Category: Medical Research & Technology

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New Diabetes Management Device Combines Testing and Injection

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Photo by Lisa Fotios from Pexels

By combining blood glucose measurement with insulin administration in a single device, the complicated process of blood sugar management could be made easier for people with diabetes.

Patients with diabetes often use two types of insulin to control their blood sugar levels: long-acting insulin, which helps control glucose levels over a 24-hour period, and short-acting insulin, which is injected at mealtimes. Patients first measure their blood glucose levels with a glucose meter with a finger prick. They must also estimate how many carbohydrates are in their meal and combine this information with their blood glucose levels to calculate and inject the proper insulin dose.

Existing technologies such as continuous blood glucose monitors and insulin pumps can help with some parts of this process. However, these devices are not widely available, so most patients must rely on finger pricks and syringes. To this end, MIT researchers have developed devices to simplify the process, which they describe in the Journal of Controlled Release.

“Every day, many patients need to do this complicated procedure at least three times,” explained MIT postdoc Hen-Wi Huang. “The main goal of this project is to try to facilitate all of these complex procedures and also to eliminate the requirement for multiple devices. We also used a smartphone camera and deep learning to create an app that identifies and quantifies food content, which can aid in carbohydrate counting.”

The researchers came up with two all-in-one devices, both of which incorporate the new smartphone app. Using a photo, the app estimates the volume of food and carbohydrate content.

The first device that consolidates many of the existing tools that patients use now, including a lancet for drawing blood and glucose test strips. The device conveys blood glucose information to the smartphone app via Bluetooth, and the app works out the correct insulin dose, delivered via a needle in the same device.

“What our device is doing is automating the procedures to prick the skin, collect the blood, calculate the glucose level, and do the computation and insulin injection,” Dr Huang says. “The patient no longer needs a separate lancing device, glucose meter, and insulin pen.”

Many of the components included in this device are already FDA-approved, but the device has not been tested in human patients yet. Tests in pigs showed that the system could accurately measure glucose levels and dispense insulin.

For their second device, the researchers wanted to come up with a system that would require just one needle prick. To achieve that, they designed a novel glucose sensor that could be incorporated into the same needle that is used for insulin injection.

The researchers designed a flexible electronic sensor that can be attached to the needle and measure glucose levels in the interstitial fluid, just below the surface of the skin. Once the needle penetrates the skin, it takes between five and 10 seconds to measure the glucose levels. This information is transmitted to the smartphone app, which calculates the insulin dose and delivers it through the inserted needle.

In tests in the pigs, the researchers showed that they could accurately measure glucose levels with this system, and that glucose levels dropped after insulin injection.

Because this device uses a novel type of glucose sensor, the researchers expect that it will require further development to get to a point where it could be tested in patients.

Source: MIT

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Why Public ‘Big Data’ Initiatives Failed to Deliver on COVID

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Source: Pixabay

Experts from a data-driven initiative to aid the COVID response have outlined major obstacles to making successful use of new data released by technology companies in times of crisis. Harvard University’s Caroline Buckee and colleagues presented these views in the open-access journal PLOS Digital Health.

Technology companies collect vast amounts of data on their users, including their geographic locations. During the COVID pandemic, many companies made some of their user data available in order to aid public health efforts, such as monitoring the impact of social distancing policies or travel restrictions. However, Buckee and colleagues note, many efforts to harness these “data for good” failed to make a significant impact.

The authors are part of Crisis Ready, in which epidemiologists help policy makers understand and use insights from human mobility data released by technology companies. In this capacity, they have now identified challenges that hinder other efforts to use novel forms of data as part of disaster response.

Firstly, data-sharing agreements between researchers and technology companies were hastily arranged during the pandemic. They recommend pre-established agreements that will be ready for implementation in future crises.

Buckee and colleagues also observed that a lack of standardisation, interoperability, and clarity on uncertainties or biases in novel datasets resulted in the need for highly specialised professionals to process this data. To address this challenge, data access and characteristics can be negotiated prior to a disaster.

The authors also call for global investment in training more professionals that can analyse complex data to provide information in a disaster. In addition, they strongly emphasise the need for local response agencies to collaborate closely with regional scientists.

Without such efforts, no amount of data donated by technology companies will be useful in a crisis.

“It is still very difficult to translate the vast amounts of digital data that are owned by companies into useful public health tools, despite their incredible potential for transforming decision-making during health emergencies,” said Buckee. “We need to build a global cohort of data scientists and epidemiologists who can support local governments, and put in place the data pipelines and analysis tools before disasters hit, so that local responders have context-specific information when they need it most.”

Source: News-Medical.Net

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New Coating Makes the Nanomedicine Go Down

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Upon injection into the blood, nanomedicines (blue spheres) are immediately attacked by proteins of the immune system called complement proteins (orange). Complement proteins cause rapid destruction of the nanomedicine, and also induce an anaphylaxis-like reaction. By attaching complement-degrading proteins (yellow ninjas made of protein) to the surface of nanomedicines, Penn researchers have largely solved this problem, potentially allowing more diseases to be safely treated by nanomedicine. Credit: University of Pennsylvania

In nanomedicine, immune reactions against the nanoparticles that contain the medicine or vaccine, reducing its effectiveness. Researchers have now come up with a new method to prevent the body from treating nanomedicines like foreign invaders, by covering those nanoparticles with a coating to suppress the immune response.

As soon as they are injected into the bloodstream, unmodified nanoparticles are swarmed by complement proteins, triggering an inflammatory response and preventing the nanoparticles from reaching their treatment targets. Penn Medicine researchers, whose findings are published in Advanced Materials, have devised a coating for nanoparticles that suppresses complement activation.

Nanoparticles are tiny capsules, typically made from proteins or fat-related molecules, that contain certain types of treatment or vaccine. The best-known examples of nanoparticle-delivered medicines are mRNA COVID vaccines.

“It turned out to be one of those technologies that just works right away and better than anticipated,” said study co-senior author Jacob Brenner, MD, PhD.

RNA- or DNA-based therapies generally need delivery systems to get them through the bloodstream into target organs. Harmless viruses often have been used as carriers or “vectors” of these therapies, but nanoparticles are increasingly considered safer alternatives. Nanoparticles also can be tagged with antibodies or other molecules that make them hone in precisely on targeted tissues.

The complement attack problem has been a serious impediment to nanomedicine. Circulating complement proteins treat nanoparticles as if they were bacteria, immediately coating nanoparticle surfaces and summoning macrophages to engulf them. Researchers have attempted to reduce the problem by pre-coating nanoparticles with camouflaging molecules, such as forming a watery, protective shell around nanoparticles using polyethylene glycol (PEG).

But nanoparticles camouflaged with substances like PEG still draw at least some complement attack. In general, nanoparticle-based medicines that move through the bloodstream (mRNA COVID vaccines are injected into muscle, not the bloodstream) have had a very low efficiency in getting to their target organs, usually under 1%.

In the study, the researchers came up with a new approach to protect nanoparticles, based on natural complement-inhibitor proteins that circulate in the blood, attaching to human cells to help protect them from complement attack.

In vitro tests using standard PEG-protected nanoparticles with one of these complement inhibitors, called Factor I, provided dramatically better protection from complement attack. In mice, the same strategy prolonged the half-life of standard nanoparticles in the bloodstream, allowing a much larger fraction of them to reach their targets.

“Many bacteria also coat themselves with these factors to protect against complement attack, so we decided to borrow that strategy for nanoparticles,” said co-senior author Jacob Myerson, PhD, a senior research scientist in the Department of Systems Pharmacology and Translational Therapeutics at Penn.

In a set of experiments in mouse models of severe inflammatory illness, the researchers also showed that attaching Factor I to nanoparticles prevents the hyper-allergic reaction that otherwise could be fatal.

Further testing will be needed before nanomedicines incorporating Factor I can be used in people, but in principle, the researchers said, attaching the complement-suppressing protein could make nanoparticles safer and more efficient as therapeutic delivery vehicles so that they could be used even in severely ill patients.

The researchers now plan other protective strategies for medical devices, such as catheters, stents and dialysis tubing, which are similarly susceptible to complement attack. They also plan to investigate other protective proteins.

“We’re recognising now that there’s a whole world of proteins that we can put on the surface of nanoparticles to defend them from immune attack,” Dr Brenner said.

Source: University of Pennsylvania School of Medicine

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Space Could be Ideal Place for Stem Cell Production

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Astronaut Raja Chari sequences DNA from bacteria samples to understand the microbial environment on the International Space Station. Credit: NASA

The lack of gravity in outer space could be the key to the efficient production of large quantities of stem cells. Scientists at Cedars-Sinai have found that the microgravity environment in space stations can potentially aid life-saving advances on Earth by facilitating the rapid mass production of stem cells.

A new paper in Stem Cell Reports outlines key opportunities discussed at a space biomanufacturing symposium to expand the manufacture of stem cells in space.

With new rocket technology, the cost of access to space has plummeted, opening up new opportunities for research and industry, as well as spaceflight by private citizens. Biomanufacturing of therapeutic and research biomaterials can be more productive in microgravity conditions.

“We are finding that spaceflight and microgravity is a desirable place for biomanufacturing because it confers a number of very special properties to biological tissues and biological processes that can help mass produce cells or other products in a way that you wouldn’t be able to do on Earth,” said stem cell biologist Arun Sharma, PhD, head of a new Cedars-Sinai research laboratory.

“The last two decades have seen remarkable advances in regenerative medicine and exponential advancement in space technologies enabling new opportunities to access and commercialise space,” he said.

Attendees at the virtual space symposium in December identified more than 50 potential commercial opportunities for conducting biomanufacturing work in space, according to the Cedars-Sinai paper. The most promising fell into three categories: Disease modelling, biofabrication, and stem-cell-derived products.

Scientists use disease modelling, to study diseases and possible treatments by replicating full-function structures – whether using stem cells, organoids or other tissues.

Decades of spaceflight experience has shown that when the body is exposed to low-gravity conditions for extended periods of time, it experiences accelerated bone loss and ageing. By developing disease models based on this accelerated ageing process, research scientists can better understand the mechanisms of the ageing process and disease progression.

“Not only can this work help astronauts, but it can also lead to us manufacturing bone constructs or skeletal muscle constructs that could be applied to diseases like osteoporosis and other forms of accelerated bone ageing and muscle wasting that people experience on Earth,” explained Dr Sharma.

Biofabrication, another major topic of discussion at the symposium, produces materials like tissues and organs with 3D printing a core technology.

A major issue with biofabrication on Earth involves gravity-induced density, which makes it hard for cells to expand and grow. This requires the use of scaffolding structures, but it generally cannot support the small, complex shapes found in vascular and lymphatic pathways. With the lack of gravity in space, scientists are hopeful that they can use 3D printing to print unique shapes and products, like organoids or cardiac tissues, in a way that can’t be replicated on Earth. This technology is being tested on the International Space Station.

The third category has to do with the production of stem cells and understanding how some of their fundamental properties are influenced by microgravity. Some of these properties include potency, or the ability of a stem cell to renew itself, and differentiation, the ability for stem cells to turn into other cell types.

Understanding some of the effects of spaceflight on stem cells can potentially lead to better ways to manufacture large numbers of cells in the absence of gravity. In coming months, Cedars-Sinai scientists will send stem cells into space to test whether it is possible to produce large batches in a low gravity environment.

“While we are still in the exploratory phase of some of this research, this is no longer in the realm of science fiction,” Dr Sharma said. “Within the next five years we may see a scenario where we find cells or tissues that can be made in a way that is simply not possible here on Earth. And I think that’s extremely exciting.”

Source: Cedars-Sinai Medical Center

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Cannabis Use Risks Harmful Drug–Drug Interactions

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Photo by Crystalweed Cannabis on Unsplash

Using cannabis alongside other drugs may come with a significant risk of harmful drug-drug interactions, according to a pair of new studies in the journal Drug Metabolism and Disposition.

The researchers examined cannabinoids and their major metabolites found in the blood of cannabis users and found that they interfere with two families of enzymes that help metabolise a wide range of prescription drugs. Because of this, the drugs’ effectiveness might decrease or their negative effects might increase with too much building up in the body, causing unintended side effects such as toxicity or accidental overdose.

The authors note that despite the early stage of this research, it is important to be careful when using cannabis with other prescription drugs.

“Physicians need to be aware of the possibility of toxicity or lack of response when patients are using cannabinoids,” said Professor Philip Lazarus, senior author on the papers. “It’s one thing if you’re young and healthy and smoke cannabis once in a while, but for older people who are using medications, taking CBD or medicinal marijuana may negatively impact their treatment.”

One study focused on a family of enzymes known as cytochrome P450s (CYPs), whereas the other looked at UDP-glucuronosyltransferases (UGTs), another enzyme family. Together, these two enzyme families help metabolise and eliminate more than 70% of the most commonly used drugs from the body.

While some previous research focused on potential drug interactions caused by cannabinoids, this new research provides the first known comprehensive look at the interaction between three of the most abundant cannabinoids (tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN)) and their metabolites and all of the major CYP enzymes. This is also the first known research that looked for interactions between these cannabinoids and UGT enzymes, specifically.

“Cannabinoids stay in your body only for about 30 minutes before they are rapidly broken down,” said first author Shamema Nasrin. “The metabolites that result from that process stay in your body for much longer – up to 14 days – and at higher concentrations than cannabinoids and have been overlooked in previous studies, which is why we thought we should focus on those as well.”

Using human kidney cells, they found that cannabinoids and the major THC metabolites strongly inhibited several CYP enzymes. One key discovery was that one of the most abundant THC metabolites, called THC-COO-Gluc seems to play a major role in inhibiting several key enzymes in the liver. Looking at the UGT enzyme family, the researchers found that all three cannabinoids, but especially CBD, inhibited two of the primary UGT enzymes present in the liver. CBD was also found to block three enzymes that account for about 95 percent of kidney UGT metabolism, which helps clear toxins and certain drugs from the body.

“If you have a kidney disease or you are taking one or more drugs that are metabolised primarily through the kidney and you’re also smoking marijuana, you could be inhibiting normal kidney function, and it may have long-term effects for you,” Prof Lazarus said.

Nasrin added that these interactions between CBD and UGT enzymes could be inhibiting kidney function in patients with acute kidney disease or kidney cancer, who may be using CBD to treat pain or to try to reduce the side effects from anti-cancer drugs.

“Taking CBD or marijuana might help your pain but could be making the other drug you’re taking more toxic, and that increase in toxicity may mean that you can’t continue taking that drug,” Nasrin said. “So, there could be serious ramifications for anti-cancer drugs, and that’s only one example of the many drugs that could potentially be affected by the cannabinoid-enzyme interactions we’re seeing.”

Source: Washington State University

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US Army Scientists Develop Novel Anthrax Treatment

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Capsule removal from Bacillus anthracis by treatment with Capsule Depolymerase (capsule shown in red). Credit: Photomicrograph by Wilson J. Ribot, USAMRIID

By modifying an enzyme produced by the bacterium that causes anthrax, US Army scientists were able to protect mice from infection with the deadly disease. 

Their findings, published in Science Translational Medicine, suggest a potential therapeutic strategy for treating multidrug-resistant strains of anthrax, and could aid in the development of new treatments for other bacterial infections.

Bacillus anthracis, the bacterium that causes anthrax, is one of the most significant bioterrorism threats, as well as a public health challenge in many places around the world. Its disease-causing capability arised from three main components – lethal toxin, oedema toxin, and the capsule. Researchers in this study developed a method to degrade the capsule surrounding the bacterium, allowing it to be ingested and destroyed by white blood cells, reducing virulence.

There is increasing concern about strains of anthrax that appear to be resistant to treatment with known antibiotics, said Arthur M. Friedlander, MD, the paper’s senior author. He and his team explored alternative treatment approaches that do not rely on the use of antibiotic drugs.

One promising avenue is to make the bacterium more susceptible to the innate immune system. Enzymes known as capsular depolymerases, which are naturally produced by several classes of bacteria, have emerged as a potential new line of antivirulence agents.

“Identification of the capsule depolymerase enzyme within the anthrax bacillus led us to attempt to use that enzyme to remove the capsule,” said Friedlander. “When this proved successful, we utilised recombinant DNA technology and protein engineering methods to engineer and reconfigure the enzyme in new ways.”

Those “engineering changes” included enhancing stability and making production easier, and pegylation, to improve pharmacokinetics. The team then tested the pegylated enzyme, known as PEG-CapD-CPS334C, to be sure it had retained its enzymatic activity.

In the study, 10 out of 10 mice infected with anthrax spores from a nontoxigenic encapsulated strain were completely protected after treatment with PEG-CapD-CPS334C, compared to only 1 of 10 control mice surviving. Similarly, treatment of mice infected with a fully virulent encapsulated strain using PEG-CapD-CPS334C protected 8 of 10, while only 2 of 10 controls survived.

“This strategy renders B. anthracis susceptible to the innate immune responses and does not rely on antibiotics,” the authors concluded. “These findings suggest that enzyme-catalysed removal of the capsule may be a potential therapeutic strategy for the treatment of multidrug-resistant anthrax and other bacterial infections.”

It could also allow the treatment of soldiers exposed to anthrax through natural means or enemy attacks.

Source: EurekAlert!

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Differences in Drug Onset Explain Development of Resistance

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HIV invading a human cell
HIV invading a human cell: Credit NIH

Researchers examining the development of resistance to HIV drugs have uncovered a mechanism of drug resistance development in combination therapy, where ‘windows’ open up for resistance to develop.

In the late 1980s, when HIV treatments were first introduced, patients would often develop resistance to those treatments within six months. The introduction of triple-drug treatment regimens in the 1990s was intended to rectify that. Even if the virus developed resistance to one drug, two others would still knock it out – in theory. Unfortunately, some patients still develop resistance, leaving scientists with a critical question to answer: Why?

“There’s all these things that we still don’t understand, like why do we even get resistance when treating with three drugs,” said San Francisco State University Associate Professor of Biology Pleuni Pennings. “We understand why it is becoming less common, but it should have been zero all along.”

Prof Pennings and her colleagues offer explanations for this phenomenon in a study published in eLife.

Several interesting observations were noted from analysis of HIV patient records. Drug resistance can evolve years after successful therapy, often the result of sequential mutations that occur in a predictable order. Current models could not explain these observations, and while some studies identify mutations that confer drug resistance, they don’t address how and where they arise.

Drawing on two computational models, the researchers suggest that these observations may result from drug heterogeneity over time and throughout the body. While patients receive three HIV therapies simultaneously, drugs have different half-lives and patients do not always adhere to therapy regimens. This could create opportunities for drug resistance evolution, during a window when only one drug is active. Drugs also don’t uniformly penetrate the entire body, meaning that in some locations in a patient’s body, only one of the drugs might be active, creating another evolution and escape opportunity.

“I think one main reason why we should care is actually not because of HIV but because of drug resistance in other situations,” Prof Pennings explained.

Although drug resistance among patients with HIV is fairly low, drug resistance to multidrug therapies is a big problem for diseases such as malaria and tuberculosis. In addition, the COVID pandemic and the rise of variants show how our understanding of evolving pathogens is still lacking.

“In a way, HIV is the poster child of how we solved drug resistance. … [But] if we don’t understand how we did it, then it’s really hard to take these lessons to other situations,” Prof Pennings said.

Source: San Francisco State University

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Understanding Mechanisms of Antibiotic Resistance

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Source: NCI

If nothing is done, the problem of multidrug-resistant bacterial infections could be catastrophic by 2050, killing nearly 10 million people each year, according to experts’ predictions.

One person seeking solutions is Joseph Boll, assistant professor of biology at The University of Texas at Arlington, to identify and inhibit the defense mechanisms of Acinetobacter baumannii, a common pathogen in hospitals and clinical settings.

A. baumannii can cause infections in the blood, urinary tract and lungs, or in wounds in other parts of the body. Antibiotics are usually used to treat the infections, but many strains are resistant, including drugs of last resort, carbapenems.

“In previous research, we discovered that when A. baumannii experiences stress, such as antibiotic treatment, it modifies its cell envelope to tolerate the antibiotic for extended periods of time,” Prof Boll said. “Specific modifications allow the bacteria to survive long enough to acquire true antibiotic resistance, which can lead to antibiotic treatment failure. This can happen within 24 hours of antibiotic exposure.”

His team expects to identify what adaptations in the cell envelope allow the pathogen to survive in the presence of antibiotics and how survival contributes to the acquisition of true resistance.

In a recent study published in mBio, the team demonstrated that two LD-transpeptidase enzymes remodel A. baumannii’s cell envelope to promote its survival when under stress, such as the kind experienced during antibiotic treatment.

With this breakthrough, Hannah Bovermann, a senior double-major in biology and microbiology, is dissecting the genes that encode the bacteria’s LD-transpeptidases to learn what stress conditions induce their activation. She isolates the LD-transpeptidase promoters, the part of the DNA that controls when other parts of DNA are used, and glues it to a different gene whose function is to turn the bacterial cell blue. When the cell is in an environment where it wants to modify its cell envelope to protect itself, it turns blue, letting her observe the timing of the change.

To provoke this reaction, she administers antibiotics, experiments with various temperature changes, exposes the cell to pH gradients and subjects the cell to nutrient deprivations.

“Each response brings us closer to an understanding of how cell envelope modifications keep the bacterial cell intact in stress,” Bovermann said.

The researchers hope to find new targets on the cell surface for antibiotics to attack, strengthening existing medications’ potency against A. baumannii infections.

Clinicians have been pushed into using combinatorial therapies, where multiple drugs are employed to treat bacterial infections, but even those methods are becoming increasingly ineffective, Prof Boll said.

“It has become a game. Researchers discover a new antimicrobial, then bacteria become resistant to it. We are running out of options,” Prof Boll said. “Bacterial resistance is quickly outpacing new antibiotic development.”

Source: EurekAlert!

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Nicotine Linked to Sleep Apnoea Risk

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Source: Pawel Czerwinski on Unsplash

In a first-of-its-kind, scientists from the Heart Research Institute (HRI) have made the link between amounts of nicotine in the blood and their sleep apnoea risk.

Sleep apnoea occurs when a person’s throat and upper airway become partly or totally blocked during sleep, causing short periods where breathing ceases.

In a new paper published in ESC Heart Failure, Heart Research Institute (HRI) scientists found increases in nicotine levels were associated with a 2.3 minute increase in the time spent with oxygen saturations below 90%.

One of the markers of severity of sleep apnoea is time spent with an oxygen saturation less than 90%.

Lead researcher Dr John O’Sullivan, said this meant that for every cigarette a person smoked, the more they increased the risk of “dangerously low” oxygen levels.

“People who spend more time with an oxygen saturation less than 90 percent end up with more cardiovascular death than people who don’t,” Dr O’Sullivan said.

“We know smoking is bad for the heart – it’s one of the major risks for heart attacks – and although smoking is known to reduce oxygen concentration in the blood, the interaction of smoking with sleep apnoea has not been quantified. Using blood concentrations of the major nicotine metabolite, we were able for the first time to quantify the effect of smoking on oxygen concentrations at night in people with sleep apnoea.

“A standardised increase in levels of this metabolite was associated with 2.3 more minutes with an oxygen concentration less than 90 percent in people with sleep apnea. Time with an oxygen concentration less than 90% is a proven indicator of bad cardiovascular outcome.”

Sleep apnoea and congestive heart failure comorbidities are common, but their interaction is unclear. To find out more, Dr O’Sullivan’s team used hundreds metabolites to understand this interaction.

“Believe it or not, stiff heart failure – when the heart muscle can still pump blood but is stiff and cannot relax properly – is the most common form of heart failure today and we have almost no treatment options,” Dr O’Sullivan said.

“We measured molecules in the blood called metabolites and looked at the changes in these metabolites and related these to the severity of sleep apnoea.”

Metabolomics is a relatively new field of study that investigates metabolites, which are the components of your metabolism and play key roles in disease. They can provide insight into how one disease is linked to another, like in this case the consequences of sleep apnea and heart failure. Several metabolites are also key fuels for the working heart, and others form the units of energy by which the heart works.

The team studied metabolites and lipids in 3443 people from two US studies, including the landmark Framingham study.

Dr O’Sullivan said Framingham was known as the “town that changed America” because of the multi-generational study started in 1948 that subsequently identified the cardiovascular risk factors we still use today. Much research using this study is openly available internationally, enabling researchers around the world.

“Accurate measurement of disease combined with blood metabolite levels is far more accurate than self-reported questionnaires – that’s one of the strengths of this study,” he said.

While sleep apnoea is very common (up to one in four adults), its consequences and interactions with other diseases remain poorly understood. Almost no studies  have sleep study data, heart failure data, and metabolomic data in the same individuals, which is a major new feature of this study.

Source: Heart Research Institute

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Why Some Drugs Have Side Effects

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Photo by Myriam Zilles on Unsplash

Researchers have discovered how unwanted side effects can result from how some drugs affect various membrane-spanning proteins in addition to their intended target. The findings, published in PNAS, illuminate one of the main problems of drug discovery and point to new strategies to overcome it.

Any class of drug can have side effects, but those that interact directly with cellular membranes have been especially problematic. “Those drugs tend to affect many membrane proteins, and we suspected that there’s some kind of non-specific mechanism at work,” said first author Dr Radda Rusinova, assistant professor of research in physiology and biophysics at Weill Cornell Medicine. “We wanted to see whether it could be linked to the cell membrane.”

Dr Rusinova and her colleagues used sensitive assays that allowed them to compare how different drugs affected the activities of two channel proteins that span membranes: the gramicidin ion channel and a potassium channel called KcsA. Gramicidin was used to measure the magnitude of drugs’ effect on the membrane while KcsA reflected effects these drugs could have on typical membrane proteins.  They found that membrane-associated drugs can affect KcsA in at least three ways: by interacting directly with the proteins, by interfering with the proteins’ structural connections to the membrane, or by causing broad changes in membrane characteristics such as thickness or elasticity.

Changes in membrane characteristics have well-known effects on the gramicidin ion channel, an antibiotic isolated from bacteria that has long been used as a standard tool for studying such changes. “Gramicidin is a probe essentially for changes in bilayer and membrane properties, and will report on the magnitude of the changes,” said Dr. Rusinova.

“But we needed to go further to see how a more typical cell membrane protein would react,” Dr. Rusinova said. KcsA belongs to a class of proteins – potassium channels – that drive many aspects of cell physiology in everything from bacteria to humans, making it a good comparative probe.

The comparative assay results revealed a more nuanced process than the  straightforward model currently used to explain how membrane-binding drugs can affect membrane-spanning proteins.

“The more data that Dr Rusinova got, the more it became apparent that this simple model did not actually cover the full spectrum of effects that we saw,” said senior author Dr Olaf Andersen, professor of physiology and biophysics.

“The investigators who are looking into molecules that can move into the cell membrane need to worry about at least three mechanisms for off-target effects,” Dr Rusinova said.

However, not all is bad news: in some cases, off-target effects at the cellular level cause no trouble to the organism, and in a few instances they can even be beneficial. Dr Rusinova points to two of the drugs her team tested as an example: amiodarone, a heart medication whose membrane-mediated effects actually boost its efficacy, and troglitazone, an anti-diabetic drug whose side effects included liver toxicity, ultimately forcing regulators to pull it from the market.

The investigators hope to develop more predictive models for such off-target effects. “We would like to determine the structural characteristics of a membrane protein that would make it more or less sensitive to bilayer effects,” Dr Rusinova said.

Source: Weill Cornell Medicine