Measuring Chaos: Using Machine Learning to Satisfy Our Need to Know

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How do we measure chaos and why would we want to? Together, Penn engineers Dani S. Bassett, J. Peter Skirkanich Professor in Bioengineering and in Electrical and Systems Engineering, and postdoctoral researcher Kieran Murphy leverage the power of machine learning to better understand chaotic systems, opening doors for new information analyses in both theoretical modeling and real-world scenarios.

Humans have been trying to understand and predict chaotic systems such as weather patterns, the movement of planets and population ecology for thousands of years. While our models have continued to improve over time, there will always remain a barrier to perfect prediction. That’s because these systems are inherently chaotic. Not in the sense that blue skies and sunshine can turn into thunderstorms and torrential downpours in a second, although that does happen, but in the sense that mathematically, weather patterns and other chaotic systems are governed by physics with nonlinear characteristics. 

“This nonlinearity is fundamental to chaotic systems,” says Murphy. “Unlike linear systems, where the information you start with to predict what will happen at timepoints in the future stays consistent over time, information in nonlinear systems can be both lost and generated through time.”

Like a game of telephone where information from the original source gets lost as it travels from person to person while new words and phrases are added to fill in the blanks, outcomes in chaotic systems become harder to predict as time passes. This information decay thwarts our best efforts to accurately forecast the weather more than a few days out.

“You could put millions of probes in the atmosphere to measure wind speed, temperature and precipitation, but you cannot measure every single atom in the system,” says Murphy. “You must have some amount of uncertainty, which will then grow, and grow quickly. So while a prediction for the weather in a few hours might be fairly accurate, that growth in uncertainty over time makes it impossible to predict the weather a month from now.”

In their recent paper published in Physical Review Letters, Murphy and Bassett applied machine learning to classic models of chaos, physicists’ reproductions of chaotic systems that do not contain any external noise or modeling imperfections, to design a near-perfect measurement of chaotic systems to one day improve our understanding of systems including weather patterns. 

“These controlled systems are testbeds for our experiments,” says Murphy. “They allow us to compare with theoretical predictions and carefully evaluate our method before moving to real-world systems where things are messy and much less is known. Eventually, our goal is to make ‘information maps’ of real-world systems, indicating where information is created and identifying what pieces of information in a sea of seemingly random data are important.” 

Read the full story in Penn Engineering Today.

Highways to Health: Bicontinuous Structures Speed Up Cell Migration

by Ian Scheffler

Bicontinuous materials, like this representation of a cube of gelatin and hyaluronic acid, have greater internal surface area, allowing cells to travel faster between two points. (Credit: Karen Xu)

One of the most important but least understood aspects of healing is cell migration, or the process of cells moving from one part of the body to another. “If you are an ambulance out in the woods,” says Karen Xu, an M.D/Ph.D. student in Medicine and Bioengineering, “and there are no paths for you to move forward, it will be a lot harder for you to get to a site that needs you.”

Earlier this year, Xu co-authored a paper in Nature Communications describing a new cue to help cells get to where they need to go: a material made chiefly of hyaluronic acid and gelatin, two gooey substances commonly found outside cells in joints and connective tissue.

“Hundreds of thousands of people tear their meniscus every year,” says Robert Mauck, Mary Black Ralston Professor in Orthopaedic Surgery in Penn Medicine and Professor in Bioengineering at Penn Engineering and one of Xu’s advisors, as well as a senior author on the paper. “This material could potentially speed up their recovery.”

What makes the material — known as a hydrogel due to its blend of gelatinous matter and water — unique is that the combination of hyaluronic acid and gelatin forms a complex network of paths, providing cells many different ways to travel between two points.

This property is known as bicontinuity, and is exemplified by two discrete continuous phases that are each connected throughout the entire volume of the material (for example with a sponge, with phases of cellulose and air; in the hydrogel, this is comprised of gelatin and hyaluronic acid) resulting in a dizzying array of patterns that dramatically increase the surface area inside the material.

To test the hydrogel’s efficacy, Xu and her collaborators — including co-advisor Jason Burdick, formerly the Robert D. Bent Professor in Bioengineering at Penn Engineering and now the Bowman Endowed Professor at the University of Colorado Boulder, and the paper’s other senior author — first created several different versions of the hydrogel to find the sweet spot at which the constituents formed the bicontinuous structure and had the highest internal surface area. “We found that a precise combination of the various hydrogel components and control over their mixing was needed to form the bicontinuous structure,” says Burdick.

Read the full story in Penn Engineering Today.

Shedding Light on Cellular Metabolism to Fight Disease

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Enamored by the chemical processes of life, Yihui Shen, J. Peter and Geri Skirkanich Assistant Professor of Innovation in Bioengineering, started her research career as a chemist studying the way that proteins fold and the intricate dynamics underlying life processes.

“As an undergraduate, I studied physical chemistry, thinking that one day I’d be addressing challenges in hardcore STEM fields,” she says. “It wasn’t until I observed the dynamics of a single protein molecule that I fell in love with microscopy. I realized that this imaging tool could not only help us observe biological processes on a small scale, but it could also provide new insight at the interface of engineering, chemistry and physics and solve problems on a large scale.”

When Shen turned her attention to microscopy, the field itself was advancing quickly, with improvements being made and new techniques being released every month. Without missing a beat, Shen dove deeper into the most current tools available when she joined Dr. Wei Min’s lab at Columbia University as a doctoral student.

“Professor Wei Min is a pioneer in a new imaging technique called coherent Raman imaging,” says Shen. “In this type of microscopy, we focus light on a very specific point in the cell and measure the amount of scattered light that comes back after exchanging energy with the molecular vibration. This approach allows us to visualize the spatial distribution of different molecules, the very chemistry of life I had studied as an undergraduate, at a high enough resolution to gain insights into biological processes, such as tissue organization, drug distribution and cellular metabolism.”

With this new tool under her belt, Shen was able to ask the kinds of questions that could connect the use of this observation tool to practical applications for real-world challenges.

“I started thinking outside the box,” says Shen. “What if we could observe the chemical exchanges involved in metabolism as they are happening on the scale of a single cell, and then use that insight to pinpoint the exact metabolic pathways and molecules that facilitate tumor growth and disease?”

Read the full story in Penn Engineering Today.

Penn Pioneers a ‘One-Pot Platform’ to Promptly Produce mRNA Delivery Particles

by Nathi Magubane

Lipid nanoparticles present one of the most advanced drug delivery platforms to shuttle promising therapeutics such as mRNA but are limited by the time it takes to synthesize cationic lipids, a key component. Now, Michael Mitchell and his team at the School of Engineering and Applied Science have developed a faster way to make cationic lipids that are also more versatile, able to carry different kinds of treatments to target specific organs. (Image: iStock / Dr_Microbe)

Imagine a scenario where a skilled hacker must upload critical software to update a central server and thwart a potentially lethal virus from wreaking havoc across a vast computer network. The programmer, armed with the lifesaving code, must navigate through treacherous territory teeming with adversaries, and success hinges on promptly getting a safe, stealthy delivery vehicle that can place the hacker exactly where they need to be.

In the context of modern medicine, messenger RNA (mRNA) serves as the hacker, carrying genetic instructions to produce specific proteins within cells that can induce desired immune responses or sequester maladaptive cellular elements. Lipid nanoparticles (LNPs) are the stealthy delivery vehicles that transport these fragile mRNA molecules through the bloodstream to their target cells, overcoming the body’s defenses to deliver their payload safely and efficiently.

However, much like building an advanced stealth vehicle, the synthesis of cationic lipids—a type of lipid molecule that’s positively charged and a key component of LNPs—is often a time-consuming process, involving multiple steps of chemical synthesis and purification.

Now, Michael Mitchell and a team at the University of Pennsylvania have addressed this challenge with a novel approach that leverages a compound library fabrication technique known as “click-like chemistry” to create LNPs in a single, simple step. Their findings, published in the journal Nature Chemistry, show that this method not only speeds up the synthesis process but also presents a way to equip these delivery vehicles with a “GPS” to better target specific organs such as the liver, lungs, and spleen, potentially opening new avenues for treating a range of diseases that arise in these organs.

“We’ve developed what we call an amidine-incorporated degradable (AID) lipid, a uniquely structured biodegradable molecule,” Mitchell says. “Think of it as an easy-to-build custom mRNA vehicle with a body kit that informs its navigation system. By adjusting its shape and degradability, we can enhance mRNA delivery into cells in a safe manner. By adjusting the amount of the AID lipid that we incorporate into the LNP, we can also guide it to different organs in the body, much like programming different destinations into a GPS.”

First author Xuexiang Han, a former postdoctoral researcher in the Mitchell Lab, explains that their new approach allows the rapid creation of diverse lipid structures in just an hour, compared to the weekslong process traditionally required.

Read more in Penn Today.

2024 Graduate Research Fellowships for Penn Bioengineering Students

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Congratulations to the fifteen Bioengineering students to receive 2024 National Science Foundation Graduate Research Fellowship Program (NSF GRFP) fellowships. The prestigious NSF GRFP program recognizes and supports outstanding graduate students in NSF-supported fields. The recipients were selected from a highly-competitive, nationwide pool. Further information about the program can be found on the NSF website.

The following Ph.D. students in Bioengineering received awards:

Anushka Agrawal – Mitchell Lab

Amanda Bluem  – incoming student

Stephen Ching – incoming student, Research Staff in the Hast Lab

Ana Crysler – incoming student, de la Fuente Lab

Ellie Feng – incoming student

Stephen Lee – Alvarez lab

Jenlu Pagnotta – incoming student

Schyler Rowland – incoming student

Rayna L. Schoenberger – incoming student, Gottardi Lab

Eva Utke – incoming student

Delaney Wilde – Bugaj Lab

The following BE undergraduate students also received awards and will be pursuing graduate study:

Aditi Ghalsasi – Recent M&T program graduate (Bioengineering and Finance), Mitchell Lab

Ryan Lim – Recent B.S.E. graduate, incoming Ph.D. student at Harvard-MIT

Angela Song – Recent B.S.E. graduate, Wallace Lab

Dorix Xu – Recent B.S.E. graduate, Center for Neuroengineering and Therapeutics

The following students received honorable mention:

Ekta Singh – Recent Master’s in BE graduate, incoming Ph.D. student, Witschey Lab

Ksenija Tasich – incoming Ph.D. student

Emma Warrner – incoming Ph.D. student

Alison Pouch Wins 2024 Cardiac Center Innovation Award

Alison Pouch

Congratulations to Alison Pouch, Assistant Professor in Bioengineering in the School of Engineering and Applied Science, and in Radiology in the Perelman School of Medicine, on winning a 2024 Cardiac Center Innovation Award for scientific research from the Children’s Hospital of Philadelphia (CHOP)’s Philly Spin-In. Pouch’s study, titled “Systemic Semilunar Valve Mechanics and Simulated Repair in Congenital Heart Disease,” is a collaboration with Matthew Jolley, Assistant Professor of Anesthesiology and Critical Care at CHOP:

“Through biomechanical assessment, Drs. Matthew Jolley and Alison Pouch are leading an interdisciplinary CHOP-Penn team that plans to determine why current approaches to systemic semilunar valve (SSV) repair fail. They will also investigate methods to design improved repairs before going to the operating room by using computational simulation to iteratively optimize repair.

‘We believe that understanding biomechanics of abnormal SSVs and explorations of simulated repair will markedly improve our ability to characterize, risk stratify, and surgically treat SSV dysfunction, thereby improving long-term outcomes and quality of life in patients with SSV dysfunction,’ Dr. Jolley said.”

Pouch’s lab focuses on 3D/4D segmentation and modeling of heart valves in echocardiographic images with applications to surgical treatment of valvular regurgitation as part of the Penn Image Computing and Science Laboratory.

Read the full awards announcement in the CHOP Cornerstone Blog.

How to Learn About a World-class Double Bass? Give it a CT

by Darcy Lewis  

The instrument imaging team, from left: Philadelphia Orchestra bassist Duane Rosengard; Peter Noël, PhD, director of CT Research at the Perelman School of Medicine; luthier Zachary S. Martin; Leening Liu, a PhD student in Noël’s Laboratory of Advanced Computed Tomography Imaging; and Mark Kindig.

When you’re an expert in medical CT imaging, two things are bound to happen, says Peter Noël, PhD, associate professor of Radiology and director of CT Research at the Perelman School of Medicine. One: You develop an insatiable curiosity about the inner workings of all kinds of objects, including those unrelated to your research. And two: Both colleagues and complete strangers will ask for your help in imaging a wide variety of unexpected items.

Over the course of his career, in between managing his own research projects, Noël has imaged diverse objects ranging from animal skulls to tree samples from a German forest, all in the name of furthering scientific knowledge. But none has intrigued him as much as his current extracurricular project: the first known attempt to perform CT imaging of some of the world’s finest string basses. 

The goal is to crack the code on what makes a world-class instrument. This knowledge could both increase the ability to better care for masterworks built between the 17th and 19th centuries, as well as providing insights into refining the building of new ones, including possibly shifting from older, scarcer European wood to the use of sustainably harvested U.S. wood.

That’s why Noël and Leening Liu, a PhD student in Noël’s Laboratory of Advanced Computed Tomography Imaging, have found themselves volunteering to run the basses through a Penn CT scanner occasionally, when they’re not developing next-generation CT technology. 

“We always learn something out of projects like this … the more appealing part is that medical research can also be applied to non-medical things,” Noël said. “We have the opportunity to take what we learn in medicine and use it for something else—in this case, moving the arts forward.”

Read the full story in Penn Medicine News.

Peter Noël is Assistant Professor of Radiology in the Perelman School of Medicine and member of the Penn Bioengineering Graduate Group.

Leening Liu is a Ph.D. student in Bioengineering. She is a member of the Laboratory for Advanced Tomography Imaging (LACTI) with research interests including clinical applications of spectral CT and spectral CT thermometry.

Who, What, Why: Lasya Sreepada on Decoding Alzheimer’s Disease

by Nathi Magubane

Lasya Sreepada, Ph.D. student in Bioengineering

Lasya Sreepada has always been fascinated by the brain and the underlying biology that shapes how people develop and age. “My curiosity traces back to observing differences between myself and my sister,” says Sreepada, a Ph.D. candidate in Bioengineering whose research unites efforts across Penn Medicine and Penn Engineering. “We grew up in the same environment but had remarkably different personalities, which led me to question what drove these differences and which brought me to the brain.”

Her academic journey began by applying medical imaging to understand how brain injuries sustained by professional athletes or military veterans impact their brain structure and chemistry over time. She became curious about how neurotrauma impacts aging and degeneration in the long term. Now, she leverages large, multimodal datasets to investigate neurodegenerative disease, with a particular focus on Alzheimer’s.

Read the full story in Penn Today.

Lasya Sreepada is a Bioengineering Ph.D. student at the Bioinformatics in Neurodegenerative Disease (BiND) Lab at Penn, advised by Corey McMillan and Dave Wolk, both Associate Professors in Neurology and members of the Bioengineering Graduate Group.

The Penn Forum on Quantum Systems (FoQuS), QUIEST’s First Inaugural Symposium, Hosts International Experts in Quantum Research

by Melissa Pappas

Dawn Bonnell gave the opening remarks of FoQuS.

Sometimes, nature’s smallest objects have the biggest impact. Take the quantum realm, which involves the building blocks of matter itself. 

Quantum science aims to understand the behavior of matter and energy at the scale of atoms and subatomic particles. Because particles frequently defy human intuition at this scale, the field likely offers great, untapped potential to solve some of our most complex issues.

“Bringing ‘quantum superstars’ from academia and industry to a space where scientists of all levels could interact, exchange ideas and gain inspiration is just one way we can foster collaboration in advancing the field and exploring new possibilities,” says Lee Bassett, Associate Professor in Electrical and Systems Engineering (ESE) and Director of the Center for Quantum Information, Engineering, Science and Technology (QUIEST).

Established in June 2023, QUIEST hosted its first symposium, The Penn Forum on Quantum Systems (FoQuS), last month, which reached over 150 attendees and included keynote speakers from across the country and globe. 

“The event was a wonderful success,” says Bassett. “External speakers appreciated being part of these discussions and seeing the exciting things happening at Penn. Penn faculty and students were thrilled to learn more about the state-of-the-art quantum research happening around the world in industry and in national labs.”

The forum’s goals were to connect researchers, raise awareness about regional, national and international efforts in quantum engineering and help guide research and education priorities for the QUIEST Center. 

Touching on all four research domains of the Center (Materials for QUIEST, Quantum Devices, Quantum Systems and QUIEST Impact), the forum left attendees, including faculty as well as graduate, undergraduate and high school students, with new inspiration for future research. 

Read the full story in Penn Engineering Today.

Dawn Bonnell, Henry Robinson Towne Professor in Materials Science and Engineering, Senior Vice Provost for Research, and member of the Penn Bioengineering Graduate Group, delivered opening remarks of FoQuS.

Looking to AI to Solve Antibiotic Resistance

by Nathi Magubane

Cesar de la Fuente (left), Fangping Wan (center), and Marcelo der Torossian Torres (right). Fangping holds a 3D model of a unique ATP synthase fragment, identified by their lab’s deep learning model, APEX, as having potent antibiotic properties.

“Make sure you finish your antibiotics course, even if you start feeling better’ is a medical mantra many hear but ignore,” says Cesar de la Fuente of the University of Pennsylvania.

He explains that this phrase is, however, crucial as noncompliance could hamper the efficacy of a key 20th century discovery, antibiotics. “And in recent decades, this has led to the rise of drug-resistant bacteria, a growing global health crisis causing approximately 4.95 million deaths per year and threatens to make even common infections deadly,” he says.

De la Fuente, a Presidential Assistant Professor, and a team of interdisciplinary researchers have been working on biomedical innovations tackling this looming threat. In a new study, published in Nature Biomedical Engineering, they developed an artificial intelligence tool to mine the vast and largely unexplored biological data—more than 10 million molecules of both modern and extinct organisms— to discover new candidates for antibiotics.

“With traditional methods, it takes around six years to develop new preclinical drug candidates to treat infections and the process is incredibly painstaking and expensive,” de la Fuente says. “Our deep learning approach can dramatically reduce that time, driving down costs as we identified thousands of candidates in just a few hours, and many of them have preclinical potential, as tested in our animal models, signaling a new era in antibiotic discovery.” César de la Fuente holds a 3D model of a unique ATP synthase fragment, identified by his lab’s deep learning model, APEX, as having potent antibiotic properties. This molecular structure, resurrected from ancient genetic data, represents a promising lead in the fight against antibiotic-resistant bacteria.

These latest findings build on methods de la Fuente has been working on since his arrival at Penn in 2019. The team asked a fundamental question: Can machines be used to accelerate antibiotic discovery by mining the world’s biological information? He explains that this idea is based on the notion that biology, at its most basic level, is an information source, which could theoretically be explored with AI to find new useful molecules.

Read the full story in Penn Today.