Cancer-killing Virus Shrinks Tumours of A Third of the Patients

A new type of cancer therapy that uses a common virus to infect and destroy harmful cells is showing big promise in early  human trials, say UK scientists. One patient’s cancer vanished, while others saw their tumours shrink. The drug is a weakened form of the cold sore virusherpes simplex – that has been modified to kill tumours. Larger and longer studies will be needed, but experts say the injection might ultimately offer a lifeline to more people with advanced cancers.

Krzysztof Wojkowski, a 39-year-old builder from west London, is one of the patients who took part in the ongoing phase one safety trial, run by the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust. He was diagnosed in 2017 with cancer of the salivary glands, near the mouth. Despite surgery and other treatments at the time, his cancer continued to grow.

I was told there was no options left for me and I was receiving end-of-life care. It was devastating, so it was incredible to be given the chance to join the trial.” A short course of the virus therapy – which is a specially modified version of the herpes virus which normally causes cold sores – appears to have cleared his cancer. “I had injections every two weeks for five weeks which completely eradicated my cancer. I’ve been cancer-free for two years now.”

The injections, given directly into the tumour, attacks cancer in two ways – by invading the cancerous cells and making them burst, and by activating the immune system. About 40 patients have tried the treatment as part of the trial. Some were given the virus injection, called RP2, on its own. Others also received another cancer drug – called nivolumab – as well.

The findings, presented at a medical conference in Paris, France, show that three out of nine patients given RP2 only, which included Krzysztof, saw their tumours shrink.

Source: https://www.bbc.com/

Self-assembling Molecules Asphyxiate Cancerous Cells

Treatment of cancer is a long-term process because remnants of living cancer cells often evolve into aggressive forms and become untreatable. Hence, treatment plans often involve multiple drug combinations and/or radiation therapy in order to prevent cancer relapse. To combat the variety of cancer cell types, modern drugs have been developed to target specific biochemical processes that are unique within each cell type.

However,  are highly adaptive and able to develop mechanisms to avoid the effects of the treatment.

We want to prevent such adaptation by invading the main pillar of cellular life—how cells breathe—that means take up oxygen—and thus produce  for growth,” says David Ng, group leader at the MPI-P.

The research team produced a synthetic drug that travels into cells where it reacts to conditions found inside and triggers a chemical process. This allows the drug’s molecules to bind together and form tiny hairs that are a thousand times thinner than . “These hairs are fluorescent, so you can look at them directly with a microscope as they form,” says Zhixuan Zhou, an Alexander-von-Humboldt-fellow and first author of the paper.

The scientists monitored the oxygen consumption in different cell types and found that the hairs stop all of them from converting oxygen into ATP, a molecule that is responsible for energy delivery in cells. The process worked even for those cells derived from untreatable metastatic cancer. As a result, the cells die rapidly within four hours. After some more years of research, the scientists hope that they can develop a new method to treat up-to-now untreatable cancer.

Weil, Ng and colleagues have shown an exciting outcome under controlled laboratory culture and will continue to unravel deeper insights on the basis of how these  prevent the conversion of oxygen to chemical energy. With further development, these objects could in the future possibly also be manipulated to control other cellular processes to address other important diseases.

They have published their results in the Journal of the American Chemical Society.

Source: https://phys.org/

Smart Contact Lenses for Cancer Diagnostics and Screening

Scientists from the Terasaki Institute for Biomedical Innovation (TIBI) have developed a contact lens that can capture and detect exosomes, nanometer-sized vesicles found in bodily secretions which have the potential for being diagnostic cancer biomarkers. The lens was designed with microchambers bound to antibodies that can capture exosomes found in tears. This antibody- conjugated signaling microchamber contact lens (ABSM-CL) can be stained for detection with nanoparticle-tagged specific antibodies for selective visualization. This offers a potential platform for cancer pre-screening and a supportive diagnostic tool that is easy, rapid, sensitive, cost-effective, and non-invasive.

Exosomes are formed within most cells and secreted into many bodily fluids, such as plasma, saliva, urine, and tears. Once thought to be the dumping grounds for unwanted materials from their cells of origin, it is now known that exosomes can transport different biomolecules between cells. It has also been shown that there is a wealth of surface proteins on exosomes – some that are common to all exosomes and others that are increased in response to cancer, viral infections, or injury. In addition, exosomes derived from tumors can strongly influence tumor regulation, progression, and metastasis.

Because of these capabilities, there has been much interest in using exosomes for cancer diagnosis and prognosis/treatment prediction. However, this has been hampered by the difficulty in isolating exosomes in sufficient quantity and purity for this purpose. Current methods involve tedious and time-consuming ultracentrifuge and density gradients, lasting at least ten hours to complete.

Source: https://terasaki.org/

Nanobody Penetrates Brain Cells to Halt the Progression of Parkinson’s

Researchers from the Johns Hopkins University School of Medicine have helped develop a nanobody capable of getting through the tough exterior of brain cells and untangling misshapen proteins that lead to Parkinson’s disease, Lewy body dementia, and other neurocognitive disorders. The research, published last month in Nature Communications, was led by Xiaobo Mao, an associate professor of neurology at the School of Medicine, and included scientists at the University of Michigan, Ann Arbor. Their aim was to find a new type of treatment that could specifically target the misshapen proteins, called alpha-synuclein, which tend to clump together and gum up the inner workings of brain cells. Emerging evidence has shown that the alpha-synuclein clumps can spread from the gut or nose to the brain, driving the disease progression.

Nanobodies—miniature versions of antibodies, which are proteins in the blood that help the immune system find and attack foreign pathogens—are natural compounds in the blood of animals such as llamas and sharks and are being studied to treat autoimmune diseases and cancer in humans. In theory, antibodies have the potential to zero in on clumping alpha-synuclein proteins, but have a hard time getting through the outer covering of brain cells. To squeeze through these tough brain cell coatings, the researchers decided to use nanobodies instead. The researchers had to shore up the nanobodies to help them keep stable within a brain cell. To do this, they genetically engineered them to rid them of chemical bonds that typically degrade inside a cell. Tests showed that without the bonds, the nanobody remained stable and was still able to bind to misshapen alpha-synuclein.

The team made seven similar types of nanobodies, known as PFFNBs, that could bind to alpha-synuclein clumps. Of the nanobodies they created, onePFFNB2—did the best job of glomming onto alpha-synuclein clumps and not single molecules, or monomer of alpha-synuclein, which are not harmful and may have important functions in brain cells. Additional tests in mice showed that the PFFNB2 nanobody cannot prevent alpha-synuclein from collecting into clumps, but it can disrupt and destabilize the structure of existing clumps.

The structure of alpha-synuclein clumps (left) was disrupted by the nanobody PFFNB2. The debris from the disrupted clump is shown on the right.

Strikingly, we induced PFFNB2 expression in the cortex, and it prevented alpha-synuclein clumps from spreading to the mouse brain’s cortex, the region responsible for cognition, movement, personality, and other high-order processes,” says Ramhari Kumbhar, the co-first author and a postdoctoral fellow at the School of Medicine.

The success of PFFNB2 in binding harmful alpha-synuclein clumps in increasingly complex environments indicates that the nanobody could be key to helping scientists study these diseases and eventually develop new treatments,” Mao says.

Source: https://hub.jhu.edu/

Engineering the Microbiome to Cure Disease

Residing within the human gut are trillions of bacteria and other microorganisms that can impact a variety of chronic human ailments, including obesity, type 2 diabetes, atherosclerosis, cancer, non-alcoholic fatty liver disease and inflammatory bowel disease. Numerous diseases are associated with imbalance or dysfunction in gut microbiome. Even in diseases that don’t involve the microbiome, gut microflora provide an important point of access that allows modification of many physiological systems.

Modifying to remedy, perhaps even cure these conditions, has generated substantial interest, leading to the development of live bacterial therapeutics (LBTs). One idea behind LBTs is to engineer bacterial hosts, or chassis, to produce therapeutics able to repair or restore healthy microbial function and diversity.

Existing efforts have primarily focused on using probiotic bacterial strains from the Bacteroides or Lactobacillus families or Escherichia coli that have been used for decades in the lab. However, these efforts have largely fallen short because engineered bacteria introduced into the gut generally do not survive what is fundamentally a hostile environment.

The inability to engraft or even survive in the gut requires frequent re-administration of these bacterial strains and often produces inconsistent effects or no effect at all. The phenomenon is perhaps most apparent in individuals who take probiotics, where these beneficial bacteria are unable to compete with the individual’s native microorganisms and largely disappear quickly.

The lack of engraftment severely limits the use of LBTs for chronic conditions for curative effect or to study specific functions in the gut microbiome,” said Amir Zarrinpar, MD, PhD, assistant professor of medicine at UC San Diego School of Medicine and a gastroenterologist at UC San Diego Health. “Published human trials using engineered LBTs have demonstrated safety, but still need to demonstrate reversal of disease. We believe this may be due to problems with colonization.

In a proof-of-concept study, published in the August 4, 2022, online issue of Cell , Zarrinpar and colleagues at University of California San Diego School of Medicine report overcoming that hurdle by employing native bacteria in mice as the chassis for delivering transgenes capable of inducing persistent and potentially even curative therapeutic changes in the gut and reversing disease pathologies. Using this method, the group found they can provide long-term therapy in a mouse model of type 2 diabetes.

Source: https://health.ucsd.edu/

How to Train AI to Generate Medicines and Vaccines

Scientists have developed artificial intelligence software that can create proteins that may be useful as vaccines, cancer treatments, or even tools for pulling carbon pollution out of the air. This research was led by the University of Washington School of Medicine and Harvard University.

The proteins we find in nature are amazing molecules, but designed proteins can do so much more,” said senior author David Baker, a professor of biochemistry at UW Medicine. “In this work, we show that machine learning can be used to design proteins with a wide variety of functions.

For decades, scientists have used computers to try to engineer proteins. Some proteins, such as antibodies and synthetic binding proteins, have been adapted into medicines to combat COVID-19. Others, such as enzymes, aid in industrial manufacturing. But a single protein molecule often contains thousands of bonded atoms; even with specialized scientific software, they are difficult to study and engineer. Inspired by how machine learning algorithms can generate stories or even images from prompts, the team set out to build similar software for designing new proteins. “The idea is the same: neural networks can be trained to see patterns in data. Once trained, you can give it a prompt and see if it can generate an elegant solution. Often the results are compelling — or even beautiful,” said lead author Joseph Watson, a postdoctoral scholar at UW Medicine.

The team trained multiple neural networks using information from the Protein Data Bank, which is a public repository of hundreds of thousands of protein structures from across all kingdoms of life. The neural networks that resulted have surprised even the scientists who created them.

Deep machine learning program hallucinating new ideas for vaccine molecules

The team developed two approaches for designing proteins with new functions. The first, dubbed “hallucination” is akin to DALL-E or other generative A.I. tools that produce new output based on simple prompts. The second, dubbed “inpainting,” is analogous to the autocomplete feature found in modern search bars and email clients.

Most people can come up with new images of cats or write a paragraph from a prompt if asked, but with protein design, the human brain cannot do what computers now can,” said lead author Jue Wang, a postdoctoral scholar at UW Medicine. “Humans just cannot imagine what the solution might look like, but we have set up machines that do.

To explain how the neural networkshallucinate’ a new protein, the team compares it to how it might write a book: “You start with a random assortment of words — total gibberish. Then you impose a requirement such as that in the opening paragraph, it needs to be a dark and stormy night. Then the computer will change the words one at a time and ask itself ‘Does this make my story make more sense?’ If it does, it keeps the changes until a complete story is written,” explains Wang.

Both books and proteins can be understood as long sequences of letters. In the case of proteins, each letter corresponds to a chemical building block called an amino acid. Beginning with a random chain of amino acids, the software mutates the sequence over and over until a final sequence that encodes the desired function is generated. These final amino acid sequences encode proteins that can then be manufactured and studied in the laboratory.

The research is published in the journal Science.

Source: https://newsroom.uw.edu/

One Blood Test Can Detect Over 50 Types of Cancer

Researchers are one step closer to making a multi-cancer early detection (MCED) test, that can detect over 50 types of cancer, available to select candidates: those who are age 50 and older, asymptomatic, and considered high risk for the disease. Findings from the third and final phase of the Circulating Cell-free Genome Atlas (CCGA) study have been published in the Annals of Oncology. Study findings confirm that the test is proficient in detecting and classifying cell-free DNA (cfDNA), or tumor byproducts deposited in the bloodstream of a person with cancer. The test can also identify the site of the originating tumor, even in patients with no cancer-related symptoms.

Eric A. Klein, MD, first author of the paper and Chairman Emeritus of the Glickman Urological & Kidney Institute, says these findings corroborate those of a previous CCGA sub-study, but at a larger scale and with an independent validation set. He says these results set the stage for a new cancer screening paradigm.

With the multi-cancer early detection tests, we have the opportunity to diagnose and treat cancer earlier. Used alongside other screening modalities, this could significantly reduce cancer-related deaths,” he says. For some high-mortality cancers – including liver, pancreatic and esophageal – this is the first screening test available.

Currently, only five cancer screening tests are available for patients in the United States; this includes tests for prostate, lung, breast, colorectal and cervical cancers. They each have limitations, including varying levels of invasiveness, discrepancies in use across clinical practice and high false-positive rates, which can lead to overdiagnosis and overtreatment. The promise of this new assay is raising hopes that a new paradigm is afoot. It can detect the presence of circulating cfDNA through a single blood draw and is particularly effective when it comes to identifying more lethal and later-stage cancers, believed to have more cfDNA. However, this also underscores the importance of combining the MCED with existing screening tests until further refinements are made. “Prostate cancer, for example, sheds comparatively less DNA than other tumors, making it less likely to be detected by the novel assay,” explains Dr. Klein, a urologic oncologist. GRAIL, Inc. a California-based biotech company, developed the assay and has funded international research efforts. The MCED test is now available in the United States by prescription only.

Source: https://www.thebrighterside.news/

Drug that increases human lifespan to 200 years is in the works

The idea of living for hundreds of years was once thought to be the pipe dream of billionaires and tech moguls. But scientists at the forefront of anti-ageing research believe they are on the cusp of developing a pill that could lead to people living to the age of 200 and beyond. Medical advances in the last century have led to humans in wealthy nations living into their 80s, almost double the average life expectancy at the turn of the 20th century.

Improved nutrition, clean water, better sanitation and huge leaps in medicine have been key in prolonging human life. The oldest known person — the Frenchwoman Jeanne Calment, who sold canvases to Vincent Van Gogh when she was a girl in the late 1800s — lived to the age of 122, dying in 1997.  There is some debate about whether humans can naturally live much beyond that age, but it is hoped that science will take human lifespans beyond what is currently thought possible.

Dr Andrew Steele, a British computational biologist and author of a new book on longevity, said there is no biological reason humans can’t reach the age of 200. He believes the big breakthrough will come in the form of drugs that removezombie cells‘ in the body, which are thought to be one of the main culprits of tissue and organ decay as we age. Pills that flush these cells out of the body are already in human trials in and could be on the market in as little as 10 years, according to Dr Steele, who believes someone reading this could make it to 150 with the help of the drugs.

Another field in particular that piques the interest of anti-ageing scientists is the study of DNA of reptiles and other cold-blooded animalsMichigan State University experts have begun studying dozens different types of long-living reptiles and amphibians — including crocodiles, salamanders and turtles that can live as long as 120 years. The team hope they will uncover ‘traits‘ that can also be targeted in humans.

Some experts think that eradicating the big killerscancer, dementia and heart disease — could be the true key to longevity.

 ‘I don’t think there is any kind of absolute cap on how long we can live. ‘Studies come out every few years that propose some kind of fundamental limit on human lifespan, but they’re always missing one crucial piece: we’ve never tried treating the ageing process before. ‘I can’t see physical or biological reason why people couldn’t live to 200 — the challenge is whether we’ve can develop the biomedical science to make it possible.’ says Dr Steele, the author of Ageless: The New Science of Getting Older Without Getting Old.

https://www.dailymail.co.uk/

‘Masked’ Cancer Drug Sneaks Through Body

Many cancer treatments are notoriously savage on the body; they attack healthy cells at the same time as tumor cells, causing a plethora of side effects. Now, researchers at the University of Chicago’s Pritzker School of Molecular Engineering (PME) have designed a method to keep one promising cancer drug from wreaking such havoc. The team has engineered a new “masked” version of the immunotherapy drug interleukin-12 that is activated only when it reaches a tumor.

Researchers have long suspected that interleukin-12 could be a powerful cancer treatment, but it caused dangerous side effects. Now, Pritzker Molecular Engineering researchers have developed a version of the molecule not activated until it reaches a tumor, where it eradicates cancer cells.

Our research shows that this masked version of IL-12 is much safer for the body, but it possesses the same anti-tumor efficacy as the original,” said Aslan Mansurov, a postdoctoral research fellow and first author of the new paper. He carried out the IL-12 engineering work with Jeffrey Hubbell, the Eugene Bell Professor in Tissue Engineering, who co-leads PME’s Immunoengineering research theme with professor Melody Swartz.

Researchers know that IL-12 potently activates lymphocytes, immune cells with the potential to destroy tumor cells. But, in the 1990s, early clinical trials of IL-12 were halted because of severe, toxic side effects in patients. The same immune activation that started a cascade of events killing cancer cells also led to severe inflammation throughout the body. IL-12, at least in its natural form, was shelved.
The research on the molecule, also known as IL-12, is described in the journal Nature Biomedical Engineering.

But Mansurov, Hubbell, Swartz, and colleagues had an idea to reinvigorate the possibility of IL-12. What if the drug could slip through the body without activating the immune system? They designed a “masked molecule with a cap covering the section of IL-12 which normally binds immune cells. The cap can be removed only by tumor-associated proteases, a set of molecular scissors found in the vicinity of tumors to help them degrade surrounding healthy tissue. When the proteases chop off the cap, the IL-12 becomes active, able to spur an immune response against the tumor.

The masked IL-12 is largely inactive everywhere in the body except at the site of the tumor, where these proteases can cleave off the mask,” explained Mansurov.

Source: https://pme.uchicago.edu/

CRISPR to Boost Tomatoes’ Vitamin D Levels

By making a few genetic tweaks using CRISPR technology, scientists have designed a special sun-dried tomato packed to the leaves with vitamin D. The flesh and peel of the fruit were genetically engineered to contain the same vitamin D levels as two eggs or 28 grams of tuna, both of which are currently recommended sources of the vital nutrient.

Researchers used gene editing to turn off a specific molecule in the plant’s genome which increased provitamin D3 in both the fruit and leaves of tomato plants. It was then converted to vitamin D3 through exposure to UVB lightVitamin D is created in our bodies after skin’s exposure to UVB light, but the major source is food. This new biofortified crop could help millions of people with vitamin D insufficiency, a growing issue linked to higher risk of cancer, dementia, and many leading causes of mortality. Studies have also shown that vitamin D insufficiency is linked to increased severity of infection by Covid-19.

Tomatoes naturally contain one of the building blocks of vitamin D3, called provitamin D3 or 7-dehydrocholesterol (7-DHC), in their leaves at very low levels. Provitamin D3, does not normally accumulate in ripe tomato fruits. Researchers in Professor Cathie Martin’s group at the John Innes Centre (in UK) used CRISPR-Cas9 gene editing to make revisions to the genetic code of tomato plants so that provitamin D3 accumulates in the tomato fruit. The leaves of the edited plants contained up to 600 ug of provitamin D3 per gram of dry weight. The recommended daily intake of vitamin d is 10 ug for adults. When growing tomatoes leaves are usually waste material, but those of the edited plants could be used for the manufacture of vegan-friendly vitamin D3 supplements, or for food fortification.

We’ve shown that you can biofortify tomatoes with provitamin D3 using gene editing, which means tomatoes could be developed as a plant-based, sustainable source of vitamin D3,” said Professor Cathie Martin, corresponding author of the study which appears in Nature Plants. “Forty percent of Europeans have vitamin D insufficiency and so do one billion people world-wide. We are not only addressing a huge health problem, but are helping producers, because tomato leaves which currently go to waste, could be used to make supplements from the gene-edited lines.”

Previous research has studied the biochemical pathway of how 7-DHC is used in the fruit to make molecules and found that a particular enzyme Sl7-DR2 is responsible for converting this into other molecules. To take advantage of this the researchers used CRISPR-Cas 9 to switch off this Sl7-DR2 enzyme in tomato so that the 7DHC accumulates in the tomato fruit. The researchers then tested whether the 7-DHC in the edited plants could be converted to vitamin D3 by shining UVB light on leaves.

After treatment with UVB light to turn the 7-DHC into Vitamin D3, one tomato contained the equivalent levels of vitamin D as two medium sized eggs or 28g tuna – which are both recommended dietary sources of vitamin D. The study says that vitamin D in ripe fruit might be increased further by extended exposure to UVB, for example during sun-drying.

Source: https://www.jic.ac.uk/