Research Engine

URI builds a collaborative research platform in brain science

The story of EPhysBio provides an illustrative tale of how to build an innovation hub

Photo by Richard Asinof

Margaret Levin, Ph.D., the principal at EPhysBio, a drug development research firm which will soon celebrate its first anniversary at URI in affiliation with the Ryan Institute for Neuroscience.

By Richard Asinof
Posted 9/3/18
The recruitment of EPhysBio to be one of the affiliated research drug discovery firms at URI is a model of collaborative research that other colleges and universities in Rhode Island should consider implementing.

When will CommerceRI announce a decision for its investment in the new innovation campus in Rhode Island? Is there a way to reframe the discussion around life sciences investments to reflect the regional research enterprise, rather than a driver of job creation? What opportunities are there for collaborative research platforms involving nursing and primary care? As the business model for hospitals and health systems changes, how will that change the investment model for clinical applications and new medical devices?
As much as the focus by the Governor’s Task Force on Overdose Prevention and Intervention has been reducing the number of deaths, the larger issues around what sociologist Shannon Monnat calls the diseases of despair – the high mortality rates from suicide, alcohol and drugs, particularly for young people between the ages of 25-24 in Rhode Island – have not been addressed.
Now, under the leadership of South County Healthy Bodies, Healthy Minds, one of nine health equity zones operating in Rhode Island, a new, five-year, federally funded initiative is being launched, called “Zero Suicide.”
South County has the highest rate of suicide in Rhode Island, a statistic not well known. An opportunity exists with the launch of the new initiative to conduct public health research that looks at the factors involved with suicide – how it is related to isolation, economic turmoil and the destruction of the middle class, the lack of access to affordable health care, and trauma from sexual violence or child abuse, among others.
What is the best metric to measure results of the initiative? With drug overdoses, the metric has been deaths, rather than deaths avoided and people in recovery. Perhaps the “zero suicide” initiative will also contribute to a different metric looking at something other than death rates.

PROVIDENCE – There was a lot to learn at the recent gathering sponsored by MedMates on the rooftop of Providence G on Aug. 30 by engaging in conversation with some of the shakers and movers in the biotech world in Rhode Island, far beyond what is revealed in promotional snapshots and silos of rewritten news releases.

Rubius Therapeutics, which is constructing a $155 million pharmaceutical manufacturing facility on the site of the former Alexion Pharmaceuticals in Smithfield, is apparently busy doing its homework.

Representatives from Rubius recently met with biotech students at the University of Rhode Island to talk about the work being planned and the potential demand for future employment. [See links below to ConvergenceRI stories, “Lessons to be learned from Alexion,” and “Rubius Therapeutics to construct $155M biopharma facility in Smithfield.]

The decision by Rubius to expand its manufacturing operations in Rhode Island reflects a growing recognition that the sweet spot for the state is potential regional opportunities for biopharma and biotech companies headquartered in Boston and Cambridge to draw upon the talent of Rhode Island scientists and researchers. [See link below to ConvergenceRI story, “RI as a scalable research lab in a regional universe.”]

A similar move was made by Semma Therapeutics, headquartered in Cambridge, with its focus on developing an artificial pancreas, when it purchased CytoSolv, a Rhode Island firm, in 2015, known for its encapsulated cell technology, but decided to maintain and expand the CytoSolv operations in its Providence location. [See link below to ConvergenceRI story, “RI biotech firm CytoSolv acquired by Semma Therapeutics.”]

At the MedMates gathering, there was an official announcement of the grand opening scheduled for Tuesday, Sept. 11, of the New England Medical Innovation Center, or NEMIC, at 116 Chestnut St. in Providence, which will also serve as the new headquarters for MedMates.

Perhaps the most significant conversation took place with Margaret Levin, Ph.D., the head of new drug research company, EPhysBio, which will soon celebrate its first anniversary at its location at the University of Rhode Island. EPhysBio is one of a number of new firms, including MindImmune, affiliated with the George and Anne Ryan Institute for Neuroscience.

Moving beyond competition toward collaboration
Levin’s story is illustrative of both the competitive, up-and-down nature of biopharma research in Boston and Cambridge as well as the opportunities that Rhode Island can create to attract talented scientists by forging a collaborative research environment.

Levin had been working as a researcher with Galenea, a drug research firm headquartered in Cambridge, Mass., which had been co-founded by Dr. Susumu Tonegawa, the 1987 Nobel Prize winner in Medicine, who is also a professor at the Massachusetts Institute of Technology.

Under the direction of Tonegawa, researchers at Galenea isolated a genetic defect associated with schizophrenia – and then built a mouse model incorporating that defect as a target platform for drug discovery.

Much of the work was conducted under a contract with Otsuka, a Japanese pharmaceutical company which manufactures Abilify, what is known as an “atypical antipsychotic” drug used to treat indications for schizophrenia and bipolar disorders.

As Levin explained it, Otsuka wanted to go beyond only alleviating the negative and positive [psychotic] symptoms of schizophrenia, and create a drug that addressed the cognitive deficits associated with the disease, such as working memory and executive function deficits. These cognitive deficits are the main reason why people suffering from schizophrenia remain disabled throughout life.

[Editor's note: Clinicians often refer to the psychosis-related symptoms of schizophrenia as “positive symptoms,” since they are symptoms which are not present in healthy individuals. In comparison, “negative symptoms” usually refer to non-psychosis-related behavioral attributes which are common in healthy adults, but are lacking in individuals with schizophrenia.  These include reductions in the outward expression of emotion. “Cognitive symptoms" are a third category of schizophrenia symptoms, which include deficits in attention, executive function, and working memory.]

“We based our science on the gene that was defective schizophrenia and incorporated into the mouse model,” Levin told ConvergenceRI. “My job, at that time, was to figure out what other genes or neural pathways became defective downstream of this primary, or causal gene.”

Once Levin came up with a potential list of genes that she thought were affected, “I had to validate them. The question was: how do you know that the gene is going to be [involved with] something that I wanted to target with a drug.”

New research platform tools

Levin’s questions about validation led to the work by her and her team to deploy a platform measurement tool, electroencephalography, or EEG, which uses electrophysiology to measure the synchronized, patterned activity of neurons in brain networks.

“Neurons in networks "fire" to stimulate other neurons that they are connected to,” Levin said. “Neurons not only need to fire properly, they need to fire in a certain pattern, or synchronized activity. That network of synchronized patterns is what gives rise to 'brain waves' or network oscillations. When you measure this network activity, you are measuring the synchronized neuronal activity.”

Lots of research now indicates that the network oscillations in mice are very similar to those in humans, Levin explained. "This means that when we found interesting changes in network oscillations caused by our new drug candidates in our mouse model, we could be reasonably certain that these drug candidates would the same in humans."

Levin continued: “That is what I started to do at the company, to develop the tools to measure network modulations in our mouse. That is how I got started in this type of work.”

“We were a typical drug discovery research company,” Levin said. “We had a mouse [model]; we had a target; we had a drug that we were developing. We wanted to validate that. I had decided that we really needed to look at neural activity for validation.”

Survival after the contract ends
The contract with Otsuka was for six years, and the original investment was around $50 million, according to Levin, who praised the working relationship between the firms.

Levin said that Otsuka had even sent their scientists to work side-by-side in the Galenea research lab. “They were a really nice organization to work with.”

However, what happened next in the story is an all too commonplace occcurrence among drug research discover firms: the contract with Galenea ended, and Otsuka took the research on the gene targeted for potential drug development and moved on. “Our collaboration ended,” Levin said, succinctly.

Developing technology platform tools

After the Otsuka collaboration ended, part of Galenea was bought out by another firm, Q State Pharmaceuticals, an optogenetics company focused on a platform that employed in vitro rsearch, which focused on conducting research in a laboratory dish. Levin and her research team wanted to continue the in vivo research working with mouse models. Her group was able to secure two NIH grants, one for $1 million, an RC1 challenge grant, and another for $2.5 million RO1 grant, to further develop the technology platform for assays using electrophysiology recordings.

The business model was to attempt to market these technology platforms to Big Pharma and biotech firms, functioning as a kind of contract research organization, conducting the assays in a fee-for-service model.

The service was to connect assays from mouse models and human models to find points of convergence, to make the leap from preclinical mouse models to the clinic more translatable by finding similar patterns of synchonicity in brain waves in the "conserved" regions of the brain, such as the auditory cortex in mice and humans.

A new home in Rhode Island
Finding an affordable home in Cambridge for her new business proved difficult. Then, in 2017, Frank Menniti, one of the co-founders and chief science officer at MindImmune, suggested that Levin bring her research group to the University of Rhode Island and work in affiliation with the Ryan Institute for Neuroscience.

After meeting with Paula Grammas, the executive director of the Ryan Institute, and William Renehan, the associate director, Levin agreed to set up shop at URI in October of 2017, leasing space.

The idea behind the collaboration, Levin explained, was that “between us and MindImmune, with our industry pharmaceutical experience, we could help the mission of the Institute, to help develop the science that leads to therapeutics that can conquer neurodegenerative diseases such as Alzheimer’s.”

Levin expressed enthusiasm for the role of her company, EPhysBio, to work as both advisors and collaborators in the research enterprise at the University of Rhode Island.

The goal of the research is to connect assays from mouse models and human models to find the points of convergence, to make the leap from mouse models to clinical trials more efficacious by finding similar patterns of synchronicity in brain waves in the auditory cortex in mice and humans.

Different than the model of a shared working space, Levin said, the model at URI seeks to nurture the companies in-house, in more of a collaborative working relationship.

Levin said that she believed the business model of embedding research drug discovery firms at URI was the first of its kind in Rhode Island, although she had heard that Brown was considering moving in a similar direction.

“I liken it to working together as a consortium, sharing ideas and techniques,” Levin said, something that was often difficult to find and maintain in Cambridge. “I would like to get our in vivo electrophysiology [EEG] assays out there, so we can advance the field.”

At the same time, Levin acknowledged that she was straddling this mission-driven approach, keeping the costs down for companies so that they will use the assays to develop drugs and advance the science and keep enough money flowing into the company to pay the salaries of her team.

“The Ryan Institute is unique,” Levin said, thrilled to be part of an evolving collaborative research enterprise.

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