While we still have more to learn about the Delta variant, this emerging data is important because it shows us that what we might think of as just a mild winter cold — a runny nose and a sore throat — could be a case of COVID-19.

This data highlight the power of public science. At the same time, we need to remember the results haven’t yet been fully analysed or stratified. That is, “host factors” such as age, gender, other illnesses, medications and so on haven’t been accounted for, as they would in a rigorous clinical trial.

And as is the case with all self-reported data, we have to acknowledge there may be some flaws in the results.

Does vaccination affect the symptoms?

Although new viral variants can compromise the effectiveness of vaccines, for Delta, the vaccines available in Australia (Pfizer and AstraZeneca) still appear to offer good protection against symptomatic COVID-19 after two doses.



Importantly, both vaccines have been shown to offer greater than 90% protection from severe disease requiring hospital treatment.

A recent “superspreader” event in New South Wales highlighted the importance of vaccination. Of 30 people who attended this birthday party, reports indicated none of the 24 people who became infected with the Delta variant had been vaccinated. The six vaccinated people at the party did not contract COVID-19.

In some cases infection may still possible after vaccination, but it’s highly likely the viral load will be lower and symptoms much milder than they would without vaccination.

We all have a role to play

Evidence indicating Delta is more infectious compared to the original SARS-CoV-2 and other variants of the virus is building.

It’s important to understand the environment is also changing. People have become more complacent with social distancing, seasons change, vaccination rates vary — all these factors affect the data.

But scientists are becoming more confident the Delta variant represents a more transmissible SARS-CoV-2 strain.


Read more: What’s the difference between mutations, variants and strains? A guide to COVID terminology


As we face another COVID battle in Australia we’re reminded the war against COVID is not over and we all have a role to play. Get tested if you have any symptoms, even if it’s “just a sniffle”. Get vaccinated as soon as you can and follow public health advice.

By: Research Leader in Virology and Infectious Disease, Griffith University

Source: The symptoms of the Delta variant appear to differ from traditional COVID symptoms. Here’s what to look out for

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Critics:

Deltacoronavirus (Delta-CoV) is one of the four genera (Alpha-, Beta-, Gamma-, and Delta-) of coronaviruses. It is in the subfamily Orthocoronavirinae of the family Coronaviridae. They are enveloped, positive-sense, single-stranded RNA viruses. Deltacoronaviruses infect mostly birds and some mammals.

genesis

While the alpha and beta genera are derived from the bat viral gene pool, the gamma and delta genera are derived from the avian and pig viral gene pools.

Recombination appears to be common among deltacoronaviruses.Recombination occurs frequently in the viral genome region that encodes the host receptor binding protein. Recombination between different viral lineages contributes to the emergence of new viruses capable of interspecies transmission and adaptation to new animal hosts.

References

  1. Lau SKP, Wong EYM, Tsang CC, Ahmed SS, Au-Yeung RKH, Yuen KY, Wernery U, Woo PCY. Discovery and Sequence Analysis of Four Deltacoronaviruses from Birds in the Middle East Reveal Interspecies Jumping with Recombination as a Potential Mechanism for Avian-to-Avian and Avian-to-Mammalian Transmission. J Virol. 2018 Jul 17;92(15):e00265-18. doi: 10.1128/JVI.00265-18. Print 2018 Aug 1. PMID: 29769348

External links

The Cancer Custodians Hidden Truths

woman-with-headscarf-getting-chemo-treatment-article

Part of Dennis Plenker’s daily job is growing cancer. And a variety of different ones, too. Depending on the day and the project, different tumors may burgeon in the petri dishes stocked in the Cold Spring Harbor Laboratory where Plenker works as a research investigator. They might be aggressive breast cancers.

They might be glioblastomas, one of the deadliest brain tumors that rob patients of their ability to speak or read as they crowd out normal cells. Or they might be pancreatic cancers, the fast and vicious slayers that can overtake a healthy person within weeks or even days.

These tiny tumor chunks are transparent and bland—they look like little droplets of hair gel that accidentally plopped into a plastic dish and took hold. But their unassuming appearance is deceptive. If they were still in the human bodies they came from, they would be sucking up nutrients, rapidly growing and dodging the immune system defenses.

But in Plenker’s hands—or rather in the CSHL’s unique facility—these notorious killers don’t kill anyone. Instead, scientists let them grow to devise the most potent ways to kill them. These tumor chunks are called organoids. They are three-dimensional assemblages of malignant growths used to study cancer behavior and vulnerability to chemotherapy and the so-called “targeted drugs”—the next generation therapies.

Scientists used to study tumors at a single-cell level, but because tumors grow as cell clusters in the body, it proved to be inefficient. The three-dimensional structures make a difference. For example, chemo might destroy the tumor’s outer cell layer, but the inner ones can develop resistance, so where single cells may die, a 3D mass will bounce back. Organoids can provide a window into these little-known mechanisms of drug resistance.

They can reveal how normal tissues turn malignant and where the cellular machinery goes off-track to allow that to happen. As their name suggests, organoids are scientists’ windows into organs, whether healthy or stricken with disease. You need to know your enemy to beat it, Plenker says, and cancer organoids offer that opportunity.

Taken from patients currently undergoing cancer treatments, these tumor chunks will reveal their weaknesses so scientists can find the cancers’ Achilles’ heel and devise personalized treatments. “Organoids are essentially patients in a dish,” Plenker says. Only unlike real patients, the organoids can be subjected to all sorts of harsh experiments to zero in on the precise chemo cocktails that destroy them in the best possible way.

And they will likely provide a more realistic scenario than drug tests in mice or rats, as animal models aren’t perfect proxies for humans.

These notorious killers don’t kill anyone. Instead, scientists devise the most potent ways to kill them.

The way that cancer proliferates in the body is hard to reproduce in the lab. Stem-cell research made it possible. After scientists spent a decade understanding how various cells multiply and differentiate into other cell types based on molecular cues and nourishment, they were able to make cells grow and fuse into tissues.

To stick together like bricks in a nicely laid wall, cells need a biological scaffold that scientists call an extracellular matrix or ECM, which in the body is made from collagen and other materials. Today, the same collagen scaffolds can be mimicked with a gooey substance called Matrigel—and then seeded with specific cells, which take root and begin to multiply.

Some tissue types were easy to grow—Columbia University scientists grew viable bones as early as 2010.1 Others, like kidney cells, were trickier. They would grow into immature tissues incapable of performing their job of cleaning and filtering blood. It took scientists time to realize that these cells wanted more than scaffolding and food—they needed to “feel at home,” or be in their natural habitat. Kidney cells needed the feeling of liquid being washed over them, the Harvard University group found, when they first managed to grow functioning kidney tissue in 2018.2

Cancers have their own growth requirements. In the body, they manage to co-opt the organism’s resources, but keeping them happy in a dish means catering to their dietary preferences. Different cancers need different types of molecular chow—growth factors, hormones, oxygen and pH levels, and other nutrients. Pancreatic adenocarcinoma thrives in low-oxygen conditions with poor nutrients.3 Glioblastomas feed on fatty acids.4 These nutrients are delivered to organoids via a specific solution called growth medium, which the lab personnel regularly doles out into the dishes.

Plenker is charged with keeping this murderous menagerie alive and well. He is the one who designs the cancers’ dietary menu, a specific protocol for each type. And while his official title is facility manager and research investigator who works closely with David Tuveson, director of the CSHL’s Cancer Center, he is essentially a cancer custodian, a curator of a unique collection that aims to change the paradigm of cancer treatment.

Plenker’s research area is pancreatic cancer—one of the most notorious killers known. Often diagnosed late and resistant to treatment, it is essentially a death sentence—only 8 to 10 percent of patients remain alive five years after diagnosis. The chemo drugs used to treat it haven’t changed in 40 years, Plenker says. In the past decade, physicians tried combining multiple drugs together with relative success. Identifying winning combos can save lives, or at least prolong them—and that’s what the organoids will help clinicians do better.

In a groundbreaking clinical trial called PASS-01 (for Pancreatic Adenocarcinoma Signature Stratification for Treatment), Plenker’s team collaborates with other American and Canadian colleagues to identify the most effective chemo cocktails and to understand the individual patients’ tumor behaviors, which would lead to more personalized treatments.5

Scientists know the same cancer types behave differently in different patients. Typically, all malignancies have the so-called “driver mutation”— the cancer’s main trigger caused by a mutated gene. But tumors also often have “passenger mutations” that happen in nearby genes. These additional mutated genes can generate various proteins, which may interfere with treatment.

Or not. Scientists call these mutated gene combinations tumor mutational signatures, which can vary from one patient to the next. With some cancers, doctors already know what mutations signatures they may have, but with pancreatic cancer they don’t have good tale-telling signs, or biomarkers. “There aren’t many biomarkers to help clinicians decide which chemo may be better for which patient,” explains oncologist Grainne O’Kane, who treats pancreatic cancer patients at the Princess Margaret Hospital in Toronto, Canada.

That’s the reason O’Kane participates in the PASS-01 trial—it will give doctors a better view into the exact specifics of their patients’ malignancies. As they take their patients’ biopsies, they are sending little cancer snippets to the CSHL to be grown into organoids, which will be subjected to chemo cocktails of various combinations to design more personalized regiments for them.

The hospital treats all patients with the so-called standard of care chemotherapy, which is more of a one-size-fits-all approach. Some patients will respond to it but others won’t, so the goal is to define the second line of chemo defense in a more personalized fashion. “That’s where the biopsies we send to Tuveson’s lab might be useful,” O’Kane says. “They can help us find something to benefit patients after the first line of chemo stopped working.”

Organoids are patients in a dish. Unlike real patients, organoids can be subjected to experiments.

Scientists can try all kinds of combos on the tumorous organoids, which they can’t do in living people. “You can treat 100 organoids with 100 different compounds and see which one works, or which compound does a good job and which ones don’t work at all,” Plenker says. That would also allow scientists to define the precise amount of chemo, so doctors wouldn’t have to over-treat patients with harsh drugs that create sickening side effects. Ultimately, organoids should take a lot of guesswork out of the process.

With about 150 patients’ adenocarcinomas already collected, the team hopes to come up with some answers. O’Kane says her team already has three patients for which they were able to design the more personalized second line of defense chemo, based on what their organoids revealed. They haven’t yet tried it, because the trial has only started recently, but this would be the next step.

“Being able to piece all this information together in real time as patients are moving through their therapies can really improve the outcomes,” O’Kane says. And while they may not be able to save all of those who graciously donated their biopsy snippets to science, it will help build better treatments in the future. “Even if we won’t be able to help these specific patients we’re hoping to use this info in the future clinical trials,” O’Kane says.

Organoids can also help understand how cancer develops. This is particularly true for breast cancers, says Camilla dos Santos, associate professor and a member of the CSHL Cancer Center. She studies the inner life of human mammary glands, more commonly referred to as breasts, and is also part of the cancer custodian crew. The hormonal changes that women go through during pregnancy subsequently modify breast cancer risk, sometimes lowering it and sometimes increasing—a complex interplay of the body’s chemicals.

“We know that women who get pregnant for the first time before they turn 25 years old, have a 30 percent decrease in breast cancer incidents later in life,” dos Santos says. “When they turn 60 or 70, 30 percent of them will not develop cancer.” On the contrary, those who are pregnant past 38 have a 30 to 50 percent increase in developing aggressive breast cancer types. Clearly, some molecular switches are involved, but they are very hard to study within the body. That’s where organoids can provide a window into the surreptitious process.

Using breast organoids, scientists can model the complex life of mammary glands at various stages of a woman’s life. And while most women wouldn’t want their breasts poked and pierced when they are pregnant or breastfeeding, many donate their tissues after breast reduction surgery or prophylactic mastectomy due to high-risk mutations like the BRCA gene.

That’s where organoids shine because scientists can not only grow them, but also give them the pregnancy hormonal cues, which will make cells generate milk, stop lactating, or do it again—and study the complex cellular interactions that take place in real life.

There’s a lot to study. At birth, mammary glands are similar in both genders—just little patches of the mammary epithelium tissue. But when puberty hits, the female glands fill up with the so-called mammary tree—a system of ducts for future milk production, which fully “blooms” in pregnancy.

“When a woman becomes pregnant, the duct tree expands, growing two types of cells—luminal and myoepithelial ones,” explains Zuzana Koledova, assistant professor of Masaryk University in Czech Republic who also uses organoids in her work. When the baby is born, the luminal cells, which line the inside of the ducts, produce the proteins that comprise milk.

The myoepithelial cells reside outside the ducts and work as muscles that squeeze the ducts to push milk out. Dos Santos likens this pregnancy mammary gland growth to the changes of the seasons. The images of sprouting ducts look like blossoming trees in the spring while later they shrivel like plants do in the fall.

The body governs these processes via the molecular machinery of hormones, which stimulate breast cells growth during pregnancy, and later cause them to die out. The two pregnancy-related hormones, prolactin and oxytocin, are responsible for milk production. Prolactin induces the luminal cells to make milk while oxytocin makes the myoepithelial cells contract. Once the baby is weaned, the levels of these hormones drop, causing cells to shrink back to their non-pregnant state.

With organoids scientists can observe these cellular dynamics at work. Koledova’s team had watched breast organoids secrete milk based on biological cues. They even recorded movies of cells pumping tiny milk droplets in the dish they were growing in. Using tiny snippets of donated breast tissue, the team grew the organoids inside the Matrigel matrix in the growth media and then added the two pregnancy hormones into the mix, explains Jakub Sumbal, a mammary gland researcher in Koledova’s group.

As they began to secret proteins that compose milk, the organoids, which looked like little domes inside the dish, changed from translucent to opaque. “At first, you can see through them, but then as they produce these proteins, they kind of darken,” Sumbal says. “And you can see them pushing out these little droplets.”

Cancer patients would no longer have to undergo chemotherapy by trial and error.

Dos Santos’s team, who also did similar work, outlined molecular changes that follow such dish-based hormonal cues in their recent study.6 In response to hormonal messages, cells produce proteins, which they display on their surfaces, like status symbols. During pregnancy the burgeoning cells prepping for milk production display the “proteins flags” that make them look important, attracting nourishment. When it’s time to die, they commit a cellular suicide.

They signal to the bypassing macrophages—immune system cleanup crew—to devour them. “They essentially say ‘come eat me!’ to the macrophages,” dos Santos says. “Because I’m no longer needed.”

The ability to mimic these processes in a dish, allows scientists to study the molecular switches that trigger breast cancer development—or minimize it. Scientists know that cancerous cells can hide from the immune system and even co-opt it into protecting themselves. They do it by displaying their own “do not eat me” protein flags on the surface and avoid destruction.

“Sometimes cancer cells can recruit specific types of immune cells to protect them,” dos Santos says. “They can not only say ‘do not eat me,’ but say ‘come hang out with me’ to the macrophages, and the macrophages will send suppressive signals to the B-cells or T-cells, the body defenders.” It is as if the cancer requests protection—a crew of guardians around it to defend against other cells that would otherwise wipe it out.

Scientists can’t telescope into the body to peek at these interactions, but they now can watch these stealth battles unfolding in a dish. “Right now we are looking at the proteins that are secreted by the organoids—the proteins that go on the surface of the organoids’ cells and what they would communicate to the immune system,” dos Santos says.

“Even when there’s no immune system surrounding them, they would still be doing that.” There’s a way to mimic the immune system, too. Scientists can add B-cells, T-cells, macrophages, and other players into the growth medium and watch the full-blown cellular warfare in action. “That’s the next step in our research,” dos Santos says.

Understanding what hormonal fluxes trigger breast cancer, and how it recruits other cells for safekeeping, can give scientists ideas for pharmaceutical intervention. “We can find drugs that pharmacologically turn off the switches that trigger cancer or interrupt its signaling for protection,” dos Santos says. “That opens novel ways to treat people.”

Can organoid research lead to a new standard of care for cancer patients? That’s the ultimate goal, researchers say. That’s why Plenker works at keeping his collection of cancer glops alive and well and thriving—he calls it a living biobank. And he keeps a stash in the cryogenic freezer, too.

He is also developing protocols that would allow commercial companies to grow organoids the same way chemical industries make reagents or mice suppliers grow rodents for research. A benefit of organoid experiments is they don’t involve animals at all.

Hospitals may one day start growing organoids from their patients’ biopsies to design and test personalized chemo cocktails for them. Once science crosses over to that reality, the entire treatment paradigm will change. Cancer patients won’t have to undergo chemotherapy by trial and error.

Instead their cancer organoids will be subjected to this process—knocked out by a gamut of drug combinations to find the winning one to use in the actual treatment. Plenker notes that once enough data is gathered about the tumors’ mutational signatures, scientists may create a database of tumor “mugshots” matching them to the chemo cocktails that beat them best.

And then just sequencing a biopsy sample would immediately inform oncologists what drug combo the patient needs. “We may be about 10 years away from that,” Plenker says, but for now there’s a lot more research to do. And a lot more cancers to grow.

By: Lina Zeldovich

Lina Zeldovich grew up in a family of Russian scientists, listening to bedtime stories about volcanoes, black holes, and intrepid explorers. She has written for The New York Times, Scientific American, Reader’s Digest, and Audubon Magazine, among other publications, and won four awards for covering the science of poop. Her book, The Other Dark Matter: The Science and Business of Turning Waste into Wealth, will be released in October 2021 by Chicago University Press. You can find her at LinaZeldovich.com and @LinaZeldovich.

Source: The Cancer Custodians – Issue 102: Hidden Truths – Nautilus

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Critics:

Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bleeding, prolonged cough, unexplained weight loss, and a change in bowel movements. While these symptoms may indicate cancer, they can also have other causes. Over 100 types of cancers affect humans.

Tobacco use is the cause of about 22% of cancer deaths. Another 10% are due to obesity, poor diet, lack of physical activity or excessive drinking of alcohol. Other factors include certain infections, exposure to ionizing radiation, and environmental pollutants. In the developing world, 15% of cancers are due to infections such as Helicobacter pylori, hepatitis B, hepatitis C, human papillomavirus infection, Epstein–Barr virus and human immunodeficiency virus (HIV).

These factors act, at least partly, by changing the genes of a cell. Typically, many genetic changes are required before cancer develops. Approximately 5–10% of cancers are due to inherited genetic defects. Cancer can be detected by certain signs and symptoms or screening tests. It is then typically further investigated by medical imaging and confirmed by biopsy.

Most cancers are initially recognized either because of the appearance of signs or symptoms or through screening. Neither of these leads to a definitive diagnosis, which requires the examination of a tissue sample by a pathologist. People with suspected cancer are investigated with medical tests. These commonly include blood tests, X-rays, (contrast) CT scans and endoscopy.

The tissue diagnosis from the biopsy indicates the type of cell that is proliferating, its histological grade, genetic abnormalities and other features. Together, this information is useful to evaluate the prognosis and to choose the best treatment.

Further reading

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