Artificial Intelligence is Leveling Up the Fight Against Infectious Diseases

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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.

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.

Balancing Dentistry and Engineering to Bring New Innovations to the Clinic

by Liana F. Wait

Kyle Vining, who is jointly appointed in the School of Dental Medicine and the School of Engineering and Applied Science, hopes that his research will help to push forward the state of clinical dentistry.

When trying to choose between two career paths—dentistry and engineering—Kyle Vining decided ‘Why not both?’ Vining joined Penn in July 2022 and is jointly appointed in the School of Dental Medicine and the School of Engineering and Applied Science.

“During my training, I saw that there was overlap where I could do clinical work and science at the same time, and so that’s what I’ve been doing ever since,” Vining says. “As far back as middle school, I always wanted to be a biomedical engineer, and then the clinical side became interesting to me because I didn’t want to only do the theoretical or research side of things. I also wanted the hands-on, practical interaction of a skilled profession.”

The benefits of a dual career: Variety and opportunities to give back

Vining finds that wearing two hats offers the best of both worlds: opportunities to help both individual patients and to contribute to scientific and clinical progress.

“On the dentistry side, what I enjoy is getting to see patients, solving clinical problems, and trying to perform the best treatment I can; it has this rapid pace, which is kind of exciting and keeps you motivated,” Vining says. “And then research allows me to explore my interests and think about making an impact more broadly, not just in dentistry, but in medicine or in the world in general.”

Vining says dental school was demanding, yet a good time to explore his varied interests. He says he’d encourage others to pursue dentistry with an interdisciplinary approach. “Having exposure to different fields or different knowledge while you’re a student is really good for students and the profession in general,” he says.

The path towards a dual career

Vining first delved into research as a biomedical engineering undergraduate at Northwestern University. “I had the opportunity to work in a materials science lab studying the chemistry of surfaces. We would use molecules to modify the properties and surfaces that environments or cells could interact with,” he says.

Then, as a student at the University of Minnesota School of Dentistry, Vining realized that this same materials science research had many applications in dentistry. While in dental school, Vining conducted independent research in a materials science lab and also took the opportunity to do a yearlong fellowship in a cell and developmental biology lab at the National Institutes of Health.

Vining credits this fellowship with launching him towards a Ph.D., which he completed in bioengineering at Harvard in 2020. After earning his Ph.D., Vining conducted research at the Dana-Farber Cancer Institute prior to joining Penn.

Using biomaterials to understand how cells and tissues interact

Vining’s research at Penn aims to understand how the biophysical properties of materials impact cellular processes such as inflammation and fibrosis.

“Fibrosis is a physical change in tissues that produces a scar-like matrix that can inhibit healing, impair cancer treatment, and in general is not compatible with tissues regeneration,” Vining says. “There’s been a lot of effort on antifibrotic drugs, but we’re trying to look at fibrosis a little bit differently. Instead of directly inhibiting fibrosis, we’re trying to understand its consequences for the immune system because the immune system can be hijacked and become detrimental for your tissues.”

Through a better understanding the feedback loop between fibrotic tissue and the immune system, Vining hopes to design interventions to facilitate wound healing and tissue remodeling during restorative dental procedures and for treating diseases including head and neck cancer.

He’s also investigating how biomaterials like the resin used in tooth fillings interact with dental tissues. “Dental fillings rely on decades-old technologies that have been grandfathered in and contain toxic monomers that are not safe for biological systems,” Vining says. “We found a biocompatible resin chemistry that supports cells in vitro, and we’re trying to apply this to new types of dental fillings that promote repair or generation of dental tissues.”

Fostering interdisciplinary collaborations at Penn

Vining was recruited to be part of the Center for Innovation & Precision Dentistry (CiPD), the joint center of Penn Dental Medicine and Penn Engineering.

“Dr. Vining is an ideal fit for the vision and mission of the CiPD,” says Penn Dental’s Hyun (Michel) Koo, co-founder and co-director of the CiPD. “With a secondary appointment in the School of Engineering, he will be instrumental in continuing to strengthen our engineering collaborations and teaching our students to work across disciplines to advance research, training, and entrepreneurship in this realm.”

Ultimately, Vining says it was Penn’s scientific community and the opportunities for interdisciplinary collaborations that drew him here.

“It was very apparent that there were a lot of potential research paths to pursue here and a lot of opportunities for collaborations,” Vining says. “One of the most exciting things for me so far has been meeting with faculty, whether it’s at Penn Medicine, the School of Engineering, Wharton, Penn Dental, or the Veterinary School. These meetings have already opened up new projects and collaborations.”

One such collaboration is with Michael Mitchell, associate professor of bioengineering. The pair were awarded the second annual IDEA (Innovation in Dental Medicine and Engineering to Advance Oral Health) Prize in May 2023 to kickstart a project exploring the potential for using lipid nanoparticles to treat dental decay.

The collaboration sparked when Vining saw Mitchell present on a new technology that uses lipid nanoparticles to bind and target bone marrow cells at the 2022 CiPD first annual symposium. “It got me thinking because the dentin inside of teeth is a mineralized tissue very similar to bone, and the pulp inside the dentin is analogous to bone marrow tissue,” Vining says.

Read the full story in Penn Today.

Vining and Koo are members of the Penn Bioengineering Graduate Group.

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.

César de la Fuente Receives 2023 Rao Makineni Lectureship Award

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César de la Fuente
César de la Fuente

The American Peptide Society has selected César de la Fuente, Presidential Assistant Professor in Psychiatry, Microbiology, Bioengineering and in Chemical and Biomolecular Engineering, as the recipient of the prestigious 2023 Rao Makineni Lectureship Award.

Presented at the biennial American Peptide Symposium, the Makineni Lectureship Award recognizes an individual who has made a recent contribution of unusual merit to research in the field of peptide science, and is intended to acknowledge original and singular discoveries.

Established in 2003 by an endowment by PolyPeptide Laboratories and Murray and Zelda Goodman, this lectureship honors Rao Makineni, a long-time supporter of peptide science, peptide scientists, and the American Peptide Society.

This story originally appeared in Penn Engineering Today.

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.

Penn Dental Medicine Collaboration Identifies New Bacterial Species Involved in Tooth Decay

S. sputigena cells form a honeycomb-like structure that encapsulates S. mutans to greatly increase and concentrate acid production that boost caries development and severity.
Image: Courtesy of Penn Dental Medicine

Collaborating researchers from the University of Pennsylvania School of Dental Medicine and the Adams School of Dentistry and Gillings School of Global Public Health at the University of North Carolina have discovered that a bacterial species called Selenomonas sputigena can have a major role in causing tooth decay.

Scientists have long considered another bacterial species, the plaque-forming, acid-making Streptococcus mutans, as the principal cause of tooth decay—also known as dental caries. However, in the study, published in Nature Communications, the Penn Dental Medicine and UNC researchers showed that S. sputigena, previously associated only with gum disease, can work as a key partner of S. mutans, greatly enhancing its cavity-making power.

“This was an unexpected finding that gives us new insights into the development of caries, highlights potential future targets for cavity prevention, and reveals novel mechanisms of bacterial biofilm formation that may be relevant in other clinical contexts,” says study co-senior author Hyun (Michel) Koo, a professor in the Department of Orthodontics and Divisions of Pediatrics and Community Oral Health and co-director of the Center for Innovation & Precision Dentistry at Penn Dental Medicine.

The other two co-senior authors of the study were Kimon Divaris, professor at UNC’s Adams School of Dentistry, and Di Wu, associate professor at the Adams School and at the UNC Gillings School of Global Public Health.

“This was a perfect example of collaborative science that couldn’t have been done without the complementary expertise of many groups and individual investigators and trainees,” Divaris says.

Read the full story in Penn Today.

Michel Koo is a professor in the Department of Orthodontics and divisions of Community Oral Health and Pediatric Dentistry in Penn Dental Medicine and co-director of the Center for Innovation & Precision Dentistry. He is a member of the Penn Bioengineering Graduate Group.

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.

RNA Nanoparticle Therapy Stops the Spread of Incurable Bone Marrow Cancer

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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.

Engineered White Blood Cells Eliminate Cancer

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“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.