Through a broad network of research centers, Rensselaer researchers are creating new routes to drug discovery and development, understanding the fundamental mechanisms of disease, as well as examining mechanisms for enabling affordable health care technologies and improving human health.
Therapeutic Intervention in Alzheimer’s Research
Rensselaer researchers have followed the trail of two genetic mutations to uncover how they lead to biochemical changes that are associated with Familial Alzheimer's, while a researcher in the LRC has used lighting to help seniors avoid falls during the night. Full Story
Drug Discovery and High-Throughput Screening
A team of researchers has developed a type of biochip that could enable pharmaceutical companies to start doing quick, reliable, high-throughput toxicity testing significantly earlier in the process of the testing of drug candidates. Full Story
Research is being carried out on developing new surgical tools and techniques for cutting and drilling bone that take into account both the age of individual patients as well as the particular microstructure of their bone, which could lead to faster recovery times and fewer revision surgeries for patients. Full Story
Biomanufacturing: Synthetic Heparin
Researchers have created a synthetic form of low-molecular-weight heparin that can be reversed in cases of overdose and would be safer for patients with poor kidney function. Full Story
Antimicrobial Research: Fighting Toxins and Pathogens
A new protein engineering technique developed at Rensselaer gives researchers a powerful new tool for fighting potentially harmful toxins and pathogens. Full Story
New research, led by Rensselaer researcher Chunyu Wang, has solved one mystery in the development of Familial Alzheimer’s Disease (FAD), a genetic variant of the disease that affects a small fraction of the Alzheimer’s population. In a paper published in the journal Nature Communications, Wang and his team follow the trail of two genetic mutations—V44M and V44A—known to cause FAD, and show how the mutations lead to biochemical changes long linked to the disease.
“The mutations that cause FAD lead to an increased ratio of Aβ42 over Aβ40,” said Wang, an associate professor of biological sciences within the School of Science, director of the biochemistry and biophysics graduate program, and member of the Rensselaer Center for Biotechnology and Interdisciplinary Studies, who co-wrote the paper with Wen Chen, who recently earned his doctorate at Rensselaer. “That’s the biochemistry, and that has been observed by many people. But the question we asked is: how? How do the mutations lead to this increased ratio?”
There are hundreds of known genetic mutations linked to FAD, but they are all related to the processing of a large protein, the amyloid precursor protein (APP), which starts its life partially embedded in the cell membrane of brain cells, and is later cut into several pieces, one of which becomes either Aβ42 or Aβ40.
In a multi-step process, enzymes make several cuts to APP, and the location of the cuts dictates whether a resulting snippet of APP becomes Aβ42 or Aβ40. If an enzyme, β-secretase, makes an initial cut at an amino acid within APP called Threonine 48 (T48), the remaining cuts result in Aβ42, whereas if the first cut is made at amino acid Leucine 49, the process will result in Aβ40.
“The mutations that cause FAD lead to an increased ratio of Aβ42 over Aβ40...But the question we asked is: how? How do the mutations lead to this increased ratio?”
Wang’s team used solution nuclear magnetic resonance spectroscopy to study the three-dimensional structure and dynamics of the transmembrane portion of APP affected by the two genetic mutations, and they discovered that the mutations cause a critical change to the T48 amino acid. That change makes it more likely that β-secretase will prefer a cut at T48, leading to production of Aβ42, and increased concentrations of Aβ42 found in the brains of patients with FAD.
“The basic idea is that—in the mutated versions—this site, T48, becomes more open, more accessible to β-secretase,” said Wang. “What we found is that the FAD mutation basically opens up the T48 site, which makes it more likely for β-secretase to produce Aβ42 peptide.”
Rensselaer Press Release
'Bluish' Light May Help Alzheimer's Patients Find Bearings
Researchers in the Lighting Research Center at Rensselaer are trying to help Alzheimer's patients experience fewer behavioral issues. Robert Siegel of NPR speaks with professor Mariana Figueiro.
“Mariana Figueiro showed me something that she has developed to help seniors avoid falls in the night...Her project is a nightlight. But it's not just a single bulb. It's a string of yellow lights that border the darkened entrance to, say, a bathroom. It's a doorway, and around the frame of the doorway are the yellow LEDs.” —Robert Siegel NPR
A team of researchers has developed a new type of biochip that emulates the metabolism of a human liver. The device could one day eliminate the need to harvest and use liver cells from human cadavers to test the toxicity of potential new drugs and drug candidates.
The new biochip technology is the result of a collaboration between researchers from Rensselaer, the University of California, Berkeley, Samsung Electro-Mechanics, and Solidus Biosciences Inc.
Once ingested, food or medicine is chemically transformed, or metabolized, by the human body. The liver plays the major role in this metabolism. An important part of the drug discovery process is testing drug candidates for both efficacy and toxicity. Drug metabolism often results in enhanced toxicity, particularly to the liver. Metabolism-induced toxicity is a common reason why many compounds fail during the drug discovery process.
Generally, this toxicity testing is conducted using human hepatocytes, a major type of liver cell involved in metabolism. “These cells, however, are known to be challenging to work with,” said Jonathan Dordick, vice president for research and the Howard P. Isermann Professor at Rensselaer, who helped lead the study. “Because they are harvested from the livers of cadavers, hepatocytes are expensive, delicate, and vary significantly in their metabolic capacity and profile. This variability often results in loss of the predictive capacity of in vitro tests to emulate what happens in the human body,” he said.
The research team’s new biochip, called the Transfected Enzyme and Metabolism Chip, or TeamChip, addresses the widely known and recognized challenge of using hepatocytes for liver toxicity testing. The TeamChip mimics a hepatocyte, but in a manner that is less expensive and more reliable, Dordick said. Additionally, the TeamChip can be fine-tuned to mimic hepatocytes from an individual, which is critical in the development of more personalized drug toxicity assessment, he said.
“A high-throughput alternative to using human hepatocytes would speed up the testing process and reduce costs, while alleviating the problems related to sourcing the cells from cadavers. The new TeamChip technology is a highly flexible platform that addresses these challenges directly.”—Jonathan Dordick
“Drug discovery is a highly competitive enterprise that requires significant up-front investment and suffers a low success rate,” said Douglas Clark, dean of the College of Chemistry and the Gilbert Newton Lewis Professor at UC Berkeley, who led the study with Dordick. “A high-throughput alternative to using human hepatocytes would speed up the testing process and reduce costs, while alleviating the problems related to sourcing the cells from cadavers. The new TeamChip technology is a highly flexible platform that addresses these challenges directly.”
Each TeamChip features 532 individual assays that consist of these liver cells. The cells are “printed” onto the chip, each with different combinations and concentrations of viruses. The cells print as a liquid, but then quickly form gelatinous 3-D structures..
The researchers took immortalized liver cells that lacked the ability to perform metabolism, and used an approach called viral transduction to “infect” these cells with viruses containing specific drug-metabolizing genes that lead to the expression of drug-metabolizing enzymes. Once expressed, these enzymes enable the liver cells to metabolize drugs and drug candidates. The cells can be engineered to express any number of enzymes, all in high-throughput.
Each TeamChip features 532 individual assays that consist of these liver cells. The cells are “printed” onto the chip, each with different combinations and concentrations of viruses. The cells print as a liquid, but then quickly form gelatinous 3-D structures. These 3-D structures are likely to more accurately mimic the conditions within the human body than a flat, 2-D sample, Clark said.
Once all of the samples have been printed, the chip is incubated for up to three days. Afterward, it is removed from incubation and then analyzed for cell viability. Cells that generate drug candidate metabolites that are toxic result in lower cell viability.
Traditionally, toxicity testing is conducted late in the preclinical phase of the drug discovery process. Dordick and Clark said the TeamChip could enable pharmaceutical companies to start doing quick, reliable, high-throughput toxicity testing significantly earlier in the process.
“This technology is a good way to determine, very early on, both the efficacy and the potential toxicity of a drug candidate,” Dordick said. “Having this information as early in the process as possible enables pharma companies to focus their limited resources on pushing forward only the most promising candidates with good efficacy and low toxicity.”
This project was funded with support from the National Institute of Environmental Health Sciences, and partial support from Samsung Electro-Mechanics.
Material design and advanced manufacturing expert Johnson Samuel, assistant professor in the Department of Mechanical. Aerospace, and Nuclear Engineering at Rensselaer, has won a prestigious Faculty Early Career Development Award (CAREER) from the National Science Foundation (NSF).
Samuel will use the five-year, $400,000 grant to advance his research into developing new surgical tools and techniques for cutting and drilling bone that take into account both the age of individual patients and the particular microstructure of their bone. This kind of patient-specific surgery approach holds the potential to benefit many different bone procedures by reducing patient recovery times and the need for follow-up surgeries.
Cutting or drilling into bone is an important technique used around the world as part of surgeries performed every day—from using screws to fix a bone fracture, to knee and hip replacements, to various medical implants. In 2010, for example, 600,000 total knee replacement surgeries were performed in the United States. The tools and procedures used to machine bone, however, do not take into account the bone properties and bone health of the individual patient, Samuel said.
“Bone properties and bone microstructure vary from patient to patient, based on an individual’s age and health history,” Samuel said. “Accounting for these variations will result in less damage to the bone during the procedure which, in turn, will lead to faster recovery times and fewer revision surgeries for patients.”
With his CAREER project, titled “Microstructure-Specific Machining Strategies for Bone,” Samuel seeks to characterize how bones with different properties and microstructures respond to being cut and drilled. Specifically, he will look into different types of cortical bones and their microstructural components, including osteon fibers, interstitial matrix, cement lines, and voids. This work lies at the intersection of manufacturing research and biomedical research, and could help inform a new generation of bone machining tools and surgery planning techniques.
“Bone properties and bone microstructure vary from patient to patient, based on an individual’s age and health history. Accounting for these variations will result in less damage to the bone during the procedure which, in turn, will lead to faster recovery times and fewer revision surgeries for patients.”
Samuel said his vision is a system where patients undergoing bone surgical procedures could be routinely classified into different categories, depending on the microstructure of their bones. Based on this classification, the surgeon would then be able to choose specific tool geometries, tool paths, machining conditions, and surgery-aiding devices that are designed to reduce the extent of the surface damage inflicted on the bone.
Educational outreach is an important part of Samuel’s CAREER Award. As part of the project, he plans to develop Lego-based lesson plans for middle and high school students to learn about manufacturing. Additionally, he plans to partner with local high schools to help implement a new “Exploring Advanced Manufacturing” curriculum that highlights the educational and career opportunities provided by the manufacturing sector. For this outreach work, Samuel will collaborate with alumnus David DeWitt ’68, who heads Phase65 Inc., a social media company dedicated to promoting manufacturing in the United States.
Samuel joined the Rensselaer faculty in 2011, after serving as a postdoctoral research associate at the University of Illinois at Urbana-Champaign, and a postdoctoral fellow at the Indian Institute of Technology, Bombay.
He received his bachelor’s degree in mechanical engineering from the University of Mumbai, and his master’s degree in industrial engineering and doctoral degree in mechanical engineering from the University of Illinois at Urbana-Champaign.
Researchers at Rensselaer and the University of North Carolina at Chapel Hill (UNC) have created a synthetic form of low-molecular-weight heparin that can be reversed in cases of overdose and would be safer for patients with poor kidney function.
“We took this drug and not only made it cost effectively, but we’ve also improved the properties of the drug,” said Robert Linhardt, the Ann and John H. Broadbent Jr. ’59 Senior Constellation Professor of Biocatalysis and Metabolic Engineering, a member of the Center for Biotechnology and Interdisciplinary Studies (CBIS), and one of the inventors of the new drug. “The synthetic version that we’ve made is reversible, it can be used in renal patients, and it doesn’t come from animals, which is a critical advance in safety.”
Heparin is an anticoagulant, and is most commonly extracted from pig intestines in two forms: unfractionated heparin, which is commonly used in procedures such as dialysis, and a more-refined low-molecular-weight (LMW) heparin, which is used around the world for preventing dangerous blood clots. A team led by Linhardt and Jian Liu, a professor in the UNC Eshelman School of Pharmacy, created a synthetic version of LMW heparin for which there is an existing antidote. Their creation is described in an article published online in the journal Nature Chemical Biology.
“The synthetic version that we’ve made is reversible, it can be used in renal patients, and it doesn’t come from animals, which is a critical advance in safety.”—Robert Linhardt
Linhardt and Liu used a chemo-enzymatic process to synthesize the drug, an approach they developed in research on a simpler anticoagulant drug published in Science in October 2011. Synthesizing LMW heparin allowed them to make many improvements on the animal-derived form of the drug currently available. Linhardt’s research supports the School of Science interdisciplinary theme of biomedical science and applications, and is part of a research focus on biocatalysis and metabolic engineering within CBIS. His research on LMW heparin was funded by the National Institutes of Health.
Up to 5 percent of patients receiving heparin experience some form of uncontrolled bleeding. Patients receiving unfractionated heparin are in less danger because there is an existing Federal Drug Administration-approved antidote (protamine) available. Protamine is not as effective in reversing naturally derived LMW heparin, so Linhardt and Liu engineered their drug’s molecular structure so that protamine is able to deactivate it.
Naturally produced LMW heparin is cleared from the body by the kidneys, which can make it unsuitable for patients with a weakened renal system, a relatively common condition among patients requiring anticoagulation. Linhardt and Liu made additional changes allowing their drug to bind to receptors that clear it through the liver.
LMW heparin makes up more than half the U.S. market for heparin. Linhardt and Liu said the new version they created is a safe, economically viable alternative to the existing animal-derived supply. But the new drug would require FDA approval, and would probably also undergo alteration on the path to market.
Robert Linhardt, the Ann and John H. Broadbent Jr. ’59 Senior Constellation Professor of Biocatalysis and Metabolic Engineering, is internationally known for his research on the study of bioactive carbohydrates, particularly the complex polysaccharide heparin.
Heparin prevents blood clots from forming and is most often used during and after such procedures as kidney dialysis, heart bypass surgery, stent implantation, and knee and hip replacement. Its side effects can include uncontrolled bleeding and thrombocytopenia (too few platelets in the blood). The worldwide sales of heparin are estimated at $4 billion annually.
The natural form of the drug was in the spotlight in spring 2008 when more than 80 people died and hundreds of others suffered adverse reactions to it, leading to recalls of heparin in countries around the world. Authorities linked the problems to a contaminant in raw natural heparin from China.
“Whenever you mix the food chain and the drug chain together, you end up with potential for disaster. Whether it comes from contamination, adulteration, impurities like viruses or prions—any of those possibilities are much more likely when you make something in an uncontrolled environment,” said Linhardt.
“This is a drug that millions of people rely upon, and it’s important to develop a safe, synthetic alternative to the current supply chain.”
Liu and Linhardt’s co-authors include Lingyun Li, a Rensselaer research assistant professor, and Chao Cai, a postdoctoral fellow.
A new protein engineering technique developed at Rensselaer gives researchers a powerful new tool for fighting potentially harmful toxins and pathogens.
The research team, led by Ravi Kane, the P. K. Lashmet Professor at Rensselaer, designed a new approach to precisely control the molecular properties of protein therapeutics that inhibit the potency and deadliness of anthrax toxin. Unlike antibiotics, these engineered molecules do not attack bacteria. Instead, the inhibitors block specific binding sites on anthrax toxin and prevent the toxic enzymes from entering target cells.
Anthrax toxin, secreted by the anthrax bacterium, is made of proteins and toxic enzymes that bind together to inflict damage to a host organism. Even if antibiotics are used to treat an anthrax bacterial infection, the secreted anthrax toxin continues to spread and do damage. As a result, Kane and other researchers have been investigating methods for preventing anthrax toxin from entering cells.
“To really understand how these inhibitor molecules work,we need to be able to control valency independent of spacing, and end up with inhibitors that are molecularly uniform.” —Ravi Kane
Kane and his colleagues have been designing polyvalent molecules, in which multiple copies of active peptides are attached to a polymer chain. These polyvalent molecules can demonstrate significantly more inhibitory activity than free monomeric peptides. The effectiveness of previous approaches was limited, however, because the peptide ligands were attached randomly across the polymer chain, and the number of ligands varied from chain to chain. Both parameters have a major impact on the functionality of the overall inhibitor.
“To really understand how these inhibitor molecules work,” said Kane, “we need to be able to control valency independent of spacing, and end up with inhibitors that are molecularly uniform.”
To accomplish this, Kane and the researchers employed protein and genetic engineering techniques to create polypeptide inhibitors with uniform ligand spacing and valency.
“As a result, we can now systematically control all of these properties, and tune them in order to influence the activity of the inhibitor molecules,” Kane said. The research team developed inhibitors of anthrax toxin that were over 10,000 times more potent than the monomeric peptide.
This work, funded by the U.S. National Institutes of Health (NIH), could be broadly applicable to inhibit toxins and pathogens, Kane said. His research group is currently looking at how to use this technique to develop inhibitors for the human immunodeficiency virus (HIV).
A manuscript based on the study, entitled “Design of Monodisperse and Well-Defined Polypeptide-Based Polyvalent Inhibitors of Anthrax Toxin,” was published online April 6 by the journal Angewandte Chemie International Edition. See the paper at: http://ow.ly/wiOjG
Kane is a faculty member of the Department of Chemical and Biological Engineering (CBE) at Rensselaer. This research took place in the Rensselaer Center for Biotechnology and Interdisciplinary Studies (CBIS).
Along with Kane, co-authors of the paper are: Rensselaer CBE graduate students Sanket Patke, Jacob T. Martin, Matthew Brier, and Tania Rosen; Rensselaer undergraduate student Ian Harvey; Rensselaer CBIS research associates Manish Arha, Marc Douaisi, Mohan Boggara, Ronak Maheshwari, and Sunit Srivastava; and Jeremy Mogridge, associate professor in the Department of Laboratory Medicine and Pathobiology at the University of Toronto.
This research was supported by the NIH National Institute of Allergy and Infectious Diseases under grant number U01AI056546 and the NIH National Institute of Biomedical Imaging and Bioengineering under grant number R01EB015482. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Rensselaer has joined as a charter partner of Optum Labs, the collaborative research and innovation center founded by Optum and Mayo Clinic committed to improving the quality and value of patient care.
As a partner of Optum Labs, Rensselaer has access to information resources, proprietary analytical tools, and scientific expertise to help drive the discovery of new applications, testing of new care pathways, and other opportunities to drive innovation in wellness and care delivery.
“Rensselaer Polytechnic Institute is globally transforming biomedical research through the intersection of data science/analytics with biological sciences/bioengineering,” said Jonathan Dordick, Ph.D., vice president for research at Rensselaer. “Working with Optum Labs and the other partners, Rensselaer will forge a path from fundamental science to technology development that will result in innovation and discovery. The results of this new partnership will enable health care organizations to make better decisions, make better products, and ultimately, reduce costs of health care delivery.”
“Rensselaer Polytechnic Institute is globally transforming biomedical research through the intersection of data science/analytics with biological sciences/bioengineering. Working with Optum Labs and the other partners, Rensselaer will forge a path from fundamental science to technology development that will result in innovation and discovery.” —Jonathan Dordick
“The collaboration between our diverse group of partners will help Optum Labs accelerate the pace of innovation, paving the way for exciting new research initiatives that can be directly translated to improvements in patient care,” said Paul Bleicher, M.D., Ph.D., CEO of Optum Labs, and a member of the Rensselaer Class of 1976.
Optum Labs brings together a community of health care stakeholders dedicated to improving patient care by sharing information assets, technologies, knowledge, tools, and scientific expertise. Research is linked to the clinical environment through prototyping and testing in Optum and partners’ care settings, with a goal of achieving knowledge that improves health care delivery and patient outcomes.
Dordick said the partnership with Optum Labs provides a significant opportunity to help advance fundamental and translational research taking place at Rensselaer in the areas of drug discovery, human toxicology, and improved patient outcomes on a personalized basis. Other areas of interest include drug repurposing, health care analytics, clinical outcomes predictions, and novel target identification. The partnership with Optum Labs brings together two major research platforms at Rensselaer, the Center for Biotechnology and Interdisciplinary Studies (CBIS) and the Institute for Data Exploration and Applications (the Rensselaer IDEA).
Affiliation Agreement With Icahn School of Medicine at Mount Sinai
An affiliation agreement between the Icahn School of Medicine at Mount Sinai and Rensselaer in May 2013 enables collaboration on educational programs, research, and development of new diagnostic tools and treatments that promote human health.
The institutions launched the initiative to use their expertise—engineering and invention prototyping at Rensselaer and biomedical research and patient care at Mount. Sinai—to provide synergy in their promotion of human health. Rensselaer and the Icahn School of Medicine are developing complementary research programs in neuroscience and neurological diseases, genomics, imaging, orthopaedics, cancer, cardiovascular disease, and scientific and clinical targets that capitalize on each institution’s unique strengths. Joint funding in research programs is being sought in the areas of precision medicine, drug discovery, stem cell biology, robotics and robotic surgery, novel imaging techniques, cellular engineering, and computational neurobiology.
Initially, the key areas of focus are genomics, imaging, tissue engineering, and neuroscience. With the Icahn School of Medicine’s $3 million investment to build the Minerva supercomputer and the Rensselaer high-performance computing center at the the Center for Computational Innovations — featuring a new IBM Blue Gene/Q supercomputing system — the two institutions will implement some of the most advanced high-performance supercomputing in the world. This will enable them to quickly and efficiently produce sophisticated computer algorithms that analyze genomic data and develop predictive models of disease, which can better help diagnose and treat patients. Mount Sinai’s newly opened Hess Center for Science and Medicine and the Rensselaer Center for Biotechnology and Interdisciplinary Studies (CBIS) will serve as hubs for research and development.
This agreement was enhanced by the creation of the Mount Sinai Institute of Technology (MSIT), part of a $100 million public-private initiative to boost biotechnology innovation in New York. MSIT aims to educate a new generation of experts and create new technologies to help address and solve the world’s most critical health-care challenges.
Additionally, 8 joint research projects have been seeded by the partnership.