Computer-generated Antibiotics, Biosensor Band-Aids, and the Quest to Beat Antibiotic Resistance

By Michele W. Berger

Imagine if a computer could learn from molecules found in nature and use an algorithm to generate new ones. Then imagine those molecules could get printed and tested in a lab against some of the nastiest, most dangerous bacteria out there — bacteria quickly becoming resistant to our current antibiotic options.

Or consider a bandage that can sense an infection with fewer than 100 bacterial cells present in an open wound. What if that bandage could then send a signal to your phone letting you know an infection had started and asking you to press a button to trigger the release of the treatment therapy it contained?

These ideas aren’t science fiction. They’re projects happening right now, in various stages, in the lab of synthetic biologist , who joined the University as a Presidential Professor in May 2019. His ultimate goal is to develop the first computer-made antibiotics. But beyond that, his lab — which includes three postdoctoral fellows, a visiting professor, and a handful of graduate students and undergrads — has many other endeavors that sit squarely at the intersection of computer science and microbiology.

Computer-generated antibiotics

Antibiotic resistance is becoming a dangerous problem, both in the United States and worldwide. According to the , each year in the U.S., at least 2.8 million people get infections that antibiotics can’t help, and more than 35,000 die from those infections. Around the world, common ailments like pneumonia and food-borne illness are getting harder to treat.

De la Fuente poses near Penn’s “Biopond”
De la Fuente earned his bachelor’s degree in biotechnology, then a doctorate in microbiology and immunology and a postdoc in synthetic biology and computational biology. Combining these fields led him to the innovative work his lab does today.

New antibiotics are needed, and according to de la Fuente, it’s time to look beyond the traditional approach.

“We’ve relied on nature as a source of antibiotics for many, many years. My whole hypothesis is that nature has perhaps run out of inspiration,” says de la Fuente, who has appointments in the and the . “We haven’t been able to discover any new scaffolds for many years. Can we digitize that information, nature’s chemistry, to be able to create and discover new molecules?”

To do that, his team turned to amino acids, the building blocks of protein molecules. The 20 that occur naturally bond in countless sequences and lengths, then fold to form different proteins. The sequencing possibilities are expansive, more than the number of stars in the universe. “We could never synthesize all of them and just see what happens,” says postdoc Marcelo Melo. “We have to combine the chemical knowledge — decades of chemistry on these tell us how they behave — with the computational side, because a computer can find patterns unlike any human could.”

Using machine learning, the researchers provide the computer with natural molecules that successfully work against bacteria. The computer learns from those examples, then generates new, artificial molecules. “We try this back and forth and hopefully we find patterns, new patterns that we can explore, instead of blindly searching,” Melo says.

The computer can then test each artificial sequence virtually, setting aside the most successful components and tossing the rest, in a form of computational natural selection. Those pieces with the highest potential get used to create new sequences, theoretically producing better and better ones each time.

De la Fuente’s team has seen some promising results already: “A lot of the molecules we’ve synthesized have worked,” he says. “The best ones worked in animal models. They were able to reduce infections in mice — which was pretty cool, given that the computer generated the whole thing.” Still, de la Fuente says the work is years away from producing anything close to a shelf-ready antibiotic.

Continue reading on .

Penn Nanoparticles are Less Toxic to T Cells Engineered for Cancer Immunotherapy

An artist’s illustration of nanoparticles transporting mRNA into a T cell (blue), allowing the latter to express surface receptors that recognize cancer cells (red). (Credit: Ryan Allen, Second Bay Studios)

New cancer immunotherapies involve extracting a patient’s T cells and genetically engineering them so they will recognize and attack tumors. This type of therapy is not without challenges, however. Engineering a patient’s T cells is laborious and expensive. And when successful, the alterations to the immune system immediately make patients very sick for a short period of time, with symptoms including fever, nausea and neurological effects.

Now, Penn researchers have demonstrated a new engineering technique that, because it is less toxic to the T cells, could enable a different mechanism for altering the way they recognize cancer, and could have fewer side effects for patients.

The technique involves ferrying messenger RNA (mRNA) across the T cell’s membrane via a lipid-based nanoparticle, rather than using a modified HIV virus to rewrite the cell’s DNA. Using the former approach would be preferable, as it only confers a temporary change to the patient’s immune system, but the current standard method for getting mRNA past the cell membrane can be too toxic to use on the limited number of T cells that can be extracted from a patient.

Michael Mitchell, Margaret Billingsley, and Carl June

The researchers demonstrated their technique in a study published in the journal Nano Letters. It was led by Michael Mitchell, Skirkanich Assistant Professor of Innovation of bioengineering in the School of Engineering and Applied Science, and Margaret Billingsley, a graduate student in his lab.

They collaborated with one of the pioneers of CAR T therapy: Carl June, the Richard W. Vague Professor in Immunotherapy and director of the Center for Cellular Immunotherapies in the Abramson Cancer Center and the director of the Parker Institute for Cancer Immunotherapy at the Perelman School of Medicine.

Read more at Penn Engineering blog.

Alex Hughes Receives the First MIRA Award of Penn SEAS

by Sophie Burkholder

Alex Hughes, Ph.D.

We would like to congratulate Assistant Professor in Bioengineering Alex Hughes, Ph.D., on receiving the Maximizing Investigators’ Research Award (MIRA) from the National Institutes of Health (NIH), which funds investigators to create flexible and forward-thinking research programs. Hughes is the first recipient of this award in Penn’s School of Engineering and Applied Science, marking a major accomplishment for him and his lab.

The award recognizes Hughes’ efforts to create new  tools used for tissue engineering, in particular by fusing concepts from developmental biology into tissue construction efforts. Hughes believes this approach will have impacts on fundamental understanding human disease, leading to new strategies to combat them. Hughes and his lab specifically focus on kidney disease. As Hughes says, “defects in the kidney and urinary tract account for up to a third of all birth defects.” Furthermore, because kidney development involves many different kinds of cell interactions, there’s a gap in understanding exactly how these defects occur.

Unlike other grants that focus on funding projects, the MIRA prioritizes the people behind the research, giving them funding as a sign of faith in the future work they’ll choose to do. “The MIRA has allowed us significant leeway to integrate several complementary approaches here,” Hughes says. Because of this flexibility, Hughes and his lab thinks it will allow them to reach for more innovative and risky approaches in their research, in the hopes that this will lead to a better understanding of kidney defects and modes of treatment for them.

Bioengineering Round-Up (January 2020)

by Sophie Burkholder

University of Washington Researchers Engineer a New Way to Study Circulatory Obstruction

Capillaries are one of the most important forms of vasculature in our body, as they allow our blood to transfer nutrients to other parts of our body. But for how much effect capillary functionality can have on our health, their small size makes them extremely difficult to engineer into models for a variety of diseases. Now, researchers at the University of Washington led by Ying Zheng, Ph. D., engineered a three-dimensional microvessel model with living cells to study the mechanisms of microcirculatory obstruction involved with malaria.

Rather than just achieving a physical model of capillaries, these researchers created a model that allowed them to study typical flow and motion through capillaries, before comparing it to deficiencies in this behavior involved with diseases like malaria. The shape of the engineered model is similar to that of an hourglass, allowing the researchers to study instances where red blood cell transit may encounter bottlenecks between the capillaries and other vessels. Using multiphoton technology, Zheng and her team created 100mm capillary models with etched-in channels and a collagen base, to closely model the typical size and rigidity of the vessels. Tested with malaria-infected blood cells, the model showed similar circulatory obstructive behavior to that which occurs in patients, giving hope that this model can be transferred to other diseases involving such obstruction, like sickle cell anemia, diabetes, and cardiovascular conditions.

Understanding a Cell Membrane Protein Could Be the Key to New Cancer Treatments

Almost every cell in the body has integrins, a form of proteins, on its membrane, allowing cells to sense biological information from beyond their membranes while also using this feedback information to initiate signals within cells themselves. Bioengineers at the Imperial College of London recently looked at the way another membrane protein, called syndecan-4, interacts with integrins as a potential form of future cancer treatment. Referred to as “cellular hands” by lead researcher of the study Armando del Rio Hernandez, Ph.D., syndecan-4 sometimes controls the  development of diseases or conditions like cancer and fibrosis. Hernandez and his team specifically studied the ties of syndecan-4 to yes-associated protein (YAP) and enzyme called P13K, both of which are affiliated with qualities of cancer progression like halted apoptosis or cell stiffening. Knowing this, Hernandez and his team hope to continue research into understanding the mechanisms of syndecan-4 throughout the cell, in search of new mechanisms and targets to focus on with future developments of cancer treatments.

A New Medical Device Could Improve Nerve Functionality After Severe Damage

Serious nerve damage remains difficult to repair surgically, often involving the stretching of nerves for localized damage, or the transfer of healthy nerve cells from another part of the body to fill larger gaps in nerve damage. But these imperfect solutions limit the return of full nerve function and movement to the damaged part of the body, and in more serious cases with large areas of nerve damage, can also risk damage in other areas of the body that healthy nerves are borrowed from for treatment. A new study from the University of Pittsburgh published in Science Translational Medicine led by Kacey Marra, Ph. D., has successfully repaired nerve damage in mice and monkeys using a biodegradable tube that releases growth factors called glial-cell-derived neurotrophic factors over time.

Marra and her team showed that this new device restored nerve function up to 80% in nonhuman primates, where current methods of nerve replacement often only achieve 50-60% functionality restoration. The device might have an easier time getting FDA-approval, since it doesn’t involve the use of stem cells in its repair mechanisms. Hoping to start human clinical trials in 2021, Marra and her team hope that the device will help both injured veterans and typical patients with nerve damage, and see potential future applications in facial nerve damage as well.

A New Computational Model Could Improve Treatments for Cancer, HIV, and Autoimmune Diseases

With cancer, HIV, and other autoimmune diseases, the best treatment options for patients are often determined with trial-and-error methods, leading to prolonged instances of ineffective approaches and sometimes unnecessary side effects. A group of researchers led by Wesley Errington, Ph.D., at the University of Minnesota decided to take a computational approach this problem, in an effort to more quickly and efficiently determine the most appropriate treatment for a given patient. Based on parameters controlling interactions between molecules with multiple binding sites, the team’s new model looks primarily at binding strength, linkage rigidity, and size of linkage arrays. Because diseases can often involve issues in molecular binding, the model aimed to model the 78 unique binding configurations for cases of when interacting molecules only have three binding sites, which are often difficult to observe experimentally. This new approach will allow for faster and easier determination of treatments for patients with diseases involving these molecular interactions.

Improved Drug Screening for Glioblastoma Patients

A new microfluidic brain chip from researchers at the University of Houston could help improve treatment evaluations for brain tumors. Glioblastoma patients, who have a five-year survival rate of a little over 5%, are some of the most common patients suffering from malignant brain tumors. This new chip, developed by the lab of Yasemin Akay, Ph.D., can quickly determine cancer drug effectiveness by analyzing a piece of cultured tumor biopsy from a patient by incorporating different chemotherapy treatments through the microfluidic vessels. Overall, Akay and her team found that this new chip holds hope as a future efficient and inexpensive form of drug screening for glioblastoma patients.

People and Places

The brain constructs maps to guide people, not just of physical spaces but also to connect stimuli around them, like conversations and other people. It’s long been known that the brain area responsible for this spatial navigation—the medial temporal lobe—is also involved in recalling memories.

Michael Kahana (left) is principal investigator in the Defense Advanced Research Projects Agency’s RAM program and a professor in the Department of Psychology. Ethan Solomon is an M.D./Ph.D. student in the Department of Bioengineering of the School of Engineering and Applied Science and in the Perelman School of Medicine.

Now, neuroscientists at the University of Pennsylvania have discovered that the signals the brain produces during spatial navigation and episodic memory recall look similar. Low-frequency brain waves called the theta rhythm appear as people jump from one memory to the next, as many prior studies looking only at human navigation have shown. The new findings, which suggest that the brain structures responsible for helping people navigate the world may also “navigate” a mental map of prior experiences, appear in the Proceedings of the National Academy of Sciences.

Read the rest of this story featuring Penn Bioengineering’s Graduate Group member Michael Kahana and M.D./Ph.D. student Ethan Solomon on Penn Today.

The Florida Institute of Technology recently announced plans to start construction in spring 2020 on a new Health Sciences Research Center, set to further establish biomedical engineering and pre-medical coursework and research at the institute. With plans to open the new center in 2022, Florida Tech anticipates increased enrollment in the two programs, and hopes that the center will offer more opportunities in a growing professional field.

Anson Ong, Ph.D., the Associate Dean of Administration and Graduate Programs at the University of Texas at San Antonio, was recently elected to the International College of Fellows of Biomaterials Science and Engineering. With a focus on research in biomaterial implants for orthopaedic applications, Ong’s election to the college honors his advancement and contribution to the field of biomaterials research.

Jennifer Phillips-Cremins Featured in Nature’s ‘Technologies to Watch in 2020’

Jennifer Phillips-Cremins, Ph.D.

Nature, one of the world’s most prestigious scientific journals, recently reached out to a panel of researchers from a variety of fields, asking them what technological trends they see as having the most impact on their disciplines in the coming year.

Jennifer Phillips-Cremins, assistant professor in the Department of Bioengineering, was among these panelists. As an expert in “3D epigenetics,” or the way the genome’s highly specific folding patterns influence how and when individual genes are expressed, she highlighted a slate of new techniques that will allow researchers to take a closer look at those relationships.

Read the full post at Penn Engineering blog. Media contact Evan Lerner.

Danielle Bassett Among Science’s ‘Favorite Photos of 2019’

MATTHEW BENDER/JAMES BARTOLOZZI

Among shots of a towering thunderstorm reaching into the stratosphere, the moon Daphnis peeking through Saturn’s rings, and an extremely close-up of a highly-endangered pangolin in Mozambique, one of Science’s favorite photos of 2019 was taken in Penn Engineering’s Raisler Lounge.

There, Danielle Bassett, J. Peter Skirkanich Professor in the Department of Bioengineering, poses underneath a giant visualization of the brain’s structural connections, projected on the wall behind her. Bassett’s research combines elements of physics, mathematics, engineering and neuroscience to provide a new look at how brain function arises from these networks of neurons.

Kelly Servick of Science profiled Bassett last year, revealing how a child whose parents discouraged her from attending college went on to become a pioneer in a highly interdisciplinary way of understanding the brain.

Read Bassett’s profile in Science here, and see the rest of the journal’s favorite photos of the year here.

Originally posted on the Penn Engineering blog. Media contact Evan Lerner.

Ravi Radhakrishnan Named Chair of the Department of Bioengineering

The Department of Bioengineering would like to congratulate and welcome our new Chair, Dr. Ravi Radhakrishnan! Read the post below, originally posted on the Penn Engineering blog, and visit the Radhakrishnan Lab’s website for more information on his research.

Ravi Radhakrishnan, Ph.D.

Ravi Radhakrishnan has been named Chair of the Department of Bioengineering.

Radhakrishnan holds joint appointments in the Department of Bioengineering and the Department of Chemical and Biomolecular Engineering. He is a founding member and the current Director of the Penn Institute for Computational Science, as well as a member of the Penn Physical Sciences in Oncology Center, Institute for Translational Medicine and Therapeutics, and several graduate groups, including Materials Science and Engineering, Genomics and Computational Biology, and Biochemistry and Molecular Biophysics.

In addition to these roles at Penn, Radhakrishnan holds many editorial board positions in the research community, including Nature Publishing’s Scientific Reports.

Beyond being a passionate teacher and advocate for his students, Radhakrishnan’s research interests lie at the interface of chemical physics and molecular biology. His lab’s goal is to provide molecular level and mechanistic characterization of biomolecular and cellular systems and formulate quantitatively accurate microscopic models for predicting the interactions of various therapeutic agents with innate biochemical signaling mechanisms.

David Meaney Named Senior Associate Dean of Penn Engineering

David Meaney
David Meaney, Ph.D.

David F. Meaney, Solomon R. Pollack Professor of Bioengineering, has been named the Senior Associate Dean of Penn Engineering, effective January 1, 2020. This newly created leadership position will have oversight responsibilities in budget, space and infrastructure planning; facilities and research services; and will create and cultivate new interschool partnerships that will expand Penn Engineering’s footprint on campus.

Meaney is well known not only for his scholarship and innovation in neuroengineering and concussion science, but also for his leadership during his highly successful tenure as Chair of the Department of Bioengineering.

“Dave’s strong connections to the health schools will help strengthen Penn Engineering’s initiatives throughout campus,” says Vijay Kumar, Nemirovsky Family Dean of Penn Engineering. “He will have oversight of Penn Health-Tech, the Center for Engineering MechanoBiology and other efforts between engineering and the health schools, and Dave brings his unique creativity, energy and leadership experience to these collaborative efforts.”

Read the full story on the Penn Engineering blog.

Penn Bioengineers Help Unlock Secrets of Cell Nuclei after Mitosis

By Izzy Lopez

A collaborative study conducted by researchers at the Children’s Hospital of Philadelphia (CHOP), Penn Engineering and Pennsylvania State University has uncovered new information about how chromosomal material in cell nuclei reorganizes itself after cell division.

While a deep understanding of the cell cycle is a cornerstone of biology and health sciences, research into the complex relationship between three-dimensional chromatin structure and gene transcription is still in its infancy. The results of this study will contribute to a more robust understanding of chromatin rebuilding after mitosis and potentially aid in the treatment of genetic diseases.

Jennifer E. Phillips-Cremins, Ph.D.

Jennifer E. Phillips-Cremins, Assistant Professor in the Department of Bioengineering, contributed to the study alongside Gerd A. Blobel, Frank E. Weise III Endowed Chair in Pediatric Hematology at CHOP and Ross C. Hardison, an expert in gene regulation at Penn State.

Phillips-Cremins’ research uses genetic engineering approaches to discover the mechanisms regulating chromatin organizing principles in cells, as well as computational approaches to investigate cellular function. Her lab’s techniques provide ways of mapping the three-dimensional organization of genes while they are folded together in the genome and how those spatial relationships impact gene expression.

The research team performed their experiments in blood-forming cells from a well-established mouse model. They used sophisticated techniques called high throughput chromosome conformation capture (Hi-C) that detect and map interactions across three-dimensional space between specific sites in chromosomal DNA. These maps also allowed the scientists to measure such interactions at different time points in the cell cycle. In all, the tools detected roughly 2 billion interactions during mitosis and thereafter, when the daughter nuclei are rebuilt.

Members of the Cremins Lab, Daniel J. Emerson, Thomas G. Gilgenast and Katelyn R. Titus, also contributed to the study, which was published in Nature.

Read more about this study in CHOP News.

Jason Burdick Named National Academy of Inventors Fellow

Robert D. Bent Chair
Jason Burdick, PhD

Jason Burdick, Robert D. Bent Professor in the Department of Bioengineering, has been named a Fellow of the National Academy of Inventors (NAI), an award of high professional distinction accorded to academic inventors. Elected Fellows have demonstrated a prolific spirit of innovation in creating or facilitating outstanding inventions that have made a tangible impact on quality of life, economic development and the welfare of society.

Burdick’s research interests include developing degradable polymeric biomaterials that can be used for tissue engineering, drug delivery, and fundamental polymer studies. His lab focuses on developing polymeric materials for biomedical applications with specific emphasis on tissue regeneration and drug delivery. Burdick believes that advances in synthetic chemistry and materials processing could be the answer to organ and tissue shortages in medicine. The specific targets of his research include: scaffolding for cartilage regeneration, controlling stem cell differentiation through material signals, electrospinning and 3D printing for scaffold fabrication, and injectable hydrogels for therapies after a heart attack.

Read the full story on the Penn Engineering blog.