September 2, 2022
Barry Bunin, PhD
Founder & CEO
Collaborative Drug Discovery
AlphaFold: "I'm On it More than Spotify." The rave reviews continue to pour in about AlphaFold, DeepMind's protein structure program, which set the world of biologic research into overdrive when it was announced last month that a team had predicted structures for most of the known proteins. Of course it is an open question, how many unknown proteins and post-translational modified proteins and tiny proteins (< 100 AAs) we will discover in the future. Derek Lowe mentioned the "official" figure for the number of human genes that code for proteins is between 19 and 20 thousand (I think that the current number is 19,370). Bloomberg carries an article headlined "Drug Discovery Is About to Get Faster. Thank AI." The article quotes Jay Bradner, president of the Novartis Institutes for BioMedical Research, the pharma company's research arm for the past 7 years, as saying: "Anybody who could have thought that machine learning was not yet relevant for drug hunting surely must feel different. I'm on it more than Spotify." David Liu, a professor at the Broad Institute of MIT and Harvard and founder of multiple biotech companies, told Bloomberg that the technology allows researchers in his lab to "achieve that Zen-like understanding state" to decide where to tinker with a protein to change its properties. (Speaking of Zen-like, parenthetically, my eyes were wide open seeing David Liu's recent shared African Safari photos of an aggressively huge hippopotamus yawn and an overly curious male white rhino - check out over 100 breathtaking pictures here…the chatter on Twitter was that Professor Liu might have a future career with National Geographic).
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"What is Schizophrenia in a Dish?" One of the Answers Sought as New Yorkers Donate DNA. The Mount Sinai Health System has begun an effort to build a vast database of patient genetic information that can be studied by researchers-including Regeneron and other pharmaceutical companies, according to a recent article in The New York Times, titled "Hospital and Drugmaker Move to Build Vast Database of New Yorkers' DNA." The program seeks to collect DNA from more than a million volunteers during routine blood draws, with sequencing performed by Regeneron. In return, the company will gain access to the genetic sequences and partial medical records of each participant, according to Mount Sinai doctors leading the program. Mount Sinai also intends to share data with other researchers as well, according to the story. Mount Sinai Health System has seven hospitals in New York City, and draws blood from at least 300,000 patients annually. It's expected that about 80 percent will consent to having their blood used for genetic research. While the DNA sequencing should have broad value across medical research, Dr. Alexander Charney, a professor at the Icahn School of Medicine at Mount Sinai, who is overseeing the project, is involved in studying DNA sequencing of patients with schizophrenia. He anticipates the database will accelerate the work. "Essentially what we're saying is: 'What is schizophrenia in a dish?'" Trying to answer that question, Dr. Charney said, "can help you hone in on what is the actual disease process."
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Chaperones Help Keep Things Safe … Including for Molecules. Derek Lowe has a fascinating blog post on the significance of a recent paper published in ScienceDirect titled "A campaign targeting a conserved Hsp70 binding site uncovers how subcellular localization is linked to distinct biological activities." Lowe's blog in Science has a more fanciful title: "Where Are Your Drug Molecules, Really?" He says of the paper, "Here's the sort of detailed look that we'd all like to get in our drug discovery efforts, but rarely do." The paper looks at Hsp70 inhibitors, which Lowe describes as "a well-known family of 'heat shock proteins', molecular chaperones that get expressed under stress and help to prevent damage to important protein partners. I believe that pretty much everything living has Hsp70-type proteins; they're one of those deep foundational pieces that make cellular life possible. As the name indicates, they get ramped up under thermal stress, but also on exposure to heavy metals and other toxic materials as well as oxidative stress in general." He notes: "Increased expression of these chaperones has been proposed as a way to slow neurodegeneration and age-related declines in cellular function in general." But he also cautions there are two sides to the coin. "Hsp70 proteins are (for example) overexpressed in a number of different types of cancer cells, where they keep things hanging together in that metabolically demanding environment, both by improving protein quality and by directly inhibiting apoptosis (a hallmark of many tumor cells is their ability to dodge the 'fall on your sword and die, you mutant' apoptosis signaling networks that should otherwise clear them out). Every attempt to keep cells that you'd like from dying runs the risk of keeping some going that really should be killed off!"
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Chamomile, Parsley, Onions … and the Effort to Add a Tail to Aquaporin 4 to Sweep the Brain Clean of Beta Amyloid. Alzheimer's is a challenging disease that has resisted many, many therapeutic efforts to date. FIERCE Biotech carries an blog post headlined "Cleaning House: Scientists Find Genetic Quirk May Help Clear Out Beta Amyloid, Treat Alzheimer's," about a recent study published in Brain. Researchers at the Washington University School of Medicine in St. Louis have discovered that increasing a genetic quirk-dubbed a readthrough-helped clear out waste in the brains of mice, according to the study. Readthrough, which creates an extended version of proteins, was only found in structures related to waste clearance in the brain. The FIERCE Biotech article notes: "The St. Louis researchers found the long form of aquaporin 4-but not the short one-in the endfeet of astrocytes, which are star-shaped support cells that help keep a barrier between the brain and the rest of the body. The endfeet help regulate blood flow and could help keep the brain free of unwanted proteins by flushing waste into the bloodstream." Researchers screened compounds that may have the ability to increase readthrough of the aquaporin 4 gene and found two with potential: apigenin, a dietary flavone in chamomile, parsley, onions and other plants; and sulphaquinoxaline, a veterinary antibiotic." Both substances cleared amyloids in mice engineered to create them, though sulphaquinoxaline is considered unsafe for humans, and it wasn't clear what the uptake of flavones would be. The team is currently working to find other substances to enhance readthrough.
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Barry A. Bunin, PhD, is the Founder & CEO of Collaborative Drug Discovery, which provides a modern approach to drug discovery research informatics trusted globally by thousands of leading researchers. CDD Vault® is a hosted biological and chemical database that securely manages your private and external data.