(From left to right) Xuexiang Han, Michael Mitchell and Mohamad-Gabriel Alameh
The COVID-19 vaccine swiftly undercut the worst of the pandemic for hundreds of millions around the world. Available sooner than almost anyone expected, these vaccines were a triumph of resourcefulness and skill.
Messenger RNA vaccines, like the ones manufactured by Moderna or Pfizer/BioNTech, owed their speed and success to decades of research reinforcing the safety and effectiveness of their unique immune-instructive technology.
In addition to outlining a more flexible and effective COVID-19 vaccine, this work has potential to increase the scope of mRNA vaccines writ large, contributing to prevention and treatment for a range of different illnesses.
Michael Mitchell, associate professor in Penn Engineering’s Department of Bioengineering, Xuexiang Han, postdoctoral fellow in Mitchell’s lab, and Mohamad-Gabriel Alameh, postdoctoral fellow in Drew Weissman’s lab at Penn Medicine and incoming assistant professor in the Department of Pathology and Laboratory Medicine at the Perelman School of Medicine, recently published their findings in Nature Nanotechnology.
mRNA, or messenger ribonucleic acid, is the body’s natural go-between. mRNA contains the instructions our cells need to produce proteins that play important roles in our bodies’ health, including mounting immune responses.
The COVID-19 vaccines follow suit, sending a single strand of RNA to teach our cells how to recognize and fight the virus.
Fabrication steps of the biodegradable BC substrate and the electrochemical devices. (1) Incubation of the bacterium Gluconacetobacter hansenii. (2) BC substrate collected and treated, resulting in a clear sheet. (3) The biodegradable BC sheet is screen-printed, (4) resulting in a device with 3 electrodes, (4) which are cut out using a scissor, (5) resulting in a portable, biodegradable, and inexpensive electrochemical sensor.
The availability of rapid, accessible testing was integral to overcoming the worst surges of the COVID-19 pandemic, and will be necessary to keep up with emerging variants. However, these tests come with unfortunate costs.
Polymerase chain reaction (PCR) tests, the “gold standard” for diagnostic testing, are hampered by waste. They require significant time (results can take up to a day or more) as well as specialized equipment and labor, all of which increase costs. The sophistication of PCR tests makes them harder to tweak, and therefore slower to respond to new variants. They also carry environmental impacts. For example, most biosensor tests developed to date use printed circuit boards, or PCBs, the same materials used in computers. PCBs are difficult to recycle and slow to biodegrade, using large amounts of metal, plastic and non-eco-friendly materials.
In addition, most PCR tests end up in landfills, resulting in material waste and secondary contamination. An analysis by the World Health Organization (WHO) estimated that, as of February 2022, “over 140 million test kits, with a potential to generate 2,600 tonnes of non-infectious waste (mainly plastic) and 731,000 litres of chemical waste (equivalent to one-third of an Olympic-size swimming pool) have been shipped.”
In order to balance the need for fast, affordable and accurate testing while addressing these environmental concerns, César de la Fuente, Presidential Assistant Professor in Bioengineering and Chemical and Biomolecular Engineering in the School of Engineering and Applied Science, with additional primary appointments in Psychiatry and Microbiology within the Perelman School of Medicine, has turned his attention to the urgent need for “green” testing materials.
The de la Fuente lab has been working on creative ways to create faster and cheaper testing for COVID-19 since the outbreak of the pandemic. Utilizing his lab’s focus on machine biology and the treatment of infectious disease, they created RAPID, an aptly named test that generates results in minutes with a high degree of accuracy. An even more cost-effective version, called LEAD, was created using electrodes made from graphite. A third test, called COLOR, was a low-cost optodiagnostic test printed on cotton swabs.
The team’s latest innovation incorporates the speed and cost-effectiveness of previous tests with eco-friendly materials. In a paper published in Cell Reports Physical Science, the group introduces a new test made from Bacterial Cellulose (BC), an organic compound synthesized from several strains of bacteria, as a substitute for PCBs.
Artificial intelligence is a new addition to the infectious disease researcher’s toolbox. Yet in merely half a decade, AI has accelerated progress on some of the most urgent issues in medical science and public health. Researchers in this field blend knowledge of life sciences with skill in computation, chemistry and design, satisfying decades-long appeals for interdisciplinary tactics to treat these disorders and stop their spread.
Diseases are “infectious” when they are caused by organisms, including parasites, viruses, bacteria and fungi. People and animals can contract infectious diseases from their environments or food, or through interactions with one another. Some, but not all, are contagious.
Infectious diseases are an intractable global challenge, posing problems that continue to grow in severity even as science has offered a steady pace of solutions. The world continues to become more interconnected, bringing people into new kinds and levels of relation, and the climate crisis is throwing environmental and ecological networks out of balance. Diseases that were once treatable by drugs have become resistant, and new drug discovery is more costly than ever. Uneven resource distribution means that certain parts of the world are perennial hotspots for diseases that others never fear.
In the paper, de la Fuente and co-authors assess the progress, limitations and promise of research in AI and infectious diseases in three major areas of inquiry: anti-infective drug discovery, infection biology, and diagnostics for infectious diseases.
A cross-kingdom partnership between bacteria and fungi can result in the two joining to form a “superorganism” with unusual strength and resilience. It may sound like the stuff of science fiction, but these microbial groupings are very much part of the here and now.
Found in the saliva of toddlers with severe childhood tooth decay, these assemblages can effectively colonize teeth. They were stickier, more resistant to antimicrobials, and more difficult to remove from teeth than either the bacteria or the fungi alone, according to the research team, led by University of PennsylvaniaSchool of Dental Medicine scientists.
What’s more, the assemblages unexpectedly sprout “limbs” that propel them to “walk” and “leap” to quickly spread on the tooth surface, despite each microbe on its own being non-motile, the team reported in the journal Proceedings of the National Academy of Sciences.
“This started with a very simple, almost accidental discovery, while looking at saliva samples from toddlers who develop aggressive tooth decay,” says Hyun (Michel) Koo, a professor at Penn Dental Medicine and a co-corresponding author on the paper. “Looking under the microscope, we noticed the bacteria and fungi forming these assemblages and developing motions we never thought they would possess: a ‘walking-like’ and ‘leaping-like’ mobility. They have a lot of what we call ‘emergent functions’ that bring new benefits to this assemblage that they could not achieve on their own. It’s almost like a new organism—a superorganism—with new functions.”
Hyun (Michel) Koo is a professor in the Department of Orthodontics and the divisions of Community Oral Health and Pediatric Dentistry in the School of Dental Medicine, co-founder of the Center for Innovation & Precision Dentistry (CiPD) at the University of Pennsylvania, and member of the Penn Bioengineering Graduate Group.
César de la Fuente, Presidential Assistant Professor in Psychiatry, Bioengineering, Microbiology, and in Chemical and Biomolecular Engineering has been honored with a 2022 Young Investigator Award by the Royal Spanish Society of Chemistry (RSEQ) for his pioneering research efforts to combine the power of machines and biology to help prevent, detect, and treat infectious diseases.
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.
Created in the lab of César de la Fuente, this miniaturized, portable version of rapid COVID-19 test, which is compatible with smart devices, can detect SARS-CoV-2 within four minutes with nearly 100% accuracy. (Image: Courtesy of César de la Fuente)
The lab of Penn’s César de la Fuente sits at the interface of machines and biology, with much of its work focused on innovative treatments for infectious disease. When COVID-19 appeared, de la Fuente and his colleagues turned their attention to building a paper-based biosensor that could quickly determine the presence of SARS-CoV-2 particles from saliva and from samples from the nose and back of the throat. The initial iteration, called DETECT 1.0, provides results in four minutes with nearly 100% accuracy.
Clinical trials for the diagnostic began Jan. 5, with the goal of collecting 400 samples—200 positive for COVID-19, 200 negative—from volunteers who also receive a RT-PCR or “reverse transcription polymerase chain reaction” test. This will provide a comparison set against which to measure the biosensor to determine whether the results the researchers secured at the bench hold true for samples tested in real time. De la Fuente expects the trial will take about a month.
If all goes accordingly, he hopes these portable rapid breath tests could play a part in monitoring the COVID status of faculty, students, and staff around Penn.
César 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, the Machine Biology Group, does today. (Photo: Eric Sucar)
Taking on COVID-19 research in this fashion made sense for this lab. “We’re the Machine Biology Group, and we’re interested in existing and emerging pathogens,” says de la Fuente, who has appointments in the Perelman School of Medicine and School of Engineering and Applied Science. “In this case, we’re using a machine to rapidly detect SARS-CoV-2.”
To this point in the pandemic, most SARS-CoV-2 diagnostics have used RT-PCR. Though effective, the technique requires significant space and trained workers to employ, and it is costly and takes hours or days to provide results. De la Fuente felt there was potential to create something inexpensive, quicker, and, perhaps most importantly, scalable.
When the immune system detects a foreign pathogen, a cascade of chemical signals call white blood cells to the scene. Neutrophils are the most common and abundant type of these cells and while they start accumulating at the site of an infection within minutes, they are essentially at the mercy of the circulatory system’s one-way flow of traffic to get them where they need to go.
Now, research from the University of Pennsylvania’s School of Engineering and Applied Science shows how these cells can be coaxed to fight the direction of blood flow, crawling upstream along the walls of veins and arteries.
The in vitro study suggested that this technique could get neutrophils to the sites of infections faster when they are restricted to the direction of blood flow.
Alexander Buffone and Daniel Hammer
Daniel A. Hammer, Alfred G. and Meta A. Ennis Professor in the Department of Bioengineering, and Alexander Buffone, Jr., a research associate in his lab, led the research. Nicholas R. Anderson, a graduate student in the Hammer lab, also contributed to the study.
Detecting Infectious Diseases with Paper-Based Devices
Dr. Linnes’ paper device. Image used courtesy of Erin Easterling, Purdue College of Engineering.
Despite great advancements in diagnostics technology over the past few decades, patient accessibility to these technologies remains one of the biggest challenges of the field today. Particularly in low-resource areas, even simple processes can end up taking weeks or months to return results from tests that are normally completed in days. But what if these tests could be simplified to smaller, at-home tests based on properties of microfluidics – something like a pregnancy test but for infectious diseases like HIV?
Jacqueline Linnes, Ph.D., and her team of researchers at Purdue University are working towards finding a way to do just that by creating paper-based devices that use microfluidics to help carry out the necessary diagnostic tests. Specifically, her lab designed such a paper-based system that can detect HIV nucleic acids within 90 minutes of receiving a drop of patient blood. The success of this design shows promise for producing devices for diseases whose diagnostics process involve similar pathways of pathogen detection, opening the door to more applications of at-home tests based in the properties of paper microfluidics.
Here at Penn, undergraduate bioengineering students enrolled in the two-semester laboratory course Bioengineering Modeling, Analysis, and Design (BE 309 & BE 310) have the chance to create their own models of paper microfluidics delivery systems based on given time constraints in a multi-step process. Though the students’ challenge only involves water as a substrate, Linnes’ research demonstrates the later implications of studying fluid flow through a medium as cheap and accessible as paper.
Watch the video below demonstrating Dr. Linnes’ device:
Funding for Cancer Research in Tumor Mimicry and Imaging
Two of the deadliest forms of cancer today are breast cancer and pancreatic cancer, with the latter having a five-year survival rate of only about 8%. Because cancer treatments are often adjusted according to a unique patient-to-patient basis, learning how to improve predictions of tumor behavior could help determine proper therapies sooner.
Chien-Chi Lin, Ph.D., an associate professor of biomedical engineering at Indiana University – Purdue University Indianapolis, recently received a grant from the National Institute of Health to advance his research in pancreatic cancer treatment. His project under the grant involves the development of bio-inspired, responsive, and viscoelastic (BRAVE) cell-laden hydrogels to help understand cell interactions in pancreatic ductal adenocarcinoma, which is the most common form of malignancy in the pancreas. These hydrogels mimic tumor tissue, as well as model tumor development over time, helping to eventually find better ways of treating pancreatic cancer.
In other news surrounding cancer-related research, a team of researchers led by Kenneth Tichauer, Ph.D., at the Illinois Institute of Technology won the university’s Nayar Prize for their development of the Agent-Dependent Early Photon Tomography (ADEPT) Cancer Imager, a machine designed to find early tumor development in the lymph nodes of breast cancer patients. Through the use of a special dyeing process that now dyes the entire lymph node, providing a sharper image that allows for a quicker discovery of smaller tumors.
Penn’s Women in Computer Science (WiCS) Hosts FemmeHacks
Penn President Amy Gutmann and Penn Engineering Dean Vijay Kumar stopped by FemmeHacks at the Pennovation Center Feb. 9. The annual event is a beginner-friendly collegiate hackathon for women-identifying people with an interest in computer programming, and featured a day of all-levels workshops Feb. 8. The event is sponsored by Penn’s Women in Computer Science student organization.
Though the event is not specifically tailored towards applications in bioengineering, skills relating to coding and software development are increasingly important for those interested in pursuing a career in medical device design. In fact, in the evaluation of new medical devices, the FDA often focuses more on software over hardware, as the former is associated with more security liabilities, due to its relative novelty.
Case Western Reserve University and Cleveland Clinic announced the launch of an alliance last year with the goal of creating better synergy across the two renowned institutions, hoping to provide more opportunities for students with interest in medicine at all levels, from high school to postdoctoral education. Though researchers from both institutions frequently partner on projects, this new alliance will create a more structured platform for future collaborations.
We would like to commend Steven George, M.D./Ph.D., on his new position as the chair of the Department of Biomedical Engineering at the University of California at Davis. His research involves the development of “organ-on-a-chip” technologies using stem cells and microfluidics to mimic human organ functions of vascularized cardiac, tumor, and pancreatic tissues.
Finally, we want to congratulate Paul Yock, M.D., on his being chosen to receive the National Academy of Engineering’s 2019 Fritz J. and Dolores H. Russ Prize. The prize honors two of Dr. Yock’s inventions from his research in interventional cardiology, one of which is Rapid Exchange, which is a kind of stenting and balloon angioplasty system. Dr. Yock is the Martha Meier Weiland Professor in the School of Medicine and Professor of Bioengineering.
Speaker: 
