From The University of California-Santa Cruz: “RNA Rescue challenge invites players to solve puzzles and advance RNA therapeutics”

From The University of California-Santa Cruz

2.21.23
Tim Stephens
stephens@ucsc.edu

Researchers at The University of California-Santa Cruz have developed a new puzzle challenge for the online game Eterna, enlisting players to help design a novel RNA drug to treat hemophilia A.

Introducing “OpenASO: RNA Rescue”

Researchers at The University of California-Santa Cruz working to develop novel RNA-based medicines are teaming up with a new group of collaborators—players of the online game Eterna. The game’s new “OpenASO: RNA Rescue” challenge will tap into the collective intelligence of Eterna’s 250,000 registered users to help design an RNA drug for the treatment of hemophilia A.

An antisense oligonucleotide (ASO) can bind to a messenger RNA molecule, as shown in this illustration, and, in some cases, can correct defects in RNA splicing caused by genetic mutations. (Image credit: Sharif Ezzat/Eterna)

“The Eterna player community may be able to come up with designs that we wouldn’t get using traditional screening methodologies for drug development,” said Michael Stone, professor of chemistry and biochemistry at The University of California-Santa Cruz.

Eterna is an open science platform that has been engaging citizen scientists in RNA-related puzzles for over 10 years. Previous challenges have included “OpenVaccine”, to design a more stable mRNA vaccine against COVID-19, and “OpenTB”, to develop a new diagnostic device to detect tuberculosis.

Stone and his colleagues at The University of California-Santa Cruz—including molecular biologist Jeremy Sanford and geneticist Olena Vaske, both faculty in the Department of Molecular, Cell and Developmental Biology—have been working to develop therapies for diseases caused by genetic mutations that disrupt the processing of RNA in the cell. One approach that has shown promise in treating this type of disease is called antisense oligonucleotide (ASO) therapy.

In all cells RNA molecules copy information from DNA and direct the synthesis of proteins. ASOs are short segments of RNA designed to bind to specific cellular RNA molecules. They can modify gene expression or RNA processing and, in some cases, correct defects caused by genetic mutations. But developing an ASO that has the desired effect typically requires “brute force” screening efforts that can take many years to yield positive results.

“One of the goals of our project is to accelerate that discovery process,” Stone said. “That’s where Eterna comes in.”

Rhiju Das, who leads Eterna and is a Howard Hughes Medical Institute investigator at Stanford University School of Medicine, said Eterna players have come up with RNA design solutions that out-performed the results of supercomputers and expert research teams.

When Stone told Das about his team’s work on developing an RNA-based therapy for hemophilia A, Das said he thought the Eterna community might be able to help.

“The community of Eterna players has discovered unusual principles for designing new kinds of RNA diagnostics and stabilizing mRNA vaccines, resulting in dozens of scientific papers. It will be exciting to see what they can now do in ASO therapeutics with experimental feedback from experts at The University of California-Santa Cruz,” Das said.

Hemophilia A is caused by mutations in the gene for the blood clotting factor 8 (F8), a protein required for the normal clotting of blood to control bleeding. When a protein-coding gene like F8 is activated, its DNA code is copied into RNA molecules called messenger RNAs. Before these messenger RNAs can direct protein synthesis, however, they undergo a modification process called RNA splicing that involves removing certain sections of the sequence. This RNA splicing process can be derailed by genetic mutations.

“It turns out that many genetic diseases involve splicing defects,” Stone said. “Jeremy Sanford’s research team has identified hemophilia-causing mutations in the factor 8 gene that lead to RNA-splicing defects, and we want to target this ‘toxic RNA’ with ASOs.”

In the OpenASO: RNA Rescue challenge, Eterna players are tasked with designing an RNA oligonucleotide that can bind to the F8 messenger RNA in a way that will correct the splicing defect. “Our idea is to design an oligonucleotide to disrupt a certain tract of the RNA that modulates splicing,” Stone explained. “But as players start to dig in, they’ll come up with solutions based on their own criteria, which may have nothing to do with biology but which might actually work.”

Winning solutions are determined by the votes of the player community. The University of California-Santa Cruz researchers will then synthesize the top candidates and test them in laboratory experiments, reporting the results back to the players.

“We’re all very excited to see how this goes,” Stone said. “There is a long list of mutations that appear to cause RNA splicing defects and a lot of interest in exploring the potential for ASO therapies.”

The University of California-Santa Cruz team’s preliminary work on Factor 8 mutations was funded by a seed grant from The University of California-Santa Cruz Office of Research. In addition, critical contributions to the investigation of RNA splicing defects in F8 were made by undergraduates in Sanford’s lab, funded by a National Science Foundation grant to support course-based undergraduate research experience (CURE) labs at The University of California-Santa Cruz.

See the full article here .

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UC Santa Cruz campus.

The University of California-Santa Cruz, opened in 1965 and grew, one college at a time, to its current (2008-09) enrollment of more than 16,000 students. Undergraduates pursue more than 60 majors supervised by divisional deans of humanities, physical & biological sciences, social sciences, and arts. Graduate students work toward graduate certificates, master’s degrees, or doctoral degrees in more than 30 academic fields under the supervision of the divisional and graduate deans. The dean of the Jack Baskin School of Engineering oversees the campus’s undergraduate and graduate engineering programs.

The University of California-Santa Cruz is a public land-grant research university in Santa Cruz, California. It is one of the ten campuses in the University of California system. Located on Monterey Bay, on the edge of the coastal community of Santa Cruz, the campus lies on 2,001 acres (810 ha) of rolling, forested hills overlooking the Pacific Ocean.

Founded in 1965, The University of California-Santa Cruz began with the intention to showcase progressive, cross-disciplinary undergraduate education, innovative teaching methods and contemporary architecture. The residential college system consists of ten small colleges that were established as a variation of the Oxbridge collegiate university system.

Among the Faculty is 1 Nobel Prize Laureate, 1 Breakthrough Prize in Life Sciences recipient, 12 members from the National Academy of Sciences, 28 members of the American Academy of Arts and Sciences, and 40 members of the American Association for the Advancement of Science. Eight University of California-Santa Cruz alumni are winners of 10 Pulitzer Prizes. The University of California-Santa Cruz is classified among “R1: Doctoral Universities – Very high research activity”. It is a member of the Association of American Universities, an alliance of elite research universities in the United States and Canada.

The university has five academic divisions: Arts, Engineering, Humanities, Physical & Biological Sciences, and Social Sciences. Together, they offer 65 graduate programs, 64 undergraduate majors, and 41 minors.

Popular undergraduate majors include Art, Business Management Economics, Chemistry, Molecular and Cell Biology, Physics, and Psychology. Interdisciplinary programs, such as Computational Media, Feminist Studies, Environmental Studies, Visual Studies, Digital Arts and New Media, Critical Race & Ethnic Studies, and the History of Consciousness Department are also hosted alongside UCSC’s more traditional academic departments.

A joint program with The University of California-Hastings enables University of California-Santa Cruz students to earn a bachelor’s degree and Juris Doctor degree in six years instead of the usual seven. The “3+3 BA/JD” Program between University of California-Santa Cruz and The University of California-Hastings College of the Law in San Francisco accepted its first applicants in fall 2014. University of California-Santa Cruz students who declare their intent in their freshman or early sophomore year will complete three years at The University of California-Santa Cruz and then move on to The University of California-Hastings to begin the three-year law curriculum. Credits from the first year of law school will count toward a student’s bachelor’s degree. Students who successfully complete the first-year law course work will receive their bachelor’s degree and be able to graduate with their University of California-Santa Cruz class, then continue at The University of California-Hastings afterwards for two years.

According to the National Science Foundation, The University of California-Santa Cruz spent $127.5 million on research and development in 2018, ranking it 144th in the nation.

Although designed as a liberal arts-oriented university, The University of California-Santa Cruz quickly acquired a graduate-level natural science research component with the appointment of plant physiologist Kenneth V. Thimann as the first provost of Crown College. Thimann developed The University of California-Santa Cruz’s early Division of Natural Sciences and recruited other well-known science faculty and graduate students to the fledgling campus. Immediately upon its founding, The University of California-Santa Cruz was also granted administrative responsibility for the Lick Observatory, which established the campus as a major center for Astronomy research. Founding members of the Social Science and Humanities faculty created the unique History of Consciousness graduate program in The University of California-Santa Cruz’s first year of operation.

Famous former University of California-Santa Cruz faculty members include Judith Butler and Angela Davis.

The University of California-Santa Cruz’s organic farm and garden program is the oldest in the country, and pioneered organic horticulture techniques internationally.

As of 2015, The University of California-Santa Cruz’s faculty include 13 members of the National Academy of Sciences, 24 fellows of the American Academy of Arts and Sciences, and 33 fellows of the American Association for the Advancement of Science. The Baskin School of Engineering, founded in 1997, is The University of California-Santa Cruz’s first and only professional school. Baskin Engineering is home to several research centers, including the Center for Biomolecular Science and Engineering and Cyberphysical Systems Research Center, which are gaining recognition, as has the work that UCSC researchers David Haussler and Jim Kent have done on the Human Genome Project, including the widely used University of California-Santa Cruz Genome Browser. The University of California-Santa Cruz administers the National Science Foundation’s Center for Adaptive Optics.

Off-campus research facilities maintained by The University of California-Santa Cruz include the Lick and The W. M. Keck Observatory, Mauna Kea, Hawai’i and the Long Marine Laboratory. From September 2003 to July 2016, The University of California-Santa Cruz managed a University Affiliated Research System (UARC) for the NASA Ames Research Center under a task order contract valued at more than $330 million.

The University of California-Santa Cruz was tied for 58th in the list of Best Global Universities and tied for 97th in the list of Best National Universities in the United States by U.S. News & World Report’s 2021 rankings. In 2017 Kiplinger ranked The University of California-Santa Cruz 50th out of the top 100 best-value public colleges and universities in the nation, and 3rd in California. Money Magazine ranked The University of California-Santa Cruz 41st in the country out of the nearly 1500 schools it evaluated for its 2016 Best Colleges ranking. In 2016–2017, The University of California-Santa Cruz Santa Cruz was rated 146th in the world by Times Higher Education World University Rankings. In 2016 it was ranked 83rd in the world by the Academic Ranking of World Universities and 296th worldwide in 2016 by the QS World University Rankings.

In 2009, RePEc, an online database of research economics articles, ranked the The University of California-Santa Cruz Economics Department sixth in the world in the field of international finance. In 2007, High Times magazine placed The University of California-Santa Cruz as first among US universities as a “counterculture college.” In 2009, The Princeton Review (with Gamepro magazine) ranked The University of California-Santa Cruz’s Game Design major among the top 50 in the country. In 2011, The Princeton Review and Gamepro Media ranked The University of California-Santa Cruz’s graduate programs in Game Design as seventh in the nation. In 2012, The University of California-Santa Cruz was ranked No. 3 in the Most Beautiful Campus list of Princeton Review.

The University of California-Santa Cruz is the home base for the Lick Observatory.

UCO Lick Observatory’s 36-inch Great Refractor telescope housed in the South (large) Dome of main building.

The University of California-Santa Cruz Lick Observatory Since 1888 Mt Hamilton, in San Jose, California, Altitude 1,283 m (4,209 ft)

UC Observatories Lick Automated Planet Finder fully robotic 2.4-meter optical telescope at Lick Observatory, situated on the summit of Mount Hamilton, east of San Jose, California, USA.

The UCO Lick C. Donald Shane telescope is a 120-inch (3.0-meter) reflecting telescope located at the Lick Observatory, Mt Hamilton, in San Jose, California, Altitude 1,283 m (4,209 ft).

Search for extraterrestrial intelligence expands at Lick Observatory

New instrument scans the sky for pulses of infrared light

March 23, 2015
By Hilary Lebow
Astronomers are expanding the search for extraterrestrial intelligence into a new realm with detectors tuned to infrared light at The University of California-Santa Cruz’s Lick Observatory. A new instrument, called NIROSETI, will soon scour the sky for messages from other worlds.

“Infrared light would be an excellent means of interstellar communication,” said Shelley Wright, an assistant professor of physics at The University of California-San Diego who led the development of the new instrument while at The University of Toronto (CA)’s Dunlap Institute for Astronomy and Astrophysics (CA).

Infrared light would be a good way for extraterrestrials to get our attention here on Earth, since pulses from a powerful infrared laser could outshine a star, if only for a billionth of a second. Interstellar gas and dust is almost transparent to near infrared, so these signals can be seen from great distances. It also takes less energy to send information using infrared signals than with visible light.

The NIROSETI instrument saw first light on the Nickel 1-meter Telescope at Lick Observatory on March 15, 2015. (Photo by Laurie Hatch.)

Astronomers are expanding the search for extraterrestrial intelligence into a new realm with detectors tuned to infrared light at University of California’s Lick Observatory. A new instrument, called NIROSETI, will soon scour the sky for messages from other worlds.

Alumna Shelley Wright, now an assistant professor of physics at The University of California- San Diego, discusses the dichroic filter of the NIROSETI instrument, developed at the University of Toronto Dunlap Institute for Astronomy and Astrophysics (CA) and brought to The University of California-San Diego and installed at the UC Santa Cruz Lick Observatory Nickel Telescope (Photo by Laurie Hatch).

“Infrared light would be an excellent means of interstellar communication,” said Shelley Wright, an assistant professor of physics at The University of California-San Diego who led the development of the new instrument while at the University of Toronto’s Dunlap Institute for Astronomy and Astrophysics (CA).

NIROSETI team from left to right Rem Stone UCO Lick Observatory Dan Werthimer, UC Berkeley; Jérôme Maire, U Toronto; Shelley Wright, The University of California-San Diego Patrick Dorval, U Toronto; Richard Treffers, Starman Systems. (Image by Laurie Hatch).

Wright worked on an earlier SETI project at Lick Observatory as a University of California-Santa Cruz undergraduate, when she built an optical instrument designed by University of California-Berkeley researchers. The infrared project takes advantage of new technology not available for that first optical search.

Infrared light would be a good way for extraterrestrials to get our attention here on Earth, since pulses from a powerful infrared laser could outshine a star, if only for a billionth of a second. Interstellar gas and dust is almost transparent to near infrared, so these signals can be seen from great distances. It also takes less energy to send information using infrared signals than with visible light.

Frank Drake, professor emeritus of astronomy and astrophysics at The University of California-Santa Cruz and director emeritus of the SETI Institute, said there are several additional advantages to a search in the infrared realm.

Frank Drake with his Drake Equation. Credit Frank Drake.

Drake Equation, Frank Drake, Seti Institute.

“The signals are so strong that we only need a small telescope to receive them. Smaller telescopes can offer more observational time, and that is good because we need to search many stars for a chance of success,” said Drake.

The only downside is that extraterrestrials would need to be transmitting their signals in our direction, Drake said, though he sees this as a positive side to that limitation. “If we get a signal from someone who’s aiming for us, it could mean there’s altruism in the universe. I like that idea. If they want to be friendly, that’s who we will find.”

Scientists have searched the skies for radio signals for more than 50 years and expanded their search into the optical realm more than a decade ago. The idea of searching in the infrared is not a new one, but instruments capable of capturing pulses of infrared light only recently became available.

“We had to wait,” Wright said. “I spent eight years waiting and watching as new technology emerged.”

Now that technology has caught up, the search will extend to stars thousands of light years away, rather than just hundreds. NIROSETI, or Near-Infrared Optical Search for Extraterrestrial Intelligence, could also uncover new information about the physical universe.

From Science Magazine: “Chemists find a recipe that may have jump-started life on Earth’

From Science Magazine

New research spells out the simple chemical steps that may have launched the RNA World. Mark Garlick/Science Source

Oct. 18, 2018
Robert F. Service

In the molecular dance that gave birth to life on Earth, RNA appears to be a central player. But the origins of the molecule, which can store genetic information as DNA does and speed chemical reactions as proteins do, remain a mystery. Now, a team of researchers has shown for the first time that a set of simple starting materials, which were likely present on early Earth, can produce all four of RNA’s chemical building blocks.

Those building blocks—cytosine, uracil, adenine, and guanine—have previously been re-created in the lab from other starting materials. In 2009, chemists led by John Sutherland at the University of Cambridge in the United Kingdom devised a set of five compounds likely present on early Earth that could give rise to cytosine and uracil, collectively known as pyrimidines. Then, 2 years ago, researchers led by Thomas Carell, a chemist at Ludwig Maximilian University in Munich, Germany, reported that his team had an equally easy way to form adenine and guanine [Nature], the building blocks known as purines. But the two sets of chemical reactions were different. No one knew how the conditions for making both pairs of building blocks could have occurred in the same place at the same time.

Now, Carell says he may have the answer. On Tuesday, at the Origins of Life Workshop here, he reported that he and his colleagues have come up with a simple set of reactions that could have given rise to all four RNA bases.

Carell’s story starts with only six molecular building blocks—oxygen, nitrogen, methane, ammonia, water, and hydrogen cyanide, all of which would have been present on early Earth. Other research groups had shown that these molecules could react to form somewhat more complex compounds than the ones Carell used.

To make the pyrimidines, Carell started with compounds called cyanoacetylene and hydroxylamine, which react to form compounds called amino-isoxazoles. These, in turn, react with another simple molecule, urea, to form compounds that then react with a sugar called ribose to make one last set of intermediate compounds.

Finally, in the presence of sulfur-containing compounds called thiols and trace amounts of iron or nickel salts, these intermediates transform into the pyrimidines cytosine and uracil. As a bonus, this last reaction is triggered when the metals in the salts harbor extra positive charges, which is precisely what occurs in the final step in a similar molecular cascade that produces the purines, adenine and guanine. Even better, the step that leads to all four nucleotides works in one pot, Carell says, offering for the first time a plausible explanation of how all of RNA’s building blocks could have arisen side by side.

“It looks pretty good to me,” says Steven Benner, a chemist with the Foundation for Applied Molecular Evolution in Alachua, Florida. The process provides a simple way to produce all four bases under conditions consistent with those believed present on early Earth, he says.

The process doesn’t solve all of RNA’s mysteries. For example, another chemical step still needs to “activate” each of RNA’s four building blocks to link them into the long chains that form genetic material and carry out chemical reactions. But making RNA under conditions like those present on early Earth now appears within reach.

See the full article here .

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From SLAC National Accelerator Lab: “Catching the dance of antibiotics and ribosomes at room temperature”

From SLAC National Accelerator Lab

August 6, 2018
Ali Sundermier

Hasan DeMirci refers to ribosomes as the 3D printers of the human body because they synthesize proteins, which are essential to life. (Dawn Harmer/SLAC National Accelerator Laboratory)

Interns in DeMirci’s lab help grow ribosome crystals. Once grown and suspended in a special chemical solution called “mother liquor,” the crystals are imaged at the LCLS to uncover how they interact with antibiotics. (Dawn Harmer/SLAC National Accelerator Laboratory)

Antibiotics have been a pillar of modern medicine since the 1940s. Streptomycin, which belongs to a class of antibiotics called aminoglycosides, was the first hint of light in the millennia-long search for a treatment for tuberculosis, which remains one of the deadliest infectious diseases in human history.

Today, aminoglycosides are the most commonly prescribed antibiotics in the world due to their low cost and high effectiveness in tackling a broad spectrum of bacterial infections. But they also bring along side effects that can have lifelong impacts. Depending on the dosage and the particular antibiotic, an estimated 10 to 20 percent of patients who take aminoglycosides suffer kidney damage and 20 to 60 percent end up with irreversible hearing loss.

Now researchers at the Department of Energy’s SLAC National Accelerator Laboratory have developed a new imaging technique to better understand the mechanisms that lead to hearing loss when aminoglycosides are introduced to the body. Using the lab’s Linac Coherent Light Source (LCLS) X-ray laser and Stanford Synchrotron Lightsource (SSRL), SLAC researchers, in collaboration with researchers at Stanford University, were able to observe interactions between the drugs and bacterial ribosomes at both extremely low and room temperatures, revealing never-before-seen details.

SLAC LCLS

SLAC/SSRL

They also demonstrated how small modifications to the antibiotics can lead to dramatic changes in ribosome shape that eliminate hearing loss. The research could lead to a better understanding of which parts of a drug molecule cause unwanted reactions in the body, which will enable the development of more effective antibiotics with fewer side effects.

The group was led by research associate and senior author Hasan DeMirci. Their results were published in Nucleic Acids Research.

3D printing proteins

Hasan DeMirci refers to ribosomes – tiny molecular machines made up of tangles of RNA and proteins clumped together and intricately wired like ramen noodles in soup – as “the 3D printers of the human body.” The ribosomes synthesize proteins using the genetic information contained in DNA, “building our bodies from the ground up.”

Ribosomes (shown here) are tiny molecular machines made up of tangles of RNA and proteins clumped together and intricately wired like ramen noodles in soup. (Hasan DeMirci/SLAC National Accelerator Laboratory)

“While one subunit of the ribosome, its brain, deciphers and translates the genetic code, the other, its hands, links together amino acids to form proteins,” DeMirci said.

Unlike viruses, which have to leech off hosts to survive, bacteria have their own ribosomes, which is where antibiotics come into play. Bacterial ribosomes are the targets of many antibiotics. So-called “cidal” antibiotics like aminoglycosides function by attacking the brains of bacterial ribosomes, causing them to make mistakes and fill the cells with protein-like garbage molecules.

“It’s like a house with a lot of hoarded junk,” DeMirci says. “There’s no going back. From that point the bacteria just die.”

The problem with this strategy is that human cells contain energy-producing factories called mitochondria that have their very own ribosomes – and since those ribosomes are dangerously similar to those found in bacteria, they’re also vulnerable to antibiotic attack.

“We’re killing the bacteria, but the same drug gets into our mitochondria and destroys the ribosomes there,” DeMirci says. “Now we cannot produce those enzymes that power us. You take an antibiotic and you start losing your hearing, your kidney fails.”

Insights into molecular machinery

DeMirci has a strong interest in aminoglycosides because he can use them to gain insight into the molecular machinery of the ribosome.

“What I really want to know is what those drugs can teach us about how ribosomes decipher the genetic code,” DeMirci said. “Drugs give us an opportunity to stop that process at different stages to understand how each and every step is catalyzed by the ribosome.”

To better understand this process, he struck up a collaboration with Anthony Ricci, a biophysicist and professor of medicine at Stanford who focuses on the inner ear. In previous research, Ricci found that aminoglycosides infiltrate specialized channels to target the sensory cells essential to hearing.

“You can think of it as a roach motel,” Ricci says. “The drugs can get in but they can’t get out. They start to build up, binding to the ribosomes and altering protein synthesis. This puts a huge metabolic load on the sensory cells, which eventually leads to their deaths.”

A major goal of Ricci’s lab has been to design and develop new aminoglycosides that kill bacteria but cannot squeeze through the channel. In order to do this, the researchers need to understand exactly how the aminoglycosides interact with the ribosomes so they can modify parts of the drug without weakening its bacteria-killing properties.

Defrosting interactions

The best way to reach this understanding, researchers have found, is through a technique called X-ray crystallography. In X-ray crystallography, researchers use the patterns formed when a beam of X-rays scatters off a crystal sample to form a 3D model of how its atoms and molecules are arranged. This technique allows researchers to observe how a drug binds to a ribosome.

While the key interactions in these processes happen at body temperature, around 37 degrees Celsius, X-ray crystallography usually has to be done at extremely low, or cryogenic, temperatures, around minus 180 degrees Celsius. This leads to gaps in the data, obscuring tiny details that could greatly inform future experiments.

“Our bodies are warm, so the important biology is happening at body temperature,” DeMirci said, “but in crystallography everything is frozen. When you cool these processes down, you miss out on thermal fluctuations, tiny movements that could change your understanding of how the drugs and ribosomes are behaving.”

In order to design better antibiotics, they need to get as close a view as they can of this interaction happening under physiological conditions. At the LCLS, using a technique called serial femtosecond crystallography, DeMirci is able to catch the intricate waltz of the drugs and ribosomes at room temperature. Rather than freeze the ribosome crystals, the researchers suspend them in ‘mother liquor,’ a special chemical solution they were grown in that keeps them stable, so they are “swimming happily, still wiggling and fluctuating,” he says.

The crystals travel from a reservoir to the interaction region through a single capillary, like a garden hose. Once in the interaction region, the crystals are zapped with a beam of X-rays from the LCLS, which scatters off of them into a detector and provides the researchers with patterns they can use to build detailed 3D models of the ribosome before and after they’ve bound with the drugs. They then use these models to piece together a simulation of the interaction.

At LCLS, crystallized ribosomes travel through a capillary into the interaction region, where they are zapped with a beam of X-rays. The X-rays scatter off the crystals into a detector, providing the researchers with patterns they can use to build detailed 3D models of interactions between the drug and ribosome. (Greg Stewart/SLAC National Accelerator Laboratory)

Uncovering hidden wiggles

To demonstrate their technique, the researchers imaged modified and unmodified drugs binding to ribosomes at both cryogenic and room temperatures to see if they could catch any differences. They found that the drug molecules were less flexible at cryogenic temperatures: Tiny wiggles essential to a better understanding of their interactions with ribosomes were frozen in place.

“Despite the fact that we’ve recorded hundreds of thousands of structures of ribosomal interactions, less than a handful of new-generation drugs have been designed based on these cryogenic structures,” DeMirci said. “That’s because every small interaction makes a huge difference, even a single hydrogen bond.”

With the images taken at room temperature, Ricci’s group identified a site where the drug could be modified without altering its effectiveness.

“We now have some idea that when the drug binds with the ribosome, a global change occurs in the ribosome that might actually be important for the function of the antibiotic and the sensitivity of the ribosome,” Ricci said.

Refining the jigsaw pieces

In the next phase of experiments, DeMirci hopes to design a setup in which the antibiotics aren’t introduced until the last second before the ribosome is imaged so that they can watch as it binds to the ribosome, rather than just taking images before and after.

Up to this point, Ricci said, his group had been doing drug synthesis with very little information or insight into how the antibiotic interacts with the ribosome.

“What this paper and overall collaboration allow is a direct investigation of the drug-ribosome interaction,” he said. “It’s like having more defined pieces to the jigsaw puzzle. You don’t have to guess about what’s happening.”

Developing antibiotics that can fight off drug-resistant bacteria with minimal side effects is essential because the rise of antibiotic resistant strains is currently the biggest threat to modern medicine, DeMirci said.

“Every year more than a million people die from tuberculosis and nearly half a million are HIV positive,” he said. “People don’t usually die from HIV or cancer, they die because their immune system is suppressed and they can’t fight off bacterial infections. That’s when you need antibiotics. But what if you don’t have one that’s effective against the resistant strains? That’s exactly what’s happening right now. This research can help us make informed decisions when designing the next generation of drugs.”

The research team included scientists from LCLS; SSRL; SLAC’s Biosciences Division; the Stanford PULSE Institute; and the Stanford School of Medicine.

See the full article here .

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SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.