New research uses AlphaFold, an artificial intelligence (AI)-powered protein structure database, to accelerate the design and synthesis of a drug to treat hepatocellular carcinoma (HCC), the most common type of primary liver cancer. It is the first successful application of AlphaFold to hit identification process in drug discovery.
This study by an international team of researchers, published last week in Chemical Science, is led by the University of Toronto’s Acceleration Consortium director Alán Aspuru-Guzik, Chemistry Nobel laureate Michael Levitt, and Insilico Medicine founder and CEO Alex Zhavoronkov.
AI is revolutionizing drug discovery and development. In 2022, the AlphaFold computer program, developed by Alphabet’s DeepMind, predicted protein structures for the whole human genome––a remarkable breakthrough in both AI applications and structural biology. This free AI-powered database is helping scientists predict the structure of millions of unknown proteins, which is key to accelerating the development of new medicines to treat disease and beyond.
In this new paper, AlphaFold was successfully applied to an end-to-end AI-powered drug discovery platform called Pharma.AI, including a biocomputational engine, PandaOmics, and a generative chemistry engine, Chemistry42.
Researchers discovered a novel target for HCC—a previously undiscovered treatment pathway—and developed a novel hit molecule—a molecule that could bind to that target—without the aid of an experimentally determined structure. This was accomplished in just 30 days from target selection and after only synthesizing 7 compounds. In a second round of AI-powered compound generation, researchers discovered a more potent hit molecule.
“While the world was fascinated with advances in generative AI in art and language, our generative AI algorithms managed to design potent inhibitors of a target with an AlphaFold-derived structure,” said Alex Zhavoronkov, founder and CEO of Insilico Medicine.
“AlphaFold broke new scientific ground in predicting the structure of all proteins in the human body,” said Feng Ren, co-author, Chief Scientific Officer and co-CEO of Insilico Medicine. “At Insilico Medicine, we saw that as an incredible opportunity to take these structures and apply them to our end-to-end AI platform in order to generate novel therapeutics to tackle diseases with high unmet need. This paper is an important first step in that direction.”
Without AI, scientists must rely on conventional trial and error methods of chemistry that are slow, expensive and limit the scope of their exploration. As COVID-19 has demonstrated, the speedy development of new drugs or new formulations of existing ones is needed and increasingly expected by the public. AI has the potential to deliver this speed by transforming materials and molecular discovery, as it has done with just about every branch of science and engineering over the last decade.
“This paper is further evidence of the capacity for AI to transform the drug discovery process with enhanced speed, efficiency, and accuracy,” said Michael Levitt, Nobel Prize winner in Chemistry, Robert W. and Vivian K. Cahill Professor of Cancer Research and Professor of Computer Science, Stanford University. “Bringing together the predictive power of AlphaFold and the target and drug design power of Insilico Medicine’s Pharma.AI platform, it’s possible to imagine that we’re on the cusp of a new era of AI-powered drug discovery.”
“What this paper demonstrates is that for healthcare, AI developments are more than the sum of their parts,” said Alan Aspuru-Guzik, a professor of chemistry and computer science at the University of Toronto and the Canada 150 Research Chair in Theoretical and Quantum Chemistry. “If one uses a generative model targeting an AI-derived protein, one can substantially expand the range of diseases that we can target. If one adds self-driving labs to the mix, we will be in uncharted territory. Stay tuned!”
Both Insilico Medicine and the Acceleration Consortium, a University of Toronto initiative that Aspuru-Guzik directs, are working actively to develop self-driving laboratories, an emerging technology that combines AI, automation and advanced computing to accelerate materials and molecular discovery. Accessible tools and data will help more scientists enter the field of AI for science, in turn helping to drive major progress in this area.
Feng Ren et al, AlphaFold accelerates artificial intelligence powered drug discovery: efficient discovery of a novel CDK20 small molecule inhibitor, Chemical Science (2023). DOI: 10.1039/D2SC05709C
University of Toronto
New study uses AlphaFold and AI to accelerate design of novel drug for liver cancer (2023, January 19)
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Rare ‘big fuzzy green ball’ comet visible in B.C. skies, a 50000-year sight
In the night sky, a comet is flying by Earth for the first time in 50,000 years.
Steve Coleopy, of the South Cariboo Astronomy Club, is offering some tips on how to see it before it disappears.
The green-coloured comet, named C/2022 E3 (ZTF), is not readily visible to the naked eye, although someone with good eyesight in really dark skies might be able to see it, he said. The only problem is it’s getting less visible by the day.
“Right now the comet is the closest to earth and is travelling rapidly away,” Coleopy said, noting it is easily seen through binoculars and small telescopes. “I have not been very successful in taking a picture of it yet, because it’s so faint, but will keep trying, weather permitting.”
At the moment, the comet is located between the bowl of the Big Dipper and the North Star but will be moving toward the Planet Mars – a steady orange-coloured point of light- in the night sky over the next couple of weeks, according to Coleopy.
“I have found it best to view the comet after 3:30 in the morning, after the moon sets,” he said. “It is still visible in binoculars even with the moon still up, but the view is more washed out because of the moonlight.”
He noted the comet looks like a “big fuzzy green ball,” as opposed to the bright pinpoint light of the stars.
“There’s not much of a tail, but if you can look through the binoculars for a short period of time, enough for your eyes to acclimatize to the image, it’s quite spectacular.”
To know its more precise location on a particular evening, an internet search will produce drawings and pictures of the comet with dates of where and when the comet will be in each daily location.
Coleopy notes the comet will only be visible for a few more weeks, and then it won’t return for about 50,000 years.
Extreme species deficit of nitrogen-converting microbes in European lakes
Sampling of Lake Constance water from 85 m depth, in which ammonia-oxidizing archaea make up as much as 40% of all microorganisms
An international team of researchers led by microbiologists from the Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures GmbH in Braunschweig, Germany, shows that in the depths of European lakes, the detoxification of ammonium is ensured by an extremely low biodiversity of archaea. The researchers recently published their findings in the prestigious international journal Science Advances. The team led by environmental microbiologists from the Leibniz Institute DSMZ has now shown that the species diversity of these archaea in lakes around the world ranges from 1 to 15 species. This is of particularly concern in the context of global biodiversity loss and the UN Biodiversity Conference held in Montreal, Canada, in December 2022. Lakes play an important role in providing freshwater for drinking, inland fisheries, and recreation. These ecosystem services would be at danger from ammonium enrichment. Ammonium is an essential component of agricultural fertilizers and contributes to its remarkable increase in environmental concentrations and the overall im-balance of the global nitrogen cycle. Nutrient-poor lakes with large water masses (such as Lake Constance and many other pre-alpine lakes) harbor enormously large populations of archaea, a unique class of microorganisms. In sediments and other low-oxygen environments, these archaea convert ammonium to nitrate, which is then converted to inert dinitrogen gas, an essential component of the air. In this way, they contribute to the detoxification of ammonium in the aquatic environment. In fact, the species predominant in European lakes is even clonal and shows low genetic microdiversity between different lakes. This low species diversity contrasts with marine ecosystems where this group of microorganisms predominates with much greater species richness, making the stability of ecosystem function provided by these nitrogen-converting archaea potentially vulnerable to environmental change.
Maintenance of drinking water quality
Although there is a lot of water on our planet, only 2.5% of it is fresh water. Since much of this fresh water is stored in glaciers and polar ice caps, only about 80% of it is even accessible to us humans. About 36% of drinking water in the European Union is obtained from surface waters. It is therefore crucial to understand how environmental processes such as microbial nitrification maintain this ecosystem service. The rate-determining phase of nitrification is the oxidation of ammonia, which prevents the accumulation of ammonium and converts it to nitrate via nitrite. In this way, ammonium is prevented from contaminating water sources and is necessary for its final conversion to the harmless dinitrogen gas. In this study, deep lakes on five different continents were investigated to assess the richness and evolutionary history of ammonia-oxidizing archaea. Organisms from marine habitats have traditionally colonized freshwater ecosystems. However, these archaea have had to make significant changes in their cell composition, possible only a few times during evolution, when they moved from marine habitats to freshwaters with much lower salt concentrations. The researchers identified this selection pressure as the major barrier to greater diversity of ammonia-oxidizing archaea colonizing freshwaters. The researchers were also able to determine when the few freshwater archaea first appeared. Ac-cording to the study, the dominant archaeal species in European lakes emerged only about 13 million years ago, which is quite consistent with the evolutionary history of the European lakes studied.
Slowed evolution of freshwater archaea
The major freshwater species in Europe changed relatively little over the 13 million years and spread almost clonally across Europe and Asia, which puzzled the researchers. Currently, there are not many examples of such an evolutionary break over such long time periods and over large intercontinental ranges. The authors suggest that the main factor slowing the rapid growth rates and associated evolutionary changes is the low temperatures (4 °C) at the bottom of the lakes studied. As a result, these archaea are restricted to a state of low genetic diversity. It is unclear how the extremely species-poor and evolutionarily static freshwater archaea will respond to changes induced by global climate warming and eutrophication of nearby agricultur-al lands, as the effects of climate change are more pronounced in freshwater than in marine habitats, which is associated with a loss of biodiversity.
Publication: Ngugi DK, Salcher MM, Andre A-S, Ghai R., Klotz F, Chiriac M-C, Ionescu D, Büsing P, Grossart H-S, Xing P, Priscu JC, Alymkulov S, Pester M. 2022. Postglacial adaptations enabled coloniza-tion and quasi-clonal dispersal of ammonia oxidizing archaea in modern European large lakes. Science Advances: https://www.science.org/doi/10.1126/sciadv.adc9392
PhDr. Sven-David Müller, Head of Public Relations, Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures GmbH
Phone: ++49 (0)531/2616-300
About the Leibniz Institute DSMZ
The Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures is the world’s most diverse collection of biological resources (bacteria, archaea, protists, yeasts, fungi, bacteriophages, plant viruses, genomic bacterial DNA as well as human and animal cell lines). Microorganisms and cell cultures are collected, investigated and archived at the DSMZ. As an institution of the Leibniz Association, the DSMZ with its extensive scientific services and biological resources has been a global partner for research, science and industry since 1969. The DSMZ was the first registered collection in Europe (Regulation (EU) No. 511/2014) and is certified according to the quality standard ISO 9001:2015. As a patent depository, it offers the only possibility in Germany to deposit biological material in accordance with the requirements of the Budapest Treaty. In addition to scientific services, research is the second pillar of the DSMZ. The institute, located on the Science Campus Braunschweig-Süd, accommodates more than 82,000 cultures and biomaterials and has around 200 employees. www.dsmz.de
Scientists are closing in on why the universe exists
Particle astrophysicist Benjamin Tam hopes his work will help us understand a question. A very big one.
“The big question that we are trying to answer with this research is how the universe was formed,” said Tam, who is finishing his PhD at Queen’s University.
“What is the origin of the universe?”
And to answer that question, he and dozens of fellow scientists and engineers are conducting a multi-million dollar experiment two kilometres below the surface of the Canadian Shield in a repurposed mine near Sudbury, Ontario.
The Sudbury Neutrino Observatory (SNOLAB) is already famous for an earlier experiment that revealed how neutrinos ‘oscillate’ between different versions of themselves as they travel here from the sun.
This finding proved a vital point: the mass of a neutrino cannot be zero. The experiment’s lead scientist, Arthur McDonald, shared the Nobel Prize in 2015 for this discovery.
The neutrino is commonly known as the ‘ghost particle.’ Trillions upon trillions of them emanate from the sun every second. To humans, they are imperceptible except through highly specialized detection technology that alerts us to their presence.
Neutrinos were first hypothesized in the early 20th century to explain why certain important physics equations consistently produced what looked like the wrong answers. In 1956, they were proven to exist.
Tam and his fellow researchers are now homing in on the biggest remaining mystery about these tiny particles.
Nobody knows what happens when two neutrinos collide. If it can be shown that they sometimes zap each other out of existence, scientists could conclude that a neutrino acts as its own ‘antiparticle’.
Such a conclusion would explain how an imbalance arose between matter and anti-matter, thus clarifying the current existence of all the matter in the universe.
It would also offer some relief to those hoping to describe the physical world using a model that does not imply none of us should be here.
Guests in this episode (in order of appearance):
Benjamin Tam is a PhD student in Particle Astrophysics at Queen’s University.
Eve Vavagiakis is a National Science Foundation Astronomy and Astrophysics Postdoctoral Fellow in the Physics Department at Cornell University. She’s the author of a children’s book, I’m A Neutrino: Tiny Particles in a Big Universe.
Erica Caden is a research scientist at SNOLAB. Among her duties she is the detector manager for SNO+, responsible for keeping things running day to day.
*This episode was produced by Nicola Luksic and Tom Howell. It is part of an on-going series, IDEAS from the Trenches, some stories are below.
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