Northwestern Engineering’s Michael Jewett and Nathan Gianneschi have been elected to the American Institute for Medical and Biological Engineering’s (AIMBE) College of Fellows. AIMBE’s College of Fellows comprises the top 2 percent of medical and biological engineers...
A new potential drug target has been identified in SARS CoV-2 — the virus that causes COVID-19 — by scientists who say multiple drugs will likely be needed to respond to the pandemic.
Scientists from Northwestern University Feinberg School of Medicine have mapped the atomic structure of two critical proteins in a complex, nsp10/16. These proteins modify the genetic material of the virus to make it look more like the host (human) cell RNA.
This allows the virus to hide from the cells, giving it time to multiply. If a drug can be developed to inhibit nsp10/nsp16, the immune system should be able to detect the virus and eradicate it faster.
“This is a really beautiful target, because it’s a protein absolutely essential for the virus to replicate,” said lead investigator Karla Satchell.
Satchell is a professor of microbiology-immunology at Northwestern and director of Center for Structural Genomics of Infectious Diseases (CSGID), an international consortium of scientists who are investigating the structure of the virus to aid drug development.
Satchell’s team is sending the new protein to Purdue University, the drug-discovery site of the center, to be screened for novel inhibitors that could be developed as new drugs.
The nsp10/nsp16 protein is called an RNA methyltransferase or MTase. It is comprised of two proteins bound together, which makes it more difficult to work with. The association of the two pieces together is required to make a functional protein, according to prior research on SARS.
The structure of nsp10/16 was released to the scientific community March 18 on the RSCB Protein Data Bank.
This is the fourth protein structure of a potential drug target of SARS-CoV-2 determined by the CSGID team of scientists.
“We need multiple drugs to treat this virus, because this disease is likely to be with us for a long time,” Satchell said. “It’s not good enough for us to develop a single drug. If COVID-19 develops a resistance to one drug, then we need others.”
The center is racing to release more structures for drug development. The center’s goal is to determine structures of all of the proteins that are potential drug targets. The team also is collaborating to provide proteins to investigators for design of improved vaccines.
Data for this structure was collected at the Northwestern managed Life Sciences Collaborative Access Team beamline at the Advanced Photon Source at Argonne National Labs. The LS-CAT staff worked quickly with APS and Satchell to provide rapid access to the beamline over a weekend specifically to collect data for this project.
“The center has shown a great ability to bring structure biology to the scientific community at an unprecedented rate,” Satchell said. But their work has become more challenging because so many universities have reduced activities and some labs have shut down entirely.
“Our ability to do experiments is abating,” Satchell said. Still, the center will continue to release new structures until they reach their goal, she said.
Structures of three other proteins important for the replication of the virus have also been released: the nsp15 endonuclease, nsp3 ADP ribose phosphate and nsp9 replicase. These structures were determined by the center scientists at University of Chicago headed by professor Andrzej Joachimiak, Distinguished Fellow of Argonne, who also is an adjunct professor at Northwestern. All work conducted by both the University of Chicago and Northwestern teams was designed by the bioinformatic team of Adam Godzik at the University of California at Riverside, based on research conducted in SARS.
The CSGID is supported by a contract from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, in part to serve as a response site to conduct structure biology research in the event of an unexpected infectious disease outbreak. NIAID has been working closely with the Center since early January to coordinate center activities with other research supported by NIAID to enable drug discovery.
This study has been funded by contract HHSN272201700060C from the National Institute of Allergy and Infectious Diseases, part of the NIH.
The original story was published in Northwestern Now on March 27, 2020 by Marla Paul.
Purification of the protein targets identified by Satchell and team was conducted by Chemistry of Life Processes Institute’s Recombinant Protein Production Core. The rPPC provides quality controlled recombinant proteins for Northwestern researchers as well as academic and industry researchers outside of the University, including CSGID scientists.
According to rPPC Managing Director Sergii Pshenychnyi, rPPC produced two SARS-CoV-2 proteins, SARS-CoV-2 papain-like protease (PLpro) and chymotrypsin-like protease (3CLpro) for CSGID and sent them to Purdue University for the purpose of testing possible drugs that inhibit the proteases central to the function of the virus.
“Data suggests that some of the compounds that made it through early stage clinical trials may be working,” says Pshenychnyl. “The process, however, will take months (possibly a year) of subsequent drug development.”
Pshenychnyl is also working with Daniel Batlle Group (FSM, Nephrology and Hypertension Department) to purify the human angiotensin-converting enzyme 2 (hACE2). SARS-CoV-2 enters the human body by binding to hACE2. He is also working on another project for Pablo Penaloza (Department of Microbiology and Immunology), producing receptor binding domain of SARS-CoV-2, Wuhan-Hu-1 Spike Glycoprotein in HEK293 cells. Both will be used to perform critical vaccine studies.
Northwestern University researchers have mapped a group of proteins that play a critical role in both gene expression and repairing damaged DNA. By understanding this protein complex, called SWI/SNF, researchers hope to better understand how cancer arises.
SWI/SNF regulates the structure of chromatin, which comprises genetic material in a cell’s nucleus and often mutates as cancer develops.
“Mutations of this essential complex have been found in more than 20 percent of all human cancers associated with a wide range of tissue types,” said Northwestern’s Yuan He, who led the study. “Understanding the molecular mechanism of the SWI/SNF complex in regulating chromatin structure and gene transcription is thereby essential for a complete understanding of how chromatin structure alterations lead to cancer.”
To determine the unique structure, the He lab used cryogenic electron microscopy (cryo-EM), a powerful technique capable of revealing the 3D shape of large protein complexes. The technique involves flash-freezing proteins at a speed where water molecules don’t have time to re-organize to form crystalline ice. These protein complexes are then directly imaged by an electron microscope, and their 3D shape can then be reconstructed in 3D using a supercomputing cluster. Before cryo-EM, researchers mainly used X-ray crystallography, which is incapable of capturing high-resolution images of important complexes such as this.
This landmark study is the first time that researchers have used cryo-EM to determine the SWI/SNF structure bound to a nucleosome, at near-atomic resolution. “cryo-EM is a revolutionary technique,” said Carole LaBonne, chair of the Department of Molecular Biosciences. “It is taking over in the critical field of structural biology. Every major research university is making major investments in this field because it is clear that it holds the key to unraveling many unanswered questions in biomedical science.”
Professor Yuan He explained that the structure will allow researchers to map and rationalize cancer-related mutations in the human SWI/SNF complex.
He added that the study will provide the molecular platform for better understanding the important functions of SWI/SNF in both healthy and cancerous states, as well as for developing potential therapeutic strategies for human malignancies.
“Our study gives insight into how the complex suppresses tumor development,” He said. “And it could contribute to developing therapeutics for cancers harboring mutations in genes encoding the SWI/SNF complex.”
The study, “Cryo-EM structure of SWI/SNF complex bound to a nucleosome,” was supported by a Cornew Innovation Award from the Chemistry of Life Processes Institute at Northwestern University, the American Cancer Society (award number IRG-15-173-21) and the National Institutes of Health (award number R01GM135651, P01CA092584, U54CA193419 and 5T32 GM008382).
The original story was published in Northwestern Now on March 11, 2020 by Rebecca Lindell.
Yuan He is a member of the Chemistry of Life Processes Institute.
As a child growing up in a large family in rural Iran, Nayereh Ghoreishi-Haack, Assistant Director, Developmental Therapeutic Core, Chemistry of Life Processes (CLP) at Northwestern University, spent her days exploring the abundant orchards, bogs and farms that dotted the countryside near her home. Little did she guess that someday her childhood pastime would transport her from the family orchards to the labs of major US-based pharmaceutical companies, small biotech firms, and a world-renown research university.
“As a nature lover, I was fascinated by life and how our biological systems work in other beings, as well as in our bodies.”
Due to the political situation in Iran at the time, Ghoreishi-Haack immigrated to US in the late 80s.
Ghoreishi-Haack earned her BS in Zoology at University of Alabama in Huntsville.
“Just by luck, I was near graduation from college and visiting my sister in Chicago during Christmas,” said Ghoreishi-Haack. “I didn’t even have a CV, but I saw these ads in the Chicago Tribune for a research scientist posted by GD Searle.”
She applied for the position and, to her surprise, got the job. While at Searle, she earned her MS in Molecular and Cellular Biology from Northeastern Illinois University.
“At first, I was very naïve. I had no idea what it meant to be a pharmacologist,” Ghoreishi-Haack said. “Eventually, I learned how critical research was in fighting diseases and drug development. That’s when I got hooked.”
While at Searle, Ghoreishi-Haack witnessed the blockbusting success of Celebrex (celecoxib), a cyclo-oxygenase-2 inhibitor for arthritis and pain that became one of the most prescribed drugs in the US at the time.
“It was fascinating to see the process of bringing a new drug from the laboratory bench to market,” she said.
Ghoreishi-Haack worked for Searle for 12 years, then moved to the Integrative Pharmacology Department at Abbott Labs. There, she evaluated compounds for their efficacy from various cancer projects and against glioblastoma. Subsequent career moves included senior pharmacologist and senior research manager at AbbVie, Naurex Inc., and Apitnyx Inc., where she performed pre-clinical testing of potential new drugs in various therapeutic areas including inflammatory pain, neuropathic pain, and neurodegenerative diseases.
At Northwestern, Ghoreishi-Haack works closely with investigators across disciplines, and oversees efforts to evaluate preclinical models and lead compounds for potential new therapies for cancer and other diseases.
“Usually researchers move from academia to industry,” says Ghoreishi-Haack. “I’ve done the reverse because I knew I could have a greater impact working at CLP. Having all the cores nearby, and access to their resources and instruments, makes the Institute like a biotech: generating vast amount of data and capable of producing numerous INDs (investigational new drugs).”
by Lisa La Vallee
One of the hallmarks of cancer is cell immortality. A Northwestern University organic chemist and his team now have developed a promising molecular tool that targets and inhibits one of cell immortality’s underlying gears: the enzyme telomerase.
This enzyme is found overexpressed in approximately 90% of human cancer cells and has become an important subject of study for cancer researchers. Normal cells have the gene for telomerase, but it typically is not expressed.
“Telomerase is the primary enzyme that allows cancer cells to live forever,” said Karl A. Scheidt, who led the research. “We want to short-circuit this immortality. Now we have designed a first-of-its-kind small molecule that irreversibly binds to telomerase, shutting down its activity. This mechanism offers a new pathway for treating cancer and understanding cellular aging.”
Scheidt is a professor of chemistry in the Weinberg College of Arts and Sciences and a professor of pharmacology at Northwestern University Feinberg School of Medicine.
The big idea for the small molecule design came from nature. A decade ago, Scheidt was intrigued by the biological activity of chrolactomycin, which is produced by bacteria and has been shown to inhibit telomerase.
Scheidt and his team used chrolactomycin as a starting point in the design of their small molecules. They produced more than 200 compounds over the years, and the compound they call NU-1 was the most effective of those tested. Its synthesis is very efficient, taking fewer than five steps.
“NU-1 inhibits telomerase unlike anything that came before it,” Scheidt said. “It does this by forming a covalent bond. Another advantage of NU-1 is that its molecular structure should enable scientists to add cargo, such as a therapeutic.”
The study was published last week by the journal ACS Chemical Biology.
All human cells have telomeres, short DNA sequences that cap the ends of each strand of DNA. Their job is to protect our chromosomes and DNA. When a cell divides, the telomeres get shorter until they can no longer do their job. Natural cell death follows.
In contrast, cancer cells, with their heightened telomerase activity, become immortal by reversing the normal telomere shortening process. The enzyme telomerase copies telomeres over and over again, lengthening the telomeres. The result is unlimited cell division and immortality. The famous HeLa cells, isolated from the cervical cancer tissue of Henrietta Lacks in the 1950s, are still dividing.
Telomerase has been a target for cancer therapeutics research for decades. In 2009, three scientists received the Nobel Prize in Physiology or Medicine for their earlier research into telomeres and telomerase.
After developing their new compounds, Scheidt and his team initiated collaborations with Professor Stephen Kron at the University of Chicago and Scott Cohen at the Children’s Medical Research Institute in Sydney to investigate the extra-telomeric role of telomerase inhibition.
The studies focused on how the new compounds interact with telomerase on a molecular level and how telomerase inhibition sensitizes cells to chemotherapies and irradiation. From this work, NU-1 rose to the top.
“By publishing this study, we are test driving this exquisite tool to see what it can do and to learn more about telomerase,” Scheidt said. “We also are continuing to make it better.”
The research was done in human cells. The next steps, Scheidt said, are to make more potent compounds and investigate them in animal models.
The study was supported by the Chicago Cancer Baseball Charities at the Lurie Cancer Center of Northwestern University, the National Institute of General Medical Sciences (training grant GM105538) and the National Institutes of Health (grant R01 CA217182).
The paper is titled “Targeted Covalent Inhibition of Telomerase.” Scheidt is the corresponding author; Rick C. Betori, who recently received his Ph.D., is the first author; and Kron and Cohen are co-authors.
Northwestern has filed a provisional patent for NU-1 and related analogs.
Scheidt also is director of Northwestern’s Center for Molecular Innovation and Drug Discovery; the executive director of NewCures, Northwestern’s biomedical accelerator; a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University; and a member of the Chemistry of Life Processes Institute.
The original story was published on March 3, 2020 in Northwestern Now by Megan Fellman.
Main image: The ends of chromosomes are protected by specific DNA sequences called telomeres, visualized here in red. Credit: National Institutes of Health
Karl Scheidt is a member of the Chemistry of Life Processes Institute.
Northwestern Proteomics, a Chemistry of Life Processes Institute-affiliated center, together with an interdisciplinary team of Northwestern mathematicians, experimentalists, biomedical engineers, and biochemists, recently published two academic papers announcing a new, game-changing technique for characterizing and identifying proteins with extreme precision.
For the first time, using the commercially available Orbitrap mass analyzer system, researchers successfully integrated two mass spectrometry (MS) approaches: native or top-down MS and, an even more pioneering technique, individual ion mass spectrometry (I2MS), both pioneered by the Kelleher Research Group. The powerful and new approach, two-and-a half years in the making, will help illuminate complex questions within fundamental biology and transform understanding of disease and infection and to accelerate the design of new therapies.
“If you want to know the distribution of molecules that are in a sample, you can now know that within an hour,” says Neil Kelleher, Walter and Mary E. Glass Professor of Molecular Biosciences and Faculty Director, Northwestern Proteomics, who led the research. Kelleher is a pioneer in the fields of native and top-down mass spectrometry. “We’ve been able to fragment a protein, read out the fragments as individual ions, and determine their charge. With that information, we then calculate their mass and resolve the protein components.”
Traditional MS measurements collect averaged data from a mixed population of multiple ions. Mass spectrometers work by measuring the mass-to-charge ratio of each item. I2MS facilitates the accurate detection of each ion and their individual charges to reveal their precise mass.
In a paper published today (March 2) in Nature Methods, first author Jared Otto Kafader, senior research associate in the Kelleher Research Group, and collaborators, detail the process for developing the I2MS method.
“We created a mass spectrum platform and applied it to a huge range of intact proteins – everything from small proteins to antibodies to virus-like particles and demonstrated that we can deconvolute masses and obtain actual mass assignments,” says Kafader.
The breakthrough has major implications for the biopharmaceutical industry and biomedical research writ large according to Kelleher, a member of the Chemistry of Life Processes Institute.
“Antibody-based drugs are comprised of a complex mixture of large molecules that are often based on proteins, or virus particles, that reach well into the megadalton range,” says Kelleher. “Now, you can get the size distribution and exact characterization of the proteins in that mixture. Instead of having some blurry view of what you’re injecting in the body as a drug, this technology allows you to get down to the molecular level and be very precise in doing so. In the old way, there would be no data.”
In a second paper published in the Journal of Proteome Research, researchers used I2MS to detect fragment ions resulting from top-down analysis, a significant leap forward in current capabilities for protein characterization. Fragment ions are crucial for characterizing a protein’s sequence and post-translational modifications. The fragments detected with I2MS were complementary with those from traditional analysis, greatly enhancing the combined level of detail for characterizing a protein.
“Whereas the first approach maps the protein universe, the second approach provides super-detailed characterization of each protein through single particle/ion counting,” says Kelleher, a member of the Chemistry of Life Processes Institute.
The new technology promises to aid understanding of disease and infection and accelerate the design of vaccines for deadly viruses, such as the coronavirus.
“This technology enables researchers to weigh the whole virus and get a mass distribution, virus particle by virus particle, and determine the difference in mass of different strains of a constantly mutating virus,” says Kelleher. “The approach will allow epidemiologists to know the efficacy of different vaccines, irrespective of how complicated the sample is. Most approaches take a long time to accomplish that. With our approach, you can do it in a matter of minutes.”
The research was supported by National Institute of General Medical Sciences, National Institutes of Health (grant P41 GM108569), and Thermo Fisher Scientific and the Sherman Fairchild Foundation.
by Lisa La Vallee
Main image: (Left-right): Jack McGee, Chemical and Biological Engineering graduate student, Professor Neil Kelleher, and Jared Otto Kafader, senior research associate, in the Kelleher Research Group.
Many people consult their friends and neighbors before making a big decision. It turns out that cells also are consulting their neighbors in the human body.
Scientists and physicians have long known that immune cells migrate to the site of an infection, which individuals experience as inflammation — swelling, redness and pain. Now, Northwestern University and University of Washington researchers have uncovered new evidence that this gathering is not just a consequence of immune activation. Immune cells count their neighbors before deciding whether or not the immune system should kick into high gear.
Understanding how to influence inflammation and activate an immune response could lead to new therapies to treat chronic autoimmune diseases or to mobilize the immune system to help fight cancer.
“This is a previously unrecognized aspect of immune function,” said Northwestern’s Joshua Leonard, a member of the Chemistry of Life Processes Institute, who co-led the study. “The cells make a coordinated decision. They don’t uniformly activate but instead collectively decide how many cells will activate, so that together, the system can fend off a threat without dangerously overreacting.”
“A key part of this work relied on the development of new computational models to interpret our experiments and elucidate how cells perform calculations to make coherent decisions,” said University of Washington’s Neda Bagheri, who co-led the work with Leonard.
The research was published today (Feb. 13) in the journal Nature Communications.
Leonard is an associate professor of chemical and biological engineering at Northwestern’s McCormick School of Engineering and a member of Northwestern’s Center for Synthetic Biology. Bagheri is an associate adjunct professor of chemical and biological engineering at McCormick and an assistant professor of chemical engineering and biology and a Distinguished Washington Research Foundation Investigator at the University of Washington. The paper’s first author is Joseph Muldoon, a graduate student in Northwestern’s Interdisciplinary Biological Sciences Graduate Program, who is co-advised by Leonard and Bagheri.
The body’s immune system is constantly working to maintain a delicate balance. When a threat is introduced, the system needs to respond strongly enough to fight off infection or disease but not so strongly that it causes harm.
“When it comes to immune responses, it’s the difference between life and death,” Leonard said. “If your body over-responds to a bacterial infection, then you could die from septic shock. If your body doesn’t respond enough, then you could die from rampant infection. Staying healthy requires the body to strike a balance between these extremes.”
Original story published in Northwestern Now by Amanda Morris.
Josh Leonard is a member of the Chemistry of Life Processes Institute. The CLP Cornew Award was awarded to both Leonard and Neda Bagheri, a former member of the Institute.
Northwestern University researchers have, for the first time, determined the 3D atomic structure of a key complex in paramyxoviruses, a family of viruses that includes mumps, human parainfluenza and respiratory syncytial virus (RSV).
This information could help others design and develop antiviral drugs for these viruses as well as for coronavirus, which functions similarly to paramyxoviruses.
“This takes some of the guesswork out of designing drugs,” said Northwestern’s Robert Lamb, who co-led the study. “Traditionally, you have to develop drugs randomly and hope you hit a target, but it doesn’t happen very often.”
To find the unique structure, researchers used cryogenic electron microscopy (cryo-EM). The relatively new technique enables researchers to peer inside molecules to determine the 3D shape of proteins, which are often thousands of times smaller than the width of a human hair. Before cryo-EM, researchers mainly used X-ray crystallography, which is incapable of capturing high-resolution images of this enzyme. Called a polymerase, the enzyme assembles RNA molecules.
“Crystallography only works for very orderly and organized proteins,” said Northwestern’s Yuan He, who co-led the study. “Virus polymerase complexes are too big to be crystallized and don’t have uniformity.”
The study will be published online this week in the Proceedings of the National Academy of Sciences.
Lamb is the Kenneth F. Burgess Professor of Molecular Biosciences in Northwestern’s Weinberg College of Arts and Sciences and an investigator of the Howard Hughes Medical Institute. Yuan He is an assistant professor of molecular biosciences in Weinberg.
Although the first documented case of mumps occurred in the 5th century and measles in the 9th century, researchers did not have the equipment to characterize their atomic structures until relatively recently. A trio of biophysicists received the 2017 Nobel Prize in Chemistry for developing cryo-EM, which ultimately opened the door for Lamb and He.
Cryo-EM works by blasting a stream of electrons at a flash-frozen sample to take many 2D images. For this study, He and his team captured hundreds of thousands of images of one sample of human parainfluenza virus 5 polymerase. The team then used computational algorithms to reconstruct a 3D image.
The resulting image was an irregular, round-shaped globule with a long tail made of four phosphoproteins (or proteins containing phosphorous). The structure contains more than 2,000 amino acids and five proteins.
“Part of the image was expected,” Lamb said. “But part of it was a surprise. Two of the proteins are completely new. They have never been seen before.”
Another surprise: the team found that this virus uses the same protein to switch between genome replication and transcription.
“This machinery has a dual-function,” He said. “It gets both jobs done with one enzyme. The virus’s genome is so small, and this gives it economy of scale.”
Original story published in Northwestern Now by Amanda Morris.
This work was partially supported by the Chemistry of Life Processes Institute’s Cornew Innovation Award.
Did you know that women comprise a mere 24 percent of the science, technology, engineering and math (STEM) workforce? Were you also aware that the National Institutes of Health NIH gives first-time male principal investigator scientists considerably more funding than women, even at the nation’s top research institutions? Women are also less likely to be hired and promoted to manager: For every 100 men promoted and hired to manager, only 72 women are promoted and hired. Men hold 62 percent of manager-level positions, while women hold just 38 percent. The number of women decreases at every subsequent level.*
In honor of the University’s year-long celebration of ‘150 Years of Women at Northwestern, Chemistry of Life Processes Institute will host the second of three ‘CLP Spills the Tea‘ events on March 11 at 4:00 p.m. in Evanston. The discussion will include four prominent women in science from diverse backgrounds who will address issues of gender disparity in the workplace and share insights on how to thrive in male-dominated science fields, from higher education and biotech to national laboratories and beyond. Tea, coffee and cookies will be served.
Lindsay Chase-Lansdale, PhD, Frances Willard Professor of Human Development and Social Policy, Vice Provost for Academics, Northwestern University
Margarita Chavez, JD, Managing Director, AbbVie Ventures
Lydia Finney, PhD, CDP, Diversity and Inclusion Partner and Physicist, Leadership Institute, Argonne National Laboratory
Kapila Viges, Director, Strategy Insights and Planning, Oncology Group, ZS Associates
Teresa K. Woodruff, PhD, Thomas J. Watkins Professor of Obstetrics and Gynecology and Dean, The Graduate School, Northwestern University
The program will be held in Cohen Commons, Northwestern University, Room L482, fourth floor north, in the Technological Institute, 2145 Sheridan Road, Evanston, IL.
* Source: LeanIn.org
Working across disciplines, several Chemistry of Life Processes Institute faculty members are accelerating the time it takes to bring new cancer therapies and diagnostic tools from the lab into clinics. In honor of World Cancer Day, here are just a few examples of our progress:
CLP startup Actuate Therapeutics has developed an exciting new treatment, currently in clinic trials, for advanced and drug-resistant cancers, including glioblastoma, melanoma, pancreatic, appendix, breast and ovarian, and select inflammatory diseases.
Among other cancer therapies, CLP spinout Monopar Therapeutics is developing new & powerful therapies currently in clinical trials for oropharyngeal cancer, pancreatic, ovarian, and metastatic breast cancer.
CLP member Nathan Gianneschi and first author Cassandra Callmann have developed a new way to deliver chemo into cancer cells with much fewer side effects and astonishing results.
In the face of great doubt, CLP member Vadim Backman and collaborators developed partial wave spectroscopy (PWS) nanocytology, a new diagnostic technology that not only views cells at these elusive length scales but also uncovers shrouded cancer malignancies in their earliest stages. #WorldCancerDay
Northwestern Neurologist, ALS Champion, Hande Ozdinler to Discuss New Approaches to Upper Motor Neuron Degeneration
CLP faculty member Hande Özdinler, PhD, Associate Professor of Neurology in the Feinberg School of Medicine at Northwestern, will present her path-breaking research on upper motor neuron degeneration at the next CLP Chalk Talk. Özdinler’s white board presentation entitled, “Why upper motor neurons get sick and how can we help them? Hint: This is a team effort.” , will take place on March 6 from 3:00 – 4:00 p.m. in The Richard and Barbara Silverman Hall for Molecular Therapeutics and Diagnostics’ third floor atrium in Evanston.
Özdinler, a member at the Mesulam Cognitive Neurology and Alzheimer’s Disease Center, the Robert H. Lurie Comprehensive Cancer Center, and the Les Turner ALS Center, received a Master’s degree in a program spanning chemical engineering, molecular biology, and genetics focusing on biotechnology. She received a PhD in Cell Biology, Anatomy and Neuroscience from Louisiana State University (LSU) Health Sciences Center. She became a postdoctoral fellow at Neurosurgery Department of Massachusetts General Hospital-Harvard Medical School, prior to joining Northwestern as the founding director of the second Les Turner ALS Laboratory.
Özdinler’s research is focused on understanding the cellular and molecular basis of selective vulnerability observed in neurodegenerative diseases. The Özdinler lab primarily focuses on understanding the biology of upper motor neurons as well as the mechanisms that are responsible for their progressive degeneration, which is a hallmark in diseases such as amyotrophic lateral sclerosis, hereditary spastic paraplegia, and primary lateral sclerosis. Her research program extends from biomarker discovery to development of drug verification platforms, and generation of mouse models of diseases to identification of novel targets for gene delivery approaches. Her work has been supported by National Institutes of Health, National Institute of Aging, and foundations, such as Les Turner ALS Foundation, ALS Association, and A Long Swim.
The Özdinler lab discovered that increased ER-stress is one cellular mechanism that is responsible for upper motor neuron vulnerability and degeneration. This discovery has been highlighted in the Northwestern Medicine Newsletter, ALSA, ALZforum and ALS Forum. She speaks at neurological conferences around the world and is actively involved in organizing meetings, seminars and symposiums so that leading scientists and clinicians can share their knowledge of ALS research and clinical care. Most recently, she organized the annual Les Turner Symposium on ALS and NeuroRepair which celebrated research, patient care and education, which included presenters from premier teaching hospitals in the Chicagoland metropolitan area.
CLP Chalk Talks are free open to all. Registration is requested, but not required.
Snacks and beverages will be provided.
Registration is requested. Click here to RSVP.
What happens when a highly interdisciplinary and integrated team of scientists, business leaders and students work together across fields of fundamental science, discovery, development, and finance? In the case of Monopar Therapeutics, a Chemistry of Life Processes Institute-affiliated spin-out, it leads to a record-breaking initial public offering.
Last month, Monopar (MNPR), a clinical stage biopharmaceutical company that develops proprietary therapeutics for cancer, experienced the “best first-day pop for an IPO since Baidu in 2005,” according to Nasdaq News. The company’s stock price rocketed 231 percent from its initial offering, reaching a market valuation of $289 million on its first day.
“It’s been a remarkable journey from the start,” says Chandler Robinson, MD, CEO of Monopar, and member of CLP’s Executive Advisory Board.
From Math Major to MD
Robinson’s academic journey began in 2002 as a math major at Northwestern. He changed direction after enrolling in Professor Thomas O’Halloran’s general chemistry course. O’Halloran, the founding director of Chemistry of Life Processes Institute, recognized Robinson’s prodigious intellect and curiosity and encouraged him to pursue science.
“Tom was always very much a mentor and a friend. He made it enjoyable,” said Robinson. “When I got to Northwestern, I had no intention of even majoring in the sciences. Because of Tom, I kept the math and picked up a second major in chemistry.”
While conducting basic research in O’Halloran’s lab, Robinson published a breakthrough paper in the journal Science analyzing the science behind the active agent in a drug that came to be known as Decuprate™, a promising inorganic therapeutic agent for the treatment of copper overload in Wilson disease.
While at Northwestern, he also founded an undergraduate research society, still operating today after more than a decade, and graduated summa cum laude. He continued with his education and earned a master’s degree in International Health Policy and Health Economics from the London School of Economics on a Fulbright Scholarship, an MBA from Cambridge University on a Gates Scholarship, and an MD from Stanford University. During breaks, he completed internships with Onyx Pharmaceuticals, Bear Stearns and helped CLP faculty and board members start Tactic Pharma to develop Decuprate and several orphan cancer drug candidates.
“My path has always been, keep an open mind, see what opportunities arise, and if a door opens up, jump through it,” explains Robinson.
The Perfect Storm
Robinson’s insights into Decuprate™ prompted O’Halloran, the Charles E. and Emma H. Morrison Professor of Chemistry and Professor of Molecular Biosciences, to contact internationally recognized drug developer Andrew Mazar, then Chief Scientific Officer at Attenuon, LLC in San Diego, to join a CLP Public Private Partnership proposal to the National Cancer Institute. After Attenuon closed its doors in 2009, Mazar accepted a research faculty appointment at Northwestern and joined CLP as the Institute’s first Entrepreneur-in-Residence. He also co-founded the Institute’s Center for Developmental Therapeutics and started the University’s first animal model facility, the Developmental Therapeutics Core.
Mazar and O’Halloran approached Chandler in 2010 about helping them launch Tactic Pharma, LLC to develop and commercialize several assets including Decuprate™.
“We had some valuable assets, but needed someone to help us start a robust company,” said O’Halloran. “I said, ‘Why don’t we take a chance and bring in this NU alum and freshly minted MBA from Cambridge Business School to lead this effort?’ Although Chandler didn’t have business development experience under his belt, he had the most important ingredients: talent, energy, and especially the drive to pull it all together.”
Robinson rose to the challenge and took an extended leave of absence from Stanford Medical School to head the new company. Michael Brown, CEO, Euronet Worldwide, and a CLP Executive Advisory Board (EAB) member, stepped up with the initial start-up funding, providing the key early stage investment capital. Within 18 months, the Tactic team had obtained orphan drug status for Decuprate™ from the Food and Drug Administration, manufactured it, and raised more than $10M in a Series A. The drug went on to get acquired by Alexion for $855 million, and is currently in phase III clinical trials.
Robinson returned to Stanford to complete his medical degree.
“It was the perfect storm,” said O’Halloran. “From the beginning, our team shared the desire to make a difference and bring drugs more quickly to the market to help people. CLP started with the mission to stimulate translation of basic science discoveries made at the bench. We want to bring our combined skill sets together to solve major problems and address unmet needs in the medical field and get new drugs and devices out into society as quickly as possible.”
Enter Monopar Therapeutics
The Tactic team then changed course and developed new partnerships to commercialize other assets. In 2015, Robinson and Mazar partnered with Christopher M. Starr, PhD, a highly successful and experienced biopharmaceutical entrepreneur who co-founded BioMarin (Nasdaq: BMRN, ~$15B market cap) and Raptor Pharma (acquired by Horizon Therapeutics for $800M). The new company, Monopar Therapeutics, was financed by Tactic and an array of new investors with the mission to build a leading oncology drug development company.
“Having known the intelligence, drive to succeed, and creativity of Chandler [Robinson] and the talent of Andrew [Mazar], I thought it would be prudent to invest in Monopar Therapeutics. After hearing about the assets they are developing, it was a no-brainer,” says Rick Silverman, Patrick G. Ryan/Aon Professor at Northwestern, and inventor of the blockbuster drug Lyrica®.
Starr brought experienced team members from his prior successful biotech companies into the rapidly growing Monopar team. They asked Brown to join the board of this new Chicago startup based in Wilmette, Illinois.
Monopar acquired its first asset from Tactic, MNPR-101, a monoclonal antibody invented by Mazar. The antibody, currently in the preclinical phase of development, targets an important receptor that acts as a choke point for cancer metastasis. Decommissioning the receptor eliminates cancer’s favorite escape routes.
“We’ve generated exciting preclinical data on some of the more aggressive deadly cancers such as pancreatic, ovarian, and metastatic breast cancer,” says Mazar.
Monopar licensed its second asset, Validive®, from a public company in France called Onxeo. Validive® prevents a very painful and debilitating condition called severe oral mucositis (SOM) in oropharyngeal cancer (OPC) patients, which is a condition that currently has no approved treatment.
Before licensing the drug, the team noted that Onxeo had conducted the phase II clinical trials of the drug in all head and neck cancer patients.
“I looked at the data and thought, ‘this really should be focused on oropharyngeal cancer,’ which is a specific type of head neck cancer,” says Mazar. “I knew this backwards and forwards because I had literally just been through treatment for oropharyngeal cancer a couple of years before that.”
They found OPC patients did considerably better on the drug than the full population. They also knew that the OPC patient population was the fastest growing because of human papillomavirus (HPV) disease.
Very positive patient responses in phase II clinical trials earned Validive® fast track designation in the US and orphan drug designation in the EU. Phase III clinical trials are anticipated to launch soon in 60-80 sites.
Monopar’s second clinical stage agent, camsirubican, is a novel analog of doxorubicin, a drug widely used to treat adults and children with solid and blood cancers, including bladder, breast, gastric and ovarian, soft tissue sarcomas, leukemias and lymphomas.
“We’re going after, as a first indication, advanced soft tissue sarcoma, which has a life expectancy of around 12-15 months from the time of diagnosis,” says Robinson. The current first-line treatment is doxorubicin. The problem with doxorubicin is that it works through a dose dependent mechanism. As you get more of the drug, you get better efficacy results, but you also get higher rates of irreversible heart damage. The patient is faced with a situation where they may die from the drug if they stay on it too long, or die from the cancer if they stop taking the drug and the cancer progresses.
After completing animal studies, as well as phase I and a small phase II clinical trial of camsirubican, the team, thus far, has seen no evidence of the irreversible heart toxicity seen with doxorubicin. A larger phase II trial will begin in the next 6 months with the hope of demonstrating the anticancer activity of doxorubicin without the irreversible heart damage.
“The oncology community is very eager for a replacement of doxorubicin in the treatment of advanced soft tissue sarcomas,” says Robinson.
With the money raised from its successful IPO last month, “we can go full steam ahead,” says Mazar.
The Secret Sauce
“It really boils down to the people. We have a team that really enjoys working together on something that we believe in, and where we are trying to make a positive impact. It is a very inspiring environment,” says Robinson. “When you bring those people and elements together, you can do something special. That’s also what I have seen consistently over time with CLP.”
Brown, who invested early in both Tactic and Monopar, concurs.
“CLP has been so effective at translating basic science to society because it brings together people that understand the business world in ways academic scientists rarely do,” says Brown. “The evolution of Tactic and Monopar are great examples of this. I have done nine Wall Street offerings, raised probably $2 billion ranging from my first deal, and I would have to say Chandler, Andrew, and the Monopar team pulled together the most amazing outcome I have seen in this IPO.”
by Lisa La Vallee
Feature image: Chandler Robinson, MD, CEO of Monopar Therapeutics
Northwestern Professors Talk Gender, Mental Health and Work-life Balance at ‘CLP Spills the Tea’ Event
Northwestern’s Chemistry of Life Processes Institute held a panel discussion between female scholars in STEM on Wednesday at the Technological Institute, with the event attracting so many students that it became standing-room only.
Sheila Judge, senior director for research, education and administration at the Chemistry of Life Processes Institute, opened the event, which was co-sponsored by One Book One Northwestern.
“The stories women tell each other are essential to our survival,” Judge said.
The panel consisted of Weinberg profs. Teri Odom and Heather Pinkett and McCormick profs. Monica Olvera de la Cruz and Danielle Tullman-Ercek. They spoke about inclusion in academia and STEM fields, their personal and professional lives and mental health issues.
The professors said academia can be lonely for women and people of color, and they emphasized the importance of building friendships.
“It was much harder to have a group of friends when I was in academia as an assistant professor,” Olvera de la Cruz said. “When you are in this career, you need a group of friends that supports you, nominates you, reviews your work and knows what you’re doing.”
Pinkett also emphasized the importance of “building a network.” She said how her graduate school friends continued to act as a support group for her and had an unspoken rule of allowing each other to vent and talk about their problems.
Responding to a question regarding how to tackle the lack of diversity in media, Odom, chair of the department of chemistry, noted that many of the metrics used to judge candidates are “male-centric.”
“Awards, numbers of papers and conference talks are often designed for somebody that went through the system the way (they) did,” Tullman-Ercek said.
Odom said issues of diversity have become more prominent in hiring and recruitment as conversations in academia have become more inclusive.
The panel also responded to career-related questions and encouraged the audience to broaden their academic horizons. Odom emphasized attending diverse talks and exposing yourself to new research ideas.
“Go to as many talks as you can stomach outside your area of expertise so that you have a more global perspective,” she said.
After the event, Pinkett said they had “an amazing turnout” and had attracted a larger crowd than she anticipated.
“Along the pipeline, you see fewer and fewer women as you go higher in academia,” she said. “So I think it’s really nice to hear from women who have been really successful in their fields, and that kind of advice is really what we need. Women look for mentors who are other women like them.”
Pinkett, who also serves as co-chair of One Book One Northwestern 2019-20, said the event served to spotlight “women who are hidden figures.”
“This is a perfect venue,” she said. “Not only to talk about our research, but also to talk about our personal lives and how we navigate both.”
A single cell contains the genetic instructions for an entire organism. This genomic information is managed and processed by the complex machinery of chromatin — a mix of DNA and protein within chromosomes whose function and role in disease are of increasing interest to scientists.
A Northwestern University research team — using mathematical modeling and optical imaging they developed themselves — has discovered how chromatin folds at the single-cell level. The researchers found chromatin is folded into a variety of tree-like domains spaced along a chromatin backbone. These small and large areas are like a mixed forest of trees growing from the forest floor. The overall structure is a 3D forest at microscale.
Chromatin is responsible for packing DNA into the cell nucleus. In humans, that’s about six feet of DNA in each cell. The new work suggests that chromatin is more structured and hierarchical in single cells than previously thought. Learning how chromatin correctly operates will help scientists understand what goes wrong with it in cancer and other diseases.
“By integrating theoretical and experimental work, we have produced a new chromatin folding picture that helps us see how the 3D genome is organized at the single-cell level,” said Igal Szleifer, the Christina Enroth-Cugell Professor of Biomedical Engineering at Northwestern’s McCormick School of Engineering. He co-led the research team with Vadim Backman.
Details of the interdisciplinary study were published today (Jan. 10) in the journal Science Advances.
“If genes are the hardware, chromatin is the software,” said Backman, the Walter Dill Scott Professor of Biomedical Engineering and director of the Center for Physical Genomics and Engineering. “If the structure of chromatin changes, it can alter the processing of the information stored in the genome, but it does not alter the genes themselves. Understanding chromatin folding holds the key to understanding how cells differentiate and how cancer happens.”
Advances in genomic, imaging and information technologies are just beginning to enable scientists to better understand how chromatin works. The Northwestern researchers used a Partial Wave Spectroscopic (PWS) microscope, optical imaging developed by Backman and colleagues, to peer deep into live cells and “sense” alterations in chromatin packing. They also used electron imaging.
“Our paradigm-shifting picture of chromatin folding is an important missing piece in the holistic view of genomic structure,” said Kai Huang, the study’s first author. Huang is a postdoctoral fellow in Backman’s research group. “The results should inspire new strategies to fight cancer.”
The research was supported by the National Science Foundation and the National Cancer Institute at the National Institutes of Health.
The paper is titled “Physical and data structure of 3D genome.” The corresponding authors are Szleifer, Backman and Huang.
Backman also is professor of medicine and of biochemistry and molecular genetics at the Feinberg School of Medicine, program leader in cancer and physical sciences at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and a member of the Chemistry of Life Processes Institute.
Original story was published on January 10, 2020 in Northwestern Now by Megan Fellman.
Main image: A 3D forest of chromatin predicted by the researchers’ model. Tree domains are colored from red to green according to their sizes.
Both Igal Szleifer and Vadim Backman are members of the Chemistry of Life Processes Institute.
In light of the University’s year-long celebration of ‘150 Years of Women at Northwestern’, Chemistry of Life Processes Institute will host first of three ‘CLP Spills the Tea‘ events on January 15 at 4:00 p.m. on the Evanston campus. The program will include tea, cookies, and conversation with four prominent Chemistry of Life Processes Institute scientists at the top of their game.
The discussion will cover career highs and lows; navigating gender-based challenges; opening doors to create greater access; juggling work/family balance; and the people who inspired them to aim high and reach for their goals.
Teri Odom, Charles E. and Emma H. Morrison Professor of Chemistry; Chair, Department of Chemistry, Weinberg College of Arts & Sciences
Monica Olvera de la Cruz, Lawyer Taylor Professor of Materials Science and Engineering; Professor of Chemistry, Chemical and Biological Engineering, Physics and Astronomy, McCormick School of Engineering
Heather Pinkett, Associate Professor of Molecular Biosciences, Weinberg College of Arts & Sciences
Danielle Tullman-Ercek, Associate Professor of Chemical and Biological Engineering, McCormick School of Engineering
Sheila Judge, Senior Director for Research, Education and Administration, Chemistry of Life Processes Institute
The program will be held in Cohen Commons, Northwestern University, Room L482, fourth floor north, in the Technological Institute, 2145 Sheridan Road, Evanston, IL.
Each cell in the human body holds a full two meters of DNA. In order for that DNA to fit into the cell nucleus — a cozy space just one hundredth of a millimeter of space — it needs to be packed extremely tight.
A new Northwestern University study has discovered that the packing of the three-dimensional genome structure, called chromatin, controls how cells respond to stress. When the chromatin packing is heterogenous and disordered, a cell demonstrates more plasticity. When the packing is neat and orderly, a cell cannot respond as easily to outside stressors.
This discovery comes with both good and bad news.
The bad news: This means cancer cells with disordered packing are more likely to adapt to and evade treatments, such as chemotherapy. The good news: Now that researchers have this information, they can develop new cancer therapies that target chromatin packing. By inhibiting cancer cells’ ability to adapt, those cells become more vulnerable to traditional treatments.
“Cancer cells are masters of change,” said Northwestern’s Vadim Backman, who co-led the research. “They have to continuously adapt to evade the immune system, chemotherapies or immunotherapies. Abnormal chromatin packing drives cancer cells’ ability to do this.”
The study was published today (Jan. 8) in the journal Science Advances.
Backman is the Walter Dill Scott Professor of Biomedical Engineering in Northwestern’s McCormick School of Engineering, director of the Center for Physical Genomics and Engineering and the associate director for Research Technology and Infrastructure at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University. He co-led the work with Igal Szleifer, the Christina Enroth-Cugell Professor of Biomedical Engineering, in McCormick.
Made of DNA, RNA and proteins, chromatin determines which genes get suppressed or expressed. In the case of cancer, chromatin can regulate expression of the genes that enable cells to become resistant to treatment.
“Genes are like hardware, and chromatin is software,” Backman said. “And chromatin packing is the operating system.”
“The genome has been sequenced, and techniques, such as CRISPR, now allow researchers to edit a cell’s ‘hardware,’” Szleifer added. “The role of chromatin structure on gene expression, however, has remained a scientific mystery.”
To help solve this mystery, Backman, Szleifer and their teams combined nanoscale imaging technologies with molecular dynamics modeling to analyze nanoscale alterations in chromatin packing structure.
Using data from The Cancer Genome Atlas, they analyzed cells from patients with colorectal, breast and lung cancers for markers of transcriptional plasticity. The researchers also used Partial Wave Spectroscopic (PWS) microscopy, which previously was developed in Backman’s laboratory, to examine chromatin in living cells in real time.
The researchers discovered an inverse relationship between patient survival and the plasticity of tumor cells. Backman says that chromatin engineering opens the door for a new class of cancer therapies, which could re-wire cells’ “operating systems” to make them less plastic.
“We found that transcriptional plasticity and chromatin packing alterations are an important marker, which is indicative of how a cancer patient may respond to anti-cancer therapies, such as chemotherapy,” said Ranya Virk, the paper’s first author. “This can be translated into a new method of predicting outcomes of cancer therapy.”
The study, “Disordered chromatin packing regulates phenotypic plasticity,” was supported by the National Science Foundation (award number EFMA-1830961) and the National Institutes of Health (award numbers R01CA228272, R01CA225002, U54CA193419 and T32GM008152). Northwestern Ph.D. candidates Ranya Virk, Wenli Wu and Luay Almassalha were the paper’s co-first authors.
Original story published in Northwestern Now by Amanda Morris.
Vadim Backman and Igal Szleifer are Chemistry of Life Processes Institute Faculty members. Their work was supported, in part, by the Chicago Region Physical Sciences-Oncology Center, the product of a partnership between the Northwestern Chemistry of Life Processes Institute and the Robert H. Lurie Comprehensive Cancer Center. Thomas O’Halloran, PhD, is the Center’s principal investigator.
Growing up in Michigan, Isabella (Bella) Borgula, a senior at Northwestern, developed a passion for chemistry earlier than most kids.
“One thing that I distinctly remember is that my dad would buy me GIANT Microbes®, these little stuffed animals of viruses and bacteria,” Borgula said. “I thought they were the coolest thing; I kept the tags on them. I think that’s where my interest in the smallest elements of science started. Not a typical thing that you buy your child.”
In addition to her father Thomas Borgula, ‘89, Borgula’s high school chemistry teacher, also fueled her interest in science.
“I fell in love with chemistry in high school. I had a wonderful chemistry class with my teacher Ms. Webb. Her enthusiasm for chemistry was palpable, and it was very easy to catch onto,” Borgula said. “We talked a lot about the applications of chemistry and I just knew that I needed to keep going in that field.”
With college decisions looming, Borgula signed up for Northwestern’s Modern Cosmology In Focus Seminar led by Dr. Andrew Rivers, in her junior year to get a better feel for the college experience.
“We went into a three hour lecture each day with a group of 20 passionate juniors in high school and we’d talk about cosmology, physics, the origins of the universe, and a bunch of really nerdy things,” says Borgula. “I decided I need to have more of this community in my life and knew I needed to apply to Northwestern. These are the people I wanted to be surrounded by—people that will encourage my passion for science and provide this supportive, constructive environment.”
Her father Tom Borgula’s own experience at Northwestern also influenced the Borgula’s decision to attend. An exceptional baseball player, Bella’s father was recruited by a number of top universities, including Northwestern. From the moment he arrived on campus, he noticed something different about the students.
“I went on a recruiting visit to Northwestern and just felt like I fit in. The students seemed much more serious about academics like me,” her father said. “The athletic department was also more serious. Whereas the other schools? You were there to play sports.”
After graduation, Borgula’s dad was drafted by the Chicago White Sox and played a year in the minor league. Later, he completed his DDS degree and orthodontics residency, moved back to Michigan, and got married. In 1997, he began his orthodontics practice and started his family of four with wife Terry.
From Collecting GIANT Microbes® to Chemistry Major
At Northwestern, Borgula enrolled in general chemistry, eager to try research.
“I was a little apprehensive at first to go Northwestern because I thought that I wouldn’t be able to compete with other students for research positions. Everyone knows Northwestern is such a good school—especially the chemistry department. It’s world renowned.” Borgula said. “I wasn’t sure if I was cut out for it, so I spent freshman year building up my confidence.”
In the fall of 2017, Borgula reached out to Thomas O’Halloran, the Morrison Professor of Chemistry and Founding Director of Chemistry of Life Processes Institute (CLP), who urged her to apply for the Institute’s Lambert Fellowship. A highly competitive two-year award for rising sophomores and juniors majoring in Chemistry, the Fellowship provides funding for hands-on laboratory research, training in how to use the equipment in CLP-affiliated core facilities, and stipends for supplies, fees and travel to academic conferences. The award also includes a mentoring plan that allows fellows to work alongside CLP faculty members and postdoctoral and graduate students who share their interests.
“I wasn’t sure if I was going to be able to compete for such a lucrative fellowship, but I spent a lot of time writing my draft and collecting feedback from people in my lab. I was fortunate enough to be given the Fellowship,” Borgula said.
O’Halloran’s groundbreaking zinc sparks research initially drew Borgula to his lab. In 2014, the group discovered that the female mammalian egg releases a dazzling burst of zinc during fertilization that passes through the protein coat and surrounds the egg. This crucial process prevents more than one sperm from fertilizing the egg.
“When a sperm is inseminated into the female reproductive track, it is developmentally mature, but it’s not yet activated for fertilization. To become capable of fertilization, it must undergo two processes. First is capacitation, where it’s starts moving a little faster, and then it undergoes the acrosome reaction,” Borgula said. “The acrosome is a little organelle that sits on the apex of the sperm head and contains a number of proteolytic enzymes that break down proteins in the female reproductive tract. My project focuses on the acrosome reaction, which is absolutely critical for fertilization.”
Lambert Fellowship Opens Doors from Switzerland to Argentina
The Lambert Fellowship, underwritten by the Institute’s generous board members, enabled Borgula to attend the International Conference on Biological Inorganic Chemistry in Switzerland last summer a rare opportunity for an undergraduate. She registered and submitted her abstract to give a poster presentation, but, to her surprise, was selected for something even more prestigious.
“I got an email from the board saying that I had been selected to give flash presentation in front of the entire conference,” Borgula said. “It was one of the most exciting, thrilling, terrifying things I’ve ever done. Having the platform to share my passion for science with so many people that are also passionate about science is something I’ve always dreamed of.”
Her biggest fan, however, was her father who accompanied her on the trip and sat through all of the talks, in addition to Bella’s.
“My dad has been such a supportive role throughout my career as a student, and now as a budding scientist,” says Borgula. “I dragged him through all the airports and it was an opportunity for him to see how much I’ve grown as an individual in college. Back at home, I’m hanging out with my family and relaxed, but he got to see me navigating cities and airports and being the adult that I’ve become while I’ve been away from home.”
The speaking opportunity elevated Borgula’s profile at the conference and attracted a number of scientists to her poster presentation about the acrosome reaction of sperm.
“Bella was up there with a bunch of graduate students doing her flash poster presentation and, to the credit of Northwestern, she sounded just like any other graduate student,” Bella’s father said. “Dr. O’Halloran has been a great PI for her. I got to meet him there and a few of his previous students who are now professor at other schools. He’s patient and treats Bella like a graduate student which has given her a lot of confidence.”
Last summer, CLP also made possible the opportunity for Borgula to travel to Argentina to conduct research in the lab of Mariano Buffone, a world-leading expert in the molecular mechanisms of mammalian sperm during fertilization.
“His lab has a mouse line that makes it much easier for us to analyze the acrosome reaction of massive number of sperm. It was an amazing opportunity to get data more quickly, and it raised a bunch of other questions about my project and procedure and where we’re going next,” Borgula says.
Borgula intends to continue investigating the interface between biochemistry and inorganic chemistry in graduate school for which she is currently applying.
“When I first stumbled upon the CLP web page, I was amazed by how many different kinds of scientists there were,” says Borgula. “Growing up as a researcher in CLP has influenced my perspectives on what a successful researcher should be and taught me the importance of collaboration. Exposure to all of these different perspectives has been extremely influential in my growth and development as a scientist.”
The appreciation goes both ways.
“Having undergraduate students as passionate as Bella in the lab is one of the reasons why I went into academic research,” says O’Halloran. “She brings this incredible enthusiasm for chemistry and biology and a willingness to try any kind of experiment, no matter how difficult. It’s pretty rare for an undergraduate to have accomplished so much at this stage and it bodes well that she will have an outstanding career in biomedical research.”
by Lisa La Vallee
Feature image (top of page): Undergraduate Isabella Borgula gives a flash poster presentation at the International Conference on Biological Inorganic Chemistry in Switzerland.
Like many first-year students, Myung Shin ’87 was undecided about his major when he arrived at Northwestern. He was initially drawn to political science, but his parents had other plans.
“They wanted me to go to medical school, but I didn’t know if that was right for me,” said Shin, who is a member of the University’s Chemistry of Life Processes Institute (CLP) Executive Advisory Board and serves as executive director and head of early discovery genetics at Merck & Co. “I always liked and did well in science, so I enrolled in the biochemistry molecular biology and cell biology program.”
Two years later, Shin decided to try research and asked Professor Rick Morimoto about opportunities in his lab. Morimoto, who had no space, suggested reaching out to Thomas O’Halloran, a new assistant professor with a joint appointment in chemistry and molecular biosciences. O’Halloran welcomed Shin into his lab, where he found his true calling.
“Having a faculty member take the time to mentor me and allow me to set up his research lab was an unbelievable experience,” Shin said. “It truly changed my life and helped me find what I really wanted to do. What excited me most about research was the ability to ask new questions, find new ways of doing things, and break new ground.”
Shin continued to work in O’Halloran’s lab for a year after graduating from Northwestern, an experience that solidified his desire to attend graduate school. Six years later, he earned his PhD in molecular biology from the University of California, Berkeley. After completing a postdoctoral fellowship at Princeton University as a Jane Coffin Childs and HHMI Postdoctoral Fellow, Shin took a faculty position at Fox Chase Cancer Center in the cellular and developmental biology program. He joined Merck in 2004.
Today, Shin leads a unit at Merck that focuses on early discovery genetics. The department’s mission is to identify targets for drug discovery based on human genetics data. The group covers a number of different therapeutics areas, including cardiovascular and liver diseases; neurological diseases like Alzheimer’s and Parkinson’s disease; and age-related retinal diseases.
Shin also supports science and innovation at Northwestern as a member of the Chemistry of Life Processes Institute (CLP) Executive Advisory Board. CLP’s expansive, transdisciplinary approach and state-of-the-art facilities accelerate drug development and biomedical discovery at the University. O’Halloran is the Charles E. and Emma H. Morrison Professor of Chemistry, professor of molecular biosciences in the Weinberg College of Arts and Sciences, and the institute’s founding director.
While a student at Northwestern, Shin met his future wife, Pheodora Shin ’87, ’89 MD, who grew up in Skokie, Illinois. She is a pediatric anesthesiologist at Morristown Medical Center in New Jersey, where the couple settled down to raise their daughter Grace.
This fall, Grace entered Northwestern undecided about her major, just as her father had been three decades earlier. Like him, she is taking advantage of the University’s vast offerings to find her own calling.
“I chose Northwestern because I felt it could give me a wide variety of options, so that no matter what I do, I would be well equipped with the resources here,” she said.
As Grace begins her Northwestern education, her parents remain active in the alumni community and contribute to their class scholarship funds for the Weinberg College of Arts and Sciences and Feinberg School of Medicine.
“Northwestern allowed us to grow as young adults and find our way,” Shin said. “My wife was not from a wealthy family and was a Pell Grant recipient. Northwestern offered her a path where she did not have a huge amount of student loans. One of the things that we commit to, along with supporting Chemistry of Life Processes Institute, is giving back to ensure as many people as possible from different backgrounds can benefit as we have from a Northwestern education.”
by Lisa La Vallee
This year, the Chemistry of Life Processes Institute celebrated a decade of transformative science. Since its debut in Silverman Hall in 2009, the Institute’s team science approach to integrating engineering, physics, chemistry, biology and medicine has led to unprecedented breakthroughs in biomedical research and the development of new drugs and diagnostics (see video).
CLP realized its vision in 2019 with numerous research collaborations among CLP’s 66 faculty members (7 new to the Institute this year), including:
- Nathan Gianneschi developed a ‘Trojan horse’ anticancer drug that disguises itself as fat.
- Neurobiologist Bill Klein pioneered a new approach to Alzheimer’s diagnostics and therapeutics, supported by CLP’s preclinical imaging expertise and instrumentation.
- Monica Olvera de la Cruz upended the current understanding of matter with the discovery that nanoparticles engineered with DNA in colloidal crystals — when extremely small — behave just like electrons.
- Richard Silverman and Neil Kelleher collaborated on new therapeutic approach to liver cancer.
CLP advanced its mission to translate faculty innovations from the laboratory to the patient bedside with new partnerships and programs:
- The Institute hosted a national investor summit in April that brought investors to campus to learn about high impact translational projects in CLP labs. Half of the presentations resulted in direct investor interest. Based on this success, a second ‘Biotech by the Lake’ event will be held in May 2020.
- To help demystify the drug development process for Northwestern faculty and students, CLP Entrepreneur-In-Residence Bill Sargent wrote and published online the ‘Beginner’s Guide to Academic Drug Development’.
Faculty innovations that have spun out from, or originated with, CLP are finding success in areas ranging from cancer treatment to agriculture:
- Actuate is expanding clinical trials of a new treatment for metastatic cancer and fibrosis.
- Durametrix is rolling out a novel screening method for toxicity to accelerate drug development.
- MicroMGx Inc. is partnering with Corteva Agriscience to accelerate development of microbial-based crop protection products using MicroMGx’s proprietary metabologenomics platform.
The Institute’s growing portfolio of critical technologies have supported and opened up many new areas of investigation:
- A $660K NIH Instrument Award to CLP’s Quantitative Bioelement Imaging Center will enable this core facility to acquire advanced instrumentation that will enable dynamic measurement of the metal content and their localization in cells from healthy and diseased tissues.
Looking to the future, the Institute continues to engage students in transdisciplinary research and translation. CLP’s NIH-funded graduate training program and donor-funded undergraduate research programs have trained budding scientists like Viswajit Kandula, Ryan McClure and Jennifer Ferrer, to work across disciplinary silos to lead the next wave of scientific discovery.
by Lisa La Vallee