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Artificial intelligence yields new antibiotic
A deep-learning model identifies a powerful new drug that can kill some antibiotic-resistant bacteria.
Using a machine-learning algorithm, MIT researchers have identified a powerful new antibiotic compound. In laboratory tests, the drug killed many of the world's most problematic disease-causing bacteria, including some strains that are resistant to all known antibiotics. It also cleared infections in two different mouse models.
The computer model, which can screen more than a hundred million chemical compounds in a matter of days, is designed to pick out potential antibiotics that kill bacteria using different mechanisms than those of existing drugs.
"We wanted to develop a platform that would allow us to harness the power of artificial intelligence to usher in a new age of antibiotic drug discovery," says James Collins, the Termeer Professor of Medical Engineering and Science in MIT's Institute for Medical Engineering and Science (IMES) and Department of Biological Engineering. "Our approach revealed this amazing molecule which is arguably one of the more powerful antibiotics that has been discovered."
In their new study, the researchers also identified several other promising antibiotic candidates, which they plan to test further. They believe the model could also be used to design new drugs, based on what it has learned about chemical structures that enable drugs to kill bacteria.
"The machine learning model can explore, in silico, large chemical spaces that can be prohibitively expensive for traditional experimental approaches," says Regina Barzilay, the Delta Electronics Professor of Electrical Engineering and Computer Science in MIT's Computer Science and Artificial Intelligence Laboratory (CSAIL).
Barzilay and Collins, who are faculty co-leads for MIT's Abdul Latif Jameel Clinic for Machine Learning in Health (J-Clinic), are the senior authors of the study, which appears today in Cell. The first author of the paper is Jonathan Stokes, a postdoc at MIT and the Broad Institute of MIT and Harvard.
A new pipeline
Over the past few decades, very few new antibiotics have been developed, and most of those newly approved antibiotics are slightly different variants of existing drugs. Current methods for screening new antibiotics are often prohibitively costly, require a significant time investment, and are usually limited to a narrow spectrum of chemical diversity.
"We're facing a growing crisis around antibiotic resistance, and this situation is being generated by both an increasing number of pathogens becoming resistant to existing antibiotics, and an anemic pipeline in the biotech and pharmaceutical industries for new antibiotics," Collins says.
To try to find completely novel compounds, he teamed up with Barzilay, Professor Tommi Jaakkola, and their students Kevin Yang, Kyle Swanson, and Wengong Jin, who have previously developed machine-learning computer models that can be trained to analyze the molecular structures of compounds and correlate them with particular traits, such as the ability to kill bacteria.
The idea of using predictive computer models for "in silico" screening is not new, but until now, these models were not sufficiently accurate to transform drug discovery. Previously, molecules were represented as vectors reflecting the presence or absence of certain chemical groups. However, the new neural networks can learn these representations automatically, mapping molecules into continuous vectors which are subsequently used to predict their properties.
In this case, the researchers designed their model to look for chemical features that make molecules effective at killing E. coli. To do so, they trained the model on about 2,500 molecules, including about 1,700 FDA-approved drugs and a set of 800 natural products with diverse structures and a wide range of bioactivities.
Once the model was trained, the researchers tested it on the Broad Institute's Drug Repurposing Hub, a library of about 6,000 compounds. The model picked out one molecule that was predicted to have strong antibacterial activity and had a chemical structure different from any existing antibiotics. Using a different machine-learning model, the researchers also showed that this molecule would likely have low toxicity to human cells.
This molecule, which the researchers decided to call halicin, after the fictional artificial intelligence system from "2001: A Space Odyssey," has been previously investigated as possible diabetes drug. The researchers tested it against dozens of bacterial strains isolated from patients and grown in lab dishes, and found that it was able to kill many that are resistant to treatment, including Clostridium difficile, Acinetobacter baumannii, and Mycobacterium tuberculosis. The drug worked against every species that they tested, with the exception of Pseudomonas aeruginosa, a difficult-to-treat lung pathogen.
To test halicin's effectiveness in living animals, the researchers used it to treat mice infected with A. baumannii, a bacterium that has infected many U.S. soldiers stationed in Iraq and Afghanistan. The strain of A. baumannii that they used is resistant to all known antibiotics, but application of a halicin-containing ointment completely cleared the infections within 24 hours.
Preliminary studies suggest that halicin kills bacteria by disrupting their ability to maintain an electrochemical gradient across their cell membranes. This gradient is necessary, among other functions, to produce ATP (molecules that cells use to store energy), so if the gradient breaks down, the cells die. This type of killing mechanism could be difficult for bacteria to develop resistance to, the researchers say.
"When you're dealing with a molecule that likely associates with membrane components, a cell can't necessarily acquire a single mutation or a couple of mutations to change the chemistry of the outer membrane. Mutations like that tend to be far more complex to acquire evolutionarily," Stokes says.
In this study, the researchers found that E. coli did not develop any resistance to halicin during a 30-day treatment period. In contrast, the bacteria started to develop resistance to the antibiotic ciprofloxacin within one to three days, and after 30 days, the bacteria were about 200 times more resistant to ciprofloxacin than they were at the beginning of the experiment.
The researchers plan to pursue further studies of halicin, working with a pharmaceutical company or nonprofit organization, in hopes of developing it for use in humans.
After identifying halicin, the researchers also used their model to screen more than 100 million molecules selected from the ZINC15 database, an online collection of about 1.5 billion chemical compounds. This screen, which took only three days, identified 23 candidates that were structurally dissimilar from existing antibiotics and predicted to be nontoxic to human cells.
In laboratory tests against five species of bacteria, the researchers found that eight of the molecules showed antibacterial activity, and two were particularly powerful. The researchers now plan to test these molecules further, and also to screen more of the ZINC15 database.
The researchers also plan to use their model to design new antibiotics and to optimize existing molecules. For example, they could train the model to add features that would make a particular antibiotic target only certain bacteria, preventing it from killing beneficial bacteria in a patient's digestive tract.
"This groundbreaking work signifies a paradigm shift in antibiotic discovery and indeed in drug discovery more generally," says Roy Kishony, a professor of biology and computer science at Technion (the Israel Institute of Technology), who was not involved in the study. "Beyond in silica screens, this approach will allow using deep learning at all stages of antibiotic development, from discovery to improved efficacy and toxicity through drug modifications and medicinal chemistry."
The research was funded by the Abdul Latif Jameel Clinic for Machine Learning in Health, the Defense Threat Reduction Agency, the Broad Institute, the DARPA Make-It Program, the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, the Canada Research Chairs Program, the Banting Fellowships Program, the Human Frontier Science Program, the Pershing Square Foundation, the Swiss National Science Foundation, a National Institutes of Health Early Investigator Award, the National Science Foundation Graduate Research Fellowship Program, and a gift from Anita and Josh Bekenstein.
- Detecting patients' pain levels via their brain signals | MIT News ›
- Using AI to predict breast cancer and personalize care | MIT News ›
- Artificial intelligence: Busting the myth of ‘neutral’ AI - Big Think ›
- New type of dual-acting antibiotic shows promise - Big Think ›
- New type of dual-acting antibiotic shows promise - Big Think ›
Inventions with revolutionary potential made by a mysterious aerospace engineer for the U.S. Navy come to light.
- U.S. Navy holds patents for enigmatic inventions by aerospace engineer Dr. Salvatore Pais.
- Pais came up with technology that can "engineer" reality, devising an ultrafast craft, a fusion reactor, and more.
- While mostly theoretical at this point, the inventions could transform energy, space, and military sectors.
The U.S. Navy controls patents for some futuristic and outlandish technologies, some of which, dubbed "the UFO patents," came to light recently. Of particular note are inventions by the somewhat mysterious Dr. Salvatore Cezar Pais, whose tech claims to be able to "engineer reality." His slate of highly-ambitious, borderline sci-fi designs meant for use by the U.S. government range from gravitational wave generators and compact fusion reactors to next-gen hybrid aerospace-underwater crafts with revolutionary propulsion systems, and beyond.
Of course, the existence of patents does not mean these technologies have actually been created, but there is evidence that some demonstrations of operability have been successfully carried out. As investigated and reported by The War Zone, a possible reason why some of the patents may have been taken on by the Navy is that the Chinese military may also be developing similar advanced gadgets.
Among Dr. Pais's patents are designs, approved in 2018, for an aerospace-underwater craft of incredible speed and maneuverability. This cone-shaped vehicle can potentially fly just as well anywhere it may be, whether air, water or space, without leaving any heat signatures. It can achieve this by creating a quantum vacuum around itself with a very dense polarized energy field. This vacuum would allow it to repel any molecule the craft comes in contact with, no matter the medium. Manipulating "quantum field fluctuations in the local vacuum energy state," would help reduce the craft's inertia. The polarized vacuum would dramatically decrease any elemental resistance and lead to "extreme speeds," claims the paper.
Not only that, if the vacuum-creating technology can be engineered, we'd also be able to "engineer the fabric of our reality at the most fundamental level," states the patent. This would lead to major advancements in aerospace propulsion and generating power. Not to mention other reality-changing outcomes that come to mind.
Among Pais's other patents are inventions that stem from similar thinking, outlining pieces of technology necessary to make his creations come to fruition. His paper presented in 2019, titled "Room Temperature Superconducting System for Use on a Hybrid Aerospace Undersea Craft," proposes a system that can achieve superconductivity at room temperatures. This would become "a highly disruptive technology, capable of a total paradigm change in Science and Technology," conveys Pais.
High frequency gravitational wave generator.
Credit: Dr. Salvatore Pais
Another invention devised by Pais is an electromagnetic field generator that could generate "an impenetrable defensive shield to sea and land as well as space-based military and civilian assets." This shield could protect from threats like anti-ship ballistic missiles, cruise missiles that evade radar, coronal mass ejections, military satellites, and even asteroids.
Dr. Pais's ideas center around the phenomenon he dubbed "The Pais Effect". He referred to it in his writings as the "controlled motion of electrically charged matter (from solid to plasma) via accelerated spin and/or accelerated vibration under rapid (yet smooth) acceleration-deceleration-acceleration transients." In less jargon-heavy terms, Pais claims to have figured out how to spin electromagnetic fields in order to contain a fusion reaction – an accomplishment that would lead to a tremendous change in power consumption and an abundance of energy.
According to his bio in a recently published paper on a new Plasma Compression Fusion Device, which could transform energy production, Dr. Pais is a mechanical and aerospace engineer working at the Naval Air Warfare Center Aircraft Division (NAWCAD), which is headquartered in Patuxent River, Maryland. Holding a Ph.D. from Case Western Reserve University in Cleveland, Ohio, Pais was a NASA Research Fellow and worked with Northrop Grumman Aerospace Systems. His current Department of Defense work involves his "advanced knowledge of theory, analysis, and modern experimental and computational methods in aerodynamics, along with an understanding of air-vehicle and missile design, especially in the domain of hypersonic power plant and vehicle design." He also has expert knowledge of electrooptics, emerging quantum technologies (laser power generation in particular), high-energy electromagnetic field generation, and the "breakthrough field of room temperature superconductivity, as related to advanced field propulsion."
Suffice it to say, with such a list of research credentials that would make Nikola Tesla proud, Dr. Pais seems well-positioned to carry out groundbreaking work.
A craft using an inertial mass reduction device.
Credit: Salvatore Pais
The patents won't necessarily lead to these technologies ever seeing the light of day. The research has its share of detractors and nonbelievers among other scientists, who think the amount of energy required for the fields described by Pais and his ideas on electromagnetic propulsions are well beyond the scope of current tech and are nearly impossible. Yet investigators at The War Zone found comments from Navy officials that indicate the inventions are being looked at seriously enough, and some tests are taking place.
If you'd like to read through Pais's patents yourself, check them out here.
Laser Augmented Turbojet Propulsion System
Credit: Dr. Salvatore Pais
It marks a breakthrough in using gene editing to treat diseases.
This article was originally published by our sister site, Freethink.
For the first time, researchers appear to have effectively treated a genetic disorder by directly injecting a CRISPR therapy into patients' bloodstreams — overcoming one of the biggest hurdles to curing diseases with the gene editing technology.
The therapy appears to be astonishingly effective, editing nearly every cell in the liver to stop a disease-causing mutation.
The challenge: CRISPR gives us the ability to correct genetic mutations, and given that such mutations are responsible for more than 6,000 human diseases, the tech has the potential to dramatically improve human health.
One way to use CRISPR to treat diseases is to remove affected cells from a patient, edit out the mutation in the lab, and place the cells back in the body to replicate — that's how one team functionally cured people with the blood disorder sickle cell anemia, editing and then infusing bone marrow cells.
Bone marrow is a special case, though, and many mutations cause disease in organs that are harder to fix.
Another option is to insert the CRISPR system itself into the body so that it can make edits directly in the affected organs (that's only been attempted once, in an ongoing study in which people had a CRISPR therapy injected into their eyes to treat a rare vision disorder).
Injecting a CRISPR therapy right into the bloodstream has been a problem, though, because the therapy has to find the right cells to edit. An inherited mutation will be in the DNA of every cell of your body, but if it only causes disease in the liver, you don't want your therapy being used up in the pancreas or kidneys.
A new CRISPR therapy: Now, researchers from Intellia Therapeutics and Regeneron Pharmaceuticals have demonstrated for the first time that a CRISPR therapy delivered into the bloodstream can travel to desired tissues to make edits.
We can overcome one of the biggest challenges with applying CRISPR clinically.
"While these are early data, they show us that we can overcome one of the biggest challenges with applying CRISPR clinically so far, which is being able to deliver it systemically and get it to the right place," she continued.
What they did: During a phase 1 clinical trial, Intellia researchers injected a CRISPR therapy dubbed NTLA-2001 into the bloodstreams of six people with a rare, potentially fatal genetic disorder called transthyretin amyloidosis.
The livers of people with transthyretin amyloidosis produce a destructive protein, and the CRISPR therapy was designed to target the gene that makes the protein and halt its production. After just one injection of NTLA-2001, the three patients given a higher dose saw their levels of the protein drop by 80% to 96%.
A better option: The CRISPR therapy produced only mild adverse effects and did lower the protein levels, but we don't know yet if the effect will be permanent. It'll also be a few months before we know if the therapy can alleviate the symptoms of transthyretin amyloidosis.
This is a wonderful day for the future of gene-editing as a medicine.
If everything goes as hoped, though, NTLA-2001 could one day offer a better treatment option for transthyretin amyloidosis than a currently approved medication, patisiran, which only reduces toxic protein levels by 81% and must be injected regularly.
Looking ahead: Even more exciting than NTLA-2001's potential impact on transthyretin amyloidosis, though, is the knowledge that we may be able to use CRISPR injections to treat other genetic disorders that are difficult to target directly, such as heart or brain diseases.
"This is a wonderful day for the future of gene-editing as a medicine," Fyodor Urnov, a UC Berkeley professor of genetics, who wasn't involved in the trial, told NPR. "We as a species are watching this remarkable new show called: our gene-edited future."
A new government report describes 144 sightings of unidentified aerial phenomena.
On June 25, 2021, the Office of the Director of National Intelligence released a much-anticipated report on UFOs to Congress.
The military has rebranded unidentified flying objects as unidentified aerial phenomena – UAPs – in part to avoid the stigma that has been attached to claims of aliens visiting the Earth since the Roswell incident in 1947. The report presents no convincing evidence that alien spacecraft have been spotted, but some of the data defy easy interpretation.
I'm a professor of astronomy who has written extensively on the search for life in the universe. I also teach a free online class on astrobiology. I do not believe that the new government report or any other sightings of UFOs in the past are proof of aliens visiting Earth. But the report is important because it opens the door for a serious look at UFOs. Specifically, it encourages the U.S. government to collect better data on UFOs, and I think the release of the report increases the chances that scientists will try to interpret that data. Historically, UFOs have felt off limits to mainstream science, but perhaps no more.
Three videos from the U.S. military sparked a recent surge in interest in UFOs.
What's in the UFO report?
The No. 1 thing the report focuses on is the lack of high-quality data. Here are the highlights from the slender nine-page report, covering a total of 144 UAP sightings from U.S. government sources between 2004 and 2021:
- “Limited data and inconsistent reporting are key challenges to evaluating UAP."
- Some observations “could be the result of sensor errors, spoofing, or observer misperception."
- “UAP clearly pose a safety of flight issue and may pose a challenge to U.S. national security."
- Of the 144 sightings, the task force was “able to identify one reported UAP with high confidence. In that case, we identified the object as a large, deflating balloon. The others remain unexplained."
- “Some UAP many be technologies deployed by China, Russia, another nation, or non-governmental entity."
UFOs are taboo among scientists
UFO means unidentified flying object. Nothing more, nothing less. You'd think scientists would enjoy the challenge of solving this puzzle. Instead, UFOs have been taboo for academic scientists to investigate, and so unexplained reports have not received the scrutiny they deserve.
One reason is that most scientists think there is less to most reports than meets the eye, and the few who have dug deeply have mostly debunked the phenomenon. Over half of sightings can be attributed to meteors, fireballs and the planet Venus.
Another reason for the scientific hesitance is that UFOs have been co-opted by popular culture. They are part of a landscape of conspiracy theories that includes accounts of abduction by aliens and crop circles. Scientists worry about their professional reputations, and the association of UFOs with these supernatural stories causes most researchers to avoid the topic.
But some scientists have looked. In 1968, Edward U. Condon at the University of Colorado published the first major academic study of UFO sightings. The Condon Report put a damper on further research when it found that “nothing has come from the study of UFOs in the past 21 years that has added to scientific knowledge."
However, a review in 1998 by a panel led by Peter Sturrock, a professor of applied physics at Stanford University, concluded that some sightings are accompanied by physical evidence that deserves scientific study. Sturrock also surveyed professional astronomers and found that nearly half thought UFOs were worthy of scientific study, with higher interest among younger and more well-informed astronomers.
If astronomers are intrigued by UFOs – and believe some cases deserve study with academic rigor – what's holding them back? A history of mistrust between ufologists and scientists hasn't helped. And while UFO research has employed some of the tools of the scientific method, it has not had the core of skeptical, evidence-based reasoning that demarcates science from pseudoscience.
A search of 90,000 recent and current grants awarded by the National Science Foundation finds none addressing UFOs or related phenomena. I've served on review panels for 35 years, and can imagine the reaction if such a proposal came up for peer review: raised eyebrows and a quick vote not to fund.
A decadeslong search for aliens
While the scientific community has almost entirely avoided engaging with UFOs, a much more mainstream search for intelligent aliens and their technology has been going on for decades.
The search is motivated by the fact that astronomers have, to date, discovered over 4,400 planets orbiting other stars. Called exoplanets, some are close to the Earth's mass and at just the right distance from their stars to potentially have water on their surfaces – meaning they might be habitable.
Astronomers estimate that there are 300 million habitable worlds in the Milky Way galaxy alone, and each one is a potential opportunity for life to develop and for intelligence and technology to emerge. Indeed, most astronomers think it very unlikely that humans are the only or the first advanced civilization.
This confidence has fueled an active search for extraterrestrial intelligence, known as SETI. It has been unsuccessful so far. As a result, researchers have recast the question “Are we alone?" to “Where are the aliens?" The absence of evidence for intelligent aliens is called the Fermi paradox. First articulated by the physicist Enrico Fermi, it's a paradox because advanced civilizations should be spread throughout the galaxy, yet we see no sign of their existence.
The SETI activity has not been immune from scientists' criticism. It was starved of federal funding for decades and recently has gotten most of its support from private sources. However, in 2020, NASA resumed funding for SETI, and the new NASA administrator wants researchers to pursue the topic of UFOs.
In this context, the intelligence report is welcome. The report draws few concrete conclusions about UFOs and avoids any reference to aliens or extraterrestrial spacecraft. However, it notes the importance of destigmatizing UFOs so that more pilots report what they see. It also sets a goal of moving from anecdotal observations to standardized and scientific data collection. Time will tell if this is enough to draw scientists into the effort, but the transparency to publish the report at all reverses a long history of secrecy surrounding U.S. government reports on UFOs.
I don't see any convincing evidence of alien spacecraft, but as a curious scientist, I hope the subset of UFO sightings that are truly unexplained gets closer study. Scientists are unlikely to weigh in if their skepticism generates attacks from “true believers" or they get ostracized by their colleagues. Meanwhile, the truth is still out there.
This article has been updated to clarify that the report was produced by the Office of the Director of National Intelligence.
Gain-of-function mutation research may help predict the next pandemic — or, critics argue, cause one.