How Broad scientists are bridging the gap between biological insights and new therapies

Throughout his 30-year career, Alex Burgin has jumped multiple times over the divide between academia and industry, working at a biotech company, a university, and another company before realizing one September morning, nearly a decade ago, that he could land squarely between the two. 

In 2012, just after a cross-country move to Boston, Burgin visited the Broad Institute of MIT and Harvard to meet collaborators. He was ushered, without introduction, into a meeting already underway, where he watched as ideas ricocheted between senior and junior researchers, academics and industry partners, with an enthusiasm that seemed invigorating and new. He’d seen companies work to make a molecule fit a certain therapeutic target as this group was trying to do, but it seemed to him that Broad was different.

“It was really clear that there was a deep understanding of biology and that was driving discovery,” Burgin said. “It was refreshing to come to an environment that placed fundamental biological questions so close to the center of every project.”

A few months after that meeting, Burgin would join the Broad as the senior scientific advisor to Todd Golub, then the institute's chief scientific officer — a job Burgin held for six years before leaving to spend two years as the executive director of the Institute for Protein Innovation. Last spring, Golub, who had recently become director of the Broad, asked Burgin to return to serve as the senior director of the Center for the Development of Therapeutics (CDoT), a group within the Broad that aims to translate biological insights into new therapeutics.

Alex Burgin
Credit: Gretchen Ertl

At CDoT, Burgin works closely with Florence Wagner, the center’s longtime associate director and director of medicinal chemistry; Cathy Forest, director of strategy and operations; and other CDoT leaders who also bring decades of experience from both industry and academia. They oversee a team of more than 100 professional scientists, including chemists, structural biologists, biophysicists, biochemists, pharmacologists, data scientists, and project managers — all specializing in different facets of the drug development pipeline. 

With its array of specialists, state-of-the-art technologies, and collaborative structure, CDoT exemplifies a hybrid model of drug discovery — a research environment that combines deep knowledge of disease biology with the pace and focus of industry to move compounds with therapeutic promise toward the clinic. Often, that means taking on ideas that a company might consider too early or risky, or bringing unique Broad expertise in imaging, proteomics, genomics, and computational science to bear on drug targets that others are also pursuing. What all of CDoT’s projects have in common, though, is that Broad faculty with deep understanding of fundamental biology are regularly engaged throughout the drug discovery process. 

“Faculty have a really deep understanding of disease, but they don’t always appreciate the complexities of what it takes to make a drug,” Burgin said. “Our role in CDoT is to help find those ideas that might have the potential to make it to the clinic.”

So far, this hybrid model is working: as of December 2021, four CDoT compounds have reached early-stage clinical trials, and the center has licensed another six to companies for the final stages of preclinical drug development. Other projects are underway to develop therapeutics for cardiovascular disease, autoimmunity, kidney disease, psychiatric disease, and cancer.

“This is a really exciting new model,” Burgin said. “Not every project will reach the clinic, but we’ll be much more likely to succeed when we’re immersed in the biology, especially with tools like genomics, proteomics, imaging, and machine learning at our fingertips.”

From bench to bedside

The pattern that CDoT’s team hopes to avoid is formidable. Ninety-five percent of drugs under development fail to reach final approval by the FDA; even a successful drug takes, on average, about 10 to 15 years and hundreds of millions of dollars (one recent study estimated $985 million) to reach the market as an approved product. Scientists have a colorful gamut of names for the length of time between new findings in the lab and new treatments for patients: everything ranging from a predicament to a crisis to, most vividly, the valley of death. 

Over the last two decades, efforts to bridge the “valley of death” have sprung up around the country, including the National Institutes of Health’s (NIH) National Center for Advancing Translational Sciences (NCATS). In 2016, the Broad created CDoT, consolidating two therapeutics groups that had existed at the institute since its founding in 2004 to centralize resources and expertise for drug discovery.

Florence "Flo" Wagner
Credit: Gretchen Ertl

By then, Wagner had already been working as a medicinal chemist at Broad for eight years. Wagner wanted to be a chemist since high school; she loved the puzzle of organic chemistry, of matter reacting with itself to form new structures. She attended the Lyon School of Chemistry and Electronics in France and earned her Ph.D. in organic chemistry at North Carolina State University. Like Burgin, she spent time at a biotech company before arriving at Broad, and also recalls how much she felt at home during her Broad job interviews. When she received the job offer in 2008, she immediately knew it was time to move to Boston. 

Reflecting on her time at Broad, Wagner said, “It’s been 13 years and I’m still as excited to be a part of CDoT.”

In contrast to Wagner’s singular focus on chemistry and its role in drug discovery, Burgin took a more meandering path toward drug development. He attended a liberal arts college in western Indiana not far from his small, rural hometown. At first, he was overwhelmed by all he didn’t know, but soon started sampling different research settings, studying ecology and biochemistry in turn before landing in genetics, where he would complete a Ph.D.   

After postdoctoral research at the NIH and a brief stint at a biotech company, Burgin joined San Diego State University as a molecular biology professor. He kept abreast of innovations in biotech, establishing an internship program for master’s students that allowed them to do industry research while writing their theses. From afar, he watched these projects and half-wished he could partake more actively. When a collaborator wanted to start a company in Seattle, Burgin leapt at the chance. He stayed at the company, then called Emerald Biosystems, until he moved to the Broad.

“Throughout my career, I’ve been back and forth between academia and industry,” he said. “I’ve seen both worlds. Broad is the perfect place for me.”

Journey of a drug at CDoT

CDoT typically begins working with biologists and clinicians when they have identified a “target” — often a protein, a gene, or a sequence of RNA — that may be druggable. CDoT scientists, in close collaboration with disease biology researchers, look for molecules that bind to the target,  modulate a key biochemical process, and hopefully alter the course of disease. 

Then, they work to optimize the potency and selectivity of the molecule, testing it in cells, animals, and ultimately humans, with the aim of gaining FDA approval. 

All this work is arduous, expensive, and far beyond the scope of any academic lab.

CDoT’s team of specialists partner with labs to provide that expertise and move projects forward. Most teams are focused on finding, characterizing, and optimizing small molecules that bind to a target in a cell. Others develop assays to test the compounds’ behavior in cells, help labs move their molecule into early animal studies, or orchestrate collaborations with industry partners. 

Wagner, who has overseen many such projects in her 13 years at the Broad and three years at CDoT, says the partnership between CDoT and disease biology labs is critical to advancing a drug through the lengthy development process. “In a pharmaceutical or biotech company, the involvement of the PI is usually somewhat limited,” Wagner said. “Our academics are involved on a weekly or bi-weekly basis. That constant engagement is really valuable.”

Cathy Forest
Credit: Donald Raymond

Cathy Forest, CDoT’s director of strategy and operations, says that keeping the disease biology experts involved throughout the course of a project not only drives drug discovery, but also generates new insight into the biology of the disease. “It's an iterative loop that makes both sides more knowledgeable about how the target pathways and drugs work,” she said.

Morgan Sheng, co-director of Broad’s Stanley Center for Psychiatric Research and one of CDoT’s collaborators, sees subtle differences in how CDoT operates compared to his work before he came to Broad in 2019, leading neuroscience research and development at the biotech company Genentech. “CDoT’s projects are more biology-driven rather than commercially-driven,” Sheng said.

Each approach to a potential drug target at CDoT looks a little different, and so does success, Burgin says. Success might be a compound that reaches clinical trials, but it could also be one that moves from the Broad to a biotech company. Success might also be a venture capital firm that can create a new company based on a biological insight from Broad researchers. Success, too, could be learning early on that a compound won’t bring about the desired results, saving researchers time and expense.

To determine the best approach for each project, Burgin attends research meetings and talks with scientists across the institute. 

Burgin and Wagner point to three projects as representative of the center’s collaborative approach, ones they hope offer new models for drug development.

Searching for cancer cell killers

The search for therapeutics has been underway at the Broad since before the start of CDoT. In 2011, then graduate student Luc de Waal of the Dana-Farber Cancer Institute (now a group leader at Broad), Cancer Program scientist and senior group leader Heidi Greulich, Broad institute member Matthew Meyerson, Broad core institute member Stuart Schreiber, and colleagues were searching for small molecules that would kill cancer cells harboring a common cancer mutation.

The researchers developed a screen to probe the cell-killing power of multiple compounds at once, and identified a molecule called DNMDP, which showed both exceptional potency and selectivity. The team then identified cell lines that were more sensitive to DNMDP and found that those cells had higher levels of the enzyme PDE3A, which binds to a protein called SLFN12.

To figure out how DNMDP causes PDE3A and SLFN12 to bind together, Greulich’s team, with help from Colin Garvie, a CDoT senior group leader and his colleagues, and Malvina Papanastasiou of the Broad’s Proteomics Platform, used an array of techniques including X-ray crystallography, cryo-electron microscopy, and mass spectrometry to study the structure of the PDE3A-SLFN12 assembly. They found that DNMDP nestles itself deep within PDE3A and forms an “adhesive” surface, like velcro, inspiring the team to name the class of DNMDP-related molecules “velcrins.” They showed that this sticky surface strengthens interactions between PDE3A and SLFN12 and the resulting structure triggers RNA degradation, causing cancer cells to self-destruct. Cells expressing both the PDE3A gene and the SLFN12 gene were more sensitive to DNMDP, suggesting that clinicians could use it or other velcrins to treat a patient whose tumor had both proteins.

With help from Timothy Lewis, a medicinal chemist then at CDoT, the scientists tweaked the chemical structure of one velcrin to improve its stability.

Heidi Greulich
Credit: Maria Nemchuk

“When we collaborated with CDoT to begin probing the medicinal chemistry and started to understand the mechanism of action, the project also became more attractive to industry,” said Greulich, who led the project with Meyerson. 

The researchers teamed up with scientists from Bayer to advance the project. When they tested their compound in tumor-bearing mice, they knew they were on the right track. After treatment with an optimized version of that velcrin, called BRD9500, the tumors disappeared completely. And in 2021, Bayer launched a clinical trial to test a velcrin molecule in patients with advanced melanoma and other solid tumors that express both PDE3A and SLFN12.

There are still significant hurdles to pass before the velcrin, still in the first of three phases of clinical trials, can even come close to becoming an approved treatment for cancer patients. Nevertheless, the scientists count these PDE3A-SLFN12 complex inducers as one of their successes. “At the end of the day, we’re really focused on unique biological insights,” Wagner said. Greulich and her colleagues say that understanding how PDE3A and SLFN12 form a structure together could well be a stepping stone to a new generation of cancer therapeutics. While most targeted cancer therapies inhibit proteins important to a tumor’s survival, velcrins instead create a completely new function by encouraging two proteins to intertwine and cause cancer cell death. This glimpse into the molecular structure and binding behavior of velcrins, the team says, could help researchers develop other velcrin-based cancer therapeutics.

Tackling rare disease

Burgin and Wagner say that among the key ingredients of CDoT is its proximity to academic labs. In one case, that proximity is literal.

Anna Greka
Credit: Allison Dougherty

The lab of Anna Greka, an institute member at the Broad, an associate professor at Harvard Medical School, and nephrologist at Brigham and Women’s Hospital, is right beside CDoT facilities at the Broad. Her group has spent the past five years working closely with the center to find a drug for a rare kidney disease that has now been taken up by industry for further development.

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a genetic disorder in which the kidney develops scar tissue and ultimately shuts down. People with the disease typically need dialysis or kidney transplants as early as their 30s. In 2013, Broad researchers identified the root cause of the disease — a mutation in the MUC1 gene causes kidney cells to churn out a shortened, misfolded MUC1 protein that accumulates and kills the cells, leading to kidney failure.

In search of molecules that might help clear the misfolded protein from cells, Greka’s lab turned to CDoT for its Drug Repurposing Hub, a library of nearly 7,000 drugs at different stages in the drug development process.

Greka’s team homed in on a molecule and found that it eliminated the misfolded protein from kidney cells while leaving the normal protein intact. But the real breakthrough came when they realized that the drug worked by binding not the misfolded protein itself, but rather a “cargo” receptor, a category of receptors involved in several additional diseases.

Greka says this finding was key to placing this rare, or “orphan,” disease within a larger group of diseases, making it more likely for drug companies to pursue. “In discovering the mechanism and a therapeutic strategy, we de-orphaned this disease, because we attached it to a whole slew of other diseases that have the same mechanism,” she explained.

Now Greka already has her sights set on the next therapeutic target.

“This project was a great example of tapping into what's available here at Broad that isn’t typically available at academic institutions, and that’s nice, but we have to do it over and over again,” she said. “We need to double down on these high-risk areas, such as rare and understudied diseases, that others aren’t touching — we can really have an impact on patients this way.”

Targeting schizophrenia and neurodegeneration

Morgan Sheng
Credit: Maria Nemchuk

Morgan Sheng, co-director of Broad’s Stanley Center for Psychiatric Research, is working with CDoT to develop a molecule to halt the loss of synapses — the connections between neurons — that occurs in schizophrenia and certain neurodegenerative disorders. This goal is personal for Burgin, whose father has Parkinson’s disease and dementia.

Sheng’s lab examines the molecular biology of synapses in neurological development and disease. The team had an idea about how to suppress the complement pathway, a part of the immune system that helps clear away bacteria and damaged cells. In the last decade, scientists at the Stanley Center and elsewhere have found that the complement pathway is also involved in “pruning” away excess synapses during brain development. In schizophrenia and other psychiatric conditions, including many neurodegenerative diseases, the pathway is overactive and attacks synapses critical for neurological function.

Sheng’s lab, led by Borislav Dejanovic, focused on a specific receptor in the complement pathway that is potentially druggable. Working with CDoT scientists, the team began making small molecule inhibitors that could bind to the receptor and turn off the overactive complement pathway. Sure enough, they found that glial cells — non-neuronal brain cells — in a dish treated with one of their inhibitors stopped consuming synapses and killing neurons. 

The team continues to study the inhibitor and related compounds that could eventually serve as an effective drug. They will need to evaluate the molecules’ specificity and potency in a realistic animal model — no easy task when the compound must target something as complex as the brain. 

“It’s a long way from a drug, but the compounds do clearly inhibit the protein and block cell killing, which is pretty amazing,” Burgin said. “Neurodegeneration is already hard enough to study, and there are no effective therapies out there. I think this could be a really important drug one day.”

The next generation

As he nears the end of his first year as senior director at CDoT, Burgin looks forward to building more collaborations with scientists who have ideas they want to bring to the clinic. He and his team are also focused on hiring more researchers who value the center’s unique approach to drug discovery. 

Burgin says many senior scientists come to CDoT from industry after witnessing a project being terminated not because of a scientific failure but because a business model changed or the company didn’t understand the biological mechanisms specific to their system. “For someone who wants to really be driven by science, driven by biology, CDoT is a special place,” he said. Some younger scientists who might be attracted to the momentum of industry might not yet appreciate CDoT’s model, he says, but he has faith they will with time.

Wagner, meanwhile, emphasizes the importance of team culture. “Drug discovery is a team sport,” she said. “Everybody's important in a team, and together we need to create the right culture in which we respect our core value of strong, rigorous scientific ethics — while also understanding the urgency and the duty that we have to deliver therapies to patients who are waiting.”