Category: issues

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“QR Code for Cancer Cells” – Uncovering Why Some Cells Become Resistant to Anti-Cancer Therapies

by Win Reynolds

QR codeA research team led by engineers at the University of Pennsylvania and Northwestern University scientists has created a new synthetic biology approach, or a “QR code for cancer cells,” to follow tumor cells over time, finding there are meaningful differences in why a cancer cell dies or survives in response to anti-cancer therapies.

Remarkably, what fate cancer cells choose after months of therapy is “entirely predictable” based on seemingly small, yet important, differences that appear even before treatment begins. The researchers also discovered the reason is not genetics, contrary to beliefs held in the field.

The findings were recently published in Nature.

The study outlined the team’s new technology platform that developed a QR code for each of the millions of cells for scientists to find and use later — much like tagging swans in a pond. The QR code directs researchers to a genome-wide molecular makeup of these cells and provides information about how they’ve reacted to cancer treatment.

“We think this work stands to really change how we think about therapy resistance,” said Arjun Raj, co-senior author and Professor in Bioengineering in the School of Engineering and Applied Science at the University of Pennsylvania. “Rather than drug-resistant cells coming in just one flavor, we show that even in highly controlled conditions, different ‘flavors’ can emerge, raising the possibility that each of these flavors may need to be treated individually.”

In the study, the lab and collaborators sought to apply synthetic biology tools to answer a key question in cancer research: What makes certain tumors come back a few months or years after therapy? In other words, could the lab understand what causes some rare cells to develop therapeutic resistance to a drug?

“There are many ways cells become different from each other,” said Yogesh Goyal, the co-senior author at Northwestern University. “Our lab asks, how do individual cells make decisions? Understanding this in the context of cancer is all the more exciting because there’s a clinically relevant dichotomy: A cell dies or becomes resistant when faced with therapies.”

Using the interdisciplinary team, the scientists put the before-and-after cloned cells through a whole genome sequencing pipeline to compare the populations and found no systematic underlying genetic mutations to investigate the hypothesis. Raj and Goyal  helped develop the QR code framework, FateMap, that could identify each unique cell that seemed to develop resistance to drug therapy. “Fate” refers to whether a cell dies or survives (and if so, how), and the scientists “map” the cells across their lifespan, prior to and following anti-cancer therapy. FateMap is the result of work from several research institutions, and it applies an amalgamation of concepts spanning several disciplines, including synthetic biology, genome engineering, bioinformatics, machine learning and thermodynamics.

“Some are different by chance — just as not all leaves on a tree look the same — but we wanted to determine if that matters,” Goyal said. “The cell biology field has a hard time defining if differences have meaning.”

Read the full story in Penn Engineering Today.

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AI-guided Brain Stimulation Aids Memory in Traumatic Brain Injury

by Erica Moser

Illustration of a human brain
Image: iStock/Ogzu Arslan

Traumatic brain injury (TBI) has disabled 1 to 2% of the population, and one of their most common disabilities is problems with short-term memory. Electrical stimulation has emerged as a viable tool to improve brain function in people with other neurological disorders.

Now, a new study in the journal Brain Stimulation shows that targeted electrical stimulation in patients with traumatic brain injury led to an average 19% boost in recalling words.

Led by University of Pennsylvania psychology professor Michael Jacob Kahana, a team of neuroscientists studied TBI patients with implanted electrodes, analyzed neural data as patients studied words, and used a machine learning algorithm to predict momentary memory lapses. Other lead authors included Wesleyan University psychology professor Youssef Ezzyat and Penn research scientist Paul Wanda.

“The last decade has seen tremendous advances in the use of brain stimulation as a therapy for several neurological and psychiatric disorders including epilepsy, Parkinson’s disease, and depression,” Kahana says. “Memory loss, however, represents a huge burden on society. We lack effective therapies for the 27 million Americans suffering.”

Read the full story in Penn Today.

Michael Kahana is the Edmund J. and Louise W. Kahn Term Professor of Psychology at the University of Pennsylvania. He is a member of the Penn Bioengineering Graduate Group.

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Artificial Intelligence is Leveling Up the Fight Against Infectious Diseases

by Devorah Fischler

Image credit: NIAID

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.

Cesar de la Fuente brings an expert eye to how AI has transformed infectious disease research in a recently published piece in Science with co-authors Felix Wong and James J. Collins from MIT.

Presidential Assistant Professor in the Department of Bioengineering and the Department of Chemical and Biomolecular Engineering at the University of Pennsylvania School of Engineering and Applied Science, with additional primary appointments in Psychiatry and Microbiology within the Perelman School of Medicine, de la Fuente brings a multifaceted perspective to his survey of the field.

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.

Read more in Penn Engineering Today.

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Penn Bioengineers Create Non-invasive Cartilage Implants for Pediatric Subglottic Stenosis

by Emily Shafer

Paul Gehret and Riccardo Gottardi accept the International Society for Biofabrication New Investigator Award onstage at the international conference.
Paul Gehret (left) and Riccardo Gottardi, PhD, at Biofabrication 2022, the International Conference on Biofabrication.

Bioengineering researchers at Children’s Hospital of Philadelphia are developing a less invasive and quicker method to create cartilage implants as an alternative to the current treatment for severe subglottic stenosis, which occurs in 10 percent of premature infants in the U.S.

Subglottic stenosis is a narrowing of the airway, in response to intubation. Severe cases require laryngotracheal reconstruction that involves grafting cartilage from the rib cage with an invasive surgery. With grant support from the National Institutes of Health, Riccardo Gottardi, PhD, who leads the Bioengineering and Biomaterials (Bio2) Lab at CHOP, is refining a technology called Meniscal Decellularized scaffold (MEND). Working with a porcine model meniscus, the researchers remove blood vessels and elastin fibers to create pathways that allow for recellularization. Dr. Gottardi and his team then harvest ear cartilage progenitor cells (CPCs) with a minimally invasive biopsy, combine them with MEND, and create cartilage implants that could be a substitute for the standard laryngotracheal reconstruction.

This work and similar work on the tympanic membrane earned Paul Gehret, a doctoral student in the Gottardi Lab, the International Society for Biofabrication New Investigator Award and the Wake Forest Institute for Regenerative Medicine Young Investigator Award.  Gehret and Dr. Gottardi accepted the awards at Biofabrication 2022, the International Conference on Biofabrication, in Pisa Italy.

While laryngotracheal reconstruction in the adult population has a success rate of up to 96%, success rates in children range from 75% to 85%, and children often require revision surgery due to a high incidence of restenosis. The procedure also involves major surgery to remove cartilage from the rib cage, which is more difficult for childrens’ smaller bodies.

“Luckily not many children suffer from severe subglottic stenosis, but for those who do, it is really serious,” said Dr. Gottardi, who also is assistant professor in the Department of Pediatrics and Department of Bioengineering at CHOP and the University of Pennsylvania. “With our procedure, we have an easily accessible source for the cartilage and the cells, providing a straightforward and noninvasive treatment option with much potential.”

Read the full story in CHOP’s Cornerstone Blog.

Riccardo Gottardi is an Assistant Professor in the Department of Pediatrics, Division of Pulmonary Medicine in the Perelman School of Medicine and in the Department of Bioengineering in the School of Engineering and Applied Science. He also holds an appointment in the Children’s Hospital of Philadelphia (CHOP).

Paul Gehret is a Ph.D. student in Bioengineering, an Ashton Fellow and a NSF Fellow. His research focuses on leveraging decellularized cartilage scaffolds and novel cell sources to reconstruct the pediatric airway.

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Why New Cancer Treatments are Proliferating

by Karen L. Brooks

Doctors performing surgery.
Image: Penn Medicine News

In the five years since the FDA’s initial approval of chimeric antigen receptor (CAR) T cell therapy, Penn Medicine has gleaned 20 additional approvals related to drugs and techniques to treat or detect cancer.

Rather than being the single disease class many people refer to, “cancer” is a blanket term that covers more than 100 distinct diseases, many of which have little in common aside from originating with rapidly dividing cells. Since different cancers demand different treatments, it follows that any given new therapy emerging from any institution would be likely to be a new cancer treatment.

But why so many in just this five-year period?

The volume of new cancer treatments makes sense, says Abramson Cancer Center (ACC) director Robert Vonderheide, attributing the flurry of new cancer drug approvals to a recent “explosion” in knowledge about cancer biology.

“Much of that knowledge is about the immune system’s ability to attack cancer, which people seriously doubted until about 20 years ago. As soon as we had a clinical validation for this Achilles heel in cancer, the dam burst for ideas about other ways to exploit that vulnerability to come forward,” he says. “The first drug that came out to activate the immune system inspired the rest of the field to find the next drug, and the one after that. We as a field have moved from serendipity and empiricism to science-driven drug design.”

The first CAR T cell therapy approval invigorated Penn faculty interested in finding new ways to harness the immune system to fight cancer.

“An approval like that makes what you’re working on more of a reality,” says Avery Posey, an assistant professor of systems pharmacology and translational therapeutics in the Perelman School of Medicine, whose lab team spends much of its time trying to identify more specific antigens for solid tumors and also studies ways to optimize engineered donor T cells. “It brings a new perspective, showing that your work is more than basic research and can actually become drugs that impact patients’ lives. That’s a real motivator to keep pushing forward.”

Honing new immunotherapies is a priority among Penn researchers, but not every recently approved new cancer treatment or detection tool developed at the institution engages the immune system. Faculty have explored and introduced widely varying approaches to improving the standard of care for cancer patients.

Read the full story in Penn Medicine Magazine.

Avery Posey is a member of the Penn Bioengineering Graduate Group. Read more stories featuring Posey here.

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Breaking Down Barriers to Blood Donation for LGBTQ+ People

by Meredith Mann

Close-up of a person's arm and hand as they donate blood.
(Image: iStock/hxdbzxy)

For decades, LGBTQ+ patients have faced stringent requirements to donate blood—most gay and bisexual men were not allowed to donate at all. Now, however, many more of them will be able to give this selfless gift. The U.S. Food and Drug Administration, which regulates blood donation in this country, has reworked the donor-screening criteria, and in the process opened the door to donation for more Americans.

The previous restriction on accepting blood from men who have sex with men (MSM) dates back to the early days of the AIDS epidemic, when blood donations weren’t able to be screened for HIV, leading to cases of transfusion-transmitted HIV. In 1985, the FDA instituted a lifetime ban on blood donation for MSM, effectively preventing gay and bisexual men from donating. (Also included were women who have sex with MSM.)

Twenty years later, the agency rescinded the ban—but added a restriction that only MSM who had been abstinent from sex for at least one year could donate. In 2020, the FDA shortened the “deferral” period to 90 days of abstinence. While the changes were welcome news for those who had been unable to donate, they still prevented many MSM from giving blood. As he wrote in an op-ed for the Philadelphia Inquirer last year, Kevin B. Johnson, the David L. Cohen University Professor with appointments in the School of Engineering and Applied Science, the Perelman School of Medicine, and Annenberg School for Communication, was one of them. He and his husband were shocked to learn when they went to donate blood during a shortage early in the COVID-19 pandemic, that despite being married and monogamous for close to 17 years, they could not donate unless they were celibate for three months.

“It is time to move quickly to a policy under which all donors are evaluated equally and fairly, and to encourage local blood collection facilities to comply with that policy,” Johnson wrote last year.

Now, such changes are underway. As the pandemic wound down, the FDA moved forward with plans to re-evaluate its donation criteria. The first big change was removal of an indefinite ban on people who lived in or spent significant amounts of time in the United Kingdom, Ireland, and France, a measure that aimed to protect the U.S. blood supply against Creutzfeldt-Jakob disease (CJD; also known as “mad cow disease”), a terminal brain condition caused by hard-to-detect prions that occurred in those countries in the 1980s and 1990s.

Extensive and careful evaluation of epidemiological studies and statistical analysis has shown that the risk of CJD transmission is no longer a concern. The changes to eligibility for LGBTQ+ patients are related to advances in medical and social science, and have also been very thoroughly studied to ensure that the changes will maintain the safety of the blood supply without being discriminatory.

“In the decades since HIV was first recognized, there have been advances in testing methods for detection of the virus, changes in how we process blood products, public health advances, and extensive study of the evolving risk of disease transmission given these advances,” says Sarah Nassau, vice chair of pathology and laboratory medicine at Lancaster General Hospital.

They also draw on rethinking the reliability of the guidelines. For example, while the rules partially or fully prevented gay and bisexual men from donating blood, they did not erect similar barriers to other people engaging in anal sex, or people who have multiple partners.

“Specifying the sexual orientation of the person rather than a behavior in which they engaged was discriminatory and not evidence based,” points out Judd David Flesch, vice chief of inpatient operations in the Department of Medicine at Penn Presbyterian Medical Center and co-director of the Penn Medicine Program for LGBT Health.

Read the full story in Penn Medicine News.

Kevin Johnson is the David L. Cohen University of Pennsylvania Professor in the Departments of Biostatistics, Epidemiology and Informatics and Computer and Information Science. As a Penn Integrates Knowlegde (PIK) University Professor, Johnson also holds appointments in the Departments of Bioengineering and Pediatrics, as well as in the Annenberg School of Communication.

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Cesar de la Fuente On the “Next Frontier” of Antibiotics

César de la Fuente
César de la Fuente

In a recent CNN feature, César de la Fuente, Presidential Assistant Professor in Bioengineering, Psychiatry, Microbiology, and in Chemical and Biomolecular Engineering commented on a study about a new type of antibiotic that was discovered with artificial intelligence:

“I think AI, as we’ve seen, can be applied successfully in many domains, and I think drug discovery is sort of the next frontier.”

The de la Fuente lab uses machine learning and biology to help prevent, detect, and treat infectious diseases, and is pioneering the research and discovery of new antibiotics.

Read “A new antibiotic, discovered with artificial intelligence, may defeat a dangerous superbug” in CNN Health.

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RNA Nanoparticle Therapy Stops the Spread of Incurable Bone Marrow Cancer

by Melissa Pappas

Myeloma cells producing monoclonal proteins of varying types, created by Scientific Animations under the Creative Commons Attributions-Share Alike International 4.0 License

Multiple myeloma is an incurable bone marrow cancer that kills over 100,000 people every year. Known for its quick and deadly spread, this disease is one of the most challenging to address. As these cancer cells move through different parts of the body, they mutate, outpacing possible treatments. People diagnosed with severe multiple myeloma that is resistant to chemotherapy typically survive for only three to six months. Innovative therapies are desperately needed to prevent the spread of this disease and provide a fighting chance for those who suffer from it.

Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in Bioengineering (BE), and Christian Figueroa-Espada, doctoral student in BE at the University of Pennsylvania School of Engineering and Applied Science, created an RNA nanoparticle therapy that makes it impossible for multiple myeloma to move and mutate. The treatment, described in their study published in PNAS, turns off a cancer-attracting function in blood vessels, disabling the pathways through which multiple myeloma cells travel.

By shutting down this “chemical GPS” that induces the migration of cancer cells, the team’s therapy stops the spread of multiple myeloma, helping to eliminate it altogether.

Read the full story in Penn Engineering Today.

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Engineered White Blood Cells Eliminate Cancer

by Melissa Pappas

“Macrophages killing cancer cell” photographed by Susan Arnold.

By silencing the molecular pathway that prevents macrophages from attacking our own cells, Penn Engineers have manipulated these white blood cells to eliminate solid tumors.

Cancer remains one of the leading causes of death in the U.S. at over 600,000 deaths per year. Cancers that form solid tumors such as in the breast, brain or skin are particularly hard to treat. Surgery is typically the first line of defense for patients fighting solid tumors. But surgery may not remove all cancerous cells, and leftover cells can mutate and spread throughout the body. A more targeted and wholistic treatment could replace the blunt approach of surgery with one that eliminates cancer from the inside using our own cells.

Dennis Discher, Robert D. Bent Professor in Chemical and Biomolecular Engineering, Bioengineering, and Mechanical Engineering and Applied Mechanics, and postdoctoral fellow, Larry Dooling, provide a new approach in targeted therapies for solid tumor cancers in their study, published in Nature Biomedical Engineering. Their therapy not only eliminates cancerous cells, but teaches the immune system to recognize and kill them in the future.

“Due to a solid tumor’s physical properties, it is challenging to design molecules that can enter these masses,” says Discher. “Instead of creating a new molecule to do the job, we propose using cells that ‘eat’ invaders – macrophages.”

Macrophages, a type of white blood cell, immediately engulf and destroy – phagocytize – invaders such as bacteria, viruses, and even implants to remove them from the body. A macrophage’s innate immune response teaches our bodies to remember and attack invading cells in the future. This learned immunity is essential to creating a kind of cancer vaccine.

But, a macrophage can’t attack what it can’t see.

“Macrophages recognize cancer cells as part of the body, not invaders,” says Dooling. “To allow these white blood cells to see and attack cancer cells, we had to investigate the molecular pathway that controls cell-to-cell communication. Turning off this pathway – a checkpoint interaction between a protein called SIRPa on the macrophage and the CD47 protein found on all ‘self’ cells – was the key to creating this therapy.”

Read the full story in Penn Engineering Today.

Multiple members in the biophysical engineering lab lead by Dennis Discher, including co-lead author and postdoctoral fellow and Penn Bioengineering alumnus Jason Andrechak and Bioengineering Ph.D. student Brandon Hayes, contributed to this study. The research was funded by grants from the National Heart, Lung, and Blood Institute and the National Cancer Institute, including the Physical Sciences Oncology Network, of the US National Institutes of Health.

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Penn Bioengineering Graduate Student on T Cell Therapy Improvements

Image: Courtesy of Penn Medicine News

 Neil Sheppard,  Adjunct Associate Professor of Pathology and Laboratory Medicine in the Perelman School of Medicine, and David Mai, a Bioengineering graduate student in the School of Engineering and Applied Science, explained the findings of their recent study, which offered a potential strategy to improve T cell therapy in solid tumors, to the European biotech news website Labiotech.

Mai is a graduate student in the lab of Carl H. June, the Richard W. Vague Professor in Immunotherapy in Penn Medicine, Director of the Center for Cellular Immunotherapies (CCI) at the Abramson Cancer Center, and member of the Penn Bioengineering Graduate Group.

Read “Immunotherapy in the fight against solid tumors” in Labiotech.

Read more about this collaborative study here.