Tag Archives: University of Pennsylvania

Katalin Kariko, RNA Hero, Future Nobel Prize

The development of the Pfizer-BioNTech coronavirus vaccine, the first approved jab in the West, is the crowning achievement of decades of work for Hungarian biochemist Katalin Kariko, who fled to the US from communist rule in the 1980s.

When trials found the Pfizer-BioNTech coronavirus vaccine to be safe and 95 percent effective in November, it was the crowning achievement of Katalin Kariko’s 40 years of research on the genetic code RNA (ribonucleic acid). Her first reaction was a sense of “redemption,” Kariko told The Daily Telegraph.

I was grabbing the air, I got so excited I was afraid that I might die or something,” she said from her home in Philadelphia. “When I am knocked down I know how to pick myself up, but I always enjoyed working… I imagined all of the diseases I could treat.”

Born in January 1955 in a Christian family in the town of Szolnok in central Hungary – a year before the doomed heroism of the uprising against the Soviet-backed communist regimeKariko grew up in nearby Kisujszellas on the Great Hungarian Plain, where her father was a butcher. Fascinated by science from a young age, Kariko began her career at the age of 23 at the University of Szeged’s Biological Research Centre, where she obtained her PhD.

It was there that she first developed her interest in RNA. But communist Hungary’s laboratories lacked resources, and in 1985 the university sacked her. Consequently, Kariko looked for work abroad, getting a job at Temple University in Philadelphia the same year. Hungarians were forbidden from taking money out of the country, so she sold the family car and hid the proceeds in her 2-year-old daughter’s teddy bear. “It was a one-way ticket,” she told Business Insider. “We didn’t know anybody.”

Not everything went as planned after Kariko’s escape from communism. At the end of the 1980s, the scientific community was focused on DNA, which was seen as the key to understanding how to develop treatments for diseases such as cancer. But Kariko’s main interest was RNA, the genetic code that gives cells instructions on how to make proteins.

At the time, research into RNA attracted criticism because the body’s immune system sees it as an intruder, meaning that it often provokes strong inflammatory reactions. In 1995, Kariko was about to be made a professor at the University of Pennsylvania, but instead she was consigned to the rank of researcher.

Usually, at that point, people just say goodbye and leave because it’s so horrible,” Kariko told medical publication Stat. She went through a cancer scare at the time, while her husband was stuck in Hungary trying to sort out visa issues. “I tried to imagine: Everything is here, and I just have to do better experiments,” she continued. Kariko was also on the receiving end of sexism, with colleagues asking her the name of her supervisor when she was running her own lab.

Kariko persisted in the face of these difficulties. “From outside, it seemed crazy, struggling, but I was happy in the lab,” she told Business Insider. “My husband always, even today, says, ‘This is entertainment for you.’ I don’t say that I go to work. It is like play.” Thanks to Kariko’s position at the University of Pennsylvania, she was able to send her daughter Susan Francia there for a quarter of the tuition costs. Francia won gold on the US rowing team in the 2008 and 2012 Olympics.

It was a serendipitous meeting in front of a photocopier in 1997 that turbocharged Kariko’s career. She met immunologist Drew Weissman, who was working on an HIV vaccine. They decided to collaborate to develop a way of allowing synthetic RNA to go unrecognised by the body’s immune system – an endeavour that succeeded to widespread acclaim in 2005. The duo continued their research and succeeded in placing RNA in lipid nanoparticles, a coating that prevents them from degrading too quickly and facilitates their entry into cells.

The researchers behind the Pfizer-BioNTech and Moderna jabs used these techniques to develop their vaccines.

Source: https://www.france24.com/

NanoRobots Injected Into Human Bodies

In 1959, former Cornell physicist Richard Feynman delivered his famous lecture “There’s Plenty of Room at the Bottom,” in which he described the opportunity for shrinking technology, from machines to computer chips, to incredibly small sizes. Well, the bottom just got more crowded. A Cornell-led collaboration has created the first microscopic robots that incorporate semiconductor components, allowing them to be controlled – and made to walk – with standard electronic signals. These robots, roughly the size of paramecium, provide a template for building even more complex versions that utilize silicon-based intelligence, can be mass produced, and may someday travel through human tissue and blood.

The collaboration is led by Itai Cohen, professor of physics, Paul McEuen, the John A. Newman Professor of Physical Science – both in the College of Arts and Sciences – and their former postdoctoral researcher Marc Miskin, who is now an assistant professor at the University of Pennsylvania.

The walking robots are the latest iteration, and in many ways an evolution, of Cohen and McEuen’s previous nanoscale creations, from microscopic sensors to graphene-based origami machines. The new robots are about 5 microns thick (a micron is one-millionth of a meter), 40 microns wide and range from 40 to 70 microns in length. Each bot consists of a simple circuit made from silicon photovoltaics – which essentially functions as the torso and brain – and four electrochemical actuators that function as legs. As basic as the tiny machines may seem, creating the legs was an enormous feat.

In the context of the robot’s brains, there’s a sense in which we’re just taking existing semiconductor technology and making it small and releasable,” said McEuen, who co-chairs the Nanoscale Science and Microsystems Engineering (NEXT Nano) Task Force, part of the provost’s Radical Collaboration initiative, and directs the Kavli Institute at Cornell for Nanoscale Science.

But the legs did not exist before,” McEuen said. “There were no small, electrically activatable actuators that you could use. So we had to invent those and then combine them with the electronics.”

The team’s paper, “Electronically Integrated, Mass-Manufactured, Microscopic Robots,” has been published  in Nature.

Source: https://news.cornell.edu/
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https://thenextweb.com/

How Gene-edited White Blood Cells Are Helping Fight Cancer

For the first time in the United States, a gene editing tool has been used to treat advanced cancer in three patients and showed promising early results in a pilot phase 1 clinical trial. So far the treatment appears safe, and more results are expected soon. To develop a safer and more effective treatment for cancer patients, scientists from the University of Pennsylvania, the Parker Institute for Cancer Immunotherapy in San Francisco and Tmunity Therapeutics, a biotech company in Philadelphia, developed an advanced version of immunotherapy. In this treatment, a patient’s own immune cells are removed from the body, trained to recognize specific cancer cells and then finally injected back into the patient where they multiply and destroy them.

Unlike chemotherapy or radiation therapy, which directly kills cancer cells, immunotherapy activates the body’s own immune system to do the work. This team used a gene editing tool called CRISPR to alter immune cells, turning them into trained soldiers to locate and kill cancer cells. By using this technique, the team hoped to develop a more effective form of immunotherapy with minimal side effects.

Better CRISPR-based gene editors for the diagnosis and treatment of cancer and other disorders, . combining chemistry, biology and nanotechnology, are used to engineer, control and deliver gene editing tools more efficiently and precisely.

The first step in making these tumor-killing cells used in the cancer drug trial was to isolate the T-cells – a type of white blood cells that fights pathogens and cancer cells – from the blood of the cancer patients. Two patients with advanced multiple myeloma and one patient with myxoid/round cell liposarcomav were enrolled for this study.

To arm the T-cells and bolster their tumor-fighting skills without harming normal cells, scientists genetically engineered the T-cellsdisabling three genes and adding one gene – before returning them to the patients.

The first two of these deleted genes encode T-cell receptors, which are proteins found on the surface of the T-cells that can recognize and bind specific molecules, known as antigens, on cancer cells. When these engineered T-cells bind to these antigens, it allows them to attack and directly kill the cancer cells. But the problem is that a single T-cell can recognize multiple different antigens in the body, making them less focused on finding the cancer cells. By eliminating these two genes, the T-cells are less likely to attack the wrong target or the host, a phenomenon called autoimmunity, In addition, they disrupted a third gene, called programmed cell death protein 1, which slows down the immune response. Disabling the programmed cell death protein 1 gene improves the efficiency of T-cells.

The final step in the transformation of these cells was adding a gene which produces a new T-cell receptor that recognizes and grabs onto a specific marker on the cancer cells called NY-ESO-1. With three genes deleted and one added, the T-cells are now ready to fight cancer.

Source: https://theconversation.com/

How To Divide By 4 The Risk Of Gastric Cancer

While it is well known within the medical community that there is a link between the bacteria Helicobacter pylori (H pylori) and rates of gastric cancer—commonly referred to as stomach cancer—the rates and risk among Americans has been largely understudied. Now, after analyzing records of close to 400,000 patients, researchers in the Perelman School of Medicine, University of Pennsylvania, have found that successfully eliminating H pylori from the gastrointestinal tract led to a 75 percent reduction in the risk of gastric cancer. Researchers also found that rates of gastric cancer after detection of H pylori infection are higher among specific populations, suggesting that people who fall into these groups could benefit from more careful monitoring. The study is published in the journal GastroenterologyH pylori is estimated to infect half of the world’s population, largely those in the eastern parts of the world. It can cause ulcers and other gastrointestinal issues but does not cause issues in the majority of people, and so many people are unaware they have it.

3D illustration of Helicobacter pylori, bacterium which causes gastric and duodenal ulcer

The problem was that all research out of the U.S. used to study gastric cancer and determine American’s risk of developing it did not take into account H pylori infection, and studies worldwide have shown this infection is actually the leading risk factor for this type of cancer,” says the study’s lead author Shria Kumar, a fellow in the division of Gastroenterology.

The research team found that African American, Asian, Hispanic and Latin, American Indian, and Inuit Americans have a significantly higher risk of H pylori infection and of developing gastric cancer. Risks, when compared to the general population, are also higher among men, those who smoke, and among those whose H pylori infection is detected at an older age.

Source: https://penntoday.upenn.edu/

Stem Cells Restore Damaged Teeth

A new study demonstrates that stem cells from baby teeth can be used to repair damaged permanent teeth in young children. The findings suggest a new treatment for childhood dental issues may be around the corner. The treatment’s potential applications go much further than just dental health. Half of all children suffer some kind of dental injury while young. Sometimes the damage isn’t to the baby teeth they will lose anyway, but to the permanent adult teeth lying below the gums that they will need for the rest of their lives. In some cases, trauma can cut off the blood supply to a tooth and rot out the living pulp inside it; a condition called “pulp necrosis.” This condition often leads to the loss of the tooth. While treatment exists, it is often unsatisfactory.

A new clinical trial by Yan Jin, Kun Xuan, and Bei Li of the Fourth Military Medicine University in Xi’an, China and Songtao Shi of the University of Pennsylvania‘s School of Dental Medicine demonstrates how to repair teeth suffering from pulp necrosis by taking stem cells from the patient’s baby teeth.

The study, carried out in China on 40 children who had both damaged adult teeth and baby teeth that had yet to fall out, was published in the journal Science Translational Medicine. The test subjects were selected to either receive the new treatment or an older treatment called apexification, which attempts to address the issue by encouraging root development. This was considered the control group.

The patients who received the stem cell treatment, called human deciduous pulp stem cell (hDPSC) treatment, had pulp tissue taken out of one of their healthy baby teeth. This pulp is rich in stem cells. The cells were grown in a lab and then placed into the injured adult tooth. The hope was that the stem cells would encourage the growth of new pulp inside the tooth.

Follow-ups were carried out for up to three years. The patients who had received the hDPSC treatment showed better blood flow in their teeth, better root systems, and thicker dentin than the patents who underwent the traditional procedure. They also had recovered sensation in their teeth, while the control group had not. The use of a patient’s own cells in the treatment also reduced the risk of their body rejecting the therapymaking the concept even more attractive. “This treatment gives patients sensation back in their teeth. If you give them a warm or cold stimulation, they can feel it; they have living teeth again,” Dr. Shi told Penn Today. “For me, the results are very exciting. To see something we discovered take a step forward to potentially become a routine therapy in the clinic is gratifying.

Source: https://penntoday.upenn.edu/

Tiny 4-Inch Wafer Holds One Million NanoRobots

Researchers have harnessed the latest nanofabrication techniques to create bug-shaped robots that are wirelessly powered, able to walk, able to survive harsh environments and tiny enough to be injected through an ordinary hypodermic needle.

When I was a kid, I remember looking in a microscope, and seeing all this crazy stuff going on. Now we’re building stuff that’s active at that size. We don’t just have to watch this world. You can actually play in it,” said Marc Miskin, who developed the nanofabrication techniques with his colleagues professors Itai Cohen and Paul McEuen and researcher Alejandro Cortese at Cornell University while Miskin was a postdoc in the laboratory for atomic and solid state physics there. In January, he became an assistant professor of electrical and systems engineering at the University of Pennsylvania.

Miskin will present his microscopic robot research on this week at the American Physical Society March Meeting in Boston. He will also participate in a press conference describing the work. Information for logging on to watch and ask questions remotely is included at the end of this news release.

Over the course of the past several years, Miskin and research colleagues developed a multistep nanofabrication technique that turns a 4-inch specialized silicon wafer into a million microscopic robots in just weeks. Each 70 micron long (about the width of a very thin human hair), the robots’ bodies are formed from a superthin rectangular skeleton of glass topped with a thin layer of silicon into which the researchers etch its electronics control components and either two or four silicon solar cells — the rudimentary equivalent of a brain and organs.

Robots are built massively in parallel using nanofabrication technology: each wafer holds 1 million machines

The really high-level explanation of how we make them is we’re taking technology developed by the semiconductor industry and using it to make tiny robots,” said Miskin.

Each of a robot’s four legs is formed from a bilayer of platinum and titanium (or alternately, graphene). The platinum is applied using atomic layer deposition. “It’s like painting with atoms,” said Miskin. The platinum-titanium layer is then cut into each robot’s four 100-atom-thick legs. “The legs are super strong,” he said. “Each robot carries a body that’s 1,000 times thicker and weighs roughly 8,000 times more than each leg.”

The researchers shine a laser on one of a robot’s solar cells to power it. This causes the platinum in the leg to expand, while the titanium remains rigid in turn, causing the limb to bend. The robot’s gait is generated because each solar cell causes the alternate contraction or relaxing of the front or back legs. The researchers first saw a robot’s leg move several days before Christmas 2017. “The leg just twitched a bit,” recalled Miskin. “But it was the first proof of concept — this is going to work!

Teams at Cornell and Pennsylvania are now at work on smart versions of the robots with on-board sensors, clocks and controllers. The current laser power source would limit the robot’s control to a fingernail-width into tissue. So Miskin is thinking about new energy sources, including ultrasound and magnetic fields, that would enable these robots to make incredible journeys in the human body for missions such as drug delivery or mapping the brain.

We found out you can inject them using a syringe and they survive — they’re still intact and functional — which is pretty cool,” he said.

Source: https://eurekalert.org/

Ultrathin, Ultralight NanoCardboard For Aerospace

When choosing materials to make something, trade-offs need to be made between a host of properties, such as thickness, stiffness and weight. Depending on the application in question, finding just the right balance is the difference between success and failure. Now, a team of Penn Engineers has demonstrated a new material they call “nanocardboard,” an ultrathin equivalent of corrugated paper cardboard. A square centimeter of nanocardboard weighs less than a thousandth of a gram and can spring back into shape after being bent in half.

Nanocardboard is made out of an aluminum oxide film with a thickness of tens of nanometers, forming a hollow plate with a height of tens of microns. Its , similar to that of corrugated cardboard, makes it more than ten thousand times as stiff as a solid plate of the same mass.

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Nanocardboard is made out of an aluminum oxide film with a thickness of tens of nanometers, forming a hollow plate with a height of tens of microns. Its sandwich structure, similar to that of corrugated cardboard, makes it more than ten thousand times as stiff as a solid plate of the same mass. A square centimeter of nanocardboard weighs less than a thousandth of a gram and can spring back into shape after being bent in half.

Nanocardboard‘s stiffness-to-weight ratio makes it ideal for aerospace and microrobotic applications, where every gram counts. In addition to unprecedented mechanical properties, nanocardboard is a supreme thermal insulator, as it mostly consists of empty space. Future work will explore an intriguing phenomenon that results from a combination of properties: shining a light on a piece of nanocardboard allows it to levitate. Heat from the light creates a difference in temperatures between the two sides of the plate, which pushes a current of air molecules out through the bottom.

Igor Bargatin, Assistant Professor of Mechanical Engineering, along with lab members Chen Lin and Samuel Nicaise, led the study.

They published their results in the journal Nature Communications.

Source: https://phys.org/

How To Treat Congenital Disease Before Birth

For the first time, scientists have performed prenatal gene editing to prevent a lethal metabolic disorder in laboratory animals, offering the potential to treat human congenital diseases before birth. Published today in Nature Medicine, research from the Perelman School of Medicine at the University of Pennsylvania and the Children’s Hospital of Philadelphia (CHOP) and offers proof-of-concept for prenatal use of a sophisticated, low-toxicity tool that efficiently edits DNA building blocks in disease-causing genes.

Using both CRISPR-Cas9 and base editor 3 (BE3) gene-editing tools, the team reduced cholesterol levels in healthy mice treated in utero by targeting a gene that regulates those levels. They also used prenatal gene editing to improve liver function and prevent neonatal death in a subgroup of mice that had been engineered with a mutation causing the lethal liver disease hereditary HT1 (HT1). HT1 in humans usually appears during infancy, and it is often treatable with a medicine called nitisinone and a strict diet. However, when treatments fail, patients are at risk of liver failure or liver cancer. Prenatal treatment could open a door to disease prevention, for HT1 and potentially for other congenital disorders.

Our ultimate goal is to translate the approach used in these proof-of-concept studies to treat severe diseases diagnosed early in pregnancy,” said study co-leader William H. Peranteau, MD, a pediatric and fetal surgeon in CHOP’s Center for Fetal Diagnosis and Treatment. “We hope to broaden this strategy to intervene prenatally in congenital diseases that currently have no effective treatment for most patients, and result in death or severe complications in infants.

We used base editing to turn off the effects of a disease-causing genetic mutation,” said study co-leader Kiran Musunuru, MD, PhD, MPH, an associate professor of Cardiovascular Medicine at Penn. “We also plan to use the same base-editing technique not just to disrupt a mutation’s effects, but to directly correct the mutation.” Musunuru is an expert in gene-editing technology and previously showed that it can be used to reduce cholesterol and fat levels in the blood, which could lead to the development of a “vaccination” to prevent cardiovascular disease.

Source: https://www.pennmedicine.org/

Red-Blood-Cell “Hitchhikers” Transport Drugs to Specific Targets

A new drug-delivery technology which uses red blood cells (RBCs) to shuttle nano-scale drug carriers, called RBC-hitchhiking (RH), has been found in animal models to dramatically increase the concentration of drugs ferried precisely to selected organs, according to a study published in Nature Communications this month by researchers from the Perelman School of Medicine at the University of Pennsylvania. This proof-of-principle study points to ways to improve drug delivery for some of the nation’s biggest killers, such as acute lung disease, stroke, and heart attack.

The vast majority of drugs fail because they spread throughout the body, landing in nearby organs where they can cause intolerable side effects, as opposed to directly targeting the areas that are really in need,” said first author Jake Brenner, MD, PhD, an assistant professor of Pulmonary Medicine and Critical Care and of Pharmacology. “By massively increasing the drug concentrations that are hitting specific tissues, the RBC hitchhikers should decrease potential side effects and improve the efficacy of drugs delivered to target organs.”

The team showed that RH can safely transport nano-scale carriers of drugs to chosen organs by targeted placement of intravascular catheters, in mice, pigs, and in ex vivo human lungs, without causing RBC or organ toxicities.

Red blood cells are a particularly attractive carrier due to their biocompatibility and known safety in transfusions,” said senior author Vladimir Muzykantov, MD, PhD, a professor of Systems Pharmacology and Translational Therapeutics. “In just a few short years since we began this work, we are now on the brink of mapping out ways to test it in clinical trials.”

The researchers found that RH drug carriers injected intravenously increased drug uptake by about 40-fold in the lungs compared to absorption of freely circulating drug carriers in blood. In addition, injecting the RH drug carriers into the carotid artery (a major blood vessel in the neck that delivers blood to the brain, neck, and face) delivers 10 percent of the injected dose to the brain, which is about 10 times higher than what is achieved through older methods such using antibodies to guide drugs to their intended targets. Such impressive drug delivery to the brain could be used to treat acute strokes, the fourth leading cause of death in the U.S.

Development of RH technology has also revealed a potentially fundamental process that hold enormous clinical promise. “The body’s largest surface area of cell-to-cell interaction is observed between red blood cells and blood vessel linings, so it is intriguing to think that our RH technology has uncovered a phenomenon in which RBCs naturally transport cargo on their surfaces,” said Muzykantov.

Source: https://www.pennmedicine.org/