Tag Archives: drugs

AI Makes Gigantic Leap And Heralds A Revolution In Biology

An artificial intelligence (AI) network developed by Google AI offshoot DeepMind has made a gargantuan leap in solving one of biology’s grandest challengesdetermining a protein’s 3D shape from its amino-acid sequence.

DeepMind’s program, called AlphaFold, outperformed around 100 other teams in a biennial protein-structure prediction challenge called CASP, short for Critical Assessment of Structure Prediction. The results were announced on 30 November, at the start of the conference — held virtually this year — that takes stock of the exercise.

A protein’s function is determined by its 3D shape

This is a big deal,” says John Moult, a computational biologist at the University of Maryland in College Park, who co-founded CASP in 1994 to improve computational methods for accurately predicting protein structures. “In some sense the problem is solved.

The ability to accurately predict protein structures from their amino-acid sequence would be a huge boon to life sciences and medicine. It would vastly accelerate efforts to understand the building blocks of cells and enable quicker and more advanced drug discovery.

AlphaFold came top of the table at the last CASP — in 2018, the first year that London-based DeepMind participated. But, this year, the outfit’s deep-learning network was head-and-shoulders above other teams and, say scientists, performed so mind-bogglingly well that it could herald a revolution in biology.

It’s a game changer,” says Andrei Lupas, an evolutionary biologist at the Max Planck Institute for Developmental Biology in Tübingen, Germany, who assessed the performance of different teams in CASP. AlphaFold has already helped him find the structure of a protein that has vexed his lab for a decade, and he expects it will alter how he works and the questions he tackles. “This will change medicine. It will change research. It will change bioengineering. It will change everything,” Lupas adds.

Source: https://www.nature.com/

Bringing drugs to the brain to treat neurodegenerative diseases

The blood-brain barrier is the main obstacle in treating neurodegenerative diseases such as Alzheimer and Parkinson. According to a recent study conducted by Jean-Michel Rabanel, a postdoctoral researcher under the supervision of Professor Charles Ramassamy, nanoparticles with specific properties could cross this barrier and be captured by neuronal cells. Researchers are confident that these results will open important prospects for releasing drugs directly to the brain. This breakthrough finding would enable improved treatment for neurodegenerative diseases affecting more than 565,000 Canadians, including 141,000 Quebecers.

The blood-brain barrier filters out harmful substances to prevent them from freely reaching the brain. But this same barrier also blocks the passage of drugs,” explains the pharmacologist Charles Ramassamy. Typically, high doses are required to get a small amount of the drug into the brain. What remains in the bloodstream has significant side effects. Often, this discomfort leads the patient to stop the treatment.  The use of nanoparticles, which encapsulate the drugs, would result in fewer collateral side effects while increasing brain efficiency.

To prove the effectiveness of this method, the research team first tested it on cultured cells, then on zebrafish. “This species offers several advantages. Its blood-brain barrier is similar to that of humans and its transparent skin makes it possible to see nanoparticles’ distribution almost in real time,” says Professor Ramassamy, Chairholder of the Louise and André Charron Research Chair on Alzheimer’s disease, from the Fondation Armand-Frappier.

Using in vivo tests, researchers were able to observe the crossing of the blood-brain barrier. They also confirmed the absence of toxicity in the library of selected nanoparticles. “We made the particles with polylactic acid (PLA), a biocompatible material that is easily eliminated by the body. A layer of polyethylene glycol (PEG) covers these nanoparticles and makes them invisible to the immune system, so they can longer circulate in the bloodstream,” he explains.

The findings have been published in the Journal of Controlled Release.

http://www.inrs.ca

All-Terrain NanoRobot Flips Through A Live Colon

A rectangular robot as tiny as a few human hairs can travel throughout a colon by doing back flips, Purdue University engineers have demonstrated in live animal models. Why the back flips? Because the goal is to use these robots to transport drugs in humans, whose colons and other organs have rough terrain. Side flips work, too. Why a back-flipping robot to transport drugs? Getting a drug directly to its target site could remove side effects, such as hair loss or stomach bleeding, that the drug may otherwise cause by interacting with other organs along the way.

The study, published in the journal Micromachines, is the first demonstration of a microrobot tumbling through a biological system in vivo. Since it is too small to carry a battery, the microrobot is powered and wirelessly controlled from the outside by a magnetic field.


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When we apply a rotating external magnetic field to these robots, they rotate just like a car tire would to go over rough terrain,” said David Cappelleri, a Purdue associate professor of mechanical engineering. “The magnetic field also safely penetrates different types of mediums, which is important for using these robots in the human body.

The researchers chose the colon for in vivo experiments because it has an easy point of entry – and it’s very messy. “Moving a robot around the colon is like using the people-walker at an airport to get to a terminal faster. Not only is the floor moving, but also the people around you,” said Luis Solorio, an assistant professor in Purdue’s Weldon School of Biomedical Engineering. “In the colon, you have all these fluids and materials that are following along the path, but the robot is moving in the opposite direction. It’s just not an easy voyage.

But this magnetic microrobot can successfully tumble throughout the colon despite these rough conditions, the researchers’ experiments showed. The team conducted the in vivo experiments in the colons of live mice under anesthesia, inserting the microrobot in a saline solution through the rectum. They used ultrasound equipment to observe in real time how well the microrobot moved around.

Source: https://www.purdue.edu/

Antibodies + Immunotherapy Result In Complete Elimination Of Tumors

Immunotherapy has revolutionized cancer treatment by stimulating the patient’s own immune system to attack cancer cells, yielding remarkably quick and complete remission in some cases. But such drugs work for less than a quarter of patients because tumors are notoriously adept at evading immune assault.

A new study in mice by researchers at Washington University School of Medicine in St. Louis has shown that the effects of a standard immunotherapy drug can be enhanced by blocking the protein TREM2, resulting in complete elimination of tumors. The findings, which are published in the journal Cell, point to a potential new way to unlock the power of immunotherapy for more cancer patients.

Immune cells infiltrate a human tumor in the four colorized images above. In a mouse study, researchers at Washington University School of Medicine in St. Louis have found that an antibody that targets the protein TREM2 empowers tumor-destroying immune cells and improves the effectiveness of cancer immunotherapy.

Essentially, we have found a new tool to enhance tumor immunotherapy,” said senior author Marco Colonna, MD, the Robert Rock Belliveau, MD, Professor of Pathology. “An antibody against TREM2 alone reduces the growth of certain tumors, and when we combine it with an immunotherapy drug, we see total rejection of the tumor. The nice thing is that some anti-TREM2 antibodies are already in clinical trials for another disease. We have to do more work in animal models to verify these results, but if those work, we’d be able to move into clinical trials fairly easily because there are already a number of antibodies available.”

T cells, a kind of immune cell, have the ability to detect and destroy tumor cells. To survive, tumors create a suppressive immune environment in and around themselves that keeps T cells subdued. A type of immunotherapy known as checkpoint inhibition wakes T cells from their quiescence so they can begin attacking the tumor. But if the tumor environment is still immunosuppressive, checkpoint inhibition alone may not be enough to eliminate the tumor.

An expert on the immune system, Colonna has long studied a protein called TREM2 in the context of Alzheimer’s disease, where it is associated with underperforming immune cells in the brain. Colonna and first author Martina Molgora, PhD, a postdoctoral researcher, realized that the same kind of immune cells, known as macrophages, also were found in tumors, where they produce TREM2 and promote an environment that suppresses the activity of T cells.

When we looked at where TREM2 is found in the body, we found that it is expressed at high levels inside the tumor and not outside of the tumor,” Colonna said. “So it’s actually an ideal target, because if you engage TREM2, you’ll have little effect on peripheral tissue.”

Colonna and Molgora — along with colleagues Robert D. Schreiber, PhD, the Andrew M. and Jane M. Bursky Distinguished Professor; and William Vermi, MD, an immunologist at the University of Brescia — set out to determine whether inhibiting TREM2 could reduce immunosuppression and boost the tumor-killing powers of T cells. As part of this study, the researchers injected cancerous cells into mice to induce the development of a sarcoma.

The mice were divided into four groups. In one group, the mice received an antibody that blocked TREM2; in another group, a checkpoint inhibitor; in the third group, both; and the fourth group, placebo. In the mice that received only placebo, the sarcomas grew steadily. In the mice that received the TREM2 antibody or the checkpoint inhibitor alone, the tumors grew more slowly and plateaued or, in a few cases, disappeared. But all of the mice that received both antibodies rejected the tumors completely. The researchers repeated the experiment using a colorectal cancer cell line with similarly impressive results.

Source: https://medicine.wustl.edu/

Blood Iron Levels Are Key To Slowing Ageing

Genes that could help explain why some people age at different rates to others have been identified by scientists. The international study using genetic data from more than a million people suggests that maintaining healthy levels of iron in the blood could be a key to ageing better and living longer. The findings could accelerate the development of drugs to reduce age-related diseases, extend healthy years of life and increase the chances of living to old age free of disease, the researchers say.

Scientists from the University of Edinburgh and the Max Planck Institute for Biology of Ageing in Germany focused on three measures linked to biological ageinglifespan, years of life lived free of disease (healthspan), and being extremely long–lived (longevity). Biological ageing – the rate at which our bodies decline over time – varies between people and drives the world’s most fatal diseases, including heart disease, dementia and cancers. The researchers pooled information from three public datasets to enable an analysis in unprecedented detail. The combined dataset was equivalent to studying 1.75 million lifespans or more than 60,000 extremely long-lived people. The team pinpointed ten regions of the genome linked to long lifespan, healthspan and longevity. They also found that gene sets linked to iron were overrepresented in their analysis of all three measures of ageing. The researchers confirmed this using a statistical method – known as Mendelian randomisation – that suggested that genes involved in metabolising iron in the blood are partly responsible for a healthy long life.

Blood iron is affected by diet and abnormally high or low levels are linked to age-related conditions such as Parkinson’s disease, liver disease and a decline in the body’s ability to fight infection in older age. The researchers say that designing a drug that could mimic the influence of genetic variation on iron metabolism could be a future step to overcome some of the effects of ageing, but caution that more work is required.

Anonymised datasets linking genetic variation to healthspan, lifespan, and longevity were downloaded from the publicly available Zenodo, Edinburgh DataShare and Longevity Genomics servers.

We are very excited by these findings as they strongly suggest that high levels of iron in the blood reduces our healthy years of life, and keeping these levels in check could prevent age-related damage. We speculate that our findings on iron metabolism might also start to explain why very high levels of iron-rich red meat in the diet has been linked to age-related conditions such as heart disease”, said Dr Paul Timmers from the Usher Institute.

The study was funded by the Medical Research Council and is published in the journal Nature Communications.

Source: https://www.ed.ac.uk/

Personalized microrobots swim through biological barriers, deliver drugs to cells

Tiny biohybrid robots on the micrometer scale can swim through the body and deliver drugs to tumors or provide other cargo-carrying functions. The natural environmental sensing tendencies of bacteria mean they can navigate toward certain chemicals or be remotely controlled using magnetic or sound signals.

To be successful, these tiny biological robots must consist of materials that can pass clearance through the body’s immune response. They also have to be able to swim quickly through viscous environments and penetrate to deliver cargo.

In a paper published this week in APL Bioengineering, from AIP Publishing, researchers fabricated biohybrid bacterial microswimmers by combining a genetically engineered E. coliMG1655 substrain and nanoerythrosomes, small structures made from red cells.

Illustration (top) and scanning electron microscopy image (bottom) of biohybrid bacterial microswimmers, which were fabricated by combining genetically engineered E. coliMG1655 and nanoerythrosomes made from red blood cells. A biotin-streptavidin interaction was used to attach nanoerythrosomes to the bacterial membrane.

Nanoerythrosomes are nanovesicles derived from red blood cells by emptying the cells, keeping the membranes and filtering them down to nanoscale size. These tiny red blood cell carriers attach to the bacterial membrane using the powerful noncovalent biological bond between biotin and streptavidin. This process preserves two important red blood cell membrane proteinsTER119 needed to attach the nanoerythrosomes, and CD47 to prevent macrophage uptake.

The E. coli MG 1655 serves as a bioactuator performing the  of propelling through the body as a molecular engine using flagellar rotation. The swimming capabilities of the bacteria were assessed using a custom-built 2-D object-tracking algorithm and 20 videos taken as raw data to document their performance.

Biohybrid microswimmers with bacteria carrying red blood cell nanoerythrosomes performed at speeds 40% faster than other E. coli-powered microparticles-based biohybrid microswimmers, and the work demonstrated a reduced immune response due to the nanoscale size of the nanoerythrosomes and adjustments to the density of coverage of nanoerythrosomes on the bacterial membrane.

These biohybrid swimmers could deliver drugs faster, due to their swimming speed, and encounter less immune response, due to their composition. The researchers plan to continue their work to further tune the immune clearance of the microrobots and investigate how they might penetrate and release their cargo in the tumor microenvironment.

Source: https://aip.scitation.org/

On Mars or Earth, biohybrid can turn CO2 into new products

If humans ever hope to colonize Mars, the settlers will need to manufacture on-planet a huge range of organic compounds, from fuels to drugs, that are too expensive to ship from Earth. University of California, Berkeley, and Lawrence Berkeley National Laboratory (Berkeley Lab) chemists have a plan for that.

For the past eight years, the researchers have been working on a hybrid system combining bacteria and nanowires that can capture the energy of sunlight to convert carbon dioxide and water into building blocks for organic molecules. Nanowires are thin silicon wires about one-hundredth the width of a human hair, used as electronic components, and also as sensors and solar cells.

A device to capture carbon dioxide from the air and convert it to useful organic products. On left is the chamber containing the nanowire/bacteria hybrid that reduces CO2 to form acetate. On the right is the chamber where oxygen is produced

On Mars, about 96% of the atmosphere is CO2. Basically, all you need is these silicon semiconductor nanowires to take in the solar energy and pass it on to these bugs to do the chemistry for you,” said project leader Peidong Yang, professor of chemistry and Energy at UC Berkeley. “For a deep space mission, you care about the payload weight, and biological systems have the advantage that they self-reproduce: You don’t need to send a lot. That’s why our biohybrid version is highly attractive.”

The only other requirement, besides sunlight, is water, which on Mars is relatively abundant in the polar ice caps and likely lies frozen underground over most of the planet, said Yang, who is a senior faculty scientist at Berkeley Lab and director of the Kavli Energy Nanoscience Institute.

The biohybrid can also pull carbon dioxide from the air on Earth to make organic compounds and simultaneously address climate change, which is caused by an excess of human-produced CO2 in the atmosphere.

In a new paper published in the journal Joule, the researchers report a milestone in packing these bacteria (Sporomusa ovata) into a “forest of nanowires” to achieve a record efficiency: 3.6% of the incoming solar energy is converted and stored in carbon bonds, in the form of a two-carbon molecule called acetate: essentially acetic acid, or vinegar.

Source: https://news.berkeley.edu/

Two New Trials of Coronavirus Treatment

Drugs used for treating arthritis are being tested as treatments for COVID-19, the disease caused by a new coronavirus, as researchers rush to find ways of helping patients and slowing the number of infectionsSanofi and Regeneron Pharmaceuticals said on Monday they began a clinical trial of their rheumatoid arthritis drug Kevzara as a coronavirus treatment, while in Spain a separate trial is studying if a combination of two drugs can slow down the spread of coronavirus among people. Enrolments for the mid-to-late stage trial of Kevzara, an immune-system modifying drug known as a monoclonal antibody, will begin immediately and test up to 400 patients, Sanofi and Regeneron said in a joint statement. Regeneron in February announced a partnership with the U.S. Department of Health and Human Services to develop a treatment for the new coronavirus, called SARS-CoV2, and said it would focus on monoclonal antibodies.

The virus that emerged in central China in December has now infected more than 179,000 people worldwide, according to the Johns Hopkins University, which is tracking these figures. Doctors have seen that many of those who become critically ill from SARS-CoV2 are experiencing a so-called cytokine storm, which happens when the immune system overreacts and attacks the body’s organs. Some researchers think drugs that can suppress the immune system, including monoclonal antibodies, might be useful for limiting this autoimmune response.

Meanwhile, Barcelona-based researchers said on Monday they would administer a drug used to treat HIV – containing darunavir and cobicistat – to a coronavirusinfected person. The patient’s close contacts would be administered hydroxychloroquine, a drug for malaria and rheumatoid conditions because laboratory experiments suggest it prevents this strain of coronavirus from reproducing. “The goal of our study is to separate the transmission chains,” Oriol Mitja, researcher at Germans Trias i Pujol Research Institute, told a news briefing. Patients with coronavirus can infect between 5% and 15% of the people they come into contact with during the 14 days after starting to show symptoms, he said. The trial’s goal is to reduce that number below 14 days and also to reduce the percentage of contacts infected and researchers plan to analyze the results in 21 days. Around 200 patients with coronavirus and 3,000 of their close contacts will take part in the trial, which has private and public funding.

Source: https://www.reuters.com/

Why Are HIV Drugs Being Used to Treat the Coronavirus?

On Tuesday, the Japanese government announced it will begin clinical trials to test treatments for the deadly new coronavirus that’s engulfed China and spread to over two dozen countries. Rather than new drugs, they’ll be studying existing medications already used to treat HIV and other viral diseases. But why exactly are researchers hopeful that these drugs can be repurposed for the new coronavirus, and how likely are they to work?

The new coronavirus, recently named SARS-CoV-2 due to its close genetic ties to the SARS coronavirus, is made out of RNA. Other RNA viruses include the ones that cause Ebola, hepatitis C, and yes, HIV/AIDS.

RNA viruses come in all shapes and sizes, and those that infect humans can do so in different ways. But many of the drugs that go after HIV and the hepatitis C virus broadly target weaknesses found in all sorts of viruses. The approved hepatitis C drug ribavirin, for instance, interferes with something called the RNA-dependent RNA polymerase, an enzyme essential for many virusesincluding coronaviruses—to produce more of themselves inside a cell. HIV drugs like lopinavir inhibit other enzymes that allow viruses to break down certain proteins, which cripples their ability to infect cells and replicate.

Broad antiviral drugs like lopinavir should be able to work against SARS-CoV-2scientists theorize. And there’s already some circumstantial evidence they do. Some of these drugs have been successfully tested out for SARS and MERS, for instance, two other nasty coronaviruses that have emerged in recent years.

In January, the Chinese government announced a trial of 41 patients in Wuhan that would use a combination therapy of lopinavir and another HIV drug, ritonavir. In February, the Chinese government also began a trial using an experimental drug that’s been tested out for Ebola, called remdesivir.

Remdesivir has already been deployed during this outbreak, with seemingly impressive results so far. Last month, the first documented U.S. patient with the virus was treated with remdesivir, following a week of worsening symptoms that had developed into full-blown pneumonia. Within a day of receiving the drug through an IV, though, the man’s symptoms started to improve, and he was eventually released from the hospital.

But one case does not a surefire treatment make. And even if remdesivir or other drugs do prove effective against SARS-CoV-2, they’ll only play a small part in stopping this current outbreak from getting worse. Most cases of COVID-19 (the official name of the disease caused by SARS-COV-2) are still mild and won’t be helped much by antiviral drugs. In terms of preventing the next pandemic, it’s more important to keep people from getting the virus at all, rather than finding drugs to treat them once they do.

Source: https://gizmodo.com/

Nanoparticles Act As Immunotherapy Agents

University of Wisconsin–Madison researchers have developed nanoparticles that, in the lab, can activate immune responses to cancer cells. If they are shown to work as well in the body as they do in the lab, the nanoparticles might provide an effective and more affordable way to fight cancer.

They are cheaper to produce and easier to engineer than the antibodies that underlie current immunotherapies, which as drugs cost tens of thousands of dollars a month.

The nanoparticles were made of sections of the T cell protein PD-1 (in blue) attached to a branched core called a dendrimer (in gray). The branches in the core of the nanoparticle allowed many chunks of the PD-1 protein to bind to the nanoparticle, increasing its effectiveness.

Immunotherapy basically boosts the patient’s own immune system to fight against cancer cells better,” says Seungpyo Hong, a professor in the UW–Madison School of Pharmacy. “The antibodies that are used right now are large, they’re expensive, they’re hard to engineer, and they don’t always show the highest level of efficacy either. So we wanted to explore other ways to activate the immune system.

Hong and postdoctoral associate Woo-jin Jeong led the study, published online Jan. 2 in the Journal of the American Chemical Society, with collaborators at the University of Illinois at Chicago. It’s the first demonstration that nanoparticles can act as immunotherapy agents.

More research is needed to understand their effectiveness in the body, but Hong has applied for a patent on the new nanoparticles and is now testing them in animal models.

In tests against lab-grown strains of cancer, the nanoparticles boosted production of the immune stimulating protein interleukin-2 by T cells, one kind of immune cell in the body, by about 50 percent compared to no treatment. They were just as effective as antibodies. The nanoparticles were also able to improve the effectiveness of the chemotherapy drug doxorubicin in similar tests.

Normally, T cells produce a protein named PD-1 that acts like an off switch for immune responses. This “checkpoint” helps keep T cells from improperly attacking healthy cells.

Source: https://news.wisc.edu/