High-Throughput Screening at the Institute for Stem Cell and Regenerative Medicine

Tim Martins knows how to go slow. After retiring from a career in research at ICOS Corp, a local BioPharmaceutical firm, he drove a school bus through the eastside suburbs of Seattle, braking every few blocks to pick up his pint-size passengers, not caring one bit about freezing traffic in all directions. For once, speed was the last thing on his mind.

That was about to change.

Across Lake Washington, a renowned University of Washington scientist named Dr. Randall T. Moon had just become the founding director of the newly minted UW Institute for Stem Cell and Regenerative Medicine (ISCRM), a multidisciplinary community where researchers from medicine, engineering, and other fields were joining forces to fight chronic disease using stem cells as tools and discovery and treatment.

Entrance to the Quellos High-Throughput Screening Core housed at the Institute for Stem Cell and Regenerative Medicine (ISCRM) at South Lake Union.newly minted UW Institute for Stem Cell and Regenerative Medicine (ISCRM), a multidisciplinary community where researchers from medicine, engineering, and other fields were joining forces to fight chronic disease using stem cells as tools and discovery and treatment.

Dr. Moon felt strongly that success for ISCRM would ultimately be measured by whether or not the institute could go beyond academic science—and develop new therapies that impact actual patients. While pursuing his academic career, Dr. Moon saw numerous examples where new technologies had just become available, and that early adopters of the technology were able to make transformative discoveries. He wanted ISCRM to invest millions of dollars to do the same at the University of Washington.

Automated technology in the Quellos High-Throughput Screening Core (HTS) is accelerating research in labs across ISCRM and UW.

The technology that Dr. Moon coveted is known as high throughput screening (HTS) – essentially, the use of robotics and other highly automated tools to conduct chemical tests or genomic screening at tens of thousands the speed of traditional methods. Dr. Moon understood that a high throughput screening core, staffed by skilled specialists, would enable ISCRM researchers developing new drugs or investigating the role of certain genes to gather critical data, accelerating the impact of entire labs and the institute itself.  To prove that this technology could be efficiently adopted by ISCRM, and UW, Dr. Moon sent two graduate students from his lab, Travis Biechele and Will Conrad to Boston, where they quickly learned the technology and what was needed to set it up.

After galvanizing support for his vision, Dr. Moon needed a single one-hour lunch to secure funding from the Quellos Group and set out to build the team to operate the Quellos High Throughput Screening Core. He knew just the man for the job.

Tim Martins recalls his decision to park the school bus and return to the lab as one of the initial Directors of the Quellos HTS Core, a position he still holds.  “For me it was the fun of getting back to the bench. I missed the science. I was excited to get my hands wet again.”

Martins and Dr. Moon soon recruited James Annis, a research scientist from a subsidiary of Merck and Co. with a background in functional genomics, a skill set that nicely complemented the experience Martins brought in chemical screening. “This fell in line with everything I’d done in my career,” says Annis. “I’ve always been in young organizations where the job was to get things up and running quickly.”

Together with Travis and Will, Martins and Annis built the Quellos HTS Core out of little more than a vision and 1,500 square feet of empty lab

Dr. Tim Martins and James Annis, research scientist, at the Quellos High-throughput Screening Core housed at the Institute for Stem Cell and Regenerative Medicine (ISCRM).

space. Their mission was to launch a revenue-generating unit that would offer screening services for internal and external clients, emulating project-driven operations common in pharmaceutical companies, but not in academic settings.

True to Dr. Moon’s founding principle, the goal was to shorten the time from discovery to treatment, for the benefit of current and future patients suffering from chronic conditions, like cancer, heart disease, Alzheimer’s, and other disorders.

According to Annis, “Randy wanted people with high technical expertise who could take a researcher’s problem and distill it down – to say, this what’s going to help you get to the next stage, and this is how we can help you do it.”

The initial customer for the Quellos HTS Core was also its founder. In addition to leading ISCRM through its startup years, Dr. Moon was researching the cellular biology of the cancer melanoma. Specifically, he wanted to know why these cancer cells continue multiplying. He knew the answer involved the Wnt pathway – a series of signals that control how certain cells become specialized – but he needed more data.

In an early milestone for the core, Martins conducted a compound screen for the Moon Lab, using the automated processes at his disposal to test how the Wnt pathway in cells responded to thousands of chemicals that could be potential drugs therapies.  Independently, Annis performed a functional genomics screen to uncover which gene or genes might be complicit in cancer formation involving the Wnt pathway.

“Our screens validated the hunch in two ways,” says Martins.  “From the compound side, which identified the inhibitor [the mechanism in the Wnt pathway that should halt cancer cells from spreading]. And, from the functional genomics side, we were able to identify and knock out the problem genes that just happened to be a target for the inhibitor we identified. The results also validated our HTS processes, which was very exciting.”

Another big moment would follow in 2011. Dr. Tony Blau and Dr. Pamela Becker, two world leaders in cancer research based at ISCRM, came to the HTS Core with a question. They wanted to know which drugs were most effective against adult acute myeloid leukemia (AML), a bone-marrow cancer.

After completing a series of pilot studies, Martins, working with just a single set of a patient’s cancer cells, was able to run a sensitivity screen against 160 potential drugs at different concentrations, producing results that helped propel Dr. Becker’s pioneering work in precision medicine. Dr. Becker now uses the Cancer Drug Sensitivity Test (CDST) to screen drugs against multiple types of cancer, including AML, Acute lymphoblastic leukemia (ALL), and Chronic myeloid leukemia (CML), with more types planned in the future.

“The Quellos HTS Core has furnished data that support several ongoing precision medicine clinical trials in blood cancers,” says Dr. Becker. “Our goal is to optimize treatment such that the best drugs are used for each individual patient.”

“When we do optimization, we know what to do to get the same results over-and-over again, to validate the screens,” says Martins. “It’s the thought process, the design of the workflow, and controlling conditions.”

Annis agrees. “It’s a certain mindset about how to think about an experiment with that many variables, and how to distill the data down to something meaningful, in the most cost-effective, efficient way.”

Since 2014, screens conducted in the HTS Core have been used in multiple clinical trials, contributing to research (presented by Dr. Becker at the 2018 annual meeting of the American Society for Hematology) on drug response patterns of stem cells taken from patients with AML. Moreover, the CLIA-certified HTS Core can now serve patients outside of clinical trials, producing data that physicians can use to make informed decisions about treatment.

High throughput screening in human organoids derived from stem cells can be used to discover new therapies in organs such as the kidneys (illustrated here). Credit: Cell Stem Cell DOI:https://doi.org/10.1016/j.stem.2018.04.022

Dr. Benjamin Freedman, another ISCRM faculty member, has turned to the HTS Core to fast-track his lab’s effort to develop a novel approach to study and treat kidney diseases by growing three-dimensional mini-kidney structures from human cells, leading to “clinical trials in dishes” to test drug responses more efficiently than current methods.

“The high throughput screening project has been one of the sweeter success stories we’ve had in the lab,” says Dr. Freedman, citing a paper published in the journal Cell Stem Cell, and preliminary data used in grant proposals, as two key outcomes from his collaboration with Martins and Annis. “James and Tim helped our lab plate cells, differentiate them into organoids, design screening experiments, and analyze the data. Perhaps the most exciting part is that this work has led to the discovery of new candidate therapeutics (hits), which we are now eager to test further.”

Ten years after returning to the lab, Tim Martins is exuberant about what the HTS Core has accomplished and looking forward to what may follow. “Getting back into the lab has been a dream,” he says. “My job is to deliver the best, highest quality work that I can deliver, and the HTS Core gives me the freedom to be nimble and creative – to find the unique solution for each unique challenge. And, we’re making real contributions to medicine, which is what matters most. I’m able to contribute in ways that were not feasible in the commercial setting.”

Dr. Moon, the scientist with the original vision, concurs. “The HTS Core has become a widely used and invaluable resource for UW,” he notes. “I am very proud of the fact that we established this facility by trusting the abilities of two graduate students and a former bus driver. I am thrilled by the new discoveries made possible by this technology, notably Dr. Becker’s work.  I think it is safe to say that exploiting  advanced technologies like  HTS, and leveraging ISCRM scientist’s deep knowledge of basic biological  processes will allow us to make even more novel discoveries and to develop new therapeutics.”