A National Institute of Allergy and Infectious Diseases lab freezer used for COVID-19 vaccine research. Both of the current mRNA-based COVID vaccines require ultra-cold freezers to prevent their mRNA from degrading, spurring research into other ways to stabilize the molecule.
As the technology behind two of the COVID-19 vaccines, Messenger RNA (mRNA) is having a moment. A single-stranded counterpart to DNA, mRNA translates its genetic code into proteins; by injecting mRNA engineered to produce proteins found on the exterior of the virus, the vaccine can train a person’s immune system to recognize the real thing without making them sick.
However, because mRNA is a relatively unstable molecule, distributing these vaccines involves extra logistical challenges. Doses must be transported and stored at ultra-cold temperatures to make sure the mRNA inside doesn’t degrade and lose the genetic information it carries.
Michael Mitchell
As mRNA vaccines and other therapies take off, researchers are looking for other ways to forestall this degradation. One of them is Michael J. Mitchell, Skirkanich Assistant Professor of Innovation in the Department of Bioengineering, who is studying the use of lipid nanoparticles to encapsulate and protect mRNA on its way into the cell. That sort of packaging would be particularly beneficial in proposed mRNA therapies for certain genetic disorders, which aim to deliver the correct protein-making instructions to specific organs, or even a fetus in utero.
But for stabilizing mRNA for vaccine distribution, many other strategies are being explored. In “Keeping covid vaccines cold isn’t easy. These ideas could help,” Wudan Yan of MIT Technology Review reached out to Mitchell for insight on LIONs, or lipid inorganic nanoparticles. These nanoparticles work the opposite way of Mitchell’s organic ones, with the mRNA stabilized by binding to their exteriors.
William H. Peranteau, Michael J. Mitchell, Margaret Billingsley, Meghana Kashyap, and Rachel Riley (Clockwise from top left)
As COVID-19 vaccines roll out, the concept of using mRNA to fend off viruses has become a part of the public dialogue. However, scientists have been researching how mRNA can be used to in life-saving medical treatments well before the pandemic.
The “m” in “mRNA” is for “messenger.” A single-stranded counterpart to DNA, it translates the genetic code into the production of proteins, the building blocks of life. The Moderna and Pfizer COVID-19 vaccines work by introducing mRNA sequences that act as a set of instructions for the body to produce proteins that mimic parts of the virus itself. This prepares the body’s immune response to recognize the real virus and fight it off.
Because it can spur the production of proteins that the body can’t make on its own, mRNA therapies also have the potential to slow or prevent genetic diseases that develop before birth, such as cystic fibrosis and sickle-cell anemia.
However, because mRNA is a relatively unstable molecule that degrades quickly, it needs to be packaged in a way that maintains its integrity as its delivered to the cells of a developing fetus.
To solve this challenge, Michael J. Mitchell, Skirkanich Assistant Professor of Innovation in the Department of Bioengineering, is researching the use of lipid nanoparticles as packages that transport mRNA into the cell. He and William H. Peranteau, an attending surgeon in the Division of General, Thoracic and Fetal Surgery and the Adzick-McCausland Distinguished Chair in Fetal and Pediatric Surgery at Children’s Hospital of Philadelphia, recently co-authored a “proof-of-concept” paper investigating this technique.
In this study, published in Science Advances, Mitchel examined which nanoparticles were optimal in the transport of mRNA to fetal mice. Although no disease or organ was targeted in this study, the ability to administer mRNA to a mouse while still in the womb was demonstrated, and the results are promising for the next stages of targeted disease prevention in humans.
Mitchel spoke with Tom Avril at The Philadelphia Inquirer about the mouse study and its implications for treatment of rare infant diseases through the use of mRNA, ‘the messenger of life.’
Penn bioengineering professor Michael J. Mitchell, the other senior author of the mouse study, tested various combinations of lipids to see which would work best.
The appeal of the fatty substances is that they are biocompatible. In the vaccines, for example, two of the four lipids used to make the delivery spheres are identical to lipids found in the membranes of human cells — including plain old cholesterol.
When injected, the spheres, called nanoparticles, are engulfed by the person’s cells and then deposit their cargo, the RNA molecules, inside. The cells respond by making the proteins, just as they make proteins by following the instructions in the person’s own RNA. (Important reminder: The RNA in the vaccines cannot become part of your DNA.)
Among the different lipid combinations that Mitchell and his lab members tested, some were better at delivering their cargo to specific organs, such as the liver and lungs, meaning they could be a good vehicle for treating disease in those tissues.
Alumni Malika Shukurova (left) and Katherine Sizov, Strella Biotechnology
Last year, Katherine Sizov (BIO ’19) and Malika Shukurova (BE ’19) earned the 2019 President’s Innovation Prize for their plan to use Internet-of-Things technology to monitor fruit ripeness and reduce waste in produce supply chains. Their company, Strella Biotechnology, received $100,000 of financial support, a $50,000 living stipend for both awardees, and a year of dedicated co-working and lab space at the Pennovation Center.
Now, it has $3.3 million on hand as it attempts to take its technology into retail stores.
Strella’s ethylene sensors are already being used by fruit packers in order to more precisely time shipments as their produce ripens. The Penn start-up company thinks retailers could similarly benefit when it comes to deciding when to put their stock out for sale.
Spencer Glantz (left) examines a scheme for light-activated protein cleavage with Dr. Brian Chow (middle) and 2014 iGEM team member Daniel Cabrera (right).
Spencer Glantz, a graduate of the Penn Bioengineering doctoral program and former member of the Brian Chow Lab, was mentioned in a recent WHYY piece highlighting the efforts of Penn labs to develop rapid, at-home testing for COVID-19. Glantz is currently a co-leader of the molecular biology team for 4Catalyzer, a medical device incubator founded by National Medal of Technology and Innovation recipient, and sponsor of the annual Rothberg Catalyzer Makerthon competition, Jonathan Rothberg. 4Catalyzer is developing the testing technology while Penn researchers are working to evaluate its effectiveness.
SpaceX launched its 17th resupply mission to the International Space Station on May 4, with bioengineering professor Dan Huh’s organ-on-a-chip experiments in tow.
Dan Huh, the Wilf Family Term Assistant Professor in the Department of Bioengineering, researches human organs and the diseases that infect them by engineering devices made of living cells that act as stand-ins for organs. Huh’s lab has developed imitations of many organs, including the placenta and the eye, but it’s his lung-on-a-chip and his bone-marrow-on-a-chip that are reaching unprecedented heights as part of a new experiment taking place at the International Space Station (ISS).
On May 4, SpaceX launched a ISS-bound cargo capsule carrying Huh’s organ-on-a-chip experiments, which will remain in space for a month. Once back on Earth, the chips that spent time in space will be compared to control chips from Huh’s lab that are being monitored in parallel. Huh’s team is looking to see how being in space affects bacterial infections in lungs and white blood cell behavior in bone marrow. The researchers’ hope is that their studies will reveal important information about how human organs function both in space and on Earth.
Daniel Oberhaus of WIRED wrote an article describing the multiple organs-on-a-chip experiments being conducted at the ISS, including the two experiments headed by Huh:
Dan Huh is a bioengineer at the University of Pennsylvania and the lead researcher on the lung tissue chip headed to the ISS. This lung chip models a human airway and will be infected with Pseudomonas aeruginosa, a species of bacteria that had previously been found on the ISS. On Earth this bacteria is usually associated with respiratory infections, which are one of the leading types of illness on long-duration missions to the ISS.
Huh says scientists still know very little about why astronauts’ immune response seems to become suppressed in orbit, and the tissue chips are aimed at building a better understanding of the phenomenon.
