Innovative Engine: Medical Research
Researchers at VP&S are rewriting the course of scientific investigation, intent on speeding up the process of discovery that will help patients with cancer, Alzheimer’s disease, diabetes, and other intractable diagnoses.
In cancer, Andrea Califano, PhD, the Clyde and Helen Wu Professor of Chemical Systems Biology and chair of the Department of Systems Biology, decided to turn cancer treatment theory on its head. The first wave of research in pursuit of personalized oncology focused on clues embedded within individual tumors. Decode the nucleic acids gone awry within the DNA of a particular patient’s cancer, or so the thinking goes, to identify treatments tailored to target that specific mutation.
It’s a fine theory, says Dr. Califano, but investigators still have a lot of work to do before the vast majority of cancers yield to that approach. “Only maybe 25 percent of patients have a mutation that could be defined as actionable,” he says.
For more than a decade, Dr. Califano has championed what might be considered an end run around cancer mutations, focusing instead on identifying and blocking the networks of normal proteins—known as master regulators—hijacked by deranged DNA to spur tumor formation and sustain tumor growth. Prevent the signals those proteins send on behalf of a cancerous mutation, and the cancer itself screeches to a halt.
In February, the New York State Health Department approved for clinical use two tests based on Dr. Califano’s work. Marketed under the names DarwinOncoTarget and DarwinOncoTreat—and developed by DarwinHealth, a Manhattan-based biotech firm co-founded by Dr. Califano in 2015—the tests are available to oncologists and researchers through the Laboratory of Personalized Genomic Medicine in the Department of Pathology & Cell Biology. DarwinOncoTarget identifies all proteins in an individual’s tumor that are acting abnormally and for which an FDA-approved or investigational drug already exists. DarwinOncoTreat homes in on the entire complement of master regulator proteins responsible for launching and maintaining a specific tumor to predict the drugs that, by interfering with these proteins, will most likely benefit the patient.
“Our tests find between five and 20 pharmacologically actionable targets per sample,” says Dr. Califano, noting that the tests include all FDA-approved compounds, not just those developed to treat cancer. “Oncologists can decide how to proceed based on toxicity, literature knowledge, and their experience using those drugs.”
Startups like DarwinHealth have become an increasingly common vehicle for speeding innovative treatment approaches conceived within VP&S laboratories into clinical use, says Orin Herskowitz, Columbia University’s senior vice president of intellectual property and tech transfer and executive director of Columbia Technology Ventures. This year, more than 400 inventions emerged from the University’s research laboratories, generating more than 200 patent applications. Among the 100-plus licenses issued this year to commercial partners, more than two dozen were written to startups founded by Columbia faculty and students.
Among them, the contingent representing VP&S stands out. “Increasingly, the most transformative therapeutics, diagnostics, and devices with the highest potential to save and improve patients’ lives are being launched via startups emerging from university research labs,” says Mr. Herskowitz. “VP&S researchers are incredibly innovative and driven to see their inventions make an impact on the world, so not surprisingly many are turning to entrepreneurship and working with venture capital investors to make sure this happens as quickly and effectively as possible.”
Consider, for example, the story of Ceracuity, co-founded in 2015 by Karen Duff, PhD, deputy director of the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and a professor in the Department of Pathology & Cell Biology. Based in New York City, Ceracuity licensed a collection of small molecules developed by Dr. Duff and collaborator Wai Haung Yu, PhD, assistant professor of pathology & cell biology, to spur autophagy—the process by which the healthy brain quickly and effectively clears abnormal, toxic proteins—as a treatment for Alzheimer’s, Parkinson’s, and frontal temporal lobe degeneration linked to tauopathy. “Think of it like a garbage truck,” says Dr. Duff, “taking out the recycling. We wanted to enhance the effectiveness of the garbage truck.”
President Jimmy Carter signed the Bayh-Dole Act in 1980, opening the door for investigators and their academic institutions to patent and license discoveries made in federally funded research enterprises. By the time Dr. Duff moved to the United States for her first academic post, in the early ’90s, universities were beginning to take a more proactive approach to educating faculty about intellectual property rights and facilitating patent applications, but academics were expected to stay in their lane. “When I first started working on neurodegenerative diseases,” says Dr. Duff, “there was a strict separation between people doing lab-based research and people doing therapeutic development.” Over the past decade, however, cultural shifts within academia and within industry have converged to spur increasingly dynamic crossover among academics, drug companies, and biotech startups. Even so, says Dr. Duff, getting to the point where an academic can form her own company and see her intellectual property all the way from laboratory to FDA approval is still relatively rare. “This is a huge landscape change.”
Dr. Duff, who was actively involved in commercialization of transgenic mouse models before joining Columbia, credits the Ceracuity launch to a serendipitous introduction facilitated by Jeffrey Lieberman, MD, the Lawrence C. Kolb Professor and Chair of the Department of Psychiatry. A group of investors had decided to apply their business experience to end Alzheimer’s and approached Dr. Lieberman, who also directs the New York State Psychiatric Institute, for access to faculty whose research might be relevant. “There’s a lot of frustration that pharma isn’t moving fast enough,” says Dr. Duff, who attended the roundtable discussion Dr. Lieberman organized and presented an overview of her lab’s work. “There’s an opening and the need for the right drug, the right business model to get medicine in people’s hands more quickly.”
After the event, Dr. Duff replied promptly to an email from the investors, asking about her vision for Alzheimer’s therapeutics. “I was just looking for a donor,” she says of the resulting correspondence. “It became clear they wanted a company format.” Together, Dr. Duff and Dr. Yu decided to explore the prospect, with Columbia Technology Ventures staff facilitating negotiations with the investors. “We patented the small molecules, Ceracuity licensed them, and the partnership has gone on from there,” says Dr. Duff, whose bona fides now include the titles co-founder, scientific advisory board chair, and member of the board of directors for Ceracuity, which completed its second round of seed funding in June.
Applied Therapeutics Inc., which initiated its first phase 1 clinical trial in February 2018, is slightly farther along the commercialization track for a diabetes treatment based on research by a group led by Donald Landry, MD, PhD, the Samuel Bard Professor and Chair of the Department of Medicine. Also a founder and board member of Tonix Pharmaceuticals, Dr. Landry holds more than 34 patents on an array of small compounds and has a long-standing relationship with the CTV team. When biotech consultant Shoshana Shendelman, a Columbia PhD graduate, approached Columbia looking for licensing opportunities for her clients, the CTV team included Dr. Landry’s patent for a compound to block the aldose reductase enzyme, which has been implicated in a laundry list of disease processes, including diabetic retinopathy and cardiomyopathy.
“I found the technology to be a really compelling opportunity for a biotech,” says Dr. Shendelman, who decided to license the technology herself and launched Applied Therapeutics Inc. to bring Dr. Landry’s work to the clinic.
Dr. Landry traces his induction into the world of commercialization to his work with catalytic antibodies when he developed the first artificial enzymes to degrade cocaine as a treatment for overdose and addiction. In his first 10 years at VP&S, Dr. Landry hired chemists to produce small molecules necessary for the cocaine research and other projects and then had to retrain those individuals to handle more biological applications in order to keep them on his lab staff. To maintain chemists as chemists, Dr. Landry approached Merck, offering the company first option for licensing small molecules developed by his group in exchange for $1 million, and with this deal the Organic Chemistry Collaborative Center (OCCC) was founded. The center spurred a substantial increase in small molecule development for investigators across the university, as CTV presented each new protein or pathway discovered by Columbia investigators to OCCC to assess its potential for drug development.
This innovative program led to the intellectual property at the heart of Applied Therapeutics, a triumph for the lead chemist on the project, Andrew Wasmuth, and Dr. Landry’s other colleagues at the OCCC. “Currently there is no cure for diabetes, and patients suffering from the complications of diabetes normally have a much lower quality of life,” says Dr. Landry. “Developing any treatment that can interrupt the pathophysiology of complications like diabetic cardiomyopathy and retinopathy would drastically change the natural history of the illness both in terms of survival and quality of life.”
To make sure all Columbia faculty and students have the tools they need to transform their discoveries into real-world products, CTV runs or helps to run a network of five lab-to-market accelerators, each tailored to a particular industry. Three are dedicated to biomedical innovation, including the Translational Therapeutics Resource (TRx). A collaboration among the Irving Institute for Clinical and Translational Research, Columbia Technology Ventures, the medical center’s Clinical Trials Office, and, most recently, the Herbert Irving Comprehensive Cancer Center, TRx was established by the Irving Institute’s director, Muredach Reilly, MBBCh, to leverage Columbia’s proficiency in target discovery and advance novel therapeutics from the lab along the path of commercialization.
Dr. Reilly began envisioning TRx even before he was recruited to Columbia in 2016. “There’s incredible basic science and clinical expertise and discovery at Columbia and many individual examples of faculty in basic and clinical research moving toward commercialization, licensing, and therapeutic programs,” he says, “but there was no systematic program for bringing together all of the services and activities to guide investigators from discovery of a protein, gene, or target to commercialization.”
Often referred to as the “valley of death,” the period that stretches from discovery to commercialization can be especially daunting in the case of drug development, spanning several years and often at great cost. “We were really focused on putting together an integrated program that would help investigators move successfully through that process,” says Dr. Reilly. “We coalesced a set of core labs for screening, organic chemistry, small molecule development, experimental validation in animal laboratories—everything an investigator needs to go from the more scientific realm to the science of commercialization.”
The VP&S commitment to supporting and facilitating commercialization was central to his own enthusiasm about joining the faculty in July 2017, says TRx co-director Akiva Mintz, MD, PhD, professor of radiology and radiology’s vice chair for translational imaging, who came to Columbia with multiple patents and experience in early-stage drug development. “One of the challenges I faced at prior institutions and companies was between the exciting discovery and translation into clinic in the valley of death,” he says. “You can have a very good idea and it goes nowhere, because people with expertise in discovery aren’t necessarily the ones with knowledge in the procedural steps required by the FDA. The environment at Columbia is special because the deep level of expertise and leadership in so many different areas enables the University to attract the best partners who work with investigators to transform ideas into treatments.”
Investigators typically get their feet wet with the TRx boot camp, an eight-week series offered every winter with guest lectures covering such topics as identifying target customers, working with the FDA, and pitching prospective investors. Boot camp alumni are eligible to apply for TRx pilot awards, which combine a grant of up to $75,000 with a tailored mentorship team whose participants are chosen for their experience in business, venture investment, the FDA application process, or some other facet of commercialization. Winners in 2017 included teams developing compounds to suppress appetite, treat cancer, and halt the progression of a specific type of schizophrenia.
“It’s not just, ‘Here’s a phone number,’” says Dr. Mintz, “but being with them on the journey, making sure things get done and they have the right partners.”
Gordana Vunjak-Novakovic, PhD, University Professor, the Mikati Foundation Professor of Biomedical Engineering, and director of the Laboratory for Stem Cells and Tissue Engineering, has launched four companies in the past five years, all based on research discoveries in her lab, which is located on the CUIMC campus. “There’s super-qualified help from CTV,” she says. “They support the filing and protecting of intellectual property and they helped on multiple occasions to get free advice from people who are skilled at filing FDA applications.” For scientific investigators, she says, the world of patent applications might as well be conducted in a foreign language, making the CTV legal team a particularly valuable resource. “You know what your innovation is, but what comes back from the lawyers is this completely incomprehensible document,” says Dr. Vunjak-Novakovic. “I’m absolutely sure that working in isolation we would never have these successes.”
To cultivate awareness of the commercialization process, Dr. Vunjak-Novakovic invites postdoctoral fellows, graduate students, and her research associates to participate in the TRx boot camps and the Columbia Biomedical Accelerator. In 2017, she and Lynne Johnson, MD, professor of medicine, received a TRx pilot award for an impregnated bandage to promote healing of bedsores and diabetic ulcers. “The TRx grant is funding critical experiments that prove the technology was viable,” she says.
Dr. Vunjak-Novakovic sees her team’s myriad patents and commercial ventures as an extension of a culture of innovation and problem solving within the VP&S community, as well as her own open-door policy welcoming clinicians on a quest for solutions. One of the largest projects underway in her lab aims to bioengineer functional lungs to make up for the shortage of organs available for transplant. “That started with a visit from a cardiothoracic surgeon who brought us a problem he was struggling with six years ago,” she says, “and now we’re en route to clinical trials.” On other occasions, a collegial clinician has spared the team from wasting time on a misguided approach. “You need the end user of your prospective technology to prevent you from doing something that is irrelevant,” says Dr. Vunjak-Novakovic. “They also help direct our research in a way that is most applicable, allowing a seamless application in the clinic.”
Biophysicist David Brenner, PhD, director of Columbia’s Center for Radiological Research, embarked on his research to find a better way to kill drug-resistant bacteria after a friend in his hometown of Liverpool, England, died from a surgical site infection after a routine hip replacement in 2012. Such deaths have been on the rise since the introduction of antibiotics in the 1940s, as the emergence of drug-resistant bacteria outpaces new antibiotic development. Deaths related to drug-resistant bacteria are even threatening to outpace deaths from cancer over the next few decades. Dr. Brenner said: Scientists have long known that ultraviolet (UV) light—which spans 200 to 400 nanometer wavelengths—efficiently kills all bacteria, drug-resistant and drug-sensitive. That’s why hospitals use ultraviolet lamps to sterilize operating theaters. But because UV light also damages human cells—causing skin cancer and cataracts—these UV lights can only be used to sterilize inanimate objects when no people are present. “Even if you clean the room completely,” says Dr. Brenner, “as soon as people come in they bring the bugs in with them, no matter how much they scrub.”
Using basic physics ideas and generously supported by a startup gift from Lynn Shostack, a member of the CUIMC Board of Advisors, Dr. Brenner and his colleagues started testing whether a type of ultraviolet light known as far-UVC—with wavelengths in the 200-220 nanometer range—might safely kill bacteria and viruses. They picked these wavelengths because they are absorbed very quickly by any biological material, so they can’t penetrate even the dead cell layer of the skin and can’t reach or damage the key cells in the skin or the eye. But bacteria and viruses in the air are far smaller, so far-UVC light can penetrate and kill these microbes. “The two big advantages of far-UVC light are that it doesn’t harm people and it doesn’t care about drug resistance, because it kills bacteria and viruses in a different way from drugs,” says Dr. Brenner.
Knowing that any resulting device would require FDA approval, Dr. Brenner checked in with the Columbia Technology Ventures team early on and received funding from a private foundation and through the Columbia-Coulter Translational Research Partnership, where would-be entrepreneurs pitch their ideas for development capital. “In principle far-UVC light is both effective and safe,” says Dr. Brenner, “but we needed to demonstrate this in as many ways as we could.” In a series of papers in the journals PLOS One and Radiation Research, he and his colleagues detailed their findings suggesting that far-UVC light effectively kills drug-resistant bacteria during surgical procedures without harming the patient.
More recently, in a paper published in the journal Scientific Reports, the team expanded its vision, showing that far-UVC lamps efficiently kill airborne microbes, such as influenza. That may make it possible for public spaces—airports, airplanes, medical offices, schools, even food prep facilities—to be equipped with overhead far-UVC lamps. “We want to safely kill airborne microbes like influenza, TB, and measles, whilst of course not harming the good bacteria that make up the human microbiome,” says Dr. Brenner.
While all faculty receive a percentage of licensing fees generated by their intellectual property and many serve on the scientific advisory boards of their respective startups, Columbia has strict policies in place to prevent conflicts of interest that might arise for faculty researchers, including a prohibition on executive posts in startups for faculty. Dr. Brenner focuses on the far-UVC science and technology development and is happy to put the entrepreneurial side of the story in the hands of the Columbia Technology Ventures team; through the team’s efforts, Dr. Brenner and colleagues were awarded their first U.S. patent for the technology.
From her perspective, Dr. Vunjak-Novakovic says policies that preserve a chasm between scientific innovators and entrepreneurial development promote both job creation and the long-term success of the resulting companies. Her former postdoctoral fellows Nina Tandon, PhD, and Sarindr Bhumiritana, PhD, now serve as chief executive officer and chief scientific officer, respectively, of Brooklyn-based Epibone, which the trio co-founded with Sidney Eisig, DDS, the George Guttmann Professor of Clinical Craniofacial Surgery and director of oral and maxillofacial surgery in the College of Dental Medicine. “The best way to ruin your company is to run it yourself,” she says. “It’s like not letting your child leave home. You have to find capable people to work there and let them do their jobs.”
For scientists intent on making a difference in the lives of real people, says Dr. Vunjak-Novakovic, commercialization promises unparalleled opportunities. “The reason I went into biomedical engineering is to see what engineering can do for medicine,” she says. “The end goal is to translate science from the laboratory into the clinic.”
This article was published in the 2018 VP&S Annual Report. The full issue is available as a PDF here.