Researchers receive NIH grant to accelerate Alzheimer's drug discovery efforts

This is a win for the field. Until now, we have been focused on immune therapies that might make tumors more vulnerable to the body's immune system, and on finding new chemotherapy combinations that kill cancer cells. This new treatment has given us a new focus, and I think it will spur a lot of scientific discovery over the next few years. There have only been a handful of KRAS researchers and their relevance to therapy was always questioned. That is about to change. The most important next step for the field is to better understand the biology of cancer. We know that many pancreatic tumors will eventually become resistant to daraxonrasib, and we need to understand how this happens. We also need to identify additional genetic pathways and treatments that can target them. That's how we will turn pancreas cancer from a deadly, deadly cancer into something we can manage-and one day, even cure.

What we're trying to do here at Benevolent is develop systems and processes that allow us to tap into the huge amount of public information and some propriety databases that we have paid to access and through that, generate hypotheses which our scientists can then triage. We've got over ten times the amount of information in our database at present (and it’s growing) than we believe that companies such as Watson have. Bringing that and filtering the signals from the ‘noise’ to our experienced drug discovery chemists and biologists, means, firstly, we can reduce the amount of time we take to triage new hypotheses, and secondly, we can develop more predictive chemical tools to allow us to make better molecules and also to reposition existing molecules for new indication.

There are several areas where AI could add value, but one of the most exciting is helping us translate complex experimental results into actionable insights for drug discovery teams. We see computational and experimental approaches as complementary rather than competing technologies. In vitro assays such as iSLAseizure generate highly relevant biological data, while AI and machine learning can help uncover patterns within that data that might otherwise be difficult to identify. One example is work I recently presented at the BioNow BioAI Symposium, in which we explored the use of structure-activity relationships (SAR) and machine learning models alongside iSLAseizure assay data. Supported by colleagues, including Dr. Louisa Zolkiewski and Dr. Kim Rockley, ApconiX has developed an in-house seizure liability dataset that we analyzed in collaboration with MedChemica. Using machine learning and chemical informatics approaches, we identified chemical substructures that show statistically significant relationships with seizure-related outcomes. The aim is not simply to predict risk, but to understand which molecular features may contribute to that risk and provide medicinal chemists with practical guidance they can apply much earlier in the discovery process. Looking ahead, I think this is where AI can have a particularly powerful impact. Rather than acting as a standalone prediction tool, it can work alongside human-relevant assays such as iSLAseizure to connect molecular structure, experimental biology, and safety outcomes. That combination has the potential to improve decision-making earlier in the discovery process, reduce late-stage safety surprises, and ultimately support the development of safer medicines for patients.

Carb cycling is an attempt to fine-tune your carbohydrate consumption to alter many aspects of your metabolism. Your plan will include the same protein intake each day but vary carbohydrates according to your activity. Your carb cycling plan may have three low or zero carb days, two moderate carb days, and two high carb days. Meeting your calorie requirements will require including more fats on low-carb days. Carb cycling needs much more planning than a usual calorie-controlled diet. One way is to match your carb cycling to your physical activity. If you go to the gym thrice a week, you could have carbs on those days. The carbs provide energy for your workout, prevent fatigue, and avoid the muscle loss sometimes seen with dieting. The days when you eat little to no carbs force your body to generate energy from other sources, like proteins and fats. But the days when you eat more carbohydrates might reverse this change. You must only eat a high-carb diet on the days you have a heavy workout, which uses up the calories.

More specifically, the study showed that the female patient produced very few cathelicidins, which is a natural toxin found in the immune cells of the lungs needed to fight tuberculosis. In most people infected by tuberculosis, tuberculosis bacteria attack the immune cells of the lungs. The immune cells fight the bacteria by eating them. But the tuberculosis bacterium has developed various evasive mechanisms that reduce the immune cells’ ability to digest and thus to kill the Mtb. “You could say that the tuberculosis bacterium has developed a way to lull the immune cells to sleep. This enables the disease the hide inside the immune cells, making it invisible to other parts of the immune system,” Martin Kongsbak-Wismann explains. This is where vitamin D enters the picture. Because vitamin D is able to counteract the soporific effect of the tuberculosis bacteria by making the immune cells produce more of the cathelicidin toxin. “Cathelicidin is like a microscopic needle that is able to pierce the tuberculosis bacteria. And when it does, it weakens the bacteria’s soporific effect on the immune cells. This restores the immune cells’ ability to kill tuberculosis bacteria,” says Martin Kongsbak-Wismann and adds: “We were amazed by the effect of vitamin D. In immune cells from healthy control subjects, vitamin D improved the cells’ ability to fight Mtb, whereas in the female patient’s immune cells we saw no response to vitamin D. This shows that vitamin D is key to the immune system’s ability to fight Mtb and prevent tuberculosis.” Al-Jaberi, F.A.H., et al. (2022) Reduced vitamin D-induced cathelicidin production and killing of Mycobacterium tuberculosis in macrophages from a patient with a non-functional vitamin D receptor: A case report. Frontiers in Immunology. doi.org/10.3389/fimmu.2022.1038960.