When it comes to running a business, even the most seasoned innovators, like Chemistry of Life Processes Institute member Richard Silverman (chemistry) who developed pregabalin, the chemical that became Lyrica®, the most financially successful drug ever to have come...
Chemistry of Life Processes Institute (CLP) recently introduced a new resource for Northwestern University academic drug developers who wish to explore the necessary steps in developing and eventual marketing of promising drug therapies discovered in their labs. The Beginner’s Guide to Academic Drug Development was developed by Dr. Bill Sargent, CLP’s Entrepreneur in Residence, drawing upon his 30-year career in the pharmaceutical industry and a decade in academic research and translation.
Hosted on the Center for Developmental Therapeutics home page, the Guide provides a detailed overview of the drug development process from discovery to filing an IND (Investigational New Drug Application) as well as links to Northwestern-specific experts.
“Drug development in an academic setting is very different from the pharmaceutical sector due to the lack of drug development experience and supporting infrastructure,” says Sargent. “In the pharmaceutical industry, once we had identified a treatable target, we created a project team with people who had all the different drug development skills sitting around the table. Having gone through that process, I thought I could bring the most important parts of it back to academia to show how we move the product from an idea to a commercially viable product that can help the patient.”
The Guide provides drug developers with information about:
- Northwestern policies and guidance
- FDA’s structure and selected guidance documents for drug development
- Scientific steps leading to identification of a patentable compound
- Northwestern fee-for-service Scientific Cores and Centers of Excellence that can assist at each step
- The patenting process, licensing and/or partnering process and Northwestern proprietary funding sources
In developing the Guide, Sargent incorporated feedback from the Institute’s transdisciplinary faculty and staff, managers of the University’s Core facilities, the Office of Research, the Innovation and New Ventures Office (INVO), NUCATS, Chicago Biomedical Consortium and other internal organizations involved in bringing innovations from the lab to society. These stakeholders form what Sargent considers “a ‘virtual’ project team” for University drug developers.
“We’ve got some really creative ideas at Northwestern. Our scientists conduct years of research to understand a biological pathway and its role in a disease process. Without this basic science, one would not know where to find a treatable target in the pathway,” says Sargent. “However, progressing from understanding basic pathways to identifying treatable targets takes a very long time, on average, about 10-15 years.”
As Entrepreneur-in-Residence, Sargent helps scientists determine whether a new discovery can address an unmet medical need in treating a specific disease process, and what other types of characteristics the drug will need in order to demonstrate efficacy in patients and to compete in the marketplace. He also helps to co-ordinate the research translation process. He hopes the Guide will stimulate researchers to press on in the development of promising treatments for clinical use.
“Many of Northwestern’s outstanding faculty in life scientists, chemistry, medicine, and engineering have phenomenal ideas about how to deliver drugs in novel ways, overcome toxicities, and target very specifically the disease tissue, or the tumor,” says Thomas O’Halloran, Founding Director of the Institute. “However, most of us do not have very much knowledge about how to develop our idea from theory to practice. This effort is an important first step.”
Sargent is available for consultation by appointment at firstname.lastname@example.org.
by Lisa La Vallee
Chemistry of Life Processes Institute Celebrates 10 Years of Transformative Science
This fall marked the ten-year anniversary of Chemistry of Life Processes (CLP) Institute’s debut in The Richard and Barbara Silverman Hall for Molecular Therapeutics and Diagnostics. To celebrate, the Institute held a recognition program to thank its Executive Advisory Board members, faculty, staff, and students for their contributions.
“CLP has become a hotbed of interdisciplinary collaboration,” said Founding Director Thomas O’Halloran, “made possible by our committed faculty, outstanding students, talented research staff and administrators, supportive Vice President for Research, and the generosity of our Executive Advisory Board and donors.”
According to O’Halloran the Institute has experienced tremendous growth since moving into Silverman Hall in 2009. The number of CLP faculty members increased 5-fold to more than 60, while Institute faculty developed four affiliated university center and eight core facilities that advance the research of hundreds of investigators across the region. In addition, the Institute faculty teamed up to create an NIH-funded training program that has enabled graduate students to work seamlessly across disciplinary boundaries, learning new methods and instruments, and opening up new areas of discovery.
During the recognition ceremony, O’Halloran thanked and presented a crystal award to each member of the Institute’s Executive Advisory Board for their ongoing support, including Stuart Cornew, who helped inspire the idea of CLP and for serving as first chair of Executive Advisory Committee, and Andrew Chan, Senior Vice President of Research Biology, Genentech, for shouldering the role of EAB chair and endowing the Institute’s Lambert Fellowship program that supports outstanding undergraduate researchers.
Richard B. Silverman, Patrick G. Ryan/Aon Professor; Professor of Chemistry, received award in recognition of his passion, dedication and generosity to the Institute. O’Halloran also expressed appreciation for the contributions of administrative and core facility staff and scientists who received gift cards and special recognition from the core leaders.
“When CLP recently underwent external program review,” said O’Halloran, “the reviewers commented on the centrality of our affiliated centers and cores to the realization of the CLP mission and were deeply impressed by the extraordinary expertise and dedication of their research faculty, postdocs and technical staff.”
Last, O’Halloran gave special thanks to Sheila Judge, the Institute’s Senior Director for Research, Education and Administration, and Research Professor, whose leadership and dedication has enabled the Institute to flourish.
After the recognition event, attendees enjoyed a fall-themed lunch under a big tent just outside of Silverman Hall and were given CLP-branded t-shirts.
by Lisa La Vallee
Four Northwestern University professors have been honored with election to the National Academy of Medicine (NAM).
Joining more than 2,200 active NAM members are Dr. David Cella, Dr. Susan Quaggin, John A. Rogers and Catherine Woolley.
Rogers, who is already a member of the National Academy of Sciences and National Academy of Engineering, becomes one of just 25 people in history elected to all three academies.
Election into NAM, which was previously known as the Institute of Medicine, is one of the highest honors in the fields of health and medicine. The academy serves as a source of expertise by providing independent, evidence-based scientific and policy advice to inspire action across the private and public sectors regarding critical issues in health, medicine and science.
Since it was founded in 1970, NAM elects no more than 90 regular members and 10 international members annually based on professional achievement and a commitment to service and advancement in the fields.
As chair of an interdisciplinary department, Cella leads the development of transdisciplinary scientific collaborations and projects, and oversees its academic and research programs, financial operations, faculty affairs and program development. An international expert in the measurement and application of patient-reported outcomes in healthcare settings, his career spans nearly 860 publications and his research has helped advance the understanding of mechanisms and measurement of health and disease to improve patients’ quality of life.
“Election to NAM is the highest honor that I can imagine because it comes from peers at the highest level of scholarship in our nation,” Cella said. “I hope that my election might inspire others who work in outcomes research and health care improvement to strive to further their career goals and make an impact on our nation’s health.”
Cella also was the first scientist to explore the use of item response theory in health measurement, which helped generate new possibilities for better determining a patients’ symptoms, functioning and perceptions of overall health and well-being.
“Getting this high recognition from my peers reassures me that the work I do has value that matters to the people that matter: our patients,” Cella said. “Going forward, I will continue to search for ways to promote better health and encourage others to take on the challenges we face in delivering truly patient-centered health care and outcomes research.”
Quaggin is the director of the Feinberg Cardiovascular and Renal Research Institute and chief of Nephrology and Hypertension in the Department of Medicine.
Quaggin first joined the medical school in 2013 and since has led efforts in closing the gap between scientific discovery and delivering innovative patient care in regards to kidney and cardiovascular diseases. Her research has helped enhance the understanding of common glomerular diseases and inspired the development of promising therapeutics, including discoveries regarding blood vessels, lymphatics and specialized hybrid circulations.
“It is an incredible honor to be elected, one that I did not expect,” Quaggin said. “It is recognition of the teamwork performed with many incredible colleagues, trainees and collaborators that I have had the privilege of working with and learning from over the course of my career.
Quaggin, also the Charles H. Mayo, MD, Professor, has authored and contributed to more than 150 publications in nephrology and vascular biology.
“The work in the lab has always been inspired by my patients and this recognition spurs me on to work harder and continue to spread the message to future physicians that there is no better career than one combining patient care and science,” Quaggin said.
Rogers is the Louis Simpson and Kimberly Querrey Professor of Materials Science and Engineering, Biomedical Engineering and Neurological Surgery in the McCormick School of Engineering and Feinberg School of Medicine.
Rogers was elected to the National Academy of Engineering in 2011 and to the National Academy of Science in 2015.
A materials scientist by training, Rogers is an innovator in bio-integrated electronic devices, joining Northwestern University in 2016 to lead the Center for Bio-Integrated Electronics at the Simpson Querrey Institute. His research expands the capabilities of current biomedical technologies through creating innovative electronic devices that can be integrated with the human body and possess a wide range of diagnostic and therapeutic functions.
“At a personal level, I’m deeply honored to be selected to join this elite group but, more significantly, this recognition represents an important validation of our collaborative, interdisciplinary style of work at the interface between medicine and engineering science,” Rogers said. “As someone whose core training is in the physical sciences, I’m delighted to receive this form of endorsement, from the highest levels of the medical community.”
Rogers has published more than 530 papers and is an inventor with more than 80 patents and patent applications. He has founded several companies based on his research. His research uses new, innovative approaches to problems with the potential to change the fields of industrial, consumer and biocompatible electronics.
“We believe that the future of medicine will depend critically on advanced engineering and innovative technology concepts,” Rogers said. “We’re in a great position here at Northwestern — the right people, the right collaborative culture and the right resources and support — to help define that future.”
Woolley has devoted her career to understanding estrogen actions in cognitive areas of the brain and sex differences in molecular mechanisms of synaptic plasticity. A neuroscientist by training, Woolley has authored and contributed to more than 75 publications over the course of her career.
“This is a great honor. I’m looking forward to engaging with members of the NAM and contributing my knowledge and expertise to the translation of basic discoveries in neuroscience to new medicines, therapies and policies to improve human health,” Woolley said.
Almost 30 years ago, as a graduate student, she discovered that estrogens drive synaptic plasticity in the hippocampus. Since then, her work has helped to explain how estrogens enhance learning and memory consolidation, and most recently her group has discovered new estrogen-based targets for anti-epilepsy therapies. Her research has also helped to develop a deeper understanding of Alzheimer’s, among many neurological diseases.
“Beyond my specific expertise as a scientist, I am also very interested in the NAM’s work on health policy and health equity,” Woolley said. “I grew up in rural southeastern Ohio, in the foothills of the Appalachian Mountains — the area I come from is one of the most beautiful places I know and also at risk from a hollowing out of the local economy and the hardships that result from this. I hope to use my experiences and connections to the area to help address the health needs of Appalachian communities, particularly related to addiction and mental health.”
Original story by Melissa Rohman appeared in Northwestern Now on 10/21/19.
Susan Quaggin, MD, is a member of the Chemistry of Life Processes Institute.
CLP startup MicroMGx Announces Collaboration with Corteva on Microbial-Based Crop Protection Products
INDIANAPOLIS, Ind., Oct. 8, 2019 — Corteva Agriscience and MicroMGx today announced a collaboration that aims to provide farmers a wider range of novel, microbial-based crop protection products.
Under the agreement, MicroMGx will apply its metabologenomics platform to accelerate the identification of new natural product starting points. In a first for the agriculture industry, Corteva will use those starting points to discover and develop naturally derived crop protection solutions. Metabologenomics modernizes natural product discovery by fusing genomics and mass-spectrometry data in a way that facilitates more targeted molecule identification.
Farmers worldwide already rely on products developed by Corteva using spinosyns, active ingredients produced by naturally fermenting soil bacteria, to protect crops from insect damage. The newest of these is Inatreq™ active, a new active ingredient that helps control fungus in wheat and bananas.
“With 20-plus years of leadership in green chemistry, Corteva Agriscience has a long and successful track record of discovering natural and naturally derived products,” said Neal Gutterson, Senior Vice President and Chief Technology Officer, Corteva Agriscience. “We are excited to collaborate with MicroMGx to explore novel approaches for speeding up the process of discovering the next generation of innovative crop protection solutions.”
“We believe in our platform’s potential to uncover impactful new crop-protection products. We’re enthusiastic to be partnering with Corteva Agriscience because of their strong portfolio of natural and naturally derived products,” said Anthony Goering, Chief Scientific Officer of MicroMGx.
MicroMGx part of a Midwest collaboration to bring exciting new technology to the world’s crop protection industry. Its metabologenomics platform was developed through a collaboration between research groups at Northwestern University’s Chemistry of Life Processes Institute and the University of Illinois’ Institute for Genomic Biology.
About MicroMGx, Inc.
MicroMGx, established in 2015, is a life sciences company dedicated to making high-throughput natural product discovery achievable. Through MicroMGx, pharmaceutical, animal health, and agriculture companies will have easy access to new natural products to fill their discovery pipelines. The MicroMGx laboratory is located at the University Technology Park at the Illinois Institute of Technology. Visit www.micromgx.com to learn more.
About Corteva Agriscience
Corteva Agriscience is a publicly traded, global pure-play agriculture company that provides farmers around the world with the most complete portfolio in the industry – including a balanced and diverse mix of seed, crop protection and digital solutions focused on maximizing productivity to enhance yield and profitability. With some of the most recognized brands in agriculture and an industry-leading product and technology pipeline well positioned to drive growth, the company is committed to working with stakeholders throughout the food system as it fulfills its promise to enrich the lives of those who produce and those who consume, ensuring progress for generations to come. Corteva Agriscience became an independent public company on June 1, 2019, and was previously the Agriculture Division of DowDuPont. More information can be found at www.corteva.com.
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Original press release issued on October 8, 2019 by Corteva Agriscience
“My plan was to become a pharmacist,” says Irawati (Angki) Kandela, PhD, Assistant Director of the Developmental Therapeutics Core (DTC), a CLP-affiliated core facility, and Research Assistant Professor in the Pharmacology Department at Northwestern. Growing up in Indonesia where most of her family members were doctors, Kandela thought she would branch out into pharmacy. Her goal was to someday rent space inside a family-owned clinic and handle patient prescriptions. During her fourth year in pharmacy school, however, a new calling emerged.
“One night, I worked from seven until midnight adding non-active ingredients to increase the solubility of indomethacin and I really got into it,” says Kandela. “I realized then that research is fun and I should continue with it.”
Upon her father’s advice, she travelled to San Francisco in 1999 to learn English and apply for graduate school. Six months later, she was accepted into the pharmaceutical sciences program at the University of Wisconsin-Madison. Finding a way to pay for school was her next challenge. Leveraging her pharmaceutical background, Kandela succeeded in securing a teaching assistant position that enabled her to graduate debt-free.
With her newly minted PhD, she accepted a position with radiopharmaceutical company Novelos, Inc. (formerly Cellectar) based in Madison, Wisconsin. Her research focused on targeted drug delivery using alkyl-phospholipid bound to radio-iodine 131 (I-131) for cancer treatment. After filing several patents, she was promoted to manager of the Biology Department.
“The job taught me a lot about GLP [good laboratory practice], IND [investigational new drug] applications to the FDA [US Food and Drug Administration], quality assurance, clinical teams, and making drugs for human beings,” says Kandela.
In 2011, she joined Northwestern University as a research associate with the primary responsibility of launching the Developmental Therapeutics Core facility within the Center for Developmental Therapeutics. Since then, more than 45 faculty members from across the University have tapped the core for its expertise in preclinical evaluation of new therapeutics, laboratory facilities and access to small animal models. Kandela was promoted to research assistant professor in the Center for Developmental Therapeutics with a secondary appointment in the department of Pharmacology in 2017.
“We work with our hands, our energy and our minds,” says Kandela. “On a typical day, I take care of all the studies in the morning to make sure the animals are checked, treated, or dosed. Afternoons are for clients and other business.”
From using models of patient-derived xenografts (PDX models) for a new cancer drug test, to evaluating the effectiveness of tiny, implanted neuro sensors, Kandela works with biologists, chemists and engineers on a variety of interesting projects. What keeps clients coming back is her work ethic, high standards, problem-solving, and positive attitude. When initial study results disappoint, Kandela will suggest a modification, such as changing the frequency or concentration of the dose, combining the drug with another second drug, or repurposing another drug. These small tweaks often help projects get back on track.
“At the end of the day, we have to let the science guide us. You can’t rush things and you must stay open-minded.”
Her motivation runs deep.
“When my grandma died of brain cancer, I made a promise to be involved in drug development so that, hopefully, one day, a new drug would be on the market and I would play a tiny part in moving that process forward. To be able to make an impact like that would be wonderful.”
And what would she have told her ten-year-old self based on what she knows now?
“Just enjoy the ride,” says Kandela.
by Lisa La Vallee
Charles Darwin was right.
In his 1859 book, “On the Origin of Species,” the famed scientist hypothesized that artificial selection (or domestication) and natural selection work in the same ways.
Now an international team, led by Northwestern University, has produced some of the first evidence that Darwin’s speculation was correct.
This time, the study’s subjects are not exotic birds in the Galapagos, but instead a roundworm, which relies on its sense of smell to assess the availability of food and nearby competition. In the Northwestern-led work, researchers found that natural selection acts on the same genes that control wild roundworms’ sense of smell as were previously found in domesticated worms in the lab.
“The evolution of traits is rarely connected to exact genes and processes,” said Northwestern’s Erik Andersen, who led the study. “We offer a clear example of how evolution works.”
The scientists used a combination of laboratory experiments, computational genomic analysis and field work. Their research also shows that natural selection acts on signal-sensing receptors rather than the downstream parts of the genetic process.
The study published this week (Sept. 23) in the journal Nature Ecology & Evolution. Andersen is an associate professor of molecular biosciences in Northwestern’s Weinberg College of Arts and Sciences.
A keystone model organism, C. elegans is a one-millimeter-long roundworm that lives in decaying organic matter — particularly rotten fruits — and feeds on bacteria. These roundworms are typically found in gardens and compost piles.
For C. elegans, having a keen sense of smell can be the difference between life or death. If they smell enough food in their environment, then they will stay, grow and reproduce. If they sense a shortage of food and/or too much competition from other worms, then they will undertake a long and potentially fatal journey in search of a more favorable environment. This process, called “dauer,” delays growth and reproduction.
In other words, dauer decreases reproductive success in the short term in order to ensure survival in the long run.
“At some point in their lives, these worms must make a gamble,” Andersen said. “In the time it takes for a worm to come out of dauer and start growing again, the worm that stayed behind has already been multiplying. If the food runs out, then the dauer worm made the right decision and wins. If the food doesn’t run out, then the dauer worm loses.”
Andersen and his collaborators found that evolution plays a significant role in a worm’s decision to stay or enter dauer. Some roundworms have one genetic receptor to process scents; other roundworms have two. The roundworms with two receptors have a heightened sense of smell, which allows them to better assess the availability of resources in their environment and make a better gamble.
“If worms can smell large numbers of worms around them, that gives them an advantage,” Andersen said. “This was discovered in a previous study of artificial selection in worms. Now we also found that result in natural populations. We can see specific evidence in these two genes that artificial and natural selection act similarly.”
The study, “Selection and gene flow shape niche-associated variation in pheromone response,” was supported by a National Science Foundation CAREER Award. Daehan Lee, a postdoctoral researcher in Andersen’s laboratory, was the paper’s first author.
Original story published in Northwestern Now on 9/26/19 by Amanda Morris.
Erik Andersen is a member of the Chemistry of Life Processes Institute.
In celebration of National Chemistry Week, Chemistry of Life Processes Institute (CLP) and Northwestern’s Undergraduate Chemistry Council will host a free viewing party of American Chemical Society’s ‘Program in-a-Box Marvelous Metals’ on Tuesday, October 22, 2019, 5:30 – 7:00 p.m. CST. The live, interactive online program will include a guest appearance and Q&A by CLP member Thomas J. Meade, PhD (Chemistry, Molecular Biosciences, Neurobiology, and Biomedical Engineering).
Thousands of students and early career chemists from around the world are expected to join to learn how chemists are developing new technologies using metals at the intersection of organic and inorganic chemistry. From innovations in medical imaging and theranostics to fundamental changes to the way we create everyday necessities like clothing, food, and energy, Meade and Vy M. Dong, PhD, Full Professor of Natural Sciences, University of California, Irvine, will demonstrate how we can harness the power of our “marvelous metals.” What to Expect
- A live interactive video broadcast featuring presentations and Q&A with experts in organometallic chemistry.
- Professor Vy Maria Dong will discuss the importance of organic chemistry processes to the industries that power modern society and how she is using metals to create improved reagents, catalysts, and strategies for a more sustainable and greener future.
- Professor Thomas J. Meade will define molecular imaging, what it can currently do in the clinic, and how his “bioactivated” or “conditionally activated” probes could revolutionize how we diagnose and even treat patients during the diagnostic phase.
- The first to answer “Marvelous Metal Trivia” on Twitter with #ACSPIB will get a shout out live on-air!
- Opportunity to meet thousands of fellow students and professionals around the world on Facebook, Twitter, and Instagram by posting with the event hashtag #ACSPIB.
- Raffle prizes, handouts, and other ACS resources.
- Free pizza, snacks, treats and beverages!
Space for the viewing party is limited. Admission is on a first-come, first-served basis.
Can’t make it to the party? Watch the program from the comfort of your own home or dorm community room. Follow #ACSPIB on Twitter and Instagram and go to www.acs.org/pib to check-in as an individual to watch the live broadcast beginning at 5:45pm CST on October 22nd, 2019.
Please contact Lisa La Vallee, email@example.com, if you have any questions, or wish to learn more.
Treating severe brain injury often requires immediate surgery, including implantation of an electronic sensor that monitors tissues and fluids and digitally provides real-time information about intracranial pressure, temperature and wound healing. These devices, however, have one major drawback: eventually, they must come out, requiring an additional surgery to extract the device from the body and concomitant risk and expense.
In a recent Nature Biomedical Engineering study, a team of Northwestern scientists led by John Rogers (materials science and engineering, biomedical engineering and neurological surgery) introduces a new type of sensor, one that completely dissolves in the body when no longer needed. The study also successfully deploys a powerful, new photonics-based optical technology developed by lead author Wubin Bai, a postdoctoral fellow in John Rogers’ lab.
“This is the first time we’ve brought the ideas of biodegradable technologies into the realm of optics and photonic systems” says Rogers. “Optical characterization of tissue can yield quantitative information on blood oxygenation levels. Fluorescence signals can reveal the presence of bacteria as a diagnostic for the formation of an infection at an internal wound site. Fluorescence-based calcium imaging can reveal metrics of brain activity. There are also ways that light can be used to activate certain biological processes and that’s a next step for us.”
The work fits into a broader context of Rogers’ lab that develops materials for electronic, semiconductor or optical systems designed to go into the body, perform diagnostic and therapeutic functions, then dissolve after a pre-determined amount of time. In addition to providing critical information about physiological function, implantable sensors also can function as electrical stimulators for accelerating the rates of neural regeneration in damaged peripheral nerves, or as drug delivery agents electronically programmed to release drugs at certain time points.
From clinical needs to breakthrough solutions
“The project started with an idea that came from a discussion with professors in the clinic,” says Bai.
From skin patches worn by Gatorade-sponsored athletes to monitor rehydration needs to wireless monitors that track the vital signs of premature babies, Rogers’ team regularly collaborates with doctors and surgeons across the country to develop innovate solutions to thorny problems that arise in the clinic. He estimates that his lab has more than 20 active Institutional Review Board-approved studies of other technologies involving human subjects underway at Northwestern alone.
Rogers’ lab is looking to expand the biodegradable electronic technology to heart applications for both adults and children, in response to inquiries from Northwestern cardiologists. The doctors identified a need for a programmable sensor to monitor the oxygen level around the heart during surgery with children. They also sought solutions for a temporary pacemaker to deliver electrical stimulation, as necessary, during a recovery period following a heart surgery. After a specific time has elapsed, the devices naturally dissolve away and disappear in the body.
“One of the biggest challenges was integrating heterogeneous biomaterials together to form a functional and bioresorbable system making all of the constituents of the materials of the devices bioresorbable,” said Bai. “We had to precisely control both the composition materials’ chemistry and the device design, and dosage of each parameters together.”
Using substances naturally found in the body, the team created coating layers that dissolved very slowly. Inside, they used primarily silicon and zinc to create the functional materials for photodetection and electrical readout. The researchers then fabricated and tested three different devices useful for specific applications, all micron scale and smaller than the tip of a needle in final form. The first was composed of a silicon nanomembrane designed to detect a light at a single wavelength to monitor changes in blood flow. The second incorporated three such devices in a stack to detect multiple colors, as a simple form of chemical spectroscopy. The third contained an optical filter allowing for precise control for sensing neuron activity.
Designing the experiments
Integral to the biological aspects of the research were five experts from Chemistry of Life Processes Institute-affiliated core facilities and coauthors of the study who worked closely with Bai to plan and implement the study’s extensive in vivo proof-of-concept experiments.
Fraser Aird, PhD, and Irawati Kandela, PhD, and Iwona Stepien with the Developmental Therapeutics Core, conducted in vivo experiments to check for any immune responses in the blood to the device. The lack of immune response meant the device was not toxic to the mice. Jessica Hornick, PhD, Biological Imaging Facility, measured immune response and tissue regrowth after implantation at various timescales. Her findings concluded tissue bounced back and the device wasn’t toxic to the body. Chad Haney, PhD, and Anlil Brikha with the Center for Advanced Molecular Imaging, performed the CT imaging. CAMI’s images provided powerful physical evidence that the device disappeared slowly from week to week until it fully reabsorbed into the body. The final test was to determine whether traces of the device remained in the organs. Keith MacRenaris, PhD, Quantitative Bioelement Imaging Center, analyzed the organs throughout the experiment to measure the different concentrations of zinc and silicon, the materials used to make the device, and found these too dissipated over time.
“The core facilities have been a fantastic resource for us,” says Rogers. “Sometimes you’re working in an out-of-the-box area and it’s very much exploratory and it can be non-trivial to find collaborators with the necessary animal expertise. As a result, there can be an activation barrier for people engaged and involved. Having the cores as an additional option for collaborator-based research around the biological aspects is great thing.”
by Lisa La Vallee
Feature image: Wubin Bai, Professor John Rogers, and Jessica Hornick huddle in the Biological Imaging Facility, a CLP-affiliated core facility that collaborated on the study.
Building Better Biologics: A Q&A with Danielle Tullman-Ercek
Like a master Lego® builder who constructs elaborate figures using tiny interlocking blocks, Chemistry of Life Processes Institute member Danielle Tullman-Ercek manipulates parts of bacteria and viruses to build new and better structures for drug delivery, diagnosis and vaccination. CLP recently caught up with Tullman-Ercek, Associate Professor of Chemical and Biological Engineering, and Director, Master of Science in Biotechnology Program, McCormick School of Engineering, to learn more about her research and what initially drew her to the field.
CLP: Before you came to Northwestern, what was the initial focus of your research?
Tullman-Ercek: I have been an associate professor in chemical and biological engineering at Northwestern since 2016. Before that, I was at UC Berkeley for seven years as an assistant professor in chemical and biomolecular engineering. Initially, my projects focused on how we can use biology to make more cost-effective fuels and chemicals for commercial use to reduce dependency on petroleum. We started with the basics: How can we use an organism to convert any substrate to a desired product, such as a fuel?
All my early work focused on how to control what goes into and out of the cell. It’s sort of like having a factory with no doors until you figure out the ‘in and out’ processes. Even though it is important that the factory makes the product you want, it is also really important that you can get the product out of the factory. We were optimistic about this approach because cells already have the machinery to control what goes in and out. We just had to learn the rules and manipulate those cellular machines.
We use techniques to manipulate proteins, the workhorses of the cells. They carry out the reactions and act as gatekeepers that sit in the membrane and control what is going across these boundaries. To control what goes in and out of the cells, we change the proteins that are already there, either by changing what they allow through, or changing how many of them are present. When the industry as a whole pivoted towards using biological organisms to make more sustainable products with higher value than fuels, we also began thinking about different ways to make chemicals, drugs and pharmaceutical products more cost effective.
CLP: Since coming to Northwestern, what projects are you working on?
Tullman-Ercek: When I came to Northwestern and became part of CLP, I started interacting with a lot more scientists that are interested in human health. I had been focused on getting things out of bacteria, but it’s a similar process to figure out how to get a drug into specific cells.
We spent quite a bit of effort in the first couple of years here on using virus-like particles because viruses are great at getting into cells in the body. Viruses also have a unique property in that they protect the cargo inside of them. Normally, that cargo is just the viral genome, which gives instructions to the cell to make more copies of the virus, but we can replace that with other things. It doesn’t have to be instructions: it can be a drug molecule, an imaging agent, or a signaling molecule. For example, we could potentially use these virus-like particles, load them up with an MRI contrast agent, and see where the cells that we are targeting are found in the body.
We start with natural building blocks, virus particles that already exist—these particles are basically the shell of the virus without its genome. We call it a particle because it’s just a carrier and not a virus anymore. It’s sort of like a naturally built Lego® with this really elaborate geometric structure, but we’re trying to figure out how we can change those building blocks a little bit to target a particular cell type, or change the size, and still form this beautiful geometric stable structure that protects its cargo.
Our methods have been working really well and giving us an unprecedented amount of information about how these building blocks assemble into the particles. We focused on one virus particle at first, and are trying to transition that into several other particles of different sizes, shapes and properties because there is not going to be a one-size-fits-all kind of carrier.
We noticed that these shells or carriers have pores that may allow us to control what is going into and out of them. Not only can we control where these are going in the body and what cells they are going into, but we can also potentially control the rate and the identity of things that go out of them. We can load them up with different therapeutics or have both a diagnostic agent and a therapeutic agent. We also look for ways to target and break them apart to kill pathogenic bacteria.
We are also working on turning these into vaccine carriers. Let’s say you want to have a vaccine against a particular bacterial infection. You would need to develop a way to trigger immunity against the sugar chains on the surface of that bacteria. The sugar chains are like fingerprints for the bacteria. Vaccines work by putting in a harmless version of what you want the body to be immune to, but you will not get an immune response just by injecting sugar chains in the body. You have to put them on a carrier that will help trigger the immunological response that you want. We think these virus particles can make excellent vaccine carriers since we can decorate the surface with whatever we want to have an immune response to and it would be completely benign because it’s just a shell— a scaffold really.
CLP: What diseases might these drug/imaging carriers target?
Tullman-Ercek: As a first pass, I would say diseases that can be treated through the bloodstream, such as certain types of cancers and heart disease. There is a good chance that we also can use them for inflammatory gut diseases, sepsis, or any kind of salmonella or food-based pathogens. We could also use them as an immunotherapy, or a more advanced targeted chemotherapy. We are trying to use these carriers in all the different ways that nature does, but first we have to learn the rules for those processes. I am very interested in the fundamentals. I want to be able to develop the technology from this basic understanding so that it can be applied to a whole slew of different diseases.
CLP: What other projects are you working on?
Tullman-Ercek: About a third of my lab works on the manufacturing of proteins. A number of products in everyday life are made out of protein, from the stain-fighting enzymes in laundry detergents to materials such as silk. Some proteins are even capable of functions we cannot do well with non-biological materials. For example, there are proteins that mediate adhesion under water, which could be useful in medicine, or in marine applications. We could also use protein to make sutures, which are essentially devices that are implanted in the body, degrade naturally and do not have any harmful side effects. Importantly, many of the top 10 drugs on the market are protein-based— important medications such as insulin and growth hormones.
Protein-based drugs are different than aspirin or Tylenol or small molecule drugs. To make protein-based drugs, you have to use an organism. You can’t just make them synthetically in a test tube. The problem is that organisms make all sorts of proteins to keep their life processes going, and it is hard to separate these proteins from the ones we want to mass produce. So, we work on using bacteria to make the protein, selectively identify the protein product we want, and secrete these protein products out of the cell, away from all the other cellular proteins. However, this process is not yet as cost effective as we like. The other problem is that we don’t make as much of the desired protein as we would like. The metric that we use is grams-per-liter. You need at least one gram-per-liter to be able to compete with other industries, preferably, 10 grams-per-liter. While the system that we are using worked in principle, it was producing about a million-fold less than what we needed at the time we started this project.
We have spent 10 years now working on this problem and are now up to a half a gram-per-liter, which is several orders of magnitude more than when we started. We’re almost there— right on the cusp of being able to commercialize it. We achieved this with lots of help from the core facilities here. It’s truly a team effort worldwide even to figure out how to manipulate these systems to make the protein we want. Now that we are so close, we are working on provisional patents for all of the technology we have developed.
CLP: What drew you to this field and to Northwestern?
Tullman-Ercek: I was always interested in science in general. I was also really good at math and did well in science, but I didn’t really—and this is hard to admit in a public form— but I hated science lab. It was boring. You are doing experiments that had been done thousands of times by other students all over the world and there was always a right answer, known to your teacher already. So, I didn’t really think I wanted to do experimental science for my career.
When I was in college [Illinois Institute of Technology], I majored in chemical engineering – math and science – and I did more theoretical and computational research while there. That was fine, but I was in a lab that was a mix of both computational and experimentalists and the experimentalists looked like they were having more fun, which baffled me because I thought that was the boring part.
When I went to graduate school [University of Texas], I chose to join a lab that studied proteins. My project was completely experimental and I loved it because it was a totally different experience trying to answer a question that nobody has ever answered and to design experiments to answer that question. It was a puzzle and a lot more fun than just doing a protocol. That is when I actually fell in love with science. I remember when I first figured out the joy of science: I had spent six months trying to make a particular construct and failed repeatedly until one day, when I read a note about the method I was using in an obscure paper and figured out why it wasn’t working. Everything fell into place and it felt so great. When you get through that, it’s exhilarating and sort of addictive. One nice result can make it all worth it.
CLP: How has being a member of the Chemistry of Life Processes Institute helped advance your research?
Tullman-Ercek: Before agreeing to move to Northwestern, I insisted on joining CLP because I wanted to be able to interact with chemists, biologists and engineers. That has turned out even better than I imagined with all the new collaborations and project directions I have now, most of which came from talking to other faculty or students in the hall, or at a CLP meeting. But there are other advantages, as well. When I visited, I got to tour core facilities and they blew me away. Seeing the capabilities here and the availability of the cores—there was no four-month waiting list to use a piece of equipment, or hoping at two in the morning that somebody would give up their time on the equipment because their experiment failed. It was eye opening.
It is one thing to have the equipment available in core facilities and it is another to have experts helping to guide the work. The scientists running the core facilities are just so knowledgeable and engaged in working with you to make sure that you are getting the most out of that experience. Some of the work that we have done has been so much better with their help. We include them as authors on our papers because they are helping design experiments. That’s not something that standard at other places. That is really transformational.
by Lisa La Vallee
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 (chemistry) and Neil Kelleher (molecular biosciences, chemistry, and medicine), McClure applied for a traineeship to further his experience. He was selected to join the training program in a highly competitive application process.
“It seemed like a very natural fit,” said McClure. “It allowed me to interact with other trainees and learn about what else is happening within the university and within the field of Chemical Biology.” The training program required additional coursework in biology and participation in an extensive suite of training activities such as workshops, graduate research forums, trainee-invited seminars, and a 10-week immersion in the lab of his secondary mentor, Neil Kelleher.
McClure’s graduate work focused on analyzing microbial natural products, chemical compounds produced by microbes that can be used as therapeutics. After growing different strains of bacteria and collecting the compounds they produced, he would then test their ability to kill other bacteria, cancer cells, or fungus. Sometimes the answer was “yes,” but more often, he admits, the answer was “no.”
Towards the end of graduate school, McClure spent the bulk of his time developing “metabologenomics,” a novel approach to natural product discovery that uses big datasets to correlate the biosynthetic genes associated with natural products.
“For every single strain of bacteria that we grew, we sequenced the genome. Concurrently, we analyzed the mixture of metabolites produced by each strain with mass spectrometry. If one compound was identified in multiple strains of bacteria, we also looked for a gene (or set of genes) that only showed up in those same bacteria,” said McClure.
By correlating the two, McClure could then determine the genes responsible for making the compound. The method led to the discovery of several new compounds as well as their chemical structures. McClure was first author on an ACS Chemical Biology paper on this topic in 2016 and coauthored 7 additional publications as a graduate student.
McClure was selected to attend a 3-day career development workshop for trainees from Midwestern NIH chemistry: biology interface (CBI) T32 training programs, which was sponsored by the National Institute for General Medical Sciences (NIGMS, a directorate within the National Institutes for Health). McClure had the opportunity to present his research and learned about various industry opportunities from big pharma to biotech startups.
Following the award of his doctoral degree in 2017, he accepted a position with AbbVie where he now works as a Senior Scientist in the Proteomics and Chemical Biology groups.
“The Chemical Biology group at AbbVie was relatively new and under transition,” said McClure, “so I have been able to help launch it and figure out the directions we want to go in, the things we want to explore, and the techniques we want to use as our bread and butter.”
As part of AbbVie’s Discovery organization, McClure identifies and tests new compounds as potential therapeutics in three main therapeutic areas: oncology, neuroscience and immunology.
“At AbbVie, there’s no one person that does everything. It can take 10 years to make a single compound into a drug. Knowing how to collaborate and how to make contributions to a project are incredibly important. The CLP training program really prepared me to contribute right away—to collect and analyze data without spending months trying to figure out a whole new system and set of instruments. It also gives you the confidence to talk with scientists from all different fields.”
by Lisa La Vallee
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 ((1S10OD025194-01).
“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, 2019 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 class 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.