Tag: biochemistry

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The NEMO Prize Goes to Research Improving Soft-Tissue Transplant Surgeries

by Melissa Pappas

Daeyeon Lee (left), Oren Friedman (center) and Sergei Vinogradov (right)

Each year, the Nemirovsky Engineering and Medicine Opportunity (NEMO) Prize, funded by Penn Health-Tech, awards $80,000 to a collaborative team of researchers from the University of Pennsylvania’s Perelman School of Medicine and the School of Engineering and Applied Science for early-stage, interdisciplinary ideas.

This year, the NEMO Prize has been awarded to Penn Engineering’s Daeyeon Lee, Russel Pearce and Elizabeth Crimian Heuer Professor in Chemical and Biomolecular Engineering, Oren Friedman, Associate Professor of Clinical Otorhinolaryngology in the Perelman School of Medicine, and Sergei Vinogradov, Professor in the Department of Biochemistry and Biophysics in the Perelman School of Medicine and the Department of Chemistry in the School of Arts & Sciences. Together, they are developing a new therapy that improves the survival and success of soft-tissue grafts used in reconstructive surgery.

More than one million people receive soft-tissue reconstructive surgery for reasons such as tissue trauma, cancer or birth defects. Autologous tissue transplants are those where cells and tissue such as fat, skin or cartilage are moved from one part of a patient’s body to another. As the tissue comes from the patient, there is little risk of transplant rejection. However, nearly one in four autologous transplants fail due to tissue hypoxia, or lack of oxygen. When transplants fail the only corrective option is more surgery. Many techniques have been proposed and even carried out to help oxygenate soft tissue before it is transplanted to avoid failures, but current solutions are time consuming and expensive. Some even have negative side effects. A new therapy to help oxygenate tissue quickly, safely and cost-effectively would not only increase successful outcomes of reconstructive surgery, but could be widely applied to other medical challenges. 

The therapy proposed by this year’s NEMO Prize recipients is a conglomerate or polymer of microparticles that can encapsulate oxygen and disperse it in sustainable and controlled doses to specific locations over periods of time up to 72 hours. This gradual release of oxygen into the tissue from the time it is transplanted to the time it functionally reconnects to the body’s vascular system is essential to keeping the tissue alive. 

“The microparticle design consists of an oxygenated core encapsulated in a polymer shell that enables the sustained release of oxygen from the particle,” says Lee. “The polymer composition and thickness can be controlled to optimize the release rate, making it adaptable to the needs of the hypoxic tissue.” 

These life-saving particles are designed to be integrated into the tissue before transplantation. However, because they exist on the microscale, they can also be applied as a topical cream or injected into tissue after transplantation. 

“Because the microparticles are applied directly into tissues topically or by interstitial injection (rather than being administered intravenously), they surpass the need for vascular channels to reach the hypoxic tissue,” says Friedman. “Their micron-scale size combined with their interstitial administration, minimizes the probability of diffusion away from the injury site or uptake into the circulatory system. The polymers we plan to use are FDA approved for sustained-release drug delivery, biocompatible and biodegrade within weeks in the body, presenting minimal risk of side effects.”

The research team is currently testing their technology in fat cells. Fat is an ideal first application because it is minimally invasive as an injectable filler, making it versatile in remodeling scars and healing injury sites. It is also the soft tissue type most prone to hypoxia during transplant surgeries, increasing the urgency for oxygenation therapy in this particular tissue type.

Read the full story in Penn Engineering Today.

Daeyeon Lee and Sergei Vinogradov are members of the Penn Bioengineering Graduate Group.

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Folding@Home: How You, and Your Computer, Can Play Scientist

by Alex Gardner

Greg Bowman kneels, working on a server.
Folding@home is led by Gregory Bowman, a Penn Integrates Knowledge Professor who has appointments in the Departments of Biochemistry and Biophysics in the Perelman School of Medicine and the Department of Bioengineering in the School of Engineering and Applied Science. (Image: Courtesy of Penn Medicine News)

Two heads are better than one. The ethos behind the scientific research project Folding@home is that same idea, multiplied: 50,000 computers are better than one.

Folding@home is a distributed computing project which is used to simulate protein folding, or how protein molecules assemble themselves into 3-D shapes. Research into protein folding allows scientists to better understand how these molecules function or malfunction inside the human body. Often, mutations in proteins influence the progression of many diseases like Alzheimer’s disease, cancer, and even COVID-19.

Penn is home to both the computer brains and human minds behind the Folding@home project which, with its network, forms the largest supercomputer in the world. All of that computing power continually works together to answer scientific questions such as what areas of specific protein implicated in Parkinson’s disease may be susceptible to medication or other treatment.

Led by Gregory Bowman, a Penn Integrates Knowledge professor of Biochemistry and Biophysics in the Perelman School of Medicine who has joint appointments in the Department of Biochemistry and Biophysics in the Perelman School of Medicine and the Department of Bioengineering in the School of Engineering and Applied Science, Folding@home is open for any individual around the world to participate in and essentially volunteer their computer to join a huge network of computers and do research.

Using the network hub at Penn, Bowman and his team assign experiments to each individual computer which communicates with other computers and feeds info back to Philly. To date, the network is comprised of more than 50,000 computers spread across the world.

“What we do is like drawing a map,” said Bowman, explaining how the networked computers work together in a type of system that experts call Markov state models. “Each computer is like a driver visiting different places and reporting back info on those locations so we can get a sense of the landscape.”

Individuals can participate by signing up and then installing software to their standard personal desktop or laptop. Participants can direct the software to run in the background and limit it to a certain percentage of processing power or have the software run only when the computer is idle.

When the software is at work, it’s conducting unique experiments designed and assigned by Bowman and his team back at Penn. Users can play scientist and watch the results of simulations and monitor the data in real time, or they can simply let their computer do the work while they go about their lives.

Read the full story at Penn Medicine News.

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Gregory Bowman Appointed Penn Integrates Knowledge University Professor

by Ron Ozio

Greg Bowman
Gregory Bowman, the Louis Heyman University Professor, has joint appointments in the Department of Biochemistry and Biophysics in the Perelman School of Medicine and the Department of Bioengineering in the School of Engineering and Applied Science. (Image: Courtesy of School of Engineering and Applied Sciences)

Gregory R. Bowman, a pioneer of biophysics and data science, has been named a Penn Integrates Knowledge University Professor at the University of Pennsylvania. The announcement was made today by President Liz Magill and Interim Provost Beth A. Winkelstein.

Bowman holds the Louis Heyman University Professorship, with joint appointments in the Department of Biochemistry and Biophysics in the Perelman School of Medicine and the Department of Bioengineering in the School of Engineering and Applied Science.

His research aims to combat global health threats such as COVID-19 and Alzheimer’s disease by better understanding how proteins function and malfunction, especially through new computational and experimental methods that map protein structures. This understanding of protein dynamics can lead to effective new treatments for even the most seemingly resistant diseases.

“Delivering the right treatment to the right person at the right time is vital to sustaining—and saving—lives,” Magill said. “Greg Bowman’s novel work holds enormous promise and potential to advance new forms of personalized medicine, an area of considerable strength for Penn. A gifted researcher and consummate collaborator, we are delighted to count him among our distinguished PIK University Professors.”

Bowman came to Penn from the Washington University School of Medicine’s Department of Biochemistry and Molecular Biophysics, where he served on the faculty since 2014. He previously completed a three-year postdoctoral fellowship at the University of California, Berkeley.

Bowman’s research utilizes high-performance supercomputers for simulations that can better explain how mutations and disease change a protein’s functions. These simulations are enabled in part through the innovative Folding@home project, which Bowman directs. Folding@home empowers anyone with a computer to run simulations alongside a consortium of universities, with more than 200,000 participants worldwide.

His research has been supported by the National Science Foundation, National Institutes of Health, National Institute on Aging, and Packard Foundation, among others, and he has received a CAREER Award from the NSF, Career Award at the Scientific Interface from the Burroughs Wellcome Fund, and Thomas Kuhn Paradigm Shift Award from the American Chemical Society. He received a Ph.D. in biophysics from Stanford University and a B.S. (summa cum laude) in computer science, with a minor in biomedical engineering, from Cornell University.

“Greg Bowman’s highly innovative work,” Winkelstein said, “exemplifies the power of our interdisciplinary mission at Penn. He brings together supercomputers, biophysics, and biochemistry to make a vital impact on public health. This brilliant fusion of methods—in the service of improving people’s lives around the world—will be a tremendous model for the research of our faculty, students, and postdocs in the years ahead.”

The Penn Integrates Knowledge program is a University-wide initiative to recruit exceptional faculty members whose research and teaching exemplify the integration of knowledge across disciplines and who are appointed in at least two schools at Penn.

The Louis Heyman University Professorship is a gift of Stephen J. Heyman, a 1959 graduate of the Wharton School, and his wife, Barbara Heyman, in honor of Stephen Heyman’s uncle. Stephen Heyman is a University Emeritus Trustee and member of the School of Nursing Board of Advisors. He is Managing Partner at Nadel and Gussman LLC in Tulsa, Oklahoma.

This story originally appeared in Penn Today.

Dr. Bowman is Penn Bioengineering’s third PIK Professor after Kevin Johnson and Konrad Kording. See the full list of University PIK Professors here.

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More Cancers May be Treated with Drugs than Previously Believed

by Alex Gardner

3D illustration of cancer cells
nucleus and membrane of pathogen micro organisms in blue background

Up to 50 percent of cancer-signaling proteins once believed to be immune to drug treatments due to a lack of targetable protein regions may actually be treatable, according to a new study from the Perelman School of Medicine at the University of Pennsylvania. The findings, published this month in Nature Communications, suggest there may be new opportunities to treat cancer with new or existing drugs.

Researchers, clinicians, and pharmacologists looking to identify new ways to treat medical conditions—from cancer to autoimmune diseases—often focus on protein pockets, areas within protein structures to which certain proteins or molecules can bind. While some pockets are easily identifiable within a protein structure, others are not. Those hidden pockets, referred to as cryptic pockets, can provide new opportunities for drugs to bind to. The more pockets scientists and clinicians have to target with drugs, the more opportunities they have to control disease.

The research team identified new pockets using a Penn-designed neural network, called PocketMiner, which is artificial intelligence that predicts where cryptic pockets are likely to form from a single protein structure and learns from itself. Using PocketMiner—which was trained on simulations run on the world’s largest super computer—researchers simulated single protein structures and successfully predicted the locations of cryptic pockets in 35 cancer-related protein structures in thousands of areas of the body. These once-hidden targets, now identified, open up new approaches for potentially treating existing cancer.

What’s more, while successfully predicting the cryptic pockets, the method scientists used in this study was much faster than previous simulation or machine-learning methods. The network allows researchers to nearly instantaneously decide if a protein is likely to have cryptic pockets before investing in more expensive simulations or experiments to pursue a predicted pocket further.

“More than half of human proteins are considered undruggable due to an apparent lack of binding proteins in the snapshots we have,” said Gregory R. Bowman, PhD, a professor of Biochemistry and  Biophysics and Bioengineering at Penn and the lead author of the study. “This PocketMiner research and other research like it not only predict druggable pockets in critical protein structures related to cancer but suggest most human proteins likely have druggable pockets, too. It’s a finding that offers hope to those with currently untreatable diseases.”

Read the full story in Penn Medicine News.

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BE Seminar: “Synthetic Biochemistry: Engineering Molecules and Pathways for Precision Medicine” (Michael Lin)

Save the date for the first Penn Bioengineering seminar of the fall 2021 semester! This year’s seminars will be hybrids, held virtually on zoom and live on campus!

Michael Lin, Ph.D.

Speaker: Michael Lin, Ph.D.
Associate Professor
Neurobiology, Bioengineering, and by courtesy Chemical and Systems Biology
Stanford Medicine, Stanford University

Date: Thursday, September 2, 2021
Time: 3:30-4:30 PM EDT
Zoom – check email for link or contact ksas@seas.upenn.edu
Location: Moore Room 216, 200 S. 33rd Street

Abstract: The most effective medicines are those that target the earliest causes of disease, rather than later manifestations. Engineering of biomolecules is a promising but underexplored approach to precisely detecting or targeting disease causes. I will present our work to develop a novel approach to treating cancer by detecting the signaling abnormalities that give rise to cancer. Interestingly, this effort involves biomolecular engineering at multiple scales: proteins, pathways, and viruses. I will also discuss how our work has translated serenditously to developing treatments for SARSCoV2.

Michael Lin Bio: Michael Z. Lin received an A.B. summa cum laude in Biochemistry from Harvard, an M.D. from UCLA, and a Ph.D. from Harvard Medical School. After training in biochemistry and neurobiology as a PhD student with Michael Greenberg at Harvard Medical School, Dr. Lin performed postdoctoral research in fluorescent protein engineering with Chemistry Nobel Laureate Roger Y. Tsien at UCSD. Dr. Lin is a recipient of a Burroughs Wellcome Career Award for Medical Scientists, a Rita Allen Scholar Award, a Damon Runyon-Rachleff Innovation Award, and a NIH Pioneer Award.

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Seminar: “The Coming of Age of De Novo Protein Design” (David Baker)

David Baker, Ph.D.

Speaker: David Baker, Ph.D.
Professor
Biochemistry
University of Washington

Date: Thursday, March 18, 2021
Time: 3:00-4:00 PM EDT
Zoom – check email for link or contact ksas@seas.upenn.edu

Title: “The Coming of Age of De Novo Protein Design”

This seminar is jointly hosted by the Department of Bioengineering and the Department of Biochemistry & Biophysics.

Abstract:

Proteins mediate the critical processes of life and beautifully solve the challenges faced during the evolution of modern organisms. Our goal is to design a new generation of proteins that address current day problems not faced during evolution. In contrast to traditional protein engineering efforts, which have focused on modifying naturally occurring proteins, we design new proteins from scratch based on Anfinsen’s principle that proteins fold to their global free energy minimum. We compute amino acid sequences predicted to fold into proteins with new structures and functions, produce synthetic genes encoding these sequences, and characterize them experimentally. I will describe the de novo design of fluorescent proteins, membrane penetrating macrocycles, transmembrane protein channels, allosteric proteins that carry out logic operations, and self-assembling nanomaterials and polyhedra. I will also discuss the application of these methods to COVID-19 challenges.

Bio:

David Baker is the director of the Institute for Protein Design, a Howard Hughes Medical Institute Investigator, a professor of biochemistry and an adjunct professor of genome sciences, bioengineering, chemical engineering, computer science, and physics at the University of Washington. His research group is a world leader in protein design and protein structure prediction. He received his Ph.D. in biochemistry with Randy Schekman at the University of California, Berkeley, and did postdoctoral work in biophysics with David Agard at UCSF. Dr. Baker is a member of the National Academy of Sciences and the American Academy of Arts and Sciences. Dr. Baker is a recipient of the Breakthrough Prize in Life Sciences, Irving Sigal and Hans Neurath awards from the Protein Society, the Overton Prize from the ISCB, the Feynman Prize from the Foresight Institute, the AAAS Newcomb Cleveland Prize, the Sackler prize in biophysics, and the Centenary Award from the Biochemical society. He has also received awards from the National Science Foundation, the Beckman Foundation, and the Packard Foundation. Dr. Baker has published over 500 research papers, been granted over 100 patents, and co-founded 11 companies. Seventy-five of his mentees have gone on to independent faculty positions.

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BE Seminar: “Multi-input Chemical Control with Computationally Designed Proteins for Research Tools and Cell Therapies” (Glenna Wink Foight)

Speaker: Glenna Wink Foight, Ph.D.
Senior Scientist
Lyell Immunopharma

Date: Thursday, February 11, 2021
Time: 3:00-4:00 PM EST
Zoom – check email for link or contact ksas@seas.upenn.edu

Title: “Multi-input Chemical Control with Computationally Designed Proteins for Research Tools and Cell Therapies”

Abstract:

Protein modules that are responsive to small molecule inputs have enabled control of cellular processes for decades’ worth of important mechanistic studies. More recently, they have gained attention as a means of control for improved safety of cellular therapies. To date, most small molecule-responsive systems have been adapted from natural proteins, which provide limited control behaviors and often rely on small molecules with non-ideal properties for use in humans. I will describe how we have used computational protein design to move beyond these naturally occurring systems to create a new set of molecular tools that are responsive to multiple clinically approved drugs. The unique architecture of our system enables more complex control behaviors for multiple cellular outputs. I will describe applications of this designed system in the control of mammalian cytoskeletal signaling, transcription, and CAR T-cell therapy.

Bio:

Dr. Glenna Foight is a Senior Scientist at Outpace Bio, where she leads a team that focuses on engineering small molecule drug-based control of cell therapies. Her work at the startups Outpace Bio and Lyell Immunopharma has involved the adaptation of technologies that she developed as a Washington Research Foundation Innovation Postdoctoral Fellow at the University of Washington. Dr. Foight received her Ph.D. in Biology from MIT and her B.S. in Biochemistry from North Carolina State University. Her background is in applying protein design and engineering to develop novel molecular interventions and control strategies for applications in basic research, cancer, and cell therapy.

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BE Seminar: “Designing Biology for Detection and Control” (Pamela A. Silver)

Speaker: Pamela A. Silver, Ph.D.
Elliot T. and Onie H. Adams Professor of Biochemistry and Systems Biology
Harvard Medical School

Date: Thursday, January 28, 2021
Time: 3:00-4:00 PM EST
Zoom – check email for link or contact ksas@seas.upenn.edu

Title: “Designing Biology for Detection and Control”

Abstract:

The engineering of Biology presents infinite opportunities for therapeutic design, diagnosis, and prevention of disease. We use what we know from Nature to engineer systems with predictable behaviors. We also seek to discover new natural strategies to then re-engineer. I will present concepts and experiments that address how we approach these problems in a systematic way. Conceptually, we seek to both design cells and proteins to control disease states and to detect and predict the severity of emerging pathogens. For example, we have engineered components of the gut microbiome to act therapeutics for infectious disease, proteins to prolong cell states, living pathogen sensors and high throughput analysis to predict immune response of emerging viruses.

Bio:

Pamela Silver is the Adams Professor of Biochemistry and Systems Biology at Harvard Medical School and the Wyss Institute for Biologically Inspired Engineering. She received her BS in Chemistry and PhD in Biochemistry from the University of California. Her work has been recognized by an Established Investigator of the American Heart Association, a Research Scholar of the March of Dimes, an NSF Presidential Young Investigator Award, Claudia Adams Barr Investigator, an NIH MERIT award, the Philosophical Society Lecture, a Fellow of the Radcliffe Institute, and election to the American Academy of Arts and Sciences. She is among the top global influencers in Synthetic Biology and her work was named one of the top 10 breakthroughs by the World Economic Forum. She serves on the board of the Internationally Genetics Engineering Machines (iGEM) Competition and is member of the National Science Advisory Board for Biosecurity. She has led numerous projects for ARPA-E, iARPA and DARPA. She is the co-founder of several Biotech companies including most recently KulaBio and serves on numerous public and private advisory boards.

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Penn Alumnus Peter Huwe Appointed Assistant Professor at Mercer University

Peter Huwe, Ph.D.

Peter Huwe, a University of Pennsylvania alumnus and graduate of the Radhakrishnan lab, was appointed Assistant Professor of Biomedical Sciences at the Mercer University School of Medicine beginning this summer 2020 semester.

Huwe earned dual B.S. degrees in Biology and Chemistry in 2009 from Mississippi College, where he was inducted into the Hall of Fame. At Mississippi College, Huwe had his first exposure to computational research in the laboratory of David Magers, Professor of Chemistry and Biochemistry. He went on to earn his Ph.D. in Biochemistry and Molecular Biophysics in 2014 in the laboratory of Ravi Radhakrishnan, Chair of the Bioengineering Department at Penn. As an NSF Graduate Research Fellow in Radhakrishnan’s lab, Huwe focused his research on using computational molecular modeling and simulations to elucidate the functional consequences of protein mutations associated with human diseases. Dr. Huwe then joined the structural bioinformatics laboratory Roland Dunbrack, Jr., Professor at the Fox Chase Cancer Center as a T32 post-doctoral trainee. During his post-doctoral training, Huwe held adjunct teaching appointments at Thomas Jefferson University and at the University of Pennsylvania. In 2017, Huwe became an Assistant Professor of Biology at Temple University, where he taught medical biochemistry, medical genetics, cancer biology, and several other subjects.

During each of his appointments, Huwe became increasingly more passionate about teaching, and he decided to dedicate his career to medical education. Huwe is very excited to be joining Mercer University School of Medicine as an Assistant Professor of Biomedical Sciences this summer. There, he will serve in a medical educator track, primarily teaching first and second year medical students.

“Without Ravi Radhakrishnan and Philip Rea, Professor of Biology in Penn’s School of Arts & Sciences, giving me my first teaching opportunities as a graduate guest lecturer at Penn, I may never have discovered how much I love teaching,” says Huwe. “And without the support and guidance of each of my P.I.’s [Dr.’s Magers, Radhakrishnan, and Dunbrack], I certainly would not be where I am, doing what I love.  I am incredibly thankful for all of the people who helped me in my journey to find my dream job.”

Congratulations and best of luck from everyone in Penn Bioengineering, Dr. Huwe!

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Getting Physical with Developmental Biology Research

macrophages Discher
Dennis Discher, Ph.D.

By Izzy Lopez

While genetics and biochemistry research has dominated the conversation about how human bodies are formed, new research — with an old twist — is proposing that there is another star in the show of human development: mechanical forces.

At the turn of the twentieth century, medical research relied on simple mechanics to explain scientific phenomena, including how human cells morph into shape from embryo to newborn and beyond. As better chemistry techniques and DNA research burst onto the scene, however, the idea that cells could be affected by physical forces took a back seat. Now researchers are referring back to this vintage idea and bringing it into the 21st century.

Dennis Discher, Robert D. Bent Professor in the Departments of Chemical and Biomolecular Engineering, Bioengineering and Mechanical Engineering and Applied Mechanics, was featured in a recent article in Knowable Magazine for his research on the human heart and how mechanical forces exerted on heart cells give the vital organ its necessary stiffness during development.

Read the full story on the Penn Engineering blog.