Before becoming a trainee in the Chemistry of Life Processes NIH Graduate Training Program at Northwestern, Ryan McClure was already performing research at the interface of chemistry and biology. A joint student between the labs of Regan Thomson...
Two Northwestern University scientists have received a $3.1 million grant from the National Institute on Aging to collaborate and investigate drug therapies for amyotrophic lateral sclerosis (ALS).
The grant was awarded to P. Hande Ozdinler, associate professor of neurology at Northwestern University Feinberg School of Medicine, and Richard B. Silverman, the Patrick G. Ryan/Aon Professor in the departments of chemistry and molecular biosciences in the Weinberg College of Arts & Sciences.
ALS, also known as Lou Gehrig’s disease, is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. There is an immense global effort to identify effective treatments.
Silverman, the inventor of Lyrica, previously received a U.S. Department of Defense grant to screen compounds that overcome protein aggregation and then modify them for enhanced potency. Protein aggregation — when nerve cell proteins accumulate and clump together — is often correlated with such neurodegenerative diseases as ALS, Alzheimer’s and Parkinson’s.
“The problem we are trying to solve is to identify a common underlying cause for many different neurodegenerative diseases,” Silverman said. “The compounds we develop initially for ALS may have broader applications for neurodegeneration.”
Silverman and Ozdinler began to collaborate to investigate whether these compounds and their derivatives would have an impact on the degenerating upper motor neurons in ALS. Ozdinler’s previous research showed that degeneration of the upper motor neurons, not just spinal neurons, is an important contributor to ALS.
“Our initial results with these compounds are quite promising, and because we use upper motor neurons, our findings will have implications in other upper motor neuron diseases as well,” Ozdinler said.
Ozdinler is able to cloak the upper motor neurons that die in ALS in green fluorescence.
“We can now track their responses to compounds both in a dish and in the brain,” Ozdinler said. “This was not possible in the drug discovery field before. “
Silverman is a member of the Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery and Center for Developmental Therapeutics. Ozdinler is a member of Les Turner ALS Center, Mesulam Center for Cognitive Neurology and Alzheimer’s Disease and the Robert H. Lurie Comprehensive Cancer Research Center of Northwestern University.
The NIH grant is 1 R01 AG061708-01A1from the National Institutes of Health.
The initial phases of research were supported by the Les Turner ALS Foundation and an N.XT grant.
Original story published on August 16, 2019 by Marla Paul.
Watching neurons die provides Richard Morimoto with clues on how he might better keep them alive. The molecular biologist specifically studies neurons exposed to cell stress as well as those expressing proteins linked to neurodegenerative diseases.
Now, a new instrument at Northwestern’s Biological Imaging Facility (BIF) is helping the Morimoto laboratory to develop — and, more importantly, monitor — small molecule therapeutics that restore neuronal cellular health and to slow, or even reverse, neuronal death.
“Our research requires many of the instruments at the Biological Imaging Facility, and the new BioTek LionheartFX allows us to generate high-resolution imaging of living neurons, a vital capacity in helping us monitor protein aggregation,” says Morimoto, the Bill and Gayle Cook Professor of Biology and director of Northwestern’s Rice Institute for Biomedical Research.
Research in Morimoto’ lab addresses a fundamental aspect of biology known as protein homeostasis, or proteostasis, the processes by which cells maintain protein vitality for good overall health. Failure in these quality control processes is the basis of hundreds of human diseases, including cystic fibrosis, cancer, metabolic diseases, and neurodegenerative diseases.
The LionheartFX was one of many new instruments highlighted during the annual Chemistry of Life Processes (CLP) Institute Core Crawl on July 11. More than 300 researchers and graduate students took part in the event, which showcased the institute’s growing portfolio of shared research facilities. CLP operates eight cores and four centers of excellence that play a critical role in accelerating research across the University. Approximately 75 administrative, technical, and research staff at the institute support more than 60-affiliated faculty working at the interface of the physical sciences, chemistry, medicine, and life sciences.
In the weeks before it was installed, Jessica Hornick, BIF operations director, says numerous labs contacted the facility to discuss the new instrumentation. Hornick hosted many of those labs during initial training sessions July 15-18.
“There was high demand for extended-period, incubated, live-cell imaging and we’ve worked with a number of principal investigators over the course of several years to identify the best instrument available,” says Hornick. The cost of the LionheartFX was subsidized by the Rice Foundation, CLP, the Office for Research, the Program in Biological Sciences, the Department of Chemistry, and the Department of Molecular Biosciences.
In another of CLP’s eight cores, research capabilities were expanded in November 2018 to include the ability to isolate and characterize very large protein complexes in a new way. The Proteomics Center of Excellence (PCE) manages the new instrument, a ThermoFisher Q-Exactive Ultra-High Mass Range (UHMR) mass spectrometer, which was funded by a 2018 National Institutes of Health shared instrumentation grant.
“The UHMR expands what our current instrumentation can detect in terms of analyzing extremely large protein complexes,” says Paul Thomas, associate director of Northwestern Proteomics. “Protein complexes are the functional engines of the cell. They represent many different proteins coming together to produce a biological effect.”
Proteomics is the large-scale study of proteins. Until the 2000s, scientists relied on breaking a protein into small pieces, analyzing them using mass spectrometry and piecing the information back together to determine their structure and function. In contrast to this traditional “bottom-up” approach, Northwestern’s Neil Kelleher, molecular biosciences, chemistry, and medicine and director of Northwestern Proteomics, helped confirm the feasibility of a “top-down” strategy, which measures intact proteins using a sophisticated technology. Since then, Kelleher, a member of CLP, has been demonstrating the power of top-down proteomics to provide complete information about the sequence and composition and variations of human proteins in health and disease.
A second new instrument in PCE will be used to train scientists on the top-down approach. The ThermoFisher Q-Exactive HF BioPharma now anchors the ThermoFisher/Northwestern University Top-Down Training Center (Housed in Hogan 4-120). PCE will host its next top-down training course November 11-14.
“The training facility allows us to have a center away from the hustle and bustle of the rest of PCE at Silverman Hall,” says Thomas. “It creates a space where we can bring in new practitioners of top-down proteomics and give them the tools for ultimate success in this burgeoning field.”
CLP is part of Northwestern’s robust ecosystem of University Research Institutes and Centers, some 50 interdisciplinary knowledge hubs that harness talent from across all areas of the institution. CLP provides investigators across Northwestern, as well as users from industry and other research institutions, access to highly specialized instrumentation as well as PhD-level expertise.
Core Expo Set For October 15
CLP presents its annual Core Expo from 11 a.m. to 1 p.m. on October 15 at the Lurie Cancer Center’s Ryan Family Atrium (West), 303 East Superior St., Chicago. Managers from nearly a dozen core facilities will showcase their innovative biomedical expertise, research, and services available to Chicagoland researchers.
Attendees can learn how centers and cores collaborate to advance potential therapeutics and diagnostics from the early stages of discovery through pre-clinical testing.
Targeted drug-delivery systems hold significant promise for treating cancer effectively by sparing healthy surrounding tissues. But the promising approach can only work if the drug hits its target.
A Northwestern University research team has developed a new way to determine whether or not single drug-delivery nanoparticles will successfully hit their intended targets — by simply analyzing each nanoparticle’s distinct movements in real time.
By studying drug-loaded gold nanostars on cancer cell membranes, the researchers found that nanostars designed to target cancer biomarkers transited over larger areas and rotated much faster than their non-targeting counterparts. Even when surrounded by non-specifically adhered proteins, the targeting nanostars maintained their distinct, signature movements, suggesting that their targeting ability remains uninhibited.
“Moving forward, this information can be used to compare how different nanoparticle characteristics — such as particle size, shape and surface chemistry — can improve the design of nanoparticles as targeting, drug-delivery agents,” said Northwestern’s Teri Odom, who led the study.
The medical field has long been searching for alternatives to current cancer treatments, such as chemotherapy and radiation, which harm healthy tissues in addition to diseased cells. Although these are effective ways to treat cancer, they carry risks of painful or even dangerous side effects. By delivering drugs directly into the diseased area — instead of blasting the whole body with treatment — targeted delivery systems result in fewer side effects than current treatment methods.
“The selective delivery of therapeutic agents to cancer tumors is a major goal in medicine to avoid side effects,” Odom said. “Gold nanoparticles have emerged as promising drug-delivery vehicles that can be synthesized with designer characteristics for targeting cancer cells.”
Various proteins, however, tend to bind to nanoparticles when they enter the body. Researchers have worried that these proteins might impede the particles’ targeting abilities. Odom and her team’s new imaging platform can now screen engineered nanoparticles to determine if their targeting function is retained in the presence of the adhered proteins.
The study, “Revolving single-nanoconstruct dynamics during targeting and nontargeting live-cell membrane interactions,” was supported by the National Institutes of Health (award number R01GM115763). Odom is a member of the International Institute for Nanotechnology, Chemistry of Life Processes Institute and Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
by Amanda Morris
Original story published by Northwestern Now on August 9, 2019.
Chemistry of Life Processes Institute recently welcomed Northwestern faculty members Amy Rosenzweig, Danielle Tullman-Ercek, and Monica Olvera de la Cruz to its Faculty Executive Committee. All three distinguished researchers are members of the Institute. The Committee oversees resource allocation and helps shape the strategic direction of the Institute whose mission is to accelerate drug development and biomedical discovery at Northwestern to advance human health. The group is comprised of CLP faculty members, many of whom serve dual roles as heads of CLP centers and cores.
Monica Olvera de la Cruz, the Lawyer Taylor Professor of Materials Science and Engineering, McCormick School of Engineering, is recognized internationally for her contributions to analyzing, modeling and designing new materials that mimic effective biological processes. She is a professor of chemical and biological engineering, chemistry, and physics and astronomy and director of the Center for Computation and Theory of Soft Materials. Olvera de la Cruz has received many honors including, the National Institutes of Health FIRST Award, the David and Lucille Packard Fellowship for Science and Engineering, the Alfred P. Sloan Fellowship, and the NSF Presidential Young Investigator Award. She is a Fellow of the American Physical Society, American Academy of Arts and Sciences, and National Security Science and Engineering Faculty.
Amy Rosenzweig, the Weinberg Family Distinguished Professor of Life Sciences and Professor of Molecular Biosciences and of Chemistry, Weinberg College of Arts and Sciences, is a leader in the fields of bioinorganic chemistry and structural biology. Her laboratory focuses on metalloproteins, which comprise up to 50 percent of all proteins. Rosenzweig’s work has provided seminal insights into how metalloenzymes catalyze complex and difficult chemical transformations and how cells acquire and distribute essential yet toxic metal ions. She is a fellow of the American Academy of Arts and Sciences and a member of the National Academy of Sciences. She is a recipient of many awards, including the Royal Society of Chemistry Joseph Chatt Award, the American Chemical Society Nobel Laureate Signature Award for Graduate Education, an Honorary Doctor of Science Degree from Amherst College, and a MacArthur Fellowship.
Danielle Tullman-Ercek, Associate Professor of Chemical and Biological Engineering, and Director, Master of Science in Biotechnology Program, McCormick School of Engineering, is a noted expert in controlling the movement of materials across biological membranes. Her team develops tools and techniques from protein engineering and synthetic biology that enable and enhance the production of pharmaceuticals, biofuels, and materials in microbes. Her honors include the Outstanding Young Alumna Award, Illinois Institute of Technology ChBE, the Searle Leadership Award, and the NSF CAREER Award.
Chemistry of Life Processes Institute is where new cures and better diagnostics begin. CLP brings together world-leading Northwestern University investigators across a wide array of disciplines to accelerate the pace of biomedical discovery to advance human health.
The deaths were palpable.
Just six years after the start of a medical career he envisioned would be filled with helping patients heal, Richard D’Aquila, instead, found himself at the forefront of the AIDS epidemic. What he did next continues to alter the lives of those living with the disease and its precursor, the human immunodeficiency virus (HIV).
“I decided that instead of going to more funerals, I would return to the lab and pursue additional research training,” says D’Aquila, director of Northwestern’s HIV Translational Research Center and the Howard Taylor Ricketts Professor of Medicine. “I was fortunate enough to connect with virologists at Yale in 1985 with ties to scientists who had actively worked to uncover the cause of AIDS.”
That answer was revealed with the 1984 discovery of HIV.
Following a research fellowship at Yale, D’Aquila joined the faculty in New Haven, about 30 miles from where he grew up in New Britain, Connecticut. His persistent interest in developing new drugs — he nearly pursued a PhD in pharmacology before obtaining an MD at Albert Einstein College of Medicine — and his clinical background in infectious diseases, led to his recruitment by Massachusetts General Hospital and Harvard Medical School, where he was able to take leadership roles in some of the earliest clinical trials and related clinical virology research for what was still considered a largely untreatable disease.
Today, more people than ever before are finding they can manage HIV more effectively as a direct result of improved antiretroviral treatment, which is often as straightforward as taking one pill daily. In the early 1990s, D’Aquila was instrumental in moving a novel “drug cocktail” — a combination of three antiretrovirals that for the first time effectively suppressed the virus — from the laboratory into the clinic. Since then, the number of pills needed to suppress the diseases, as well as their efficacy, has steadily improved. And very recently, there is evidence that having the amount of virus in the blood consistently suppressed to “undetectable” levels can also stop transmission to others; this offers a hopeful strategy for ending the epidemic.
“The memories of what it was like in the earliest days when all that we could offer was comfort haven’t faded, but we’re living in a different world in terms of what we can now do for patients,” says D’Aquila, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern Universityand Chemistry of Life Processes Institute and director of the Third Coast Center for AIDS Research (CFAR), a National Institutes of Health-funded program operated collaboratively with the University of Chicago and various community partners. “We have medications that really work, and in turn that allows my lab, and many others, to concentrate on working toward solutions to the remaining problems faced by people living with HIV: finding a ‘cure’ and avoiding common health problems that decrease the quality of life but are not life-threatening.”
D’Aquila prefers to discuss “the sustained remission of HIV after antiretroviral medications are stopped,” rather than a cure in the traditional sense. That’s because scientists are closer to slowing the virus from returning after stopping the medications than completely eliminating the virus from the body. While people living in developed nations on HIV treatment now do not suffer from the life-threatening opportunistic infections and cancers that accompanied AIDS previously, they experience more frequent and earlier disorders associated with aging. These include heart diseases and cancers that are common among those not infected with HIV. So while lifespan is beginning to approach actuarial standards, the “healthspan” is still shorter than those not infected, a challenge researchers continue to address and hope to ameliorate.
During a short elevator ride to his Feinberg School of Medicine office overlooking Michigan Avenue, the passion D’Aquila maintains for research is evident. Although he sees patients less, they still guide almost everything he does.
“We have a couple of ongoing projects in the HIV Translational Research Center where we are seeing astonishing results,” he says, noting that he couldn’t possibly shoulder the workload being carried out by medical school faculty Chisu Song and Harry Taylor, graduate students, and a postdoctoral fellow. “One of the most exciting parts in any day is learning new things from them and determining how to push different ideas forward with them.”
Research efforts focus on novel drug therapies to boost a defensive cell protein in HIV virions abbreviated as A3s and to decrease a cell’s ability to replicate HIV. The goal is to achieve sustained HIV remission after antiretrovirals are stopped and decrease the persistent inflammation that can contribute to disorders associated with aging.
In another of his multiple roles, D’Aquila is director of the Clinical and Translational Sciences Institute’s (NUCATS) Center for Clinical Research, and in 2017, he was named an associate vice president of research, which positions him as a connecting point between Northwestern administration and the directors of four University Research Institutes and Centers.
In his roles with CFAR and NUCATS, D’Aquila sees himself as a catalyst for team-based approaches to clinical investigation.
“I work in a world of similar priorities for NUCATS, CFAR, and Northwestern’s Institute for Public Health and Medicine,” says D’Aquila. “Development and implementation of new interventions so they become routine medical practice and benefit society relies on community participation.”
D’Aquila also is committed to helping early-career investigators establish their careers: “Making sure that young researchers own the advances in which they play
a central role is a critical step in establishing future generations of investigators who will help solve problems that today seem unsolvable.”
The original story was published in Research News on July 11, 2019.
Richard D’Aquila is a member of the Chemistry of Life Processes Institute.
Chemistry of Life Processes Institute members Evan Scott and Arthur Prindle were among a select group of Chicago scientists recognized as rising stars dedicated to translating research into real-world applications that meaningfully impact people’s lives in Halo’s annual ’40 under 40 Chicago Scientists’ list.
Prindle, Assistant Professor of Biochemistry and Molecular Genetics, Feinberg School of Medicine, was recognized for his vision to engineer the human microbiome to monitor and treat diseases like diabetes and cancer.
Scott, Assistant Professor of Biomedical Engineering, McCormick School of Engineering, was recognized for his work designing customizing nanomaterials to treat a wide range of disease, including heart disease, tuberculosis, cancer, glaucoma, Chagas disease, diabetes, neonatal vaccination, and transplant tolerance.
The researchers will be honored at the 2nd Annual Halo Awards on Saturday, October 12, at the Museum of Science and Industry. Click here to register for the event.
Read the original story by Kevin Leland.
Five Northwestern University professors — chemist Danna Freedman, computer scientist Han Liu, economist Mar Reguant, neuroscientist Joel Voss and surgeon Jason Wertheim — have been awarded the Presidential Early Career Award for Scientists and Engineers (PECASE). President Donald J. Trump announced the recipients of the prestigious honor last week.
This year’s recipients will be honored at a July 25 ceremony in Washington, D.C.
Established in 1996, the PECASE honors the contributions of scientists and engineers in the advancement of science, technology, education and mathematics (STEM) through scientific education, community outreach and public education. It is the highest honor bestowed by the United States government on science and engineering professionals in the early stages of their independent research careers. The White House, following recommendations from participating federal agencies, confers the awards.
The Northwestern researchers focus on a range of topics: Freedman tackles challenges in physics with synthetic inorganic chemistry; Liu uses computation to explore machine intelligence; Reguant works to quantify the effects of renewable energy; Voss develops novel treatments for memory impairment; and Wertheim explores new methods to bioengineer kidney and liver tissue for eventual transplantation.
Northwestern’s recipients are:
Associate professor of chemistry at in the Weinberg College of Arts and Sciences
Nominated by the National Science Foundation, Freedman received the PECASE for her work on quantum computing.
Freedman and her team create and implement novel design principles to synthesize better qubits, the smallest unit of a quantum computer. Developing computers with quantum objects would enable scientists to understand electron transfer in a new way, paving the way for new generations of materials for renewable energy. Freedman applies synthetic inorganic chemistry’s tools and approaches to fundamental challenges in physics, akin to the highly successful application of inorganic chemistry to challenges in biology. Within this framework, Freedman and her research group focus on three vital challenges in physics: enabling quantum information processing, creating new permanent magnets and discovering new superconductors.
Associate professor of computer science at the McCormick School of Engineering
Nominated by the National Science Foundation, Liu received the PECASE for his work in artificial intelligence and data science.
Lying at the intersection of modern artificial intelligence and computer systems, Liu’s research deploys statistical machine learning methods on edges and clouds to achieve analytical advantages. His primary research uses computation and data as a lens to explore machine intelligence. He works toward this goal by using the point of view provided by the twin windows of statistical machine learning and computer systems. Statistical machine learning provides a unified framework which combines uncertainty and logical structure to model complex, real-world phenomena, while computer systems implement the learning algorithms with the highest performance guarantees.
Associate professor of economics at Weinberg
Nominated by the National Science Foundation, Reguant received the PECASE for her research into the economics of renewable energy.
Reguant’s research examines the economics of energy, with an emphasis on electricity and the pollution associated with electricity generation. She aims to develop new theoretical and empirical strategies to assess the impacts of renewable energy. To meet this goal, she works to empirically quantify the impact of renewable energy by analyzing recent relevant experiences in wind and solar integration. Given the practical relevance of this effort, she also plans to develop open-access programs that will allow other researchers to work with the data.
Associate professor of medical social sciences, neurology, psychiatry and behavioral sciences at the Feinberg School of Medicine
Nominated by the Department of Health and Human Sciences, Voss received the PECASE for his work in cognitive neuroscience.
His laboratory uses human neuroscience methods, such as MRI and brain stimulation, to investigate mechanisms of learning and memory and their impairment in neurologic and neuropsychiatric disorders. His work with noninvasive brain stimulation has shown that it is possible to predictably influence brain networks responsible for memory in order to probe their function and to develop novel treatments for memory impairment.
Jason Wertheim, MD
Associate professor of surgery at Feinberg and associate professor of biomedical engineering at McCormick
Nominated by the Department of Veterans Affairs, Wertheim received the PECASE for innovative and applied research investigating how injured tissues and organs heal, regenerate and repair in order to develop new tissues as future treatments for chronic organ failure.
A clinical transplant surgeon and biomedical engineer, Wertheim focuses on discovering new methods to bioengineer liver and kidney tissue in the laboratory as a cutting-edge solution to donor organ shortage. Wertheim’s applied research develops bioartificial tissues, and his group has produced quantitative metrics to track how cells develop into new tissue within bioreactors. This work could uncover essential drivers of how tissues repair and regenerate to develop innovative, future cures for chronic diseases. Together, this research opens new scientific opportunities for development of future medical treatments to improve quality of life and health.
By Silma Suba
Jason Wertheim is a member of the Chemistry of Life Processes Institute.
For years, drug developers have tried, but failed, to build the perfect biological Trojan horse. Now, a new approach that disguises chemotherapeutic drugs as fat stands to outsmart, penetrate and destroy tumors. For the first time, a team of Northwestern researchers, led by Chemistry of Life Processes Institute member Nathan Gianneschi, and collaborators from the University of California, San Diego have developed a highly effective method that delivers a powerful new anticancer drug, hidden inside human serum albumin (HSA), one of the most abundant proteins found in the blood, directly into tumors. Once inside, the drug activates and suppresses tumor growth with very low toxicity to normal tissues at much higher concentrations than two leading approved chemotherapy drugs.
The results, which elucidate the design, synthesis and efficacy of this new carrier strategy for small molecule drugs, is based on exploiting the natural interactions between long-chain fatty acids (LCFAs) and HSA. The study was published today (July 18) in the Journal of the American Chemical Society (JACS).
One of the key functions of HSA is to carry molecules, such as fats, to different parts of the body. LCFAs consist of a molecular chain with a hydrophilic head and a long hydrophobic tail. The heart-shaped HSA protein contains several channels where chains of water-hating fatty acids can attach and hide with their hydrophilic heads buried inside. Like a magnet, the channels with hydrophobic walls and hydrophilic bottoms, attract and store the fats, enabling safe transport throughout the circulatory system and into tissues.
The body’s cellular receptors recognize the fats and proteins supplied by HSA and allow them inside. Fast-growing cancer cells ravenously consume nutrients much faster than normal cells.
Several years ago, Gianneschi, the Jacob and Rosaline Cohn Professor of Chemistry in Northwestern’s Weinberg College of Arts and Sciences and professor of biomedical engineering and materials science and engineering in the McCormick School of Engineering and a former Northwestern classmate Paul Bertin, Research Group Leader of Innovation at Elevance Renewable Sciences, hatched an idea.
“Paul called me one day and said, ‘ERS had developed a new type of lipid, a normal fatty acid, but with two carboxylates on either end,’” said Gianneschi. The researchers believed the lipid’s bi-functional structure offered an intriguing new platform for developing a lipidated drug.
“Imagine you have an arm with a hand on it that is able to grab onto the drug,” said Gianneschi. “The chain is like the fat with a hand on both ends: one can grab onto the drug and one can grab onto proteins. The idea is to disguise drugs as fats so that they get into cells and the body is happy to transport them around.”
Researchers have tried for years to attach chemotherapeutic drugs to the single hydrophilic head of traditional LCFAs, but presence of the drug on the head altered the chemistry of the fatty chain making it too unstable to engage securely inside the HSA channel fatty acid binding channels. Instead of putting the drug on the single hydrophilic head of a fat chain, Gianneschi and Cassandra Callmann, a graduate student in Gianneschi’s lab at the time of the study and first author of the paper, developed a new way to attach a taxane anticancer drug to the tail end of the new type of lipid. The technique preserves the head of the LCFA, ensuring a good fit inside the HSA channel enabling the drug to be securely transported without detection into cancer cells.
The experiments showed that the fatty acid with the drug attached to the tail binds HSA in the same places as normal natural fatty acids and that it also preserves the structure of the HSA so it still looks natural to the tumor tissue.
The researchers found five ideal HSA binding sites and tested the new, purified compound they called VTX (the ‘V’ for the Roman numeral five, ‘TX’ for taxane, the drug of choice here) which consisted of the drug/LCFA combination and HSA. They performed extensive in vivo studies at both UC San Diego and with the assistance of Irawati Kandela, Assistant Director, Research Assistant Professor, Chemistry of Life Processes Institute’s Developmental Therapeutics Core, at Northwestern testing VTX against two FDA-approved paclitaxel formulations over a range of conditions.
What they found astonished them: the new drug eliminated tumors in three different types of cancer: fibrosarcoma, pancreatic cancer and colon cancer.
“It’s like a Trojan horse that looks like a nice little fatty acid, so the receptors see it and invite them in. Then, the drug starts getting metabolized and kills the tumor cells,” said Gianneschi.
Remarkably, the researchers found they could deliver 20 times the dose of paclitaxel with their system, compared to two other paclitaxel-based drugs. But even at such a high quantity, the drug in Gianneschi’s system was still 17 times safer.
Together with ERS, Gianneschi formed Vybyl Biopharma to commercialize the technology and develop new applications to treat a variety of different cancers.
”Commonly used small molecule drugs get into tumors — and other cells,” said Gianneschi. “They are toxic to tumors, but also to humans. Hence, in general, these drugs have horrible side effects. Our goal is to increase the amount that gets into a tumor versus into other cells and tissues. That allows us to dose at much higher quantities without side effects which kills the tumors faster.”
In addition to Gianneshi, Callmann, and Bertin, other authors of the paper include Clare LeGuyader, Spencer Burton, Matthew Thompson, Robert Hennis, Christopher Barback, Niel Henriksen, Warren Chan, Matt Jaremko, Jin Yang, Arnold Garcia, Michael Burkart, Michael Gilson and Jeremiah Momper. The work was supported by ERS, the ARCS Foundation and the Inamori Foundation.
by Lisa La Vallee
Feature image: A modified chemotherapy drug hitches a ride through the bloodstream on human serum albumin.
Nathan Gianneshi is a member of the Chemistry of Life Processes Institute.
Congratulations to NU scientists Richard B. Silverman and Neil L. Kelleher on their recent publication in the Journal of the American Chemical Society, titled
“Mechanism of Inactivation of Ornithine Aminotransferase by (1 S,3 S)-3-Amino-4-(hexafluoropropan-2-ylidenyl)cyclopentane-1-carboxylic Acid.”
The paper addresses new efforts towards developing drugs for hepatocellular carcinoma (HCC) — the most common form of liver cancer for which there is currently no effective treatment. The inhibition / inactivation of an enzyme called ornithine aminotransferase (OAT) has been implicated as a potential therapeutic pathway for HCC and the authors of the current study have previously identified several inhibitors of OAT. Here, they proceed to characterize the mechanism(s) of OAT inactivation and report that a two-step modification resulting in an addition of a trifluoromethyl group appears to be key to the process. This discovery provides an important start-point towards further development and optimization of potential HCC therapeutics.
Rick Silverman, the Patrick G. Ryan/Aon Professor of Chemistry at NU, is senior author on the publication. Rick is an active CBC
community member and in 2018, he won an inaugural CBC Accelerator Award for the project: “Novel Drug for Hepatocellular Carcinoma.” Neil Kelleher, one of co-authors on the paper is a CBC Senior Investigator, who was hired in 2010 by NU with help from a generous CBC Recruitment Funds Award. Additional CBC connections of both researchers are listed below.
PUBLICATION LINKED TO CBC FUNDING*:
Moschitto MJ, Doubleday PF, Catlin DS, Kelleher NL, Liu D, Silverman RB. Mechanism of Inactivation of Ornithine Aminotransferase by (1 S,3 S)-3-Amino-4-
(hexafluoropropan-2-ylidenyl)cyclopentane-1-carboxylic Acid. J Am Chem Soc. 2019 Jun 28. [Epub ahead of print] (PubMed)
The inhibition of ornithine aminotransferase (OAT), a pyridoxal 5′-phosphate-dependent enzyme, has been implicated as a treatment for hepatocellular carcinoma (HCC), the most common form of liver cancer, for which there is no effective treatment. From a previous evaluation of our aminotransferase inhibitors, (1 S,3 S)-3-amino-4-(perfluoropropan-2-ylidene)cyclopentane-1-carboxylic acid hydrochloride (1) was found to be a selective and potent inactivator of human OAT ( hOAT), which inhibited the growth of HCC in athymic mice implanted with human-derived HCC, even at a dose of 0.1 mg/kg. Currently, investigational new drug (IND)-enabling studies with 1 are underway. The inactivation mechanism of 1, however, has proved to be elusive. Here we propose three possible mechanisms, based on mechanisms of known aminotransferase inactivators: Michael addition, enamine addition, and fluoride ion elimination followed by conjugate addition. On the basis of crystallography and intact protein mass spectrometry, it was determined that 1 inactivates hOAT through fluoride ion elimination to an activated 1,1′-difluoroolefin, followed by conjugate addition and hydrolysis. This result was confirmed with additional studies, including the detection of the cofactor structure by mass spectrometry and through the identification of turnover metabolites. On the basis of this inactivation mechanism and to provide further evidence for the mechanism, analogues of 1 (19, 20) were designed, synthesized, and demonstrated to have the predicted selective inactivation mechanism. These analogues highlight the importance of the trifluoromethyl group and provide a basis for future inactivator design.
Graphical abstract. (Source: dx.doi.org)
The original story was published by the Chicago Biomedical Consortium on July 8, 2019.
Rick Silverman and Neil Kelleher are both members of the Chemistry of Life Processes Institute.
A pair of recent papers helps clear up a longstanding mystery about the enzyme particulate methane monooxygenase (pMMO). The enzyme sits in the membranes of bacteria that consume methane as their main food source, and catalyzes the conversion of methane to methanol.
“Everyone in the field agrees that it’s a copper-dependent enzyme,” says Amy C. Rosenzweig, a biochemist at Northwestern University who led both studies. What researchers don’t agree on is what the copper active site might look like. Decades of conflicting studies have left the active site shrouded in mystery. Various crystal structures have shown zinc, copper, or no metal at all in the potential binding sites.
In a study published in May, Rosenzweig, Brian M. Hoffman, and their coworkers used multiple electron paramagnetic resonance (EPR) spectroscopic techniques to reveal that pMMO purified from bacterial membranes contains two metal binding sites, each of which binds a single copper ion (Science 2019, DOI: 10.1126/science.aav2572). Rosenzweig points out that the team had previously proposed that one of the sites had a dicopper center.
For one of the two sites, the researchers couldn’t isolate its EPR signal, preventing them from characterizing the site. All they could tell was how far its copper ion was from the other site’s copper ion—about 2 nm. Previous crystal structures were no help because those data had shown that the mystery site was in a chronically disordered region of the protein.
So Rosenzweig turned to Neil L. Kelleher, another Northwestern chemistry professor, for help. Kelleher used top-down native mass spectrometry to analyze the protein. In that technique, researchers reconstitute the protein in a lipid nanodisc under conditions that cause it to remain in its native state.
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Members of Kelleher’s team were able to determine the number of coppers in each of pMMO’s three subunits, named PmoA, PmoB, and PmoC (Nat. Commun. 2019, DOI: 10.1038/s41467-019-10590-6). They found a single copper binding site in each of PmoB (the one that was visible with EPR) and PmoC (the one that was obscured).
The mass spec experiment told the team something else about the enzyme. While the researchers prepared the enzyme samples for native top-down mass spectrometry, the protein lost some of its copper. By adding copper during the preparation, the researchers could help the enzyme recover the metal, particularly in PmoC. The added copper also increased the enzyme’s activity, suggesting that the PmoC site is important for enzyme activity. But questions remain about what the active site looks like.
“The fact that copper is located in subunit PmoC and correlates with activity is something of a surprise and could indicate the location of the active site,” says Thomas J. Smith, an expert on pMMO at Sheffield Hallam University. “There is still such a large amount of conflicting evidence about the location of the active center that I think additional evidence is still needed.”
by Celia Henry Arnaud
The original story was published in Chemical and Engineering News on June 26, 2019. Feature image: This methane monooxygenase’s copper binding sites are located in the PmoB (purple) and PmoC (blue) subunits. PmoA is shown in pink. Credit: Nat. Commun.
Amy C. Rosenzweig and Neil L. Kelleher are both members of the Chemistry of Life Processes Institute.
It’s not an electron. But it sure does act like one.
Northwestern University researchers have made a strange and startling discovery that nanoparticles engineered with DNA in colloidal crystals — when extremely small — behave just like electrons. Not only has this finding upended the current, accepted notion of matter, it also opens the door for new possibilities in materials design.
“We have never seen anything like this before,” said Northwestern’s Monica Olvera de la Cruz, who made the initial observation through computational work. “In our simulations, the particles look just like orbiting electrons.”
With this discovery, the researchers introduced a new term called “metallicity,” which refers to the mobility of electrons in a metal. In colloidal crystals, tiny nanoparticles roam similarly to electrons and act as a glue that holds the material together.
“This is going to get people to think about matter in a new way,” said Northwestern’s Chad Mirkin, who led the experimental work. “It’s going to lead to all sorts of materials that have potentially spectacular properties that have never been observed before. Properties that could lead to a variety of new technologies in the fields of optics, electronics and even catalysis.”
The paper will publish Friday, June 21 in the journal Science.
Olvera de la Cruz is the Lawyer Taylor Professor of Materials Science and Engineering in Northwestern’s McCormick School of Engineering. Mirkin is the George B. Rathmann Professor of Chemistry in Northwestern’s Weinberg College of Arts and Sciences.
Mirkin’s group previously invented the chemistry for engineering colloidal crystals with DNA, which has forged new possibilities for materials design. In these structures, DNA strands act as a sort of smart glue to link together nanoparticles in a lattice pattern.
“Over the past two decades, we have figured out how to make all sorts of crystalline structures where the DNA effectively takes the particles and places them exactly where they are supposed to go in a lattice,” said Mirkin, founding director of the International Institute for Nanotechnology.
In these previous studies, the particles’ diameters are on the tens of nanometers length scale. Particles in these structures are static, fixed in place by DNA. In the current study, however, Mirkin and Olvera de la Cruz shrunk the particles down to 1.4 nanometers in diameter in computational simulations. This is where the magic happened.
“The bigger particles have hundreds of DNA strands linking them together,” said Olvera de la Cruz. “The small ones only have four to eight linkers. When those links break, the particles roll and migrate through the lattice holding together the crystal of bigger particles.”
When Mirkin’s team performed the experiments to image the small particles, they found that Olvera de la Cruz’s team’s computational observations proved true. Because this behavior is reminiscent to how electrons behave in metals, the researchers call it “metallicity.”
“A sea of electrons migrates throughout metals, acting as a glue, holding everything together,” Mirkin explained. “That’s what these nanoparticles become. The tiny particles become the mobile glue that holds everything together.”
Olvera de la Cruz and Mirkin next plan to explore how to exploit these electron-like particles in order to design new materials with useful properties. Although their research used gold nanoparticles, Olvera de la Cruz said “metallicity” applies to other classes of particles in colloidal crystals.
“In science, it’s really rare to discover a new property, but that’s what happened here,” Mirkin said. “It challenges the whole way we think about building matter. It’s a foundational piece of work that will have a lasting impact.”
The research, “Particle analogs of electrons in colloidal crystals,” was supported by the Center for Bio-Inspired Science, an Energy Frontier Research Center funded by the U.S. Department of Energy (award number DE-SC0000989); the Air Force Office of Scientific Research (award number FA9550-17-1-0348); the Office of Naval Research (award number 00014-15-1-0043) and the Sherman Fairchild Foundation. Martin Girard, a PhD graduate from Olvera de la Cruz’s laboratory and current postdoctoral scholar at the Max Planck Institute for Polymer Research in Germany, is the paper’s first author.
The original story appeared in Northwestern Now on June 20, 2019.
Monica Olvera de la Cruz is a member of the Chemistry of Life Processes Institute.
Training and inspiring the next generation of interdisciplinary scientists is central to the mission of the Chemistry of Life Processes Institute at Northwestern. This year, four aspiring scientists will join a growing list of students who have received funding through the Institute’s Executive Advisory Board members to receive hands-on experience and training at the intersection of multiple scientific disciplines.
Emma Schultz, a rising junior chemistry major, received the Institute’s most prestigious undergraduate award: the Lambert Fellowship. She will be working in the laboratory of Thomas O’Halloran (chemistry), inaugural director, CLP.
“I am so grateful for the Lambert Fellowship and the opportunity to receive mentorship, learn to think in depth about research, and develop greater presentation skills,” says Schultz.
Established in 2010 by Dr. Andrew Chan, CLP Executive Advisory Board Chair, the Lambert Fellows Program provides multi-year funding for rising sophomores and juniors majoring in chemistry to conduct laboratory research under the mentorship of CLP faculty members. Awardees receive a summer stipend as well as funding that covers research supplies and conference travel. Fellows work closely with an Institute faculty member to develop their research proposals and budget allocations. Graduate student and postdoctoral associate mentors also work closely with the students. The program aims to mentor and produce a cadre of enthusiastic, well-trained undergraduates with an entrepreneurial mindset. Fellowships begin in early summer and continue throughout the academic year for a minimum period of two years.
Emma Herzog, a rising senior chemistry major, Tyler Kramlich, a rising fifth year double major in Chemical Engineering and Music Composition, and Olivia Pura, a rising senior double major in Biology and Slavic Literatures & Languages, were the recipients of the Institute’s Summer Scholars research awards. Each will receive a stipend to spend the summer quarter working in CLP faculty laboratories. Working in collaboration with CLP researchers, students will learn the most innovative approaches to problem solving using methods developed by chemists, biologists, engineers, physicists, mathematicians and clinicians.
Since the programs’ inception, more than 60 undergraduates have participated in both summer and year-round programs, including the Chicago Area Undergraduate Research Symposium Award, awarded in the fall to support academic year research. Eighty-three percent of CLP-funded graduates have pursued PhDs at top graduate schools, enrolled in Medical Scientist Training programs, or attended medical school. One former student is attending law school and another is in veterinary school. In addition, CLP undergrads have co-authored more than 45 papers based on their work.
by Lisa La Vallee
Feature image: Summer scholars Emma Herzog and Tyler Kramlich.
With more than 30 years in the pharmaceutical industry, preceded by a decade as an independent researcher in academia, Chemistry of Life Processes Institute’s Entrepreneur-in-Residence William Sargent shared his perspective and advice about potential science career opportunities in industry with the most recent crop of CLP graduate student trainees.
At a recent ‘Lunch and Learn,’ Sargent described his industry career trajectory as a series of upward movements that started with working in the field with sales reps and quickly progressed to senior-level positions at Hoechst-Roussel Pharmaceuticals, Lorex Pharmaceuticals, Searle, Pharmacia and Pfizer. As president and general manager of Lorex, he oversaw FDA approval for direct to consumer advertising for their lead product Ambien®. He also led the international launch of Sutent® for renal cell carcinoma and gastrointestinal stromal cancer while senior medical director and team leader for the anti-angiogenic portfolio at Pfizer.
Sargent outlined a number of job opportunities within the pharmaceutical industry. Regulatory affairs, for instance, a field once dominated by lawyers, is now primarily the domain of scientists who need to speak and understand the language of scientific reviewers at the US Food and Drug Administration (FDA).
“Regulatory affairs is the conduit from the pharmaceutical industry to the people at FDA who are conducting the drug reviews. The kind of people you run into at FDA generally are very, very good scientists. It’s a lot of fun if you like working on project teams.”
Scientists (MDs, PhDs and PharmDs) are also in high demand for the clinical phase of drug development. “They’re the people who look at the FDA-required end points, design drug trials and write the clinical protocols.”
In addition, Medical Affairs groups in pharmaceutical companies are staffed by scientists who negotiate between marketing and clinical development and discuss clinical trial realities with marketing. The objective is to enhance information provided to marketing about the drug that will better inform physicians about the appropriate use of the drug.
“The pharmaceutical industry really does expand not only your vision of drug development, but it also expands your knowledge of patient and physician needs due to the extensive travel you have to put into it.” Sargent estimates he spent about 40 percent of his time spent outside of the office.
After spending 10 years with Pfizer traveling across the globe, a London-based medical communications company recruited him. In this role, Sargent conducted many group conversations with practicing physicians to decipher how to triage patients into different therapeutic regimens. His company would present a patient history and then listen to the doctors’ thoughts about how to treat the patient.
“The engines of the medical communications industry are medical writers. If you like to write, it’s a perfect place for you. We’d take a contract to write a manuscript and the medical writer would then go to the literature, get caught up on that particular aspect of medicine, and then interact with the authors to plan out the paper.”
In addition to a scientific background, a good medical writer is task-oriented as well as creative, says Sargent. Skilled medical writers can look at things differently and explain very complex subjects to an audience that may not be as well versed in that specific aspect of medical treatment.
Medical writing is also a good choice for people who like the freedom of working from home.
“I had one medical writer in Colorado,” says Sargent. “He would go skiing in the morning and write for eight hours after he went skiing. That was during the winter. During the summer, he played golf in the morning and wrote in the afternoon and evening. It’s a very nice lifestyle.”
Earlier in his career, Sargent noted that most scientific career opportunities were within the pharmaceutical industry, but that is no longer the case.
Government Funding Agencies, Investment Firms and Reimbursement Agencies
“Anybody who comes into your labs selling something is from an industry that you potentially could work in,” says Sargent. “Anybody who touches a lab, or a research facility, or a pharmaceutical company needs scientists at some point to develop products, represent them and to talk to customers.”
Other examples of industries that hire scientists include:
- National funding agencies like the National Institutes for Health, National Science Foundation and the Department of Defense.
- Patient support organizations, such as JDRF (The Juvenile Diabetes Research Foundation) with about 25 MD/PhDs in their New York office alone who support more than $100 million in basic science and clinical research
- Venture capital firms and investment banks that depend on scientists to evaluate the science for a particular drug before investing
- Reimbursement agencies like United Health Care that need scientists to determine which drugs to include in their formulary for reimbursements
“Today, there are numerous and varied careers for basic science PhDs. Your first job is the entry point from which you can get in the stream of things, shoot off and away you go.”
by Lisa La Vallee
This year, three teams of Chemistry of Life Processes Institute investigators received $90,000, collectively, in CLP-Cornew Innovation Awards to pursue potentially transformative proof-of-concept studies to better detect, diagnose and treat disease. The awardees included Neha Kamat (biomedical engineering) and Julius Lucks (chemical & biological engineering) for development of a next generation biosensor; Tom Meade (chemistry) and Keith Tyo (chemical & biological engineering) to develop a more accurate, portable diagnostic kit; and Nathan Gianneschi (chemistry) and Bin Zhang (Medicine) for a proof-of-concept study for a new immunotherapy.
A next generation biosensor
From detecting pathogens in water to attacking toxins in the blood stream, an enormous need exists for biosensors in a variety of health and environmental fields. Clinicians currently must draw blood to detect the presence of molecules that signal trouble in humans, but this method can miss critical information. For instance, a molecule located near the site of a cancerous tumor can become diluted by the time it reaches the side of extraction rendering it undetectable.
Collaborators Neha Kamat and Julius Lucks want to build a radically different biosensor— one that acts as a “molecular taste bud” that can travel through the body in a carefully designed container, detect its target, record what it sees and even act as a kind of therapeutic.
One of the biggest challenges is designing a compartment that will allow the sensor to move through the body.
“What is needed is a sensor that moves through those environments, see something it’s been designed to see, and then records that event,” says Kamat. “It basically generates a memory that it saw a toxin or a low ph, or a molecule, so that when we do collect it, the sensor tells us what it saw.”
Taking a cue from the basic structure of a cell, the collaborators will use an RNA-based sensor that takes the sensing capability outside of the cell. This genetic polymer has the unique ability to detect very specific biological analytes of interest and report detection of a molecule.
“This little RNA switch is thought to be one of the more ancient ways that cells have evolved to sense their environments,” says Lucks.
The tool promises a wide range of potential diagnostic and therapeutic applications. In countries, such as India and Bangladesh, it could be a game changer. The overabundance of fluoride in the ground water in certain areas has led to a widespread health condition known as skeletal fluorosis, a painful and deforming bone disease.
Ultimately, the team hopes to build a modular tool that can diagnose a wide range of conditions, but for this project, they will focus on fluoride.
“You could make a therapeutic product that binds fluoride and pulls it out of circulation. You could make a fluorescent protein just to tell you that it’s there, which opens up the door to a huge range of responses that would expand what the biosensor does,” says Lucks.
A more accurate portable diagnostic test
CLP members Thomas Meade and Keith Tyo are developing a more accurate portable diagnostic tool that will enable patients and doctors to make better on the spot health decisions.
Currently, there are limitations to the accuracy of certain kinds of portable diagnostic tests. The hepatitis C test, for example, can accurately detect antibodies, but it can’t distinguish whether the patient was infected years ago or is experiencing an active infection.
“Typically if an antibody-based test comes back positive, they then will have to do a second round of tests that are based on a PCR and molecular diagnostics— things that are very, very lab heavy, require a lot of infrastructure and require a lot of training and personnel. It’s just not useful for a point-of-care (POC) testing,” says Catherine Majors, a postdoctoral scholar in Tyo’s lab involved in the project.
Another problem with POC diagnostic tests is that a lack of sensitivity can lead to a weak positive or false negative result. In home pregnancy testing, for example, if only a small amount of the analyte for pregnancy is detected, the test will barely register a signal, and the person reading the test may be unable to read the signal.
“What we’re trying to do is make something that’s analogous to the molecular mousetrap. There’s no such thing as a weak positive for a mouse trap,” says Tyo. “There’s no pushing halfway down on the trigger and the trap slowly turning over. It’s either snapped or it’s not fired yet.”
The first order of business is getting the molecular switch to work. Once the switch is working, the researchers will look upstream to see if they can get their test input, a hepatitis C antigen, to flip the switch. In future, they hope to use the new mechanism to detect a variety of conditions. The approach is a plug-and-play system that could easily be adapted for other tests. The team will leverage a proprietary technology developed by Meade to convert the molecular information into an electrical signal that will enable them to develop a new digital tool for reporting and analyzing test results.
“CLP allows for this intersection of interdisciplinary scientists,” says Tyo. “It is extremely enabling to combine my synthetic biology expertise with Meade’s chemistry and surface science expertise. That wouldn’t be possible otherwise. If we’re successful with our proof of concept, CLP has lots of infrastructure to help us move this forward to an actual application in the field. That’s really exciting.”
A more effective cancer immunotherapy
“The common theme is how do I deliver material? How do I deliver your drug to the bloodstream, or in the mouth, or rub it on your skin, and get it where you need it to be to have the desired effect?” says Gianneschi. “We’re trying to solve both.”
The investigators’ approach targets the signals associated with inflammation, which are found in a number of diseases like cancer and heart disease. The goal of the project is to develop a new kind of injectable immunotherapeutic designed to circulate throughout the body and localize in tumor cells while avoiding normal tissue. Over time, the material will accumulate in the tumor in just the right concentration until its signal triggers the immune system to recognize and attack not just the material, but the surrounding tumor tissue as well.
“It’s absolutely necessary that you localize the materials, but you don’t always know exactly where you want to put the drugs,” says Gianneschi. “You need to be able to do a delivery to the whole body where the drug is activated and localized only at the tumor. This is a massive global challenge with many different types of drugs that fall under the general category of targeted therapeutics.”
When Gianneschi first moved to Northwestern, he knew from experience that collaboration was essential for his kind of work. As a member of CLP, he found Zhang, a highly skilled immunology expert, and Irawati (Angki) Kandela, Assistant Director of the Developmental Therapeutics Core, who helped test and evaluate promising therapeutic agents. The researchers also utilized the imaging technology and expertise of the Center for Advanced Molecular Imaging. Both CDT and CAMI are CLP-affiliated cores.
The team hopes the Cornew Award will enable them to generate enough seed data to provide the basis for an NIH grant.
“We’ve done a lot of studies in the run up to this in CLP core facilities. This is such complicated research that involves imaging, animal dosing and the right animal models,” says Gianneschi. “It’s more than just technicians at CLP; these people are fully engaged. We’ve worked in the past with technicians who have said, ‘I did your injection— it didn’t work’ and then you’re stuck. I’d have to have half my group trying to do it. This is a totally different game here.”
The CLP-Cornew Innovation Awards
Currently in its ninth year, the CLP-Cornew Innovation Awards, are made possible by the generosity of Chemistry of Life Processes Institute Executive Advisory Board members, support promising interdisciplinary teams of CLP researchers in early stage development of high-risk, high-reward research projects with the potential to make significant impact.
Since the program’s inception in 2010, the CLP Board has awarded more than $900,00 to faculty collaborators in pilot funding. Cornew Awards have resulted in 39 publications, nine patents, and more than $18 million in new external funding to advance these projects opening up critical areas of transdisciplinary research and resulting in discoveries that impact human health and disease.
by Lisa La Vallee
Featured image: (left to right) CLP-Cornew Awardees Julius Lucks, Neha Kamat, Keith Tyo and Thomas Meade.
A major dilemma faced by many people undergoing chemotherapy for cancer is whether the drugs will cause more harm than good.
“Chemotherapeutic drugs can have serious side effects. Some of the adverse events in chemotherapy, such as heart failure, can even take as long as 10 years to manifest in people down the road,” says Steven E. Johnson, ’16 PhD, former postdoctoral fellow in Chemistry of Life Processes Institute member Ming Zhao’s laboratory.
Johnson and Ming Zhao, PhD, Associate Professor of Medicine in the Division of Cardiology, developed an innovative new imaging technology, published in Clinical Cancer Research, that surveys the entire body’s response to potentially toxic drugs in real time by assessing a marker for cell death.
Pathologically elevated cell death is an unambiguous marker for tissue injury. The collaborators’ initial proof of concept studies began with observation of cellular changes in response to cytotoxic treatments. The scientists took notice of a phenomenon called aminophospholipid externalization, in which a type of phospholipid that resides inside viable cells becomes available for binding of select imaging agents when the cell is dead or dying.
“The technique works by detecting a molecular signature of cell death, which enables the near-real time monitoring of toxic side-effects in target and susceptible tissues,” says Zhao.
The “aha” moment came when the researchers realized that they could apply this technology in a whole-body and dynamic fashion as a survey for drug toxicity by imaging the location of tissue damage in real time throughout the subject.
Excited about the translational possibilities of their research, the pair patented their new technology and started Durametrix to develop its commercial potential. They are working with Northwestern to obtain the license for the invention. Zhao and Johnson applied to NIH for a Small Business Technology Transfer (STTR) grant to test potential applications. Initially, the company would like to roll out the product to pharma industry collaborators and other researchers involved in drug discovery and development. Down the road, they hope to develop it for clinical use.
“When you want to create a new drug, you don’t start with just one molecular entity,” says Johnson, CEO of the new startup. “You start with many different compounds and narrow it down to 4-5 candidates that all look like they could be the drug that you’re going to give somebody eventually. When you test how safe and effective these candidates are, you need to go through hundreds of subjects. These studies are time-consuming, labor-intensive, and very expensive. The average time is about 2-3 years for a good drug discovery company to get to the point where they’ll say, this is what we want to actually push forward into clinical development.
“Our technology could really help drug companies make educated decisions in an expeditious and effective manner saving valuable time and money,” says Johnson.
Throughout the project, Chemistry of Life Processes Institute faculty, technical staff and administrators provided valuable assistance and guidance. Andrew Mazar, Center for Developmental Therapeutics, partnered with the researchers in developing the cytotoxicity paradigm; Chad Haney, managing director, Center for Advanced Molecular Imaging, collaborated on the imaging studies; and Jody Hirsh, senior read more…
Northwestern University graduate student and Chemistry of Life Processes Institute trainee Jennifer Rachel Ferrer will finish her PhD tomorrow as a joint student of Drs. Chad Mirkin (chemistry), and Jason Wertheim (surgery). She will present her research on how spherical nucleic acids, which are being investigated as new drug delivery systems, localize in the body. Her findings will inform design of SNAs to target specific tissues and cells for potential therapies. The daughter of immigrant parents and the first in her family to receive a doctorate, Ferrer’s thesis defense marks the culmination of years of bench work. Her graduate school years have also included advocating for women in STEM, rock climbing, and finding her community on campus.
Jen had already begun to set up dual mentorship in chemistry and biology before learning about the dual mentor requirement of the NIH-funded CLP T32 Predoctoral Training Program. She had joined a lab in Evanston focusing on chemistry, and one on the Chicago campus that emphasized tissue engineering and biology.
“The CLP Training Program was exactly what I had wanted for myself in grad school, as I was already thinking along that chemistry-biology interface,” said Ferrer. “It was great to see that there was a program here that emphasizes the transdisciplinary nature of the research we do here at Northwestern that leads to the development of different therapeutics and diagnostic tools that might one day help and treat patients.”
In addition to lab work and her participation in the CLP Training Program, Ferrer wanted to work to empower other women and was a fellow at the Center for Leadership. She created a project at the end of her fellowship, alongside three other women who were members of her leadership trainee cohort, to revive Northwestern’s chapter of the American Association of University Women (AAUW), which was no longer in existence.
The newly revived AAUW chapter at Northwestern empowers women to pursue their education through AAUW fellowships, provides interactive workshops on salary negotiation, as well as leadership training. She says that her time as a graduate student has bled into normal life, and that now, everything becomes a scientific question for which she creates hypotheses.
“I’ve noticed at conferences and in interactions at career panels, there isn’t a lot of representation at the top. There aren’t a lot of women, or people of color. Everything becomes a hypothesis, or an experiment to me now, so I ask the question why is that? How do I get there? Once I have those answers, how do I translate that back to the next generation?”
As she worked to empower other women and on her research, Ferrer says her rock-climbing hobby helped her find balance within her life, and that she became a stronger student and found community in climbing gyms.
“Grad school was a new place and a totally new environment. You’re expected to be autonomous and come up with an interesting research question on your own and you’re not yet an expert, but by the end of it, well, you are,” said Ferrer. “There are going to be ups and downs all along the way, and I think that rock climbing has helped me become more resilient in school and that all the grad school failures have helped me become a more resilient climber and person.”
Ferrer has accepted a position as a research analyst with drug development startup Monopar Therapeutics, an opportunity that arose through an interaction with CLP Executive Advisory Board member Chandler Robinson, CEO of the biotech company. While she will no longer be working at the bench, “I’m excited to expand my knowledge of the drug-development space, but still very much be connected to the science part of it,” said Ferrer.
When reflecting on her time at Northwestern, Ferrer focuses primarily on the communities she has found across campus.
“When I was writing the acknowledgements section of my thesis, it just kept going and going. On one hand, I thought this is long, but on the other, it would be a disservice if I didn’t thank all of these people because they have all been integral to my development as a scientist and a more mature person.”
Jennifer defended her thesis on June 19, 2019.
Check out her rock climbing instagram: @coconutandcantaloupe
by Lydia Rivers
Guillermo A. Ameer, professor of biomedical engineering and surgery, has been named the 18th recipient of the Martin E. and Gertrude G. Walder Award for Research Excellence. A pioneer in the emerging field of regenerative engineering, Ameer is known for his creative approach to designing biodegradable materials that promote tissue regeneration and prevent scarring.
The award, established in 2002 by alumnus Dr. Joseph A. Walder and given annually by the University provost, recognizes excellence in research at Northwestern.
“Through his pioneering work with biomaterials and leadership of the Center for Advanced Regenerative Engineering, Guillermo Ameer exemplifies innovation and excellence in research at Northwestern,” said Provost Jonathan Holloway.
“I’m honored to receive this prestigious award in recognition of our work in regenerative engineering,” Ameer said.
With appointments in the McCormick School of Engineering and Feinberg School of Medicine, Ameer is the Daniel Hale Williams Professor of Biomedical Engineering and Surgery. He also is the founding director of the Center for Advanced Regenerative Engineering (CARE), which aims to develop a range of biomedical solutions to promote growth and healing in damaged organs and tissues.
Ameer’s laboratory has pioneered the development and medical applications of antioxidant citrate-based biomaterials that can be used as a liquid or solid scaffold to regenerate new tissue. The biomaterials then break down and absorb into the body without side effects. The material’s main component — citric acid — accelerates healing due to its inherently antioxidant nature. Hundreds of researchers around the world have adopted the material for various bioengineering applications in their laboratories.
Ameer has used his citrate-based biomaterials in a range of applications to address a host of issues, including cardiovascular disease, broken bones, torn ligaments and bladder disease. To help patients with diabetes, for example, Ameer’s team used the biomaterials to develop a “regenerative bandage” for chronic, non-healing diabetic foot ulcers. His bandage heals wounds four times faster than a standard bandage without any side effects.
Named as a top 100 young innovator by Technology Review in 2013, Ameer is a fellow of the American Institute of Medical and Biological Engineering, Biomedical Engineering Society, American Institute of Chemical Engineers and the American Association for the Advancement of Science. A native of Panama, he received a key to the city of Panama City by the Panamanian government in 2018 for his contributions to science and society. He also has received the American Heart Association Established Investigator Award, the National Science Foundation CAREER Award, the Walter H. Coulter Early Career Translational Research Award and an American Immigration Law Foundation Immigrant Achievement Award.
He has authored more than 250 scientific papers, which have been published in high impact journals, including Nature Materials and the Proceedings of the National Academy of Sciences. He also has more than 50 patents issued or pending in nine countries.
Through his leadership, CARE has successfully competed for more than $10 million in extramural funding to carry out several regenerative engineering projects, sponsored by several government agencies. Ameer also is a faculty affiliate of Northwestern’s Simpson Querrey Institute, Chemistry of Life Processes Institute and International Institute of Nanotechnology.
Joseph Walder earned his doctoral and medical degrees from Northwestern, then founded a company that supplies synthetic DNA for research and clinical applications. A complete list of award recipients can be found on the Office of the Provost website.
By Amanda Morris
The original story was published on June 4 in Northwestern Now.
Northwestern University faculty members William Dichtel, Michael Jewett and Emily Weiss have been named finalists for the 2019 Blavatnik National Awards for Young Scientists. They are among 31 scientists and engineers being recognized nationally this year.
The finalists are considered to be some of America’s most important young scientific researchers aged 42 years or younger, driving the next generation of innovation by addressing today’s most complex and intriguing scientific questions. They now will compete for the largest unrestricted awards of their kind for early career scientists and engineers.
There are 10 finalists in each of three categories: life sciences, chemistry and physical sciences and engineering. The 2019 Blavatnik National Laureates, one from each category, will be announced on June 26. Each laureate will receive a cash prize of $250,000.
The annual Blavatnik Awards were established in 2007 by the Blavatnik Family Foundation and are administered by the New York Academy of Sciences.
Dichtel, the Robert L. Letsinger Professor of Chemistry at the Weinberg College of Arts and Sciences, is a finalist in chemistry. He was also a Blavatnik finalist in 2017. Dichtel works at the frontiers of organic, polymer and materials chemistry. He has pioneered efforts to understand a new frontier in polymerization — the formation of 2D grids and 3D scaffolds. These materials, as well as other disordered structures that also contain tiny pores, possess extremely high surface areas and have applications in water purification and energy storage.
Dichtel is a member of Northwestern’s International Institute of Nanotechnology.
Jewett, the Charles Deering McCormick Professor of Teaching Excellence, a professor of chemical and biological engineering in the McCormick School of Engineering and co-director of Northwestern’s Center for Synthetic Biology, is a finalist in life sciences. His work focuses bio-manufacturing therapeutics, materials and chemicals. Jewett invented cell-free techniques that harness biological systems without intact cells, creating new routes toward on-demand synthesis of medicines, expanding the chemistry of life, portable molecular diagnostics and education kits.
Jewett is a member of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University, Simpson Querrey Institute and the Chemistry of Life Processes Institute.
Weiss, the Mark and Nancy Ratner Professor of Chemistry at Weinberg, is a finalist in chemistry. She was also a Blavatnik finalist in 2018. Weiss’s transformative, cross-disciplinary work focuses on light-driven chemical reactions, high-time resolution biological imaging, chemical systems out of equilibrium and new mechanisms of charge transport in nominally insulating materials. Much of her lab’s research uses nanoscale semiconductor particles, called quantum dots, to transduce visible and near-infrared light energy to chemical and electrical energy, and for fundamental studies of processes at interfaces.
Weiss is a member of Northwestern’s International Institute of Nanotechnology.
by Amanda Morris
Original story published by Northwestern Now on May 29, 2019.