A new Center for Live Cell Genomics, funded by a five-year, $13.5-million grant from the National Institutes of Health, will bring together researchers at the UC Santa Cruz Genomics Institute to develop new methods and experimental platforms for biomedical research using live cells and tissues. The center will deploy this new biotechnology to study neurodevelopmental diseases and cancer.
UC Santa Cruz has built an international reputation as a leader in bioinformatics and genomics, working at the forefront of efforts to use genomics in precision medicine and biomedical research. With the new center, the Genomics Institute is spearheading transformational innovations in experimental platform design for large-scale, long-term genomic studies of disease processes in living cells and complex tissues. Advanced methods for growing three-dimensional cultures of human cells and tissues in the lab will be combined with “lab-on-a-chip” technologies and connected to the internet to create an inexpensive and scalable system with internet-based remote control and analysis capabilities.
“We are creating a disruptive technology with an open-source bent to it, which we hope will ignite a revolution in biotechnology comparable to what has happened in information technology,” said David Haussler, professor of biomolecular engineering and director of the UCSC Genomics Institute. “We are moving toward a new way of building equipment and doing and sharing experiments on living cells, experiments that are crucial for understanding diseases and developing new ways to treat them.”
New approach
Genomic techniques such as RNA sequencing enable scientists to study patterns of gene expression in living cells, seeing which genes get turned on and off at different times and under different conditions. These studies help researchers understand disease processes and identify potential targets for new treatments. Traditional approaches involve growing cells in culture and harvesting them to extract RNA or DNA for sequencing, killing the cells in the process. But studying how gene expression changes as complex tissues, organs, and tumors develop over time requires a new approach, said Sofie Salama, a research scientist at the Genomics Institute and adjunct professor of biomolecular engineering.
“With advances in stem cell biology, we can now grow highly complex, three-dimensional tissues that mimic either developing organs, like the brain organoids my lab works with, or that mimic tumors for cancer research,” Salama said. “Understanding these long-term cultures as they develop and get more complex over time requires a paradigm shift in our experimental approach.”
The experimental platform envisioned by the new center will be automated, scalable, and internet-connected. It will include microfluidics systems with integrated molecular analysis capabilities; continuous imaging with low-cost microscopy systems; analysis of RNA and proteins from live tissues; and the capacity to monitor and control experiments remotely, compare results to large shared datasets in the cloud, and use machine learning to improve performance.
Holger Schmidt, professor of electrical and computer engineering, is co-principal investigator of the Center for Live Cell Genomics, bringing expertise in optofluidic chip technologies for biomedical diagnostics and molecular analysis. Schmidt, who holds the Narinder Kapany Chair in Optoelectronics and directs the W. M. Keck Nanofabrication Facility at UCSC’s Baskin School of Engineering, has developed a variety of integrated chip-based platforms for processing samples and analyzing individual biomolecules and viruses.
“I’m excited to bring our devices and technologies to bear as part of a completely new paradigm, working with live cell cultures and bringing that to a more automated stage where it can be accessible to more people,” Schmidt said.
Braingeneers
The new center will bring together a broad range of researchers in different departments at UCSC, as well as collaborators at UCSF, Stanford, and other institutions. It will build on existing efforts such as the research on brain development led by Haussler, Salama, and others (the “Braingeneers” team), and the pediatric cancer genomics program (Treehouse Childhood Cancer Initiative) led by Olena Vaske, assistant professor of molecular, cell and developmental biology and Colligan Presidential Chair in Pediatric Genomics.
Development of the core live cell platform will build on several ongoing projects that have yielded devices, instruments, and software similar to most of the elements of the proposed system.
For example, Salama’s lab has been working with Mircea Teodorescu, associate professor of electrical and computer engineering, and others to develop better ways of growing cerebral organoids. As stem cells develop into cortical neurons in the lab, they self-organize into layered structures similar to the brain's cortex, providing a three-dimensional model of living brain tissue for studying how the brain’s neural circuitry develops. Using technologies such as 3D-printed scaffolding to support the developing organoid and microfluidic pumps and channels for nutrient delivery, the team is developing a sophisticated, integrated system for growing and monitoring these cerebral organoids.
UCSC researchers are also investigating a promising approach for noninvasive genomic analysis by isolating “exosomes”—extracellular vesicles released from living cells that contain cargoes of RNA, proteins, and other molecules. “With our microfluidic systems, we are pumping media in and out of the culture, and the media we pump out is gold—by analyzing the nucleic acids and metabolites in that, we can find out what’s going on in the culture,” Salama said
Picroscope
Teodorescu’s team has also developed a low-cost microscopy system, called a “picroscope,” which is compatible with standard 24-well cell culture plates and provides continuous imaging as well as remote access for monitoring the growth and morphology of live cultures. The Genomics Institute has used this system to give students at Alisal High School in Salinas the opportunity to participate remotely in biology experiments during the COVID-19 restrictions in 2020 and 2021, when students weren’t even able to enter a classroom.
“Working with their amazing biology teacher, Rebecca Ward, we had students use their cell phones to do experiments over the internet and watch zebrafish embryos develop from bundles of cells into fish,” Haussler said.
The new center’s education and outreach programs will include efforts to build on this pilot project and expand access to sophisticated biology experiments for students in under-resourced schools. Research scientist Mohammed Mostajo Radji and Genomics Institute Office of Diversity Director Zia Isola are leading efforts to promote diversity and inclusion in the roll-out of education programs focused on these new technologies.
The picroscope also exemplifies the center’s open-source, custom-built approach to biotechnology equipment, taking advantage of inexpensive off-the-shelf components and 3D printing technology. “One of the side benefits of the world's amazing consumer technology is we now have a ten-dollar camera we can put in a microscope,” Haussler said. “Imagine a lab where the equipment is built, customized, and shared with other labs—that’s the life sciences of the future. It’s a disruptive technology compared to the traditional biotech equipment made for specialized purposes.”
Haussler is also enthusiastic about the potential for connecting devices to a powerful computational infrastructure using secure communication between the cloud and internet-connected devices based on open-source Internet of Things (IoT) services. Among other things, this enables the use of artificial intelligence to monitor and control experiments.
“AI can control experiments while we sleep,” he said.
The scalability of the proposed platform also promises to make it cheaper and faster to conduct experiments. “For experiments that may cost thousands of dollars per test now, imagine if we could do tens of thousands of tests in parallel at orders of magnitude less cost per test. We need that capacity to understand the mechanisms of these complex diseases, and understanding is the first step to developing new treatments and therapies.”
The Centers of Excellence in Genomic Science (CEGS) program of the National Human Genome Research Institute (NHGRI) supports the formation of multi-investigator, interdisciplinary research teams to develop novel and innovative genomic research projects that will ultimately foster the wider application of comprehensive, high-throughput genomics methods to the study of human biology and disease.
