Research Core Facilities—Custom Science on Demand

A core facility is a shared research laboratory that offers scientists access to advanced instruments, services, and expertise. At Yale, dozens of full-service cores dot the campus at convenient locations, with 20 centrally supported open-access cores at Yale School of Medicine (YSM) alone.

The cores house special tools too expensive for any individual lab to purchase on its own, such as microarray systems capable of identifying disease-related genetic differences, and robots that test tens of thousands of potential cancer drugs. And, crucially, cores have their own staff scientists who offer researchers expert guidance in using these tools and can carry out experiments on behalf of labs.

“We’re scientists who help other scientists do their research,” says Guilin Wang, PhD, director of a core on Yale West Campus called Keck Microarray Shared Resource. “A research lab can focus on what they’re trying to solve, and we provide technological help and knowledge about cutting-edge advances.”

Part of what makes these facilities possible is that they’re a shared cost. Researchers pay access or use fees for core services out of their grant funds, but these don’t typically cover the full cost. The university also invests heavily in core facilities.

“We’re all in this together. We all chip in to help support the research,” says Ben Myers, PhD, director of research cores (central).

Here’s a look at how three cores enable YSM research.

Primary dystonia is a disorder that causes uncontrolled muscle movements. Originating from abnormal brain signals, these movements can be twisting, repetitive, and painful.

When examining cells with genetic mutations linked to primary dystonia, Christian Schlieker, PhD, chair and professor of molecular biophysics and biochemistry at YSM, discovered aberrant condensates—essentially, a buildup of toxic gunk. This gunk behaves like an unwanted sponge, soaking up quality-control proteins and blocking the cell’s ability to recycle proteins.

Working with the Yale Center for Molecular Discovery (YCMD) on Yale West Campus, Schlieker is testing tens of thousands of small drug-like molecules to see if any of them can reduce the condensate’s toxicity or even remove the stuff altogether. Such a molecule could perhaps be developed into a safe, effective drug.

He’s also hunting for cellular activity that counteracts condensates within healthy cells, reasoning that something must be going wrong with this machinery when primary dystonia occurs. Using a technique called high-throughput screening at YCMD, he deletes each gene in normal cells, one by one, to pinpoint which deletion leads condensates to build up.

“Neither of those projects could we have done without the YCMD,” Schlieker says. “We developed this together with them. They interface very strongly with the laboratories, so they are actually the ones to do the screening, but it happens in close coordination with us.”

YCMD helps researchers identify novel targets, probes, and molecules, often with an aim to translate discoveries into medical advances. These include discoveries in brain science, cancer, autoimmunity, and more. Armed with vast small-molecule and genomic collections, equipment for high-throughput screening, and related tools, the core serves dozens of labs at Yale every year, plus outside labs and companies. Staff work with researchers on not only high-throughput screening but also tailor-made, statistically rigorous assays (testing procedures). A chemist experienced in using AI helps with drug development.

“You make rookie mistakes when you start something new. Many labs don't try new methods very often, because it's detrimental to productivity,” Schlieker said. “But if you have cores that can do it, it lowers the barrier to trying out new territories.”

YCMD director Yulia Surovtseva, PhD, says their services are customized for each person and project.

“If a Yale faculty member discovers some new cancer cell line, they can come to us and say, ‘I really want to try to kill these cancer cells, but I also want non-cancerous cells to not be killed with that drug,’” Surovtseva says. “We can develop this assay where we are looking for differential toxicity of our drugs to cancer versus non-cancer cells.

“Often when people discover new targets or new mechanisms of diseases, they don't know how to take it to the next level, how to translate this discovery into patient benefits,” she adds. “That's the expertise that we have and can share.”

The vagus nerve connects the brain to multiple organs. Exploratory work taking place at the Keck Microarray Shared Resource core on Yale West Campus offers clues as to how the brain distinguishes all the signals the vagus nerve sends its way.

Along with colleagues, Le Zhang, PhD, an assistant professor of neurology and of neuroscience at YSM, used data collected at the Keck Microarray to uncover that vagus signals include independent information about the organ, tissue layer, and specific stimulus where they originate, allowing the brain to precisely discriminate different signals. The discovery led to a paper in Nature that Zhang co senior-authored with Rui Chang, PhD, associate professor of neuroscience and of cellular and molecular physiology at YSM.

Keck Microarray is conveniently located down a flight of stairs from Zhang’s lab—key for keeping cells alive during transport.

“Those single cells have to be fresh and have over 90% or even 100% viability to keep the quality,” Zhang says. “The core is only a one-minute walk from my lab. It's the same as having a core within my own lab. So it has benefited us a lot.”

A microarray, the core’s specialty, is a glass or silicon chip that can detect interactions among biological molecules. Picture a tiny checkerboard with hundreds of thousands of squares. Attached to each square is a fragment of unzipped, or denatured, DNA. Each fragment, called a probe, is slightly different from its neighbors.

A scientist exploring genetic differences that occur in a particular disease can then prepare a mixture of unzipped snippets of a patient’s DNA attached to fluorescent molecules. If they rinse the checkerboard in that mixture, complementary DNA strands will reunite, or anneal, while everything else flows away. The annealed strands will glow enough for a powerful camera to pick them up—and tell you which genetic variant the person has.

“We have sequencers to sequence the DNA and RNA, scanners to scan the array signal, and a variety of tools to do quality checks of DNA and RNA. We work streamlined, like a factory,” says Wang.

Keck Microarray can also investigate genetic material in a single cell, exploring differences in how genes are expressed between different cell types. Zhang used single-cell technology in her vagus research as well as in a study of Parkinson’s disease in which she examined cell nuclei from postmortem human brains.

Antonio Giraldez, PhD, Fergus F. Wallace Professor of Genetics at YSM, studies how a fertilized egg goes from a dormant to an awakened state, kicking off embryo development. Working with the Yale Center for Genome Analysis at Yale's West Campus, he and his colleagues found the genes that activate that “first spark.”

More recently, his team zoomed into the cell to visualize the machinery that activates the genome. They discovered that the scaffold that stores up packaged DNA, a substance called chromatin, forms highly dynamic structures capable of turning gene transcription on and off.

That research relied on expertise and technologies at the Electron Microscopy Core in the Center for Cellular and Molecular Imaging (CCMI EM) at YSM's Sterling Hall of Medicine.

“Electron microscopy allowed us to gain unprecedented resolution to visualize those events like never before,” Giraldez says. “By combining techniques that are only possible through value offered by these cores we can see these new chromatic structures in real time. Xinran [Liu, MD, PhD, the core director] has been fundamental to seeing those molecules.”

Cores are so important to Giraldez that, when he served as chair of his department from 2017 to 2023, he made sure part of his recruitment package went toward buying more microscopes for one of them.

Many people still think of electron microscopy as a simple process of putting a sample in and taking a picture—but that’s no longer the case, Liu says.

“Now we can expand from two-dimensional to three-dimensional space and provide volume data at high resolution. This can be achieved by electron tomography, similar to a CT scan, or focused ion-beam scanning electron microscopy,” Liu says. “We can now explore the intricate architecture of subcellular structures across entire cells.”

To preserve cellular structures as close to their natural state as possible, CCMI EM also uses methods that “freeze” biological activity in time. This allows them to capture dynamic processes that traditional approaches would miss. Furthermore, Liu’s team provides correlated light and electron microscopy, a method that combines live-cell fluorescence imaging (to find cells with positive signals) with high-resolution EM (which reveals underlying structures). This approach allows scientists to pinpoint the exact structure involved in signaling or other cell functions.

Before taking on a new project, Liu and his team carefully assess its feasibility. If it moves forward, they tailor every experiment to the research question, then perform the experiment and deliver image datasets, plus offer expert interpretation. Each year, the core supports around 200 projects, serving investigators from Yale and beyond, from New Haven to Palo Alto to South Korea.

“Where else can you have a world-class microscopist literally downstairs from the laboratory, where we can go and say, ‘Hey, can we image this together?’” Giraldez asks. “That is just precious.”