Conrad Prebys Center for Chemical Genomics Archives - Sanford Burnham Prebys
Institute News

Acceleration by automation

AuthorGreg Calhoun
Date

September 5, 2024

Increases in the scale and pace of research and drug discovery are being made possible by robotic automation of time-consuming tasks that must be repeated with exhaustive exactness.

Humans have long been fascinated by automata, objects that can or appear to move and act of their own volition. From the golems of Jewish folklore to Pinocchio and Frankenstein’s Creature—among the subjects of many other tales—storytellers have long explored the potential consequences of creating beings that range from obedient robots to sentient saboteurs.

While the power of our imagination preceded the available technology for such feats of automation, many scientists and engineers throughout history succeeded in creating automata that were as amusing as they were examples of technical mastery. Three doll automata made by inventor Pierre Jaquet-Droz traveled around the world to delight kings and emperors by writing, drawing and playing music, and they now fascinate visitors to the Musée d’Art et d’Histoire of Neuchâtel, Switzerland.

While these more whimsical machinations can be found in collections from the House on the Rock in Spring Green, Wis., to the Hermitage Museum in Saint Petersburg, Russia, applications in certain forms of labor have made it so more modern automation is located in factories and workshops. There is no comparing the level of automation at research institutions to that of many manufacturing facilities more than 110 years since the introduction of the assembly line, nor should there be given the differing aims. However, the mechanization of certain tasks in the scientific process has been critical to increasing the accessibility of the latest biomedical research techniques and making current drug discovery methods possible.

researcher at work in Prebys Center

As a premier drug discovery center, the Conrad Prebys Center for Chemical Genomics team is well-versed in using automation to enable the testing of hundreds of thousands of chemicals to find new potential medicines.

“Genomic sequencing has become a very important procedure for experiments in many labs,” says Ian Pass, PhD, director of High-Throughput Screening at the Conrad Prebys Center for Chemical Genomics (Prebys Center) at Sanford Burnham Prebys. “Looking back just 20-30 years, the first sequenced human genome required the building of a robust international infrastructure and more than 12 years of active research. Now, with how we’ve refined and automated the process, I could probably have my genome sampled and sequenced in an afternoon.”

While many tasks in academic research labs require hands-on manipulation of pipettes, petri dishes, chemical reagents and other tools of the trade, automation has been a major factor enabling omics and other methods that process and sequence hundreds or thousands of samples to capture incredible amounts of information in a single experiment. Many of these sophisticated experiments would be simply too labor-intensive and expensive to conduct by hand.

Where some of the automation of yore would play a tune, enact a puppet show or tell a vague fortune upon inserting a coin, scientists now prepare samples for instruments equipped with advanced robotics, precise fluid handling technologies, cameras and integrated data analysis capabilities. Automation in liquid handling has enabled one of the biggest steps forward as it allows tests to be miniaturized. This not only results in major cost savings, but also it allows experiments to have many replicas, generating very high-quality, reliable data. These characteristics in data are a critical underpinning for ensuring the integrity of the scientific community’s findings and maintaining the public’s trust.

Ian Pass headshot

Ian Pass, PhD, is the director of High-Throughput Screening at the Conrad Prebys Center for Chemical Genomics.

“At their simplest, many robotic platforms amount to one or more arms that have a grip that can be programmed to move objects around,” explains Pass. “If a task needs to be repeated just a few times, then it probably isn’t worth the effort to deploy a robot. But, once that step needs to be repeated thousands of times at precise intervals, and handled the exact same way each time, then miniaturization and automation are the answers.”

As a premier drug discovery center, the Prebys Center team is well-versed in using automation to enable the testing of hundreds of thousands of chemicals to find new potential medicines. The center installed its first robotics platform, affectionately called “big yellow,” in the late 2000s to enable what is known as ultra-high-throughput screening (uHTS). Between 2009 and 2014, this robot was the workhorse for completing over 100 uHTS of a large chemical library. It generated tens of millions of data points as part of an initiative funded by the National Institutes of Health (NIH) called the Molecular Libraries Program that involved more than 50 research institutions across the US. The output of the program was the identification of hundreds of chemical probes that have been used to accelerate drug discovery and launch the field of chemical biology.

“Without automation, we simply couldn’t have done this,” says Pass. “If we were doing it manually, one experiment at a time, we’d still be on the first screen.”

Over the past 10 years the Center has shifted focus from discovering chemical probes to discovering drugs. Fortunately, much of the process is the same, but the scale of the experiments is even bigger, with screens of over 750,000 chemicals. To screen such large libraries, highly miniaturized arrays are used in which 1536 tests are conducted in parallel. Experiments are miniaturized to such an extent that hand pipetting is not possible and acoustic dispensing (i.e. sound waves) are used to precisely move the tiny amounts of liquid in a touchless, tipless automated process. In this way, more than 250,000 tests can be accomplished in a single day, allowing chemicals that bind to the drug target to be efficiently identified. Once the Prebys Center team identifies compounds that bind, these prototype drugs are then improved by the medicinal chemistry team, ultimately generating drugs with properties suitable for advancing to phase I clinical trials in humans.

Within the last year, the Prebys Center has retired “big yellow” and replaced it with three acoustic dispensing enabled uHTS robotic systems using 1536 well high-density arrays that can run fully independently.

“We used to use big yellow for just uHTP library screening, but now, with the new line up of robots, we use them for everything in the lab we can,” notes Pass. “It has really changed how we use automation to support and accelerate our science. Having multiple systems allows us to run simultaneous experiments and avoid scheduling conflicts. It also allows us to stay operational if one of the systems requires maintenance.”

One of the many drug discovery projects at the Prebys Center focuses on the national epidemic of opioid addiction. In 2021, fentanyl and other synthetic opioids accounted for nearly 71,000 of 107,000 fatal drug overdoses in the U.S. By comparison, in 1999 drug-involved overdose deaths totaled less than 20,000 among all ages and genders.

Like other addictive substances, opioids are intimately related to the brain’s dopamine-based reward system. Dopamine is a neurotransmitter that serves critical roles in memory, movement, mood and attention. Michael Jackson, PhD, senior vice president of Drug Discovery and Development at the Prebys Center and co-principal investigator Lawrence Barak, MD, PhD, at Duke University, have been developing a completely new class of drugs that works by targeting a receptor on neurons called neurotensin 1 receptor or NTSR1, that regulates dopamine release.

The researchers received a $6.3 million award from NIH and the National Institute on Drug Abuse (NIDA) in 2023 to advance their addiction drug candidate, called SBI-810, to the clinic. SBI-810 is an improved version of SBI-533, which previously had been shown to modulate NTSR1 signaling and demonstrated robust efficacy in mouse models of addiction without adverse side effects.

Michael Jackson profile photo

Michael Jackson, PhD, is the senior vice president of Drug Discovery and Development at the Conrad Prebys Center for Chemical Genomics.

Prebys Center researchers at work

The funding from the NIH and NIDA will be used to complete preclinical studies and initiate a Phase 1 clinical trial to evaluate safety in humans.

“The novel mechanism of action and broad efficacy of SBI-810 in preclinical models hold the promise of a truly new, first-in-class treatment for patients affected by addictive behaviors,” says Jackson.


Programming in a Petri Dish, an 8-part series

How artificial intelligence, machine learning and emerging computational technologies are changing biomedical research and the future of health care

  • Part 1 – Using machines to personalize patient care. Artificial intelligence and other computational techniques are aiding scientists and physicians in their quest to prescribe or create treatments for individuals rather than populations.
  • Part 2 – Objective omics. Although the hypothesis is a core concept in science, unbiased omics methods may reduce attachments to incorrect hypotheses that can reduce impartiality and slow progress.
  • Part 3 – Coding clinic. Rapidly evolving computational tools may unlock vast archives of untapped clinical information—and help solve complex challenges confronting health care providers.
  • Part 4 – Scripting their own futures. At Sanford Burnham Prebys Graduate School of Biomedical Sciences, students embrace computational methods to enhance their research careers.
  • Part 5 – Dodging AI and computational biology dangers. Sanford Burnham Prebys scientists say that understanding the potential pitfalls of using AI and other computational tools to guide biomedical research helps maximize benefits while minimizing concerns.
  • Part 6 – Mapping the human body to better treat disease. Scientists synthesize supersized sets of biological and clinical data to make discoveries and find promising treatments.
  • Part 7 – Simulating science or science fiction? By harnessing artificial intelligence and modern computing, scientists are simulating more complex biological, clinical and public health phenomena to accelerate discovery.
  • Part 8 – Acceleration by automation. Increases in the scale and pace of research and drug discovery are being made possible by robotic automation of time-consuming tasks that must be repeated with exhaustive exactness.
Institute News

Simulating science or science fiction? 

AuthorGreg Calhoun
Date

August 27, 2024

By harnessing artificial intelligence and modern computing, scientists are simulating more complex biological, clinical and public health phenomena to accelerate discovery.

While scientists have always employed a vast set of methods to observe the immense worlds among and beyond our solar system, in our planet’s many ecosystems, and within the biology of Earth’s inhabitants, the public’s perception tends to reduce this mosaic to a single portrait.

A Google image search will reaffirm that the classic image of the scientist remains a person in a white coat staring intently at a microscope or sample in a beaker or petri dish. Many biomedical researchers do still use their fair share of glassware and plates while running experiments. These scientists, however, now often need advanced computational techniques to analyze the results of their studies, expanding the array of tools researchers must master to push knowledge forward. For every scientist pictured pipetting, we should imagine others writing code or sending instructions to a supercomputer.

In some cases, scientists are testing whether computers can be used to simulate the experiments themselves. Computational tools such as generative artificial intelligence (AI) may be able to help scientists improve data inputs, create scenarios and generate synthetic data by simulating biological processes, clinical outcomes and public health campaigns. Advances in simulation one day might help scientists more quickly narrow in on promising results that can be confirmed more efficiently through real-world experiments.

“There are many different types of simulation in the life sciences,” says Kevin Yip, PhD, professor in the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys and director of the Bioinformatics Shared Resource. “Molecular simulators, for example, have been used for a long time to show how certain molecules will change their shape and interact with other molecules.”

“One of the most successful examples is in structural biology with the program AlphaFold, which is used to predict protein structures and interactions,” adds Yip. “This program was built on a very solid foundation of actual experiments determining the structures of many proteins. This is something that other fields of science can work to emulate, but in most other cases simulation continues to be a work in progress rather than a trusted technique.”

In the Sanford Burnham Prebys Conrad Prebys Center for Chemical Genomics (Prebys Center), scientists are using simulation-based techniques to more effectively and efficiently find new potential drugs.

Click to Play VideoNanome Virtual Reality demonstration

To expedite their drug discovery and optimization efforts, the Prebys Center team uses a suite of computing tools to run simulations that model the fit between proteins and potential drugs, how long it will take for drugs to break down in the body, and the likelihood of certain harmful side effects, among other properties.

“In my group, we know what the proteins of interest look like, so we can simulate how certain small molecules would fit into those proteins to try and design ones that fit really well,” says Steven Olson, PhD, executive director of Medicinal Chemistry at the Prebys Center. In addition to fit, Olson and team look for drugs that won’t be broken down too quickly after being taken.

“That can be the difference between a once-a-day drug and one you have to take multiple times a day, and we know that patients are less likely to take the optimal prescribed dose when it is more than once per day,” notes Olson. 

Steven Olson, PhD, profile photo

Steven Olson, PhD, is the executive director of Medicinal Chemistry at the Prebys Center.

“We can use computers now to design drugs that stick around and achieve concentrations that are pharmacologically effective and active. What the computers produce are just predictions that still need to be confirmed with actual experiments, but it is still incredibly useful.”

In one example, Olson is working with a neurobiologist at the University of California Santa Barbara and an x-ray crystallographer at the University of California San Diego on new potential drugs for Alzheimer’s disease and other forms of dementia.

“This protein called farnesyltransferase was a big target for cancer drug discovery in the 1990s,” explains Olson. “While targeting it never showed promise in cancer, my collaborator showed that a farnesyltransferase inhibitor stopped proteins from aggregating in the brains of mice and creating tangles, which are a pathological hallmark of Alzheimer’s.”

“We’re working together to make drugs that would be safe enough and penetrate far enough into the brain to be potentially used in human clinical trials. We’ve made really good progress and we’re excited about where we’re headed.”

To expedite their drug discovery and optimization efforts, Olson’s team uses a suite of computing tools to run simulations that model the fit between proteins and potential drugs, how long it will take for drugs to break down in the body, and the likelihood of certain harmful side effects, among other properties. The Molecular Operating Environment program is one commercially available application that enables the team to visualize candidate drugs’ 3D structures and simulate interactions with proteins. Olson and his collaborators can manipulate the models of their compounds even more directly in virtual reality by using another software application known as Nanome. DeepMirror is an AI tool that helps predict the potency of new drugs while screening for side effects, while StarDrop uses learning models to enable the team to design drugs that aren’t metabolized too quickly or too slowly.

Steven Olson et al using VR in Prebys Center

The Prebys Center team demonstrates how the software application known as Nanome allows scientists to manipulate the models of potential drug compounds directly in virtual reality.

“In addition, there are certain interactions that can only be understood by modeling with quantum mechanics,” Olson notes. “We use a program called Gaussian for that, and it is so computationally intense that we have to run it over the weekend and wait for the results.”

“We use these tools to help us visualize the drugs, make better plans and give us inspiration on what we should make. They also can help explain the results of our experiments. And as AI improves, it’s helping us to predict side effects, metabolism and all sorts of other properties that previously you would have to learn by trial and error.”

While simulation is playing an active and growing role in drug discovery, Olson continues to see it as complementary to the human expertise required to synthesize new drugs and put predictions to the test with actual experiments.

“The idea that we’re getting to a place where we can simulate the entire drug design process, that’s science fiction,” says Olson. “Things are evolving really fast right now, but I think in the future you’re still going to need a blend of human brainpower and computational brainpower to design drugs.”


Programming in a Petri Dish, an 8-part series

How artificial intelligence, machine learning and emerging computational technologies are changing biomedical research and the future of health care

  • Part 1 – Using machines to personalize patient care. Artificial intelligence and other computational techniques are aiding scientists and physicians in their quest to prescribe or create treatments for individuals rather than populations.
  • Part 2 – Objective omics. Although the hypothesis is a core concept in science, unbiased omics methods may reduce attachments to incorrect hypotheses that can reduce impartiality and slow progress.
  • Part 3 – Coding clinic. Rapidly evolving computational tools may unlock vast archives of untapped clinical information—and help solve complex challenges confronting health care providers.
  • Part 4 – Scripting their own futures. At Sanford Burnham Prebys Graduate School of Biomedical Sciences, students embrace computational methods to enhance their research careers.
  • Part 5 – Dodging AI and computational biology dangers. Sanford Burnham Prebys scientists say that understanding the potential pitfalls of using AI and other computational tools to guide biomedical research helps maximize benefits while minimizing concerns.
  • Part 6 – Mapping the human body to better treat disease. Scientists synthesize supersized sets of biological and clinical data to make discoveries and find promising treatments.
  • Part 7 – Simulating science or science fiction? By harnessing artificial intelligence and modern computing, scientists are simulating more complex biological, clinical and public health phenomena to accelerate discovery.
  • Part 8 – Acceleration by automation. Increases in the scale and pace of research and drug discovery are being made possible by robotic automation of time-consuming tasks that must be repeated with exhaustive exactness.
Institute News

Melanoma’s mysteries revealed at Sanford Burnham Prebys

AuthorGreg Calhoun
Date

March 26, 2024

Cancer Center open house welcomes San Diego community to learn the latest about melanoma research

The Institute’s NCI-designated Cancer Center hosted the open house on Wednesday, March 20. It provided an opportunity for community members to meet scientists who seek to better understand melanoma and use this knowledge to improve treatment and prevention.

The event was sponsored by the center’s Community Advisory Board, an eight-member committee that focuses on advocacy, education and community engagement, as well as providing Cancer Center leaders and members with the perspectives of patients, survivors and their loved ones.

Open house participants could select from a variety of activities. Two labs provided brief poster presentations.

Ze’ev Ronai, PhD, director of the Sanford Burnham Prebys Cancer Center and the Jeanne and Gary Herberger Leadership Chair in Cancer Research, and his team discussed several areas of research, including the dissection of microbiota commensals which support the immune system’s fight against melanoma, the studies undertaken to understand melanoma addiction to the metabolic enzyme GCDH, and the development of new drugs to target the molecular machine that translates genetic instructions into proteins, which are known to be hyperactive in cancer cells.

Linda Bradley, PhD, professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys, and her group detailed their work on improving the immune system response to viral infections and cancer, including a new potential immune checkpoint therapy and efforts to rejuvenate overstressed immune cells to enhance the effectiveness of immunotherapy.

Attendees also could take tours of two different research facilities. Many participants enjoyed an insider’s view into the field of cryo-electron microscopy (cryo-EM), a technology that garnered three key innovators the 2017 Nobel Prize in Chemistry. The Cryo-EM core facility enables scientists to create 3D images of the cell and all its constituent parts that are accurate to the tiniest detail as it is able to capture individual atoms. Images taken using cryo-EM can be organized sequentially to develop films that show in real time how the cell’s many actors interact, helping scientists map interactions between drugs identified at Sanford Burnham Prebys and their target proteins, thereby advancing novel modalities for the treatment of melanoma and other cancers.

The second tour brought community members to the Conrad Prebys Center for Chemical Genomics. The Prebys Center is the Institute’s comprehensive center for drug discovery and chemical biology. Visitors were able to see the center’s state-of-the-art robots that enable researchers to quickly test the potential effectiveness of hundreds of thousands of compounds to find new prospective treatments. Many scientists at Sanford Burnham Prebys partner with the Prebys Center to conduct drug discovery searches based on new research findings, including those studying melanoma and other cancers.

Many of the visitors had the opportunity to visit a melanoma research laboratory to learn about research projects in the Ronai lab and view melanoma cells as seen under the microscope.

Open House guests conversing in Chairmen's Hall

Following the tours, Ronai shared an overview of the Cancer Center and highlighted recent accomplishments. Attendees interacted with Gregory Daniels, MD, PhD, a medical oncologist and melanoma expert from University of California San Diego and Steven Silverstein, a melanoma survivor, former president of the Melanoma Research Foundation and a melanoma research advocate. The open house concluded with an opportunity for guests to speak with cancer scientists and featured speakers during the evening reception.

“We were honored to provide our valued guests with the opportunity to learn about the research conducted at our Cancer Center, including ongoing melanoma research,” says Ronai. “Our open houses, which focus on different unmet needs in cancer, allow us to welcome and engage with the San Diego community, to share our findings and be inspired by patients and their loved ones.”

Institute News

Preuss internship celebrates 15 years of inspiring young scientists

AuthorMiles Martin
Date

August 2, 2023

“I liked how hands-on everything was,” says Preuss intern Amayrani Calderon “The scientists would show us how to do the experiment but then let us do it ourselves. I’d never had that type of experience in a lab before.”

Each year, Sanford Burnham Prebys welcomes a cohort of high school interns from the Preuss School, whose students strive to be the first in their family to graduate from college. This year’s Preuss interns learned hands-on research skills from scientists at the Institute’s NCI-designated Cancer Center and about career possibilities in STEM beyond research.

“My favorite part of the program and about Sanford Burnham Prebys is all the diverse people I met,” says Alejandra Ruiz Ramirez, who is first-generation Mexican American. “I had mentally prepared myself not to see any scientists that look like me, or to potentially be stereotyped as a Mexican American woman, but that isn’t what happened at all. Everybody I met was very welcoming.”

The Preuss internship is an intensive three-week program designed to jumpstart the careers of the next generation of scientific researchers. This year, the first two weeks were spent learning state-of-the art research techniques, such as staining cells for immunohistochemistry and separating proteins with gel electrophoresis.

“Seeing a real lab was a lot different than what I expected,” says Preuss intern Mohamed Haghi-Mohamed. “At school we just do labs on our desks, but seeing the incubators and other machines really changed my perspective and on how science works in the real world.”

For the final week of the program, interns shadowed staff scientists working in various labs throughout the Cancer Center, where they saw the research process firsthand.

“Consuming a lot of media makes you see science as always exciting and fast-paced, but it’s a very different experience actually working in the lab day to day,” says Preuss intern Juan Lomas Hoeung. “Sometimes there’s a lot of downtime but other times things are hectic.

The Preuss internship program also included activities outside of the lab, including panel discussions with scientists, a tour of the Conrad Prebys Center for Chemical Genomics, and a workshop on diversity and equity and STEM. The interns also had lunch with Institute staff each day, where they had the chance to learn and ask questions about varied STEM careers such as research administration, science communication, and philanthropy.

“We wanted the students to see that there are varied paths to a career in STEM, and that these paths aren’t always linear,” says Victoria Carrillo, senior program administrator for the Cancer Center, who oversaw the Preuss internship along with faculty organizer Svasti Haricharan, PhD.

The program culminated in a celebratory luncheon with students, researchers and Institute staff, where the interns had the opportunity to share what they’ve learned from their experience at Sanford Burnham Prebys.

“This was the best environment to learn in because the people here are some of the most expressive and passionate people I’ve met when they’re in the lab talking about what they do,” says Hoeung. “Everybody was so enthusiastic.”

Institute News

Presenting The Conrad Prebys Foundation fellows

AuthorMiles Martin
Date

May 15, 2023

Thanks to a generous grant from The Conrad Prebys Foundation, a diverse group of early-career researchers will gain hands-on experience in drug discovery and translational medicine.

A new educational program at Sanford Burnham Prebys has welcomed a diverse group of early-career scientists to learn how to transform research discoveries into treatments for human diseases. The program was made possible by a generous grant from The Conrad Prebys Foundation as part of its mission to increase the diversity of San Diego’s biomedical workforce.

“Our mission at The Conrad Prebys Foundation is to create an inclusive, equitable and dynamic future for all San Diegans,” says Grant Oliphant, CEO at The Conrad Prebys Foundation. “San Diego is one of the top areas in the country for biomedical research, and we’re pleased to partner with Sanford Burnham Prebys to help strengthen the pipeline of diverse talent in life sciences research.”

Graduate students and postdoctoral fellows selected for the program will complete projects at the Institute’s Conrad Prebys Center for Chemical Genomics (Prebys Center), the nation’s leading nonprofit drug discovery center. The Prebys Center specializes in finding new medicines for diseases with a substantial unmet medical need in order to develop better therapies. 

“Thank you to The Conrad Prebys Foundation. I am beyond grateful for their support,” says predoctoral Prebys fellow Michael Alcaraz, who will complete his project on the links between aging and brain disease with Professor Peter D. Adams, PhD, and Steven Olson, PhD, executive director of Medicinal Chemistry at the Prebys Center. 

To help fulfill the Foundation’s mission, Sanford Burnham Prebys students and postdocs from historically underrepresented groups were encouraged to apply for the new program.

“Promoting diversity in the biomedical workforce is a founding principle of our educational program,” says Alessandra Sacco, PhD, vice dean and associate dean of Student Affairs in the Graduate School of Biomedical Sciences at Sanford Burnham Prebys. Sacco will oversee the new program alongside Dean Guy Salvesen, PhD, and Professor Michael Jackson, PhD

“Working actively to train people from all backgrounds gives opportunities to people who may not otherwise have had them—and it also improves the quality of the research itself,” she adds.

“Translational research is one of the biggest priorities in biomedicine right now because it’s how we turn discoveries into actual medicines,” says Sacco. “This program gives students and postdocs an opportunity to build the skills they need for translational research jobs in academia or industry.”

The fellowship will culminate in a final symposium next spring, where the fellows will present their research to their peers and to the wider community. 

“I’m looking forward to gaining more experience and making my contribution to the translational science at the Prebys Center,” says predoctoral Prebys fellow Merve Demir, who will complete a structural biochemistry project with Assistant Professor Jianhua Zhao, PhD, and Eduard Sergienko, PhD, director of Assay Development at the Prebys Center. 

The full list of fellows includes:
 

Postdoctoral Fellows

– Karina Barbosa Guerra [Deshpande Lab, Ed Sergienko co-mentor]
“SGF29 as a novel therapeutic target in AML”
 
– Merve Demir [Zhao Lab, Ed Sergienko co-mentor]
“Structural studies of MtCK and GCDH enzyme drug targets”
 
– Jerry Tyler DeWitt [Haricharan Lab, TC Chung co-mentor]
“Investigating the unique molecular landscape of ER+ breast cancer in black women” 
 
– Alicia Llorente Lope [Emerling Lab, Ian Pass co-mentor]
“Exploring PI5P4Kγ as a novel molecular vulnerability of therapy-resistant breast cancer” 
 
– Van Giau Vo [Huang Lab, TC Chung co-mentor]
“Identifying enhancers of SNX27 to promote neuroprotective pathways in Alzheimer’s disease and Down Syndrome”
 
– Xiuqing Wei [Puri Lab, Anne Bang co-mentor]
“Selective targeting of a pathogenetic IL6-STAT3 feedforward loop activated during denervation and cancer cachexia”

 

Predoctoral Fellows

– Michael Alexander Alcaraz [Adams Lab, Steven Olson co-mentor]
“Activating the NAMPT-NAD+ axis in senescence to target age-associated disease”
 
– Shea Grenier Davis [Commisso Lab, Steven Olson co-mentor]
“Examining PIKfyve as a potential therapeutic target in pancreatic cancer” 
 
– Patrick Hagan [Cosford Lab, Ian Pass co-mentor]
“Discovery and development of novel ATG13 degrading compounds that inhibit autophagy and treat non-small-cell lung cancer”
 
– Texia Loh [Wang Lab, Ed Sergienko co-mentor]
“Investigating the role of HELLS in mediating resistance to PARP Inhibition in small-cell lung cancer”
 
– Michaela Lynott [Colas Lab, TC Chung co-mentor]
“Identification of small molecules inhibiting ATF7IP-SETDB1 interacting complex to improve cardiac reprogramming efficiency”
 
– Tatiana Moreno [Kumsta Lab, Anne Bang co-mentor]
“Identifying TFEB/HLH-30 regulators to modulate autophagy in age-related diseases”
 
– Utkarsha Paithane [Bagchi Lab, TC Chung co-mentor]
“Identification of small-molecule enhancers of Honeybadger, a novel RAS/MAPK inhibitor” 
 

Institute News

Using stem cells to study the biochemistry of learning

AuthorMiles Martin
Date

August 18, 2022

A method for studying human neurons could help researchers develop approaches for treating Alzheimer’s, schizophrenia and other neurological diseases

Researchers from the Conrad Prebys Center for Chemical Genomics have developed a procedure to use neurons derived from human stem cells to study the biological processes that control learning and memory. The method, described in Stem Cell Reports, uses electrodes to measure the activity of neuronal networks grown from human-induced pluripotent stem cells (iPSCs). The procedure tracks how synapses—the connections between neurons—strengthen over time, a process called long-term potentiation (LTP).

“Impaired long-term potentiation is thought to be central to many neurological diseases, including Alzheimer’s, addiction and schizophrenia,” says senior author Anne Bang, PhD, director of Cell Biology at the Prebys Center. “We’ve developed an approach to study this process in human cells much more efficiently than current methods, which could help trigger future breakthroughs for researchers working on these diseases.”

LTP helps our brain encode information, which is what makes it so critical for learning and memory. Impairment of LTP is thought to contribute to neurological diseases, but it has proven difficult to verify this hypothesis in human cells.

LTP helps our brain encode information, which is what makes it so critical for learning and memory. Impairment of LTP is thought to contribute to neurological diseases, but it has proven difficult to verify this hypothesis in human cells.

Anne Bang, PhD, director of Cell Biology at the Prebys Center.

“LTP is such a fundamental process,” says Bang. “But the human brain is hard to study directly because it’s so inaccessible. Using neurons derived from human stem cells helps us work around that.”

Although LTP can be studied in animals, these studies can’t easily account for some of the more human nuances of neurological diseases.

“A powerful aspect of human stem cell technology is that it allows us to study neurons produced from patient stem cells. Using human cells with human genetics is important in these types of tests because many neurological diseases have complex genetics underpinning them, and it’s rarely just one or two genes that influence a disease,” adds Bang.

To develop the method, first author and Prebys Center staff scientist Deborah Pré, PhD, grew networks of neurons from healthy human stem cells, added chemicals known to initiate LTP and then used electrodes to monitor changes in neuronal activity that occurred throughout the process.

The method can run 48 tests at once, and neurons continue to exhibit LTP up to 72 hours after the start of the experiment. These are distinct advantages over other approaches, which can often only observe parts of the process and are low throughput, which can make getting results more time consuming.

For this study, the researchers used neurons grown from healthy stem cells to establish a baseline understanding of LTP. The next step is to use the approach on neurons derived from patient-derived stem cells and compare these results to the baseline to see how neurological diseases influence the LTP process.

“This is an efficient method for interrogating human stem cell–derived neurons,” says Bang. “Doing these tests with patient cells could open doors for researchers to discover new ways of treating neurological diseases.”

Institute News

Conrad Prebys Foundation provides $3 million for pediatric brain cancer research

AuthorSusan Gammon
Date

April 7, 2021

Conrad Prebys was an extraordinary man and a passionate philanthropist. Today, his generosity extends beyond his life through the Conrad Prebys Foundation.

This year, the Foundation provided $3 million to Robert Wechsler-Reya, PhD, and his team of researchers to advance a potential drug to treat medulloblastoma—the most common malignant brain tumor in children.

Children with medulloblastoma often receive aggressive treatment (surgery, radiation and chemotherapy), but many still die of their disease, and survivors suffer long-term effects from therapy. Safer and more effective therapies are desperately needed.

Wechsler-Reya recently combined forces with Michael Jackson, PhD, senior vice president of Drug Discovery and Development, to find a drug(s) that would inhibit the growth of Group 3 medulloblastoma, the most aggressive form of the disease. Using high-throughput screening technology, they identified a compound that reduces levels of a protein called MYC, which is found at exceptionally high levels in Group 3 medulloblastoma, as well as in cancers of the blood, breast, lung and prostate.

“An effective MYC inhibitor could have a major impact on the survival and quality of life of patients with medulloblastoma,” says Wechsler-Reya. “We identified a compound that reduces levels of MYC in medulloblastoma cells, but now we need to learn how it works to optimize it as an anti-cancer drug and advance studies toward the clinic.

“Historically, pharmaceutical companies and funding agencies have under-invested in childhood cancers, and the majority of drugs currently used to treat these cancers were originally developed for adult cancer,” adds Wechsler-Reya. “We believe that effective drugs for pediatric brain tumors must be developed—and this award from the Foundation will help us achieve this goal.”

“We are profoundly grateful to Conrad for his generosity over the years,” says President Kristiina Vuori, MD, PhD “He has a special legacy at our Institute, which was renamed Sanford Burnham Prebys in 2015 to honor him. We are now thankful to his Foundation for including us in their inaugural grant cycle, and for supporting the critical work we do to benefit children and others suffering from cancer.”

The Conrad Prebys Foundation allocated $78 million in its inaugural grant cycle to fund 121 projects. The awards reflect areas of personal interest to Conrad Prebys—including visual and performing arts, higher education, health care, youth development and animal conservation.

Sanford Burnham Prebys joins a long list of recipients, which included other prominent San Diego institutions such as Rady Children’s Hospital, KPBS, San Diego State University, Scripps Research, Museum of Contemporary Art San Diego and the La Jolla Music Society.

Institute News

What scientists are learning about COVID-19 and the brain

AuthorMonica May
Date

December 8, 2020

We caught up with cell biologist Anne Bang, who recently teamed up with her husband to study how SARS-CoV-2 affects the brain

Brain fog. Memory loss. Dizziness and confusion. Although COVID-19 is primarily thought of as a lung disease, survivors continue to report lingering and highly concerning neurological effects—severe enough to impact their ability to work and live normal lives. Doctors are also seeing a worrisome increase in strokes in younger patients, among other observations.

To learn what scientists know so far about COVID-19 and its effect on the brain, we caught up with Anne Bang, PhD, director of Cell Biology at Sanford Burnham Prebys’ Conrad Prebys Center for Chemical Genomics. Bang recently teamed up with scientists at Penn Medicine and a virologist at Scripps Research—who also happens to be her husband—to investigate whether SARS-CoV-2 infects brain cells. Their findings were published in Cell Stem Cell.

What do scientists know about the brain and COVID-19 so far?

Unfortunately, information is still very limited. There are reports of viral replication in the brain and spinal cord fluid of people with COVID-19 who have neurological symptoms. But as you can imagine, taking brain biopsies from someone who has COVID-19 is not realistic. So we really don’t know a lot yet. For this reason, scientists are turning to systems that can model the human brain, such as brain cells created from induced pluripotent stem cells (iPSCs) and brain organoids, to study SARS-CoV-2’s impact on the brain.

What did you find in your study?

We created several types of brain cells using iPSCs and brain organoids, which we then infected with SARS-CoV-2. We found that SARS-CoV-2 primarily infects a brain cell type called choroid plexus cells—largely bypassing neurons and astrocytes. The choroid plexus is a specialized part of the blood-brain barrier, which controls what can enter your brain and produces cerebral spinal fluid. More research emerges every day, but so far, the consensus in the field seems to align with our findings.

SARS_CoV2_ Infected human choroid plexus cells a type of brain cell

The scientists found that SARS-CoV-2 (red) primarily infects brain cells called choroid plexus cells (blue), which are part of the brain’s protective blood-brain barrier.

How might this finding translate to what we’re seeing in patients?

We know that choroid plexus cells produce high levels of ACE2, which is the receptor that SARS-CoV-2 uses to enter and infect cells. Because the choroid plexus is the “gatekeeper” to the brain, it’s possible that the virus enters the brain by infecting these cells. However, much more research is needed before we can give a definitive answer to this question.

We have more questions than answers right now about COVID-19. What is one question you wish we had the answer to?

How does the virus get from the nose and mouth and spread to other parts of the body? This is a big question for me and the scientific field. Once we know how the virus travels throughout the body, we can potentially stop its spread and control the dangerous symptoms.

What was it like working with your husband? Was this your first time working together?

It was really fun. I found out that he is great to work with. We’ve been together for 30 years, and incredibly, this was the first time we worked together.

Institute News

Stepping into a scientist’s shoes at the Cancer Center Open House

AuthorMonica May
Date

June 20, 2019

Cancer research has led to new insights and novel medicines that have transformed the lives of parents, grandparents and children around the world. Yet cancer remains the number-one cause of death in San Diego (nationally, it is the second-leading cause of death). The quest for new and better treatments—and a world free of the disease—remains urgent. 

On June 13, 2019, the San Diego community—including many cancer survivors and their loved ones—had a unique opportunity to step into the shoes of a cancer researcher and see how cancer drugs are discovered at the open house of our NCI-designated Cancer Center. The facility is one of only seven National Cancer Institute (NCI)–designated basic research cancer centers in the nation. 

Following an introduction by Garth Powis, D. Phil., professor and director of the NCI-designated Cancer Center, guests embarked on guided lab tours. Attendees discovered how we’re working to find better ways to combat cancer, viewed highly specialized equipment—such as machines that model the low-oxygen environment surrounding a tumor—and donned lab coats to catch a glimpse of our ultra-high-throughput drug screening robot in action at our Prebys Center for Drug Discovery. The state-of-the-art technology at the Prebys Center can screen hundreds of thousands of potential drug candidates in one run, accelerating the time it takes to find new, promising compounds that may become tomorrow’s cancer treatments.

Guests also learned how San Diego, with a multitude of world-class research institutes, universities and biotech companies, is shaping the future of cancer diagnosis and treatment. And our Community Advisory Board, comprised of cancer research advocates and cancer survivors, were on hand to share the importance of factoring in patients’ perspectives as breakthrough science moves from “bed to bedside.”

See the science in action in these event photos.

Missed the event? We hope you can join us at our next open house in November. The event is free and open to the public. Check for more details at sbpdiscovery.org/calendar.

Many thanks to our Community Advisory Board (CAB), the host of the open house. Comprised of nine cancer research advocates, including many cancer survivors, this committee strives to create a dialogue between our scientists and the community. We are grateful for CAB’s efforts surrounding the event, which included helping our scientists prepare lay-friendly presentations and posters that were critical to the event’s success.

Interested in keeping up with our latest discoveries, upcoming events and more? Subscribe to our monthly newsletter, Discoveries.

Institute News

Drug screen conducted at Sanford Burnham Prebys identifies new therapeutic avenues for Alzheimer’s disease

AuthorMonica May
Date

February 7, 2019

A screen of more than 1,600 Food and Drug Administration (FDA)–approved drugs performed at SBP’s Conrad Prebys Center for Chemical Genomics (Prebys Center) has revealed new therapeutic avenues that could lead to an Alzheimer’s disease treatment. 

The findings come from a collaboration between SBP scientists and researchers at the University of California San Diego School of Medicine, Leiden University Medical Center and Utrecht University in the Netherlands and were published in Cell Stem Cell

The hunt is on for an effective treatment for Alzheimer’s, a memory-robbing disease that is nearing epidemic proportions as the world’s population ages. Nearly six million people in the U.S. are living with Alzheimer’s disease. This number is projected to rise to 14 million by 2060, according to the Centers for Disease Control and Prevention (CDC). 

Scientists have known for many years that a protein called tau accumulates and creates tangles in the brain during Alzheimer’s disease. Additional research is revealing that altered cholesterol metabolism in the brain is associated with Alzheimer’s. But the relationship between these two clues is unknown. 

By testing a library of FDA-approved drugs against induced pluripotent stem cells (iPSC) neurons created from people with Alzheimer’s disease, the scientists were able to identify 42 compounds that reduced the level of phosphorylated tau, a form of tau that contributes to tangle formation. The researchers further refined this group to only include cholesterol-targeting compounds. 

A detailed study of these drugs showed that their effect on tau was mediated by their ability to lower cholesteryl esters, a storage product of excess cholesterol. These results led them to an enzyme called CYP46A1, which normally reduces cholesterol. Activation of this enzyme by the drug efavirenz (brand names Sustiva® and Stocrin®) reduced cholesterol esters and phosphorylated tau in these neurons, making it a promising therapeutic target for Alzheimer’s disease. Further mapping of the enzyme’s action(s) within a cell could reveal even more therapeutic targets. 

“Our Prebys Center is designed to be a comprehensive resource that allows basic research—whether conducted at SBP, academic and nonprofit research institutions or industry—to be translated into medicines for diseases that urgently need better treatments,” says study author Anne Bang, PhD, director of Cell Biology at the Conrad Prebys Center for Chemical Genomics at SBP. “We are proud that the Prebys Centers’ drug discovery technologies helped reveal new paths that could lead to a potential treatment for Alzheimer’s, one of the most devastating diseases of our time.”


The senior author of the study is Lawrence S. B. Goldstein, PhD, distinguished professor at the University of California San Diego (UC San Diego) and scientific director of the Sanford Consortium for Regenerative Medicine. The co-first authors are Vanessa Langness, a PhD graduate student in Goldstein’s lab, and Rik van der Kant, PhD, a senior scientist at Vrije University in Amsterdam and former postdoctoral fellow in Goldstein’s lab. 

Additional study authors include Cheryl M. Herrera, Daniel Williams, Lauren K. Fong and Kevin D. Rynearson, UC San Diego; Yves Leestemaker, Huib Ovaa, Evelyne Steenvoorden and Martin Giera of Leiden University Medical Center; Jos F. Brouwers and J. Bernd Helms; Utrecht University; Steven L. Wagner, UC San Diego and Veterans Affairs San Diego Healthcare System.

Funding for this research came, in part, from the Alzheimer Netherlands Fellowship, ERC Marie Curie International Outgoing Fellowship, the National Institutes of Health (NIH) (5T32AG000216-24, IRF1AG048083-01) and the California Institute for Regenerative Medicine (RB5-07011).

Read more in UC San Diego’s press release.