Research

Our vision for 21st century science emerges from complementary strengths in drug discovery and development, preclinical imaging, proteomics, cell free synthesis, physiochemical analysis, and nanoscale imaging.

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Education

We educate, train, and inspire the next generation of transdisciplinary scientists to venture farther into the realm of unrealized research possibilities.

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Translation

We lower the barriers to discovery, and as a result, accelerate breakthroughs to solve the complexities of biology, and apply this new knowledge to improve the quality of life.

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Research

Our vision for 21st century science emerges from complementary strengths in drug discovery and development, preclinical imaging, proteomics, cell free synthesis, physiochemical analysis, and nanoscale imaging. The next waves of technology for early detection and treatment of a broad array of diseases will arise from this multi-pronged attack.

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Transforming Science. Transforming Life.

Chemistry of Life Processes Institute (CLP) researchers use the technologies of tomorrow to discover the diagnostic methods and therapies needed to save lives today. Chemists, engineers, and physicists team with life scientists and clinicians to change how we diagnose and treat cancer, cardiovascular and kidney disease, infectious diseases, neurodegenerative diseases, and trauma. Their efforts are built on extraordinary tools for discovery, analysis, and visualization developed and housed within a unique ecosystem designed to support the integration of expertise and methods across many scientific disciplines. This transdisciplinary convergence of knowledge is creating new fields of research that will have a long-lasting impact on human health and disease.

Transforming Science. Transforming Life.

Chemistry of Life Processes Institute (CLP) researchers use the technologies of tomorrow to discover the diagnostic methods and therapies needed to save lives today. Chemists, engineers, and physicists team with life scientists and clinicians to change how we diagnose and treat cancer, cardiovascular and kidney disease, infectious diseases, neurodegenerative diseases, and trauma. Their efforts are built on extraordinary tools for discovery, analysis, and visualization developed and housed within a unique ecosystem designed to support the integration of expertise and methods across many scientific disciplines. This transdisciplinary convergence of knowledge is creating new fields of research that will have a long-lasting impact on human health and disease.

Our Impact

New machine learning technique rapidly analyzes nanomedicines for cancer immunotherapy

With their ability to treat a wide a variety of diseases, spherical nucleic acids (SNAs) are poised to revolutionize medicine. But before these digitally designed nanostructures can reach their full potential, researchers need to optimize their various components.

A Northwestern University team led by nanotechnology pioneer Chad A. Mirkin has developed a direct route to optimize these challenging particles, bringing them one step closer to becoming a viable treatment option for many forms of cancer, genetic diseases, neurological disorders and more.

“Spherical nucleic acids represent an exciting new class of medicines that are already in five human clinical trials for treating diseases, including glioblastoma (the most common and deadly form of brain cancer) and psoriasis,” said Mirkin, the inventor of SNAs and the George B. Rathmann Professor of Chemistry in Northwestern’s Weinberg College of Arts and Sciences.

A new study published this week in Nature Biomedical Engineering details the optimization method, which uses a library approach and machine learning to rapidly synthesize, measure and analyze the activities and properties of SNA structures. The process, which screened more than 1,000 structures at a time, was aided by SAMDI-MS technology, developed by study co-author Milan Mrksich, Henry Wade Rogers Professor of Biomedical Engineering in Northwestern’s McCormick School of Engineering and director of the Center for Synthetic Biology.

Invented and developed at Northwestern, SNAs are nanostructures consisting of ball-like forms of DNA and RNA arranged on the surface of a nanoparticle. Researchers can digitally design SNAs to be precise, personalized treatments that shut off genes and cellular activity, and more recently, as vaccines that stimulate the body’s own immune system to treat diseases, including certain forms of cancer.

SNAs have been difficult to optimize because their structures — including particle size and composition, DNA sequence and inclusion of other molecular components — can vary in many ways, impacting or enhancing their efficacy in triggering an immune response. This approach revealed that variation in structure leads to biological activities showing non-obvious and interdependent contributions to the efficacy of SNAs. Because these relationships were not predicted, they likely would have gone unnoticed in a typical study of a small set of structures.

For example, the ability to stimulate an immune response can depend on nanoparticle size, composition and/or how DNA molecules are oriented on the nanoparticle surface.

“With this new information, researchers can rank the structural variables in order of importance and efficacy, and help establish design rules for SNA effectiveness,” said Andrew Lee, assistant professor of chemical and biological engineering in the McCormick School of Engineering and study co-author.

“This study shows that we can address the complexity of the SNA design space, allowing us to focus on and exploit the most promising structural features of SNAs, and ultimately, to develop powerful cancer treatments,” said Mirkin, who is also director of the International Institute for Nanotechnology.

The Nature Biomedical Engineering paper is titled “Addressing Nanomedicine Complexity with Novel High-Throughput Screening and Machine Learning.” Other coauthors are Neda Bagheri, Gokay Yamankurt, Eric J. Berns and Albert Xue, of Northwestern University.

The research was conducted as part of the Northwestern University Center for Cancer Nanotechnology Excellence (Northwestern CCNE), a partnership between the Robert H. Lurie Comprehensive Cancer Center and the IIN, that is solely focused on utilizing SNAs to develop next-generation cancer treatments. The program is funded through a grant from the National Cancer Institute (NCI).

— By Sheryl Hislop Cash

Original story appeared in Northwestern Now on 2/19/19.

Neda Bagheri is a member of the Chemistry of Life Processes Institute. Gkay Yamankurt is a former graduate trainee with the Institute.

A new approach to a deadly disease

A New Approach to a Deadly Disease

A career spent bucking convention leads Bill Klein to new Alzheimer’s diagnostics and therapeutics

“When I was in graduate school, three papers per month were published on Alzheimer’s disease. Now, there are thousands every month.”

Neurobiology professor Bill Klein says the last 20 years have seen a revolution in the understanding of Alzheimer’s disease. That sea change, he says, has been focused on two key abnormalities in the Alzheimer’s brain: amyloid plaques and tau protein tangles.

“Alzheimer’s has been defined as dementia with plaques and tangles,” Klein says. Dementia is a broad term, and Alzheimer’s disease is the most common form among people over age 65. Determined to both improve diagnostic tools and develop more effective treatments, Klein has spent decades looking beyond plaques and tangles toward the tiny toxins he says are the true drivers of the disease.

Tiny toxins in the brain

Early in his career, Klein was focused on amyloid plaques, but a surprise finding led him down a vastly different path. He and his colleagues initially assumed that if they could halt the growth of these amyloid plaques, they could stop Alzheimer’s from damaging cell tissue. But even after they successfully stopped plaque growth, the damage continued, prompting the researchers to look at the brain before plaque formation. It was through this work that they identified Abeta oligomers, which would become the central focus of Klein’s research.

In a healthy brain, the molecule Abeta is created and cleared at an equal rate, like the brain regularly taking out the trash. But if the brain does not clear Abeta sufficiently, the molecules form tiny clusters — Abeta oligomers. These build up in the Alzheimer’s brain — like toxic mold building up in your home.

In a breakthrough 1998 paper, Klein’s team showed that Abeta oligomers attach to nerve synapses, where they impede signaling and destroy the delicate system that forms new memories. These oligomers cause changes in the nerve cell that eventually lead to the formation of tau protein tangles.

“First, there’s the effect on signaling, and then there’s a deterioration of the synapse,” Klein says. “Ultimately, the entire neuron deteriorates.”

Following Klein’s discovery, Eliezer Masliah, director of neuroscience at the National Institute on Aging, said that “progressive accumulation of Abeta oligomers has been identified as one of the central toxic events in Alzheimer’s disease.”

Bucking convention

Despite Masliah’s proclamation, Klein says he’s swimming upstream, in that amyloid plaques — not Abeta oligomers — are still regarded by many as the hallmark of Alzheimer’s. But Klein says there is evidence to suggest the presence of plaques does not mean a person has Alzheimer’s, and the disease can occur without any plaques at all.

“We’ve worked with a team of scientists in Japan who have identified a family in the city of Osaka who develops Alzheimer’s disease because they have a mutation — the so-called Osaka mutation,” Klein says. “They get all of the pathology of Alzheimer’s disease, and they make lots of oligomers, but they don’t make plaques.”

In a related experiment, Klein’s team injected amyloid into the brains of some mice, and Abeta oligomers into the brains of others. “Amyloid was without effect, but the oligomers were incredibly potent at inhibiting the memory mechanism,” Klein says. “That was a very exciting result, and it caused a lot of pathologists to say ‘hold on’ with this amyloid theory.”

A diagnostic test

Klein’s team has developed MRI tools to identify oligomers in the Alzheimer’s brain, and Klein is now working with Northwestern urology professor Shad Thaxton to develop clinical tools to detect the toxins in blood plasma and spinal fluid. This collaboration builds on Klein’s earlier work with chemistry professors Chad Mirkin and Rick van Duyne, which showed people with Alzheimer’s disease in their spinal fluid had high levels of oligomers, while people who did not have Alzheimer’s disease had low levels of oligomers.

Klein’s lab has a broad goal — to develop a molecular basis for the cause, diagnosis and treatment of Alzheimer’s disease — and their work reflects that breadth.

“We have our fingers in lots of projects,” Klein says. “We would like to create a blood test to detect oligomers. We also continue to look at spinal fluid — and now — brain imaging as an approach for non-invasive studies.”

A (treatment) hope for the future

At least three companies are now testing therapeutics aimed at Abeta oligomers. One of these companies — Acumen Pharmaceuticals, which Klein co-founded in the 1970s, is testing an antibody vaccine licensed from Northwestern. This antibody binds to oligomers and renders them unable to damage nerve signaling.

Klein says the antibody vaccine works like an anti-venom treatment after a rattlesnake bite. In the same way the anti-venom drug neutralizes the toxin in the bite, the antibody neutralizes the oligomers in the brain.

Klein is hopeful that Acumen’s vaccine — and maybe other treatments — will be available in under a decade.

“Some people think an effective therapeutic could be out there by 2025,” he says. “I’m not thinking that that’s so crazy.”

By Clare Millikin

Original story published by Northwestern Now on January 23, 2019. 

Bill Kein is a member of the Chemistry of Life Processes Institute.  Scientists from both the Center for Advanced Molecular Imaging and the High Throughput Analysis Lab collaborated with Klein’s team to developed MRI tools to identify Abeta oligomers in the Alzheimer’s brain and found they were incredibly potent at inhibiting the memory mechanism. 

New technology gives unprecedented look inside capillaries

More than 40 billion capillaries — tiny, hair-like blood vessels — are tasked with carrying oxygen and nutrients to the far reaches of the human body. But despite their sheer number and monumental importance to basic functions and metabolism, not much is known about their inner workings.

Now a Northwestern University team has developed a new tool that images blood flow through these tiny vessels, giving insight into this central portion of the human circulatory system. Called spectral contrast optical coherence tomography angiography (SC-OCTA), the 3D-imaging technique can detect subtle changes in capillary organization for early diagnosis of disease.

“There has been a progressive push to image smaller and smaller blood vessels and provide more comprehensive, functional information,” said Vadim Backman, who led the study. “Now we can see even the smallest capillaries and measure blood flow, oxygenation and metabolic rate.”

Vadim Backman

The paper was published last week in the journal Light: Science and Applications. Backman is the Walter Dill Scott Professor of Biomedical Engineering in Northwestern’s McCormick School of Engineering.  He co-leads the Cancer and Physical Sciences Research Program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Researchers and physicians have long been able to see inside major veins and arteries with Doppler ultrasound, which uses high-frequency sound waves to measure blood flow. But this insight does not give a full picture of the circulatory system. Unlike veins and arteries, capillaries are responsible for oxygen exchange, or delivering oxygen to organs and tissues throughout the body while shuttling carbon dioxide away. Low blood oxygen can cause mild problems such as headaches to severe issues such as heart failure.

“You can have great blood flow through arteries and still have absolutely no blood sending oxygen to tissues if you don’t have the right microvasculature,” Backman said. “Oxygen exchange is important to everything the body does. But many questions about what happens in microvasculature have gone unanswered because there was no tool to study them. Now we can tackle that.”

“SC-OCTA is a valuable diagnostic tool,” added James Winkelmann, a graduate student in Backman’s laboratory and the study’s first author. “We can now detect alterations to capillary organization, which is evident in a variety of conditions ranging from cancer to cardiovascular disease. Detecting these diseases earlier has the potential to save lives.”

Researchers have had difficulties peering inside capillaries because of the vessels’ microscopic size. A single capillary is a mere 5-10 microns in diameter — so small that red blood cells must flow through in single file.

SC-OCTA works by combining spectroscopy, which looks at the various visible light wavelengths, or color spectra, with conventional optical coherence tomography (OCT), which is similar to ultrasound except uses light waves instead of sound waves. Like a radar, OCT pinpoints the tissue of interest, and then spectroscopy characterizes it.

SC-OCTA has many advantages over traditional imaging: it does not rely on injected dyes for contrast or harmful radiation. Many types of imaging also only work if the area of interest is moving (for example, ultrasound can only image blood when it is flowing) or completely still. SC-OCTA can take a clear picture of both. This enables it to image stagnant blood or moving organs, such as a beating heart.

“It can measure blood flowing regardless of how fast it goes, so motion is not a problem,” Backman said.

“SC-OCTA’s unique ability to image non-flowing blood could also become a valuable tool for the booming field of organoids, which studies how organs develop and respond to disease,” Winkelmann said. “I am excited to start exploring all the applications.”

The new technology’s only limitation is that it cannot image deeper than 1 millimeter. This might seem shallow compared to ultrasound, which can see several centimeters below the surface. Backman said this can be remedied by putting the tool on the end of an endoscopic probe. By inserting it into the body, the tool can image organs up-close. That is something that his laboratory is working on now.

The title of the paper is “Spectral contrast optical coherence tomography angiography enables single-scan vessel imaging. The research was supported by the National Science Foundation and the National Institutes of Health (award numbers R01CA200064, R01CA183101, R01CA173745 and R01CA165309).

By Amanda Morris

Original story published by Northwestern Now on January 23, 2019

Vadmin Backman is a resident member of the Chemistry of Life Processes Institute.

 

In the Immune System’s Trenches, a New Discovery

Few everyday scenarios illicit as much trepidation as a nearby sneeze during flu season. Suddenly surrounded by tens of thousands of potentially virus-filled particles, a person’s evolving cellular reaction actually matters far more than the ability to shield one’s face.

“Most people know about the body’s immune system, but not as many understand that every cell has its own immune defenses,” says Curt Horvath, molecular biosciences, who studies the cellular recognition of and response to ribonucleic acid (RNA) viruses, as well as the manner in which viruses employ immune-evasion tactics. “The cell’s defense system acts as an initial barrier and is what prevents us from getting sick from every infectious particle we’re exposed to.”

Horvath and Northwestern graduate student Roli Mandhana recently published a pathbreaking study of RNA viruses in Scientific Reports, in which they identified hundreds of new such viruses induced by infection. RNAs are responsible for the signaling cascades  — the innate immune response — that result in widespread changes to gene expression when a virus is recognized as foreign. RNAs also carry out many biological functions that keep humans healthy, including the coding, decoding, regulation, and expression of genes.

Northwestern graduate student Roli Mandhana was first author of a pathbreaking study of RNA viruses recently that was published in Scientific Reports.

The most widely studied virus-inducible RNAs (viRNAs) encode proteins that mediate virus response; however, the completion of the Human Genome Project in 2003 and technological advances in genome-wide sequencing since have provided researchers with an opportunity to explore viral dynamics further.

“As we looked more closely, we found a lot of RNAs unable to encode proteins but whose levels change because of a response to infection,” says Horvath, a professor in the Weinberg College of Arts and Sciences. “As our lab and others identify more of these noncoding viRNAs, researchers are finding unexpected functions for them.”

The Horvath lab’s experiments most frequently involve infecting cell cultures with viruses and then monitoring the RNA response with the support of Northwestern’s NUSeq Core Facility, the High Throughput Analysis Laboratory within the Chemistry of Life Processes Institute (CLP), and the University’s Quest High Performance Computing Facility.

High throughput screening is a critical aspect of Horvath’s work because it greatly reduces the time it takes to scan large numbers of cell lines.

“We can now look at every gene in the cell simultaneously through these deep sequencing approaches,” he says. “At Northwestern, we are lucky to have the support of expert core facilities to enable us to easily pursue new and technologically advanced research directions. University investment in state-of-the-art support infrastructure pays dividends to every research area.”

Having identified the novel viRNAs — which the lab refers to as nviRNAs — Horvath set out to screen different viruses, including influenza A and herpes simplex virus 1. The goal was to cast a broad net and determine which nviRNAs were generalizable and which were virus specific.

The recent discoveries build upon prior research by former graduate student Jonathan Freaney, who investigated regulators of antiviral response and found widespread activity well beyond what researchers knew. The latest findings may someday help reveal why some viral infections — like HIV — are adept at evading immune response.

“We still don’t know what role these newly discovered noncoding RNAs play, but we now know that they exist and we can further explore if they are controlling the virus infection or helping the virus to replicate,” says Horvath. “Knowing those answers would introduce the possibility of targeting them for diagnostics or therapeutics.”

As a basic scientist, Horvath will rely on his lab’s latest discoveries to apply for new grants as he continues to help construct a more complete understanding of the total cellular response to virus infection.

“The ability to take these basic research findings and translate them into some diagnostic, therapeutic, or antiviral remedy really relies on our ability to take the next steps and connect our observation to some functional mechanistic consequence during the course of a virus infection,” he says. “We will continue to make these characterizations at the cellular level, but the long-term plan is to work with additional collaborators to explore what is happening in living models.”

By Roger Anderson

Curt Horvath is a member of the Chemistry of Life Processes Institute and faculty director of the Institute’s High Throughput Analysis Laboratory, an open resource for projects involving massively parallel experiments that open up unexpected frontiers in basic science and accelerate development of new medicines. Learn more about how the HTAL can advance your research.

Original story published by Northwestern Research on January 10, 2019.

Chalk Talk

Dr. Hossein Ardehali
Professor of Medicine and Pharmacology
February 27th
11:00am – 11:30am

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CMIDD Seminar

David Nagib, PhD
Assistant Professor of Chemistry
Ohio State University
February 27th

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T32 Alumni Spotlight

Tim Toby, PhD
Senior Development Scientist
Cour Pharmaceutical
February 28th

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CMIDD Seminar

Thomas Snaddon, PhD
Assistant Professor of Chemistry
Indiana University
March 12th

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The Institute manages eight shared research facilities. These facilities represent a $25M investment in high‐end instrumentation and expertise and provide 50 new services that enable investigators to identify, design and refine potential new therapeutics and diagnostics and to visualize their activity in living cells and tissues. The cores’ PhD level personnel develop powerful new tools and methods to support new basic and translational research at Northwestern and across the Midwest.

Center for Advanced Molecular Imaging

Imaging resources span length scales of molecules to whole animals. Instruments include MRI, IVIS Spectrum, SPECT, and PET.

ChemCore

Medicinal and synthetic chemistry, molecular modeling and compound purification services.

Biological Imaging Facility

Photonic and electron instruments, allowing researchers to capture high-quality images and videos of their specimens.

Developmental Therapeutics Core

Operational laboratory that supports translational projects and exploratory drug development work.

High Throughput Analysis Laboratory

Instrumentation and expertise for the development and execution of high throughput biological analysis and screening.

Proteomics Core

Instrumentation and expertise to analyze proteins using mass spectrometry. Specializing in intact protein analysis.

Quantitative Bio-element Imaging Center

Quantitation and localization of bioelements using ICP mass spec, customized Hitachi HD2300 STEM for cryo-bio EM, and atomic absorption mass spectometry.

Recombinant Protein Production Core

Expression and purification of recombinant or synthetic biologics and cultivation of microbial, insect, and mammalian cells.