Conscience's open science competition yields hits for new Parkinson's drugs

I think we're only just scratching the surface at the moment. I think over the next couple of years, we'll start to see some major strides. Obviously, showing the effects on target identification takes some time with new molecules but, certainly, the repositioning effects should be seen in a few years. I think there is great promise in terms of being able to really tap into a much broader chemical space, so we can have a much wider and more varied chemical palette to be able to pick the best molecules for drug discovery from. Also, accelerating the ways in which we can look at the data and glean much more information from it can help us both in terms of patient selection for clinical trials and in terms of being able to pick up signals of efficacy and safety much earlier.

Biologically, vitamins are absorbed within hours and have instant metabolic effects, such as antioxidants that protect cells or compounds that are building blocks for making hormones. But, many factors impact their efficiency and could keep your body from fully absorbing them. Absorption and effects depend on each individual and what combination of vitamins they take. Gender, age, digestive health, medical conditions, and diet all play a role. One helpful practice to detect deficiencies is to look for the symptoms deficiencies create. Then, look for improvement in your symptoms with supplement intake. You are unlikely to see or feel changes if you do not lack nutrients. If you are chronically tired or see signs of unhealthy nails, hair, or skin, supplements may help as these are indicators that you are lacking nutrients in your diet. If you are unsure, your doctor can order tests to check for deficiencies in your blood.

One major example is protein structure. Methods such as AlphaFold and Boltz-2 have transformed how we generate 3D structural data. Accurate protein structure prediction has been a decades-old challenge, and while there is still work to do on underrepresented protein classes, these models have opened an extraordinary pathway. We have also seen progress in multi-output models. Just over a decade ago (circa 2013), toxicology and property prediction models often focused on one endpoint at a time. Now, multi-output models, especially from methods such as graph neural networks (GNNs) and other deep learning methods, can predict multiple endpoints simultaneously. This allows for transfer learning between related properties. That creates opportunities across ADMET (absorption, distribution, metabolism, excretion, and toxicity) prediction and toxicology. Another exciting area is machine learning potentials. Molecular simulations traditionally rely on fixed mathematical functions to describe molecular interactions, but neural potentials can now replace or augment those functions. They can, in many cases, provide highly accurate simulations and structures at lower computational cost than quantum chemistry. However, its not just down to model architectures. The biggest blind spot behind all of these advances remains careful data curation, annotation, and collection. Open databases for example ChEMBL, PubChem and Chemspider together with data initiatives such as OpenADEMT and OpenBind to name but a few are making notable progress here. We still see some data for example on formulation chemistry often receiving less attention. Its is not just about data scale, but quality that is critical here to. Accessible high quality data sets are the fuel of AI methods. Architecture matters, but high-quality, accessible and abundant data is also absolutely critical.

There are no targeted treatments approved for pancreas cancer, and we haven't had any significant progress for a long time. We've only come up with different chemotherapy combinations, and those are only moderately effective. This new treatment is staggeringly better than chemotherapy. Usually, when we think of an improvement in pancreatic cancer survival, we think of 25% improvement. This medication actually doubled survival in patients with advanced disease. We have patients who participated in the trial who are still alive, which is unheard of because the five-year survival rate for pancreatic cancer patients is only 13%-14%. If the drug is approved by the FDA, it will most likely become the new standard of care for advanced pancreatic cancer and could replace chemotherapy as a first-line treatment.

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.