For a New Generation of Antibiotics, Scientists are Bringing Extinct Molecules Back to Life – and Discovering the Hidden Genetics of Immunity Along the Way

by Devorah Fischler

Marrying artificial intelligence with advanced experimental methods, the Machine Biology Group has mined the ancient past for future medical breakthroughs, bringing extinct molecules back to life. (Image credit: Ella Marushchenko)

“We need to think big in antibiotics research,” says Cesar de la Fuente. “Over one million people die every year from drug-resistant infections, and this is predicted to reach 10 million by 2050. There hasn’t been a truly new class of antibiotics in decades, and there are so few of us tackling this issue that we need to be thinking about more than just new drugs. We need new frameworks.”

De la Fuente is 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. He holds additional primary appointments in Psychiatry and Microbiology in the Perelman School of Medicine.

De la Fuente’s lab, the Machine Biology Group, creates these new frameworks using potent partnerships in engineering and the health sciences, drawing on the “power of machines to accelerate discoveries in biology and medicine.”

Marrying artificial intelligence with advanced experimental methods, the group has mined the ancient past for future medical breakthroughs. In a recent study published in Cell Host and Microbe, the team has launched the field of “molecular de-extinction.”

Our genomes – our genetic material – and the genomes of our ancient ancestors, express proteins with natural antimicrobial properties. “Molecular de-extinction” hypothesizes that these molecules could be prime candidates for safe new drugs. Naturally produced and selected through evolution, these molecules offer promising advantages over molecular discovery using AI alone.

In this paper, the team explored the proteomic expressions of two extinct organisms –Neanderthals and Denisovans, archaic precursors to the human species – and found dozens of small protein sequences with antibiotic qualities. Their lab then worked to synthesize these molecules, bringing these long-since-vanished chemistries back to life.

“The computer gives us a sequence of amino acids,” says de la Fuente. “These are the building blocks of a peptide, a small protein. Then we can make these molecules using a method called ‘solid-phase chemical synthesis.’ We translate the recipe of amino acids into an actual molecule and then build it.”

The team next applied these molecules to pathogens in a dish and in mice to test the veracity and efficacy of their computational predictions.

“The ones that worked, worked quite well,” continues de la Fuente. “In two cases, the peptides were comparable – if not better – than the standard of care. The ones that didn’t work helped us learn what needed to be improved in our AI tools. We think this research opens the door to new ways of thinking about antibiotics and drug discovery, and this first step will allow scientists to explore it with increasing creativity and precision.”

Read the full story in Penn Engineering Today.

Penn Bioengineering Graduate Ella Atsavapranee Wins 2023 Fulbright Grant

Ella Atsavapranee (BE 2023)

Twenty-nine University of Pennsylvania students, recent graduates, and alumni have been offered Fulbright U.S. Student Program grants for the 2023-24 academic year, including eight seniors who graduated May 15.

They will conduct research, pursue graduate degrees, or teach English in Belgium, Brazil, Colombia, Denmark, Ecuador, Estonia, France, Germany, Guatemala, India, Israel, Latvia, Mexico, Nepal, New Zealand, the West Bank-Palestine territories, South Korea, Spain, Switzerland, Taiwan, and Thailand.

The Fulbright Program is the United States government’s flagship international educational exchange program, awarding grants to fund as long as 12 months of international experience.

Most of the Penn recipients applied for the Fulbright with support from the Center for Undergraduate Research and Fellowships.

Among the Penn Fulbright grant recipients for 2023-24 is Ella Atsavapranee, from Cabin John, Maryland, who graduated in May with a bachelor’s degree in bioengineering from the School of Engineering and Applied Science and a minor in chemistry from the College. She was offered a Fulbright to conduct research at the École Polytechnique Fédérale de Lausanne in Switzerland.

At Penn, Atsavapranee worked with Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor in Bioengineering, engineering lipid nanoparticles to deliver proteases that inhibit cancer cell proliferation. She has also worked with Shan Wang, Leland T. Edwards Professor in the School of Engineering and Professor of Electrical Engineering at Stanford University, using bioinformatics to discover blood biomarkers for cancer detection. To achieve more equitable health care, she worked with Lisa Shieh, Clinical Professor in Medicine at the Stanford School of Medicine,  to evaluate an AI model that predicts risk of hospital readmission and study how room placement affects patient experience.

Outside of research, Atsavapranee spread awareness of ethical issues in health care and technology as editor-in-chief of the Penn Bioethics Journal and a teaching assistant for Engineering Ethics (EAS 2030). She was also a Research Peer Advisor for the Penn Center for Undergraduate Research & Fellowships (CURF), a student ambassador for the Office of Admissions, and a volunteer for Service Link, Puentes de Salud, and the Hospital of the University of Pennsylvania. She plans to pursue a career as a physician-scientist to develop and translate technologies that are more affordable and accessible to underserved populations.

Read the full list of Penn Fulbright grant recipients for 2023-24 in Penn Today.

Brit Shields Wins Inaugural Penn Engineering Student Advocacy Award

Brit Shields
Brit Shields

Penn Engineering announced the faculty recipients of the 2023 Student Choice Awards (formerly the Teaching and Advising Awards). Each year, the Penn Engineering undergraduate student body thoughtfully selects the recipients of these awards for their dedication in teaching, mentorship and student advocacy. This year also features two new awards, the Student Advocacy Award and the Undergraduate Research Mentoring Award.

Brit Shields, Senior Lecturer in Bioengineering, is the inaugural recipient of the Student Advocacy Award. This award is presented to a member of the Penn Engineering faculty by the Underrepresented Student Advisory Board in Engineering in recognition of their outstanding commitment to women and underrepresented student advocacy, equity and inclusion.

Dr. Shields poses with her award at the annual Penn Engineering Awards Ceremony.
Dr. Shields poses with her award at the annual Penn Engineering Awards Ceremony.

Shields completed a Ph.D. at Penn in 2015 in History and Sociology of Science, with a dissertation on scientific diplomacy through the example of Richard Courant and New York University, where Shields completed an M.A. in Humanities and Social Thought: Science Studies.

She was promoted to Senior Lecturer in Bioengineering in 2019. She has  brought her expertise in the history and sociology of science to her leading role in developing and improving the ethics curriculum for all students in the School of Engineering and Applied Science.

Read other stories featuring Brit Shields in the BE Blog.

Read the full list of 2023 Penn Engineering Student Choice Award Winners in Penn Engineering Today.

Book Discussions and Bonding at the Bioengineering Retreat

by Brittany H. Scheid

Retreat participants in Mitchell Hall at the College of Physicians

This year, the lineup of new student orientation activities included a new event:  the first bioengineering retreat for incoming Ph.D. graduate students.  Sitting in the historic Mitchell Hall at the College of Physicians, the 2022 Ph.D. cohort participated in a fun and educational half-day program that included a series of bonding activities, small-group conversations, and panel discussions. Current members of the Graduate Association of Bioengineers (GABE) planned the program to strengthen personal connections among students and to lend some advice to the newcomers as they embarked on their scholastic journey.

Prior to the retreat, participants read The Immortal Life of Henrietta Lacks by Rebecca Skloot, a work that delves into the human story of Henrietta Lacks, a Black woman from Virginia whose cancer cells were obtained for scientific study in the early 1950s without her knowledge. Today, “HeLa” cells have become one of the most significant tools in cell biology, enabling the development of polio vaccines, research into radiation effects, and even research on COVID-19. Together at the retreat, we discussed the intersection of ethics and scientific discovery, and reflected on our responsibility as scientists to consider the impact of our work beyond the immediate scientific question.

“Surviving the PhD 101” Panel Discussion. From left to right: Aoifa O’Farrell, Mosha Deng, David Mai, Lasya Sreepada

Current Ph.D. students volunteered their afternoons to share in two additional activities. Aoife O’Farrell, David Mai, Lasya Sreepada, and Mosha Deng imparted sage advice about using on-campus resources, handling advisor-advisee conflicts, and finding the best bites in Philly in the “Surviving the Ph.D. 101” panel discussion. Seven other students presented a series of flash talks about their research areas and musings on the best hypothetical mascot to represent their lab. The afternoon finished with an after-hours visit to the Mütter Museum, which holds an extensive and unique collection of anatomical specimens and antique medical equipment previously used for medical education.

If the WhatsApp group formed by the new cohort during the event is any indication, the retreat was an overall success! GABE looks forward to continuing the event in the future.

Brittany H. Scheid is a Ph.D. candidate studying Bioengineering in the lab of Brian Litt, Professor in Bioengineering and Neurology, and she is Co-President of GABE at Penn.

 

Penn Bioengineering Student Laila Barakat Norford Named Goldwater Scholar

Laila Barakat Norford (Class of 2023)

Five University of Pennsylvania undergraduates have received 2022 Goldwater Scholarships, including Laila Barakat Norford, a third year Bioengineering major from Wayne, Pennsylvania. Goldwater Scholarships are awarded to sophomores or juniors planning research careers in mathematics, the natural sciences, or engineering.

She is among the 417 students named 2022 Goldwater Scholars from the 1,242 students nominated by 433 academic institutions in the United States, according to the Barry Goldwater Scholarship & Excellence in Education Foundation. Each scholarship provides as much as $7,500 each year for as many as two years of undergraduate study.

Penn has produced 23 Goldwater Scholars in the past seven years and a total of 55 since Congress established the scholarship in 1986.

Laila Barakat Norford is majoring in bioengineering with minors in computer science and bioethics in Penn Engineering. As a Rachleff Scholar, Norford has been engaged in systems biology research since her first year. Her current research uses machine learning to predict cell types in intestinal organoids from live-cell images, enabling the mechanisms of development and disease to be characterized in detail. At Penn, she is an Orientation Peer Advisor, a volunteer with Advancing Women in Engineering and the Penn Society of Women Engineers, and a teaching assistant for introductory computer science. She is secretary of the Penn Band, plays the clarinet, and is a member of the Band’s Fanfare Honor Society for service and leadership. Norford registers voters with Penn Leads the Vote and canvasses for state government candidates. She is also involved in Penn’s LGBTQ+ community as a member of PennAces. Norford plans to pursue a Ph.D. in computational biology, aspiring to build computational tools to address understudied diseases and health disparities.

The students applied for the Goldwater Scholarship with assistance from Penn’s Center for Undergraduate Research and Fellowships.

Read about all five 2022 Penn Goldwater Scholars in Penn Today.

“Educating the Next Generation of Civically Engaged Technologists”

Brit Shields, Ph.D.

Brit Shields, Senior Lecturer in Bioengineering, has brought her expertise in the history and sociology of science to her leading role in developing and improving the ethics curriculum for all students in the School of Engineering and Applied Science. Most recently, this includes adapting the core ethics engineering ethics course “Technological Innovation and Civil Discourse in a Dynamic World” (EAS 204) for the Stavros Niarchos Foundation (SNF) Paideia Program. SNF Paideia courses, open to all Penn undergraduates, “integrate students’ personal, professional, and civic development […] focus[ing] on dialogue, wellness, service, and citizenship from different disciplinary and interdisciplinary perspectives.” A recent SNF Paideia blog post goes into detail about the changes made by Shields and co-instructor Christopher Yoo, John H. Chestnut Professor of Law, Communication, and Computer and Information Science, to suit the SNF Paideia Program, including its “explicit focus on civil discourse and technology.” According to Shields:

“I really wanted to break down the false dichotomy between technological expertise or humanities training for the students and open up the opportunity for Engineering students to consider themselves to have an important role, not just creating technological systems but also being important participants in civil discourse.”

Michelle Johnson, Ph.D.

The course also includes guest lectures by Penn faculty, including Michelle Johnson, Associate Professor in Bioengineering and Physical Medicine and Rehabilitation, and students learn to analyze how guest lecturers communicate their research to the public, for example, in the case of Johnson, in the form of a TED Talk and scholarly articles: “Through her TedTalk, journal articles and visit to the class, Michelle Johnson demonstrates how researchers are attuned to the specific preferences of the rehabilitative robots they are creating for patients…engaged scholarship at its finest.”

Read “Educating the Next Generation of Civically Engaged Technologists” in SNF Paideia Perspectives.

Brit Shields Promoted to Senior Lecturer

by Sophie Burkholder

Brit Shields, Ph.D.

We would like to congratulate Brit Shields, Ph.D., of the Penn Department of Bioengineering, on her recent promotion to Senior Lecturer. Shields got her start at Penn by completing her Ph.D. here in 2015 in History and Sociology of Science, with a dissertation on scientific diplomacy through the example of Richard Courant and New York University, where Shields completed an M.A. in Humanities and Social Thought: Science Studies. Following the conclusion of her doctorate, Shields immediately joined Penn as a lecturer in the Department of Bioengineering, teaching core undergraduate classes like the Senior Thesis course for B.A.S. degree candidates, and Engineering Ethics, one of the courses that fulfills the ethics requirement for all Penn engineering students. Furthermore, Shields has served as an advisor for undergraduate students on senior thesis in the History and Sociology of Science as well as Bioengineering.

In her new position, Shields will have the chance to further develop the engineering ethics curriculum for SEAS students. She will also take on a direct role with freshman bioengineering students as one of two bioengineering faculty members in charge of advising the incoming classes. Through these opportunities to better connect with students, Shields will be able to continue improving the ethics curriculum for all engineering majors, and increase its efficacy in imparting lessons that all engineers should take to the workforce with them. Beyond her roles in the classroom and as an advisor, Shields will also continue her research in the history and sociology of science and technology focusing on both scientific diplomacy and educational programs for engineers. She says that she “look[s] forward to collaborating with the school’s administration, faculty and students to further develop the engineering ethics curriculum.  Being able to innovate in this field with such talented students is incredibly rewarding.”

Week in BioE (August 3, 2017)

There’s news in bioengineering every week, to be sure, but the big story this past week is one that’s sure to continue appearing in headlines for days, weeks, and months — if not years — to come. This story is CRISPR-Cas9, or CRISPR for short, the gene-editing technology that many geneticists are viewing as the wave of the future in terms of the diagnosis and treatment of genetic disorders.

Standing for clustered regularly interspaced short palindromic repeats, CRISPR offers the ability to cut a cell’s genome at a predetermined location and remove and replace genes at this location. As a result, if the location is one at which the genes code for a particular disease, these genes can be edited out and replaced with healthy ones. Obviously, the implCRISPRications for this technology are enormous.

This week, it was reported that, for the first time, CRISPR was successfully used by scientists to edit the genomes of human embryos. As detailed in a paper published in Nature, these scientists edited the genomes of 50 single-cell embryos, which were subsequently allowed to undergo division until the three-day mark, at which point the multiple cells in the embryos were assessed to see whether the edits had been replicated in the new cells.  In 72% of them, they had been.

In this particular case, the gene edited out was one for a type of congenital heart defect, and the embryos were created from the eggs of healthy women and the sperm of men carrying the gene for the defect. However, the experiments prove that the technology could now be applied in other disorders.

Needless to say, the coverage of this science story has been enormous, so here is a collection of links to coverage on the topic. Enjoy!

Mind Control and an Ethical Appeal

mind control brain
A “wiring diagram of the human brain,” produced using diffusion MRI scans of the brain.

A group of four scholars from the University of Pennsylvania, including Bioengineering professor Danielle Bassett, have issued a call in the journal Nature Human Behaviour for greater safeguards for patients as treatments in the field of neuroscience evolve and come ever closer to resembling “mind control.”

“While we don’t believe,” Bassett said, “that the science-fiction idea of mind control, totally overriding a person’s autonomy, will ever be possible, new brain-focused therapies are becoming more specific, targeted and effective at manipulating individuals’ mental states. As these techniques and technologies mature, we need systems in place to make sure they are applied such that they maximize beneficial effects and minimize unwanted side effects.”

Read more at the Penn News Web Site.

Henrietta Lacks Film Addresses Ethical Issues

by Andrew E. Mathis

henrietta lacks hela cells
HeLa cells after staining

In January 1951, Henrietta Lacks, a 30-year-old African-American woman from Baltimore, was diagnosed with cervical cancer at the Johns Hopkins Medical Center. She was treated with radium brachytherapy, the standard of care at the time, but her condition worsened. In August, a week after she turned 31, she was admitted to the hospital with severe abdominal pain. Less than three months later, she died. An autopsy showed widespread metastasis of the original cancer.

Henrietta Lacks had died, but strangely, her cancer cells have lived on. Unbeknownst to her and her family, Henrietta’s doctors had sampled her cancer cells for research — a common practice at the time, particularly from patients treated in wards. Those cells were given to George Gey, a JHU biologist who had been trying for years to establish a cancer cell line that could be grown outside the body. Henrietta Lacks’s cells ended up being the first cell line so established.

The cell line was named “HeLa” by Gey’s laboratory assistant, who coded cell samples using the first two letters of the donor’s first and last names. With Henrietta Lacks’s cells, Gey was able to establish an immortal cell line, i.e., a line of cells that would continue to divide indefinitely. The ability of these cells to divide like this lent itself to the line being used in numerous scientific studies since the 1950s, including Jonas Salk’s development of the polio vaccine.

Notwithstanding the tremendous accomplishments achieved using the HeLa cell line, the case nevertheless evokes serious ethical issues regarding the consent of patients to having their tissue used for research. In recent years, the case has attracted significant attention, with a book, The Immortal Life of Henrietta Lacks, published by Rebecca Skloot in 2010 and now an HBO feature film of the same title produced by and starring Oprah Winfrey as Lacks’s daughter. The film debuted on April 22.

Brittany Shields, PhD, a senior lecturer in the Department of Bioengineering at the University of Pennsylvania, discussed some of the issue raised by Lacks’s story. “Henrietta Lacks’s story has brought public attention to a number of ethical issues in biomedical research, including the role of informed consent, privacy, and commercialization in the collection, use and dissemination of biospecimens,” Dr. Shields says.

“In the United States, biomedical research at federally-funded institutions must follow the policy set by the Department of Health and Human Services. The current policy, known as the ‘Common Rule,’ calls for informed consent and oversight through Institutional Review Boards for research conducted with human beings,” she explains.

However, she continues, “these regulations may or may not apply in different situations related to biospecimens. If an anonymous biospecimen had already been collected for another purpose, informed consent is generally not required.”

In the case of Henrietta Lacks, or more precisely her descendants, an agreement was reached between the family and the National Institute of Health stipulating that the family must give consent when certain genetic information gleaned from the cell line is used. However, controversy between the family and the medical research community has persisted.