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Category Archives: Pennsylvania Stem Cells

People and places at Penn | Penn Today – Penn Today – Penn Today

Posted: August 18, 2021 at 1:51 am

For many students, attending college marks the first time away from home, the first time managing a budget, even the first time doing laundry. New spaces, new classes, new friends, new routines. This year, its not just new for the freshmen. For many, late August will mark their first return to campus since March 2019. In anticipation of Move-In, Penn Today asked six undergraduate students in the Philadelphia area this summer to divulge their favorite spots.

Ariana Jimnez found her niche on an exploratory walk, while Steven Chen and Quinn Gruber found theirs through special interests, and Lucas Monroe gravitates to athletic history. Francisco Barrera chose a study spaceand where he goes to decompress. Dorms, libraries, and outside spaces are all on the list. Morgan Bacon is most looking forward to Hey Day to kick off this semester. Its nerve-wracking to be declared a senior, but also very exciting. Ive enjoyed my time at Penn so much, she says. I can't wait to reconnect with my friends and just hang out on the grass.

Steven Chens first engagement with Penn was through the Netter Center for Community Partnerships, and as aPenn Program for Public Service intern, the biology major from Warminster, Pennsylvania now works through Netter Centers OurSpace to host weekly meetings with a group of West Philadelphia and Penn students at the LGBT Center, one of his favorite campus spots. Its a very accepting space, Chen says, a place for them to have fun and express themselves.

The sophomore is currently collaborating with the LGBT Center and the Netter Center to develop aqueer sexual health education program that utilizes peer-assisted learning. A pre-med student, Chen is interested in providing health care access to queer people and people of color. You have to be healthy to pursue your other dreams, he says. Health is the foundation.

I like a good puzzle or challenge, says Ariana Jimnez, who plans to investigate white-collar crime as an FBI agent. This requires business-industry experience, so the sophomore from Plainfield, Illinois is enrolled in the Wharton School, concentrating on finance and social impact.

She passed the benches in the engineering quad on a walk one day, and which has since become a favorite place to chill and listen to music, Jimnez says. Currently Im bingeing Taylor Swift before her new album comes out.

Jimnez is looking forward to having the opportunity to engage with people face-to-face this fall, she says. Shes also looking forward to living in New College House West. You already know Im going to be exploring that as soon as I get in there, she says. While on routine walks, Im always trying to look in to see if it looks cool, Jimnez says. And it does look cool.

Francisco Barrera of Miami, Florida is really interested in the energy problem. Barrera wants to part of the solution, so he applied to Penns Vagelos Integrated Program in Energy Research, where the senior is studying engineering and physics. Barrera spent his summer doing research with Deep Jariwala of the Device Research and Engineering Laboratory, looking into new materials and new configurations for maximizing light absorbance and efficiency for the next generation of solar cells, he says.

Barreras favorite place to study is the Fisher Fine Arts Library. Im always surrounded by STEM. The Fine Arts Library is a little bit of an escape from that, he says. I was always totally inspired by how beautiful the inside was. Its so quiet compared to other study spaces.

When not working, Barrera heads to the beach volleyball court, a great stress reliever, he says, especially during freshman year when the Miami student was adjusting to college life. The sandy court makes it more fun and athletic, Barrera says, Im more willing to throw myself down to dive for a ball.

A double major in English and Italian from Cortlandt Manor, New York, Quinn Gruber loves the Student Projects Space at the Kelly Writers House. The space is special for me because its the home of the Zine Library, a student-run collection of zines (small, self-published books/pamphlets/print objects) that Ive helped curate for three years now, with Alyson del Pino (C21) and now Victoria Garcia (C23), says Gruber, currently a senior. I love hanging out on the green beanbag with a hot cup of tea and reading the amazing zines that we have in the library, and appreciate the space as a great resource for students who make art,since we have supplies,books, and printing available for everybody.

Gruber also plays violin in a Penn Chamber Quartet, an important reprieve from the pressures of work and school, they say. Gruber enjoys visiting the Eugene Ormandy Music & Media Center to borrow whatever piece Im working on, whether for Chamber or myself, and to discover new music by just wandering through the stacks, they say.

I was always really passionate about nutrition, and more specifically childhood nutrition, says Morgan Bacon. Growing up in Philadelphia, Bacon was acutely aware of food deserts, and began working with the Food Trust. Along with social determinants, she realized how big of a role nutrition played in heath, and applied to Penn Nursing.

The Annenberg Center is one of Bacons favorite places, because the senior attended a performing arts camp here as a child, which piqued my interest in college, she says. It all seemed like a glamorous life.

Once on campus, Bacon spent two years living at Lauder College House. I just loved it so much, she says. The courtyard area was a space where the house could come together.

Im on the basketball team, so thats an easy choice for me, says Lucas Monroe of Abington, Pennsylvania, of why he chose the Palestra as one of his favorite campus spots. But Im also a huge basketball nerd and the Palestra is the cathedral. Its Mecca. More games have been played there than in any other college arena, and thats why its so historic. I like to sit at the top, he says. Ill do homework up there; Ill read up there.

Monroe, a junior majoring in political science with a minor in Africana Studies, also likes to work on the hill outside of Van Pelt-Dietrich Library. Its a peaceful spot, he says, but also one thats good for people watching. You have the library to the left of you, College Hall diagonal. The Franklin statue and the Button are all right there; theres a lot of cool things you can look at.

Homepage image: Clockwise from top left: Morgan Bacon, Ariana Jimnez, Francisco Barrera,Quinn Gruber, Lucas Monroe, and Stephen Chen introduce their favorite places at Penn.

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Millions in federal money flowed to tissue bank that collected fetal ‘heart, gonads, legs, brain’: report – Fox News

Posted: August 5, 2021 at 2:06 am

The Department of Health and Human Services (HHS) has funneled at least $2.7 million into a University of Pittsburgh (Pitt) project that utilizes a tissue bank with organs from aborted fetuses, according to a release from Judicial Watch Tuesday.

The conservative nonprofit obtained hundreds of pages of public records requests, which detail Pitt's interest in harvesting fetal organs for a project known as the GenitoUrinary Development Molecular Anatomy Project, or GUDMAP. More money was requested by the university but it's unclear exactly how much it received.

Pitt's application specified that it sought to "develop a pipeline to the acquisition, quality control and distribution of human genitourinary [urinary and genital organs and functions] samples obtained throughout development (6-42 weeks gestation)." Forty-two weeks represents more than 10 months of pregnancy.

In 2015, Pitt told HHS that it has been "collecting fetal tissue for over 10 years includ[ing] liver, heart, gonads, legs, brain, genitourinary tissues including kidneys, ureters and bladders."

It also revealed that the university sought a large number of minority fetuses, according to Judicial Watch something Center for Medical Progress founder David Daleiden described as "racist."


The university told Fox News that the higher number of minorities resulted from an emphasis on those populations most impacted by kidney disease. "Projects funded by the National Institutes of Health must ensure appropriate inclusion of women and minorities," said David Seldin, assistant vice chancellor for news.

"They should also ensure distribution of the study reflects the population needed to accomplish the scientific goals of the study. Asked another way: Does the makeup of the study reflect the populations affected by the illness in question? In the case of the GUDMAP Tissue Hub, one of the goals is to support researchers looking for treatments and cures for kidney disease."

In a PureFlix interview last year, former university employee Lori Kelly discussed a federally funded project with researchers seeking to collect bladders and kidneys from babies as late as 24 weeks into pregnancy. Kelly said that as project manager, she worked to develop "a pull-down menu of baby body parts for researchers to choose from to submit to the tissue bank, so that we could send the body parts to them."


"And these researchers were all across the United States," she said,"from Florida to California." When asked, the University of Pittsburgh did not respond to Kelly's allegations earlier this year.

Both the university and its medical center have denied any wrongdoing.

Tuesday's revelation adds mounting scrutiny to a school that has already received attention for its use of fetal tissue.

"The University of Pittsburgh complies with rigorous regulatory and ethical oversight of fetal tissue research," Paul Supowitz, the university's vice chancellor, previously told lawmakers."The researchers in this matter followed all applicable federal and state guidelines and regulations (with Pennsylvania having one of the most restrictive set of requirements in the nation), as well as strict protocols approved by the University. The Universitys Institutional Review Board approved the acquisition of stem cells."

The National Institutes of Health (NIH) has also maintained that it complies with federal law. It previously told Fox News: "NIH is committed to ensuring that research involving human fetal tissue is conducted responsibly and meets the highest ethical standards."


Earlier this year, Pennsylvania's state legislature held a hearing in which members discussed an experiment involving grafting fetal scalps, containing "full-thickness human skin," onto rodents.

That particular project utilized tissue from the university's human tissue bank. It was also supported by grants from the National Institute of Allergy and Infectious Diseases (NIAID), which is led by top coronavirus adviser Dr. Anthony Fauci. While it's unclear exactly how much federal money was spent on that project, it was funded through two large grants one $1,498,642 and one $430,270.

David Daleiden, the anti-abortion journalist who testified at May's hearing, said on Tuesday: "The NIH grant application for just one of Pitts numerous experiments with aborted infants reads like an episode of American Horror Story People are outraged by such disregard for the lives of the vulnerable. Law enforcement and public officials should act immediately to bring the next Kermit Gosnell to justice under the law."

The documents uncovered by Judicial Watch also show Pitt discussing its effort to minimize warm ischemic time, or the amount of time an organ maintains its body temperature after blood flow has been severed. It's unclear how these procedures take place, but Daleiden has raised concerns about the university's stated use of labor induction abortions.


"If the fetus heartbeat and blood circulation continue in a labor induction abortion for harvesting organs, it means the fetus is being delivered while still alive and the cause of death is the removal of the organs," reads a press release from his Center for Medical Progress. Typically, abortion procedures rely on digoxin to kill a fetus. However, both that and dismemberment tactics can ruin viable tissue intended for donations.

In a statement to Fox News, Seldin said clarified the researchers have "no part in any decisions as to timing, method, or procedures used to terminate the pregnancy."

Ischemia time, he said "refers to the time after the tissue collection procedure and before cooling for storage and transport. It does not have an impact on how the procedure is performed, which is always at the discretion of the attending physician and determined with the patients health as the top priority."

Seldin added that all tissue was obtained in compliance with the Pennsylvania Abortion Control Act, which lays out a series of regulations for performing the procedure. It also contains a section banning infanticide, noting that: "The law of this Commonwealth shall not be construed to imply that any human being born alive in the course of or as a result of an abortion or pregnancy termination, no matter what may be that human being's chance of survival, is not a person under the Constitution and laws of this Commonwealth."

In May, the university provided Fox News with a statement defending the use of fetal tissue research.


"Researchers at Pitt and other leading medical research institutions use fetal tissue in certain instances because it has proven to be an important method for combatting and curing some of our most devastating diseases, including ALS, Parkinsons disease, Alzheimers disease, spinal cord injury and others," read the statement.

On Wednesday, Seldin added that "[t]his grant supported research to find new therapies for diseases of the kidneys, bladder and urinary systems, which are a leading cause of organ failure. By providing a central hub for researchers across the country, this program allowed scientists across the country to access tissue necessary to tackle this growing public health concern."

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Bispecific Antibodies Wage a Two-Pronged Attack on Tumors –

Posted: June 23, 2021 at 1:59 am

After Michael Herman received a diagnosis of high-risk multiple myeloma in 2013, he started a treatment journey that included several years of chemotherapy and the targeted drug Venclexta (venetoclax tablets), which is investigational for the disease and was designed for patients whose cancers have certain genetic abnormalities. The medicines worked well, but as is often the case with multiple myeloma, Hermans cancer eventually returned.

In July 2019, Herman qualified for a clinical trial of teclistamab, an investigational drug thats part of an emerging class of immunotherapy medicines known as bispecific antibodies. He traveled from his home in Galena, Maryland, to the University of Pennsylvania in Philadelphia to get the treatment: a weekly shot in the abdomen.

After just one dose of teclistamab, Hermans cancer load dropped 99%. His disease is no longer detectable, and the study investigators have told him he can stay on the drug as long as it continues to be effective. In terms of side effects, Herman experiences some aches and pains, but says that it doesnt affect him from getting around.

When I was diagnosed, I was told my life expectancy was four years, says Herman, 59, a retired corporate real estate manager. This drug doubled that. Its a wonderful thing.

Teclistamab is one of several bispecific antibodies being developed to treat a range of cancers. Bispecific antibodies are designed to simultaneously bind two targets a target on immune cells and another on tumor cells pulling them together to unleash an immune attack against the cancerous cells. In the case of teclistamab, the two targets are an antigen called CD3 in the immune systems T cells, and BCMA, which is an antigen thats overexpressed in multiple myeloma.

Several other bispecific antibodies are under development to treat blood cancers and a wide range of solid tumor types, including cervical, gastric, brain and liver.

The idea behind combination immune therapies, which include bispecific antibodies, is to find ways to better target the immune system from the get-go, to minimize the chance of resistance or improve the chance of getting a good response, says Dr. Deborah Wong, an oncologist at UCLA.

The first, and so far only, bispecific antibody on the market, Blincyto (blinatumomab), is approved by the Food and Drug Administration (FDA) to treat some patients with acute lymphoblastic leukemia (ALL). The drug, referred to as a bispecific T-cell engager (also referred to as BiTE), has one arm that attaches to CD3 and a second that binds to the antigen CD19 on the surface of cancerous B cells.

In a trial of patients with relapsed or resistant B-cell precursor ALL, Blincyto increased the rate of complete remissions from 20% among patients on standard-of-care chemotherapy to 42%. In a pediatric study released in March 2021, 69% of children treated with Blincyto were still alive after nearly two years, and 93% showed no sign of disease. In a phase 2 study released in May 2021, there was a 95% response rate among patients with Philadelphia chromosome-positive ALL who received Blincyto plus the targeted drug Iclusig (ponatinib), showing the potential of treating patients without the need for chemotherapy, the researchers said.

Bispecific antibodies can cause side effects, including cytokine release syndrome, a severe inflammatory response marked by high fever, body aches and other symptoms. Although Herman experienced cytokine release after his first shot of teclistamab, he has had minimal side effects since then.

Bispecific antibodies could bring immunotherapy options to patients who arent eligible for treatments like CAR T cells, which are personalized therapies that entail removing immune cells from patients and engineering them to recognize and attack their cancer. Although these T-cell therapies can be lifesaving, they present challenges that could be avoided with bispecific antibodies, says Dr. Joshua Richter, assistant professor of medicine, hematology and medical oncology at the Icahn School of Medicine at Mount Sinai in New York.

CAR-Ts are not off-the-shelf products, so they take time for manufacturing, whereas bispecifics are off the shelf, Richter says. And even though there is a risk of side effects with bispecific antibodies, they are titratable, meaning they can be given in small doses to start and then in larger doses after the immune system is given a chance to adapt. We are concerned about giving CAR-Ts to older people because some can get quite sick (from cytokine release), Richter says. Its nice to have a more titratable alternative.

Several bispecific antibodies aimed at multiple myeloma are in clinical trials now, some of which are showing early promise. In a phase 1 dose-ranging study of an intravenous formulation of teclistamab, for example, 58% of patients on the recommended dose for phase 2 trials showed a partial response and 30% had a complete response. Although 70% of participants experienced cytokine release, none had symptoms severe enough to prompt them to pull out of the trial. Other side effects included anemia, a drop in white blood cells and fatigue. A phase 2 study of the drug in multiple myeloma is ongoing and recruiting patients.

Another trial of a BCMA-CD3-targeted bispecific antibody, elranatamab, was paused in May because of cases of peripheral neuropathy reported by some patients. The drugs developer, Pfizer, was asked to investigate the cases and report what it finds to the FDA. Patients in the trial who were benefiting from the drug were able to stay on it, but no new patients will be accepted until the investigation is complete.

There are other promising approaches to multiple myeloma in early-stage testing, Richter says, including a bispecific antibody called cevostamab, which targets CD3 and FcRH5, an antigen expressed on the surface of almost all multiple myeloma cells. Interim results from an ongoing phase 1 study that were reported in December showed an overall response rate of 53%. Responses were even seen in patients who had failed five previous treatments.

Another prospect in multiple myeloma is a bispecific antibody called GBR1342, which targets CD3 and CD38, an antigen implicated in the disease and other blood cancers. The drug, now in phase 1 testing, received orphan drug designation from the FDA in 2019, which could expedite its development path.

There are several bispecific antibodies in development to treat other blood cancers, including acute myeloid leukemia (AML). For example, a drug called flotetuzumab targets CD3 and CD123, a molecule called an interleukin-3 receptor thats prevalent on malignant cells in AML. In a trial of the drug in patients who had relapsed after other therapies, 32% of participants achieved a response, and more than half of those were able to go on to receive stem cell transplants, which put them in remission.

The flotetuzumab trial results highlighted another potential advantage of bispecific antibodies, which is that they may offer patients a bridge to other treatments that could result in more durable remissions, such as stem cell transplants. The ALL treatment Blincyto has also been shown to offer some patients a good lead-in to stem cell transplants. In a trial comparing the drug to standard-of-care chemotherapy, the overall response rate to Blincyto was 44%, and 24% of the patients receiving the drug went on to have stem cell transplants.

Oncologists at The University of Texas MD Anderson Cancer Center in Houston are now testing Blincyto in patients with newly diagnosed ALL, and there are encouraging early results. Last year, researchers reported results from a small trial in which patients with ALL started with four cycles of chemotherapy and then were placed on maintenance treatments that included Blincyto. There was a 100% response rate, and 79% of patients stayed in remission for two years.

Historically, we can cure about 40% to 50% of elderly patients with ALL, so if this response rate holds over time, it will be a tremendous improvement, essentially doubling survival rates, said Dr. Marina Konopleva, a professor and physician-scientist in the department of leukemia and stem cell transplantation at MD Anderson.

Phil Briggs, who received a diagnosis of ALL in January 2018, was treated with Blincyto in the fall of 2020, after his cancer stopped responding to standard-of-care chemotherapy. He found the drug to be far more tolerable than chemotherapy, which had caused him to lose his appetite and drop more than 50 pounds, in addition to developing peripheral nerve damage. Aside from a slight skin irritation, I felt fantastic, says Briggs, 62, who is being treated at MD Anderson.

Briggs courses of Blincyto came in a portable pump, allowing him to receive the agent on an outpatient basis without having to go to the hospital. After four months on the drug, he was able to undergo a stem cell transplant and is now in remission. I felt so much better that I was able to go straight from (Blincyto) to the stem cell trans- plant without any side effects, says Briggs, who is now planning to go back to work as an insurance salesman.

Targeting solid tumors with immunotherapy has been difficult because they lack a single target for immune cells to latch on to, and the environment that surrounds them may not be conducible for immune cells to readily attack the cancer cells. The two-pronged design of bispecific antibodies could help overcome those hurdles.

Several bispecific antibodies being developed to treat solid tumors include one treatment group that targets an immune checkpoint like PD-L1 or CTLA-4, inhibiting it so the immune system can launch an attack.

For example, a bispecific antibody called FS118, which is now being tested in a phase 1 trial in solid tumors, has one treatment group that inhibits PD-L1 and another that blocks another immune checkpoint called LAG-3. Initial results from a trial released last year showed that patients who had been treated with PD-1 or PD-L1 blockers and became resistant to them had durable stabilization of their disease on FS118.

A bispecific antibody called XmAb20717 blocks PD-1 and CTLA-4 and is being tested in patients with a number of solid tumor types. The response rate in a trial reported last November was 19% and included a complete remission in one patient with melanoma. Partial responses were seen in patients with ovarian cancer, non-small cell lung cancer (NSCLC) and castration-resistant prostate cancer.

Other bispecific antibodies in development to treat solid tumors target disease-promoting genetic mutations. One of these agents was recently approved by the FDA. Called Rybrevant (amivantamab-vmjw), it targets EGFR and MET in NSCLC with abnormalities in those genes. It is the first fully human, bispecific antibody approved in lung cancer. The approval was based on results from the phase 1 study, where the response rate to the drug was 40% in patients who had previously been treated with platinum chemotherapy, and 74% of patients saw their disease stabilize.

With so many bispecific antibodies in development across a range of cancer types, many patients could benefit from enrolling in clinical trials of these new therapies, says Wong. Clinical trials are a good option to consider, especially if youve already been on standard therapies, she says. It may be that patients who responded well to their initial therapy and then developed resistance could be good candidates for bispecific antibodies.

And because bispecifics target the immune system, they could improve the prognosis for many patients, Wong says: The beauty of immunotherapy is that the immune system has a long memory, so theres a potential for patients to have long-lasting responses to these drugs.

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Newly Discovered Glycosylated RNA Is All Over Cells: Study – The Scientist

Posted: May 25, 2021 at 1:52 am

The emergence of nucleic acids and that of proteins have sometimes been called the first and second evolution revolutions, as they made life as we know it possible. Some experts argue that glycosylationthe addition of glycans to other biopolymersshould be considered the third, because it allowed cells to build countless molecular forms from the same DNA blueprints. Its long been believed that only proteins and lipids receive these carbohydrate constructs, but a May 17 paper in Cellthat builds upon a 2019 bioRxiv preprint posits that RNAs can be glycosylated, too, and these sugar-coated nucleic acids seem to localize to cell membranes.

Anna-Marie Fairhurst, who studies autoimmunity at the Agency for Science, Technology and Research in Singapore, describes the study as exciting. Obviously, its the first time ever that weve seen this with RNA, she says, adding that the diversity of methods used to demonstrate the presence of glycoRNAs makes the findings especially robust.

What really intrigues her are the parts present in the 2021 Cellpaper that arent in the 2019 preprintin particular, that glycoRNAs appear to predominantly end up on the cells outer membrane. There, they can attach to two kinds of sialic acid-binding immunoglobulin-type lectins (Siglecs)a family of immune receptors implicated in several diseases, including systemic lupus erythematosus (SLE). All of this suggests glycoRNAs may play a role in immune signaling. Its a really exciting era of science, Fairhurst says.

Ryan Flynn, the first author on the new paper and an RNA biologist at Harvard University and Boston Childrens Hospital, says he made the startling discovery of glycoRNAs while working in chemical biologist Carolyn Bertozzis lab at Stanford University. Bertozzi says she was skeptical at first but came around after thinking about how her own assumptions might be shaping her views. We bring to every experiment all this unconscious bias, she explains, and once she re-examined her own, she found no reason to think glycoRNAs shouldnt exist. These are ancient molecules, she says. Theres no reason to just presume that they wouldnt have found a way to connect and to create new biology.

These are ancient molecules . . . Theres no reason to just presume that they wouldnt have found a way to connect and to create new biology.

Carolyn Bertozzi, Stanford University

As it happens, Flynn did set out to overturn glycosylation dogma when he joined Bertozzis lab as a postdoc in 2017although it didnt happen the way he expected. At first, he explains, he had his eye on a quirky cytosolic protein glycosylation pathway because hed noticed that one of its key enzymes has an RNA-binding domain. If theres a glycosylation enzyme with the potential to bind RNA, and its functioning in the cytosol where RNAs tend to be, he reasoned, it could be sticking sugars to RNAs, too.

To search for the existence of these structures, it was really important that I had access to things that were not dependent on high temperatures, and not dependent on metals that might otherwise degrade the RNA, he says, and thats exactly what Bertozzis lab had to offer. Shes a pioneer in the field of bioorthogonal chemistry, which aims to develop chemical methods for tracking biomolecules in their native environments. Her lab was brimming with reagents that label specific kinds of glycans without harming other molecules or setting off side-reactions.

Flynn set to work adding these glycan-labeling compounds to HeLa cells and then isolating RNA from them to see if any glycan signal remained after hed removed all proteins and lipids. He says he thought he might see a signal when he labeled the kind of glycans used in that cytosolic glycosylation pathway.

However, months of experiments failed to support that hypothesis.

Instead, something strange kept happening with what was supposed to be a negative control: cells treated with ManNAz, an azide-labeled precursor for sialoglycans, a group of glycans known for their role as modifiers of secretory and cell surface proteins and lipids. Once the cells were given the chance to incorporate ManNAz, they were lysed with TRIzol, which breaks apart cellular components without damaging RNAs, and any surviving proteins were chopped up with proteases. The idea was that thered be no azide signal at the end, as sialoglycans are attached to proteins and lipids in the endoplasmic reticulum and Golgi, where RNAs have no business being. I was like, theres no way that a reagent that labels sialoglycans is going to end up labeling an RNA, even a glycoRNA, Bertozzi says, but those experiments consistently gave Flynn positive signals.

So, the team dug further. Not only did the glycoRNAs the team found contain this specific subgroup of glycans, they appeared to largely consist of YRNAs, a family of small, highly conserved noncoding RNAs whose cellular functions remain unclear, although previous studies have suggested they may play a role in oncogenesis and autoimmunity. The specificity of both the glycans and the type of RNAs involved strongly point to their being attached to one another with an enzyme, says Bertozzi.

Furthermore, once the researchers started looking for them, they found these glycoRNAs in numerous established cell lines, including cancer-derived ones such as HeLa and T-ALL 4118 cells, as well as stem cellderived CHO and H9 cells. They were even able to detect glycoRNAs in liver and spleen cells extracted from live mice that received intraperitoneal injections of ManNAz, suggesting that glycoRNAs are everywhere.

By 2019, the team members felt they had enough supportive data to submit their findings, so they put the preprint version up on bioRxiv. It made a splash in the scientific community, but without peer review, some remained skeptical. Now, after even more experiments and a rigorous review process, the team says its data have become even more compelling.

They clearly have isolated a covalent RNA-glycan conjugate, says Laura Kiessling, a chemical biology researcher who studies carbohydrates at MIT and was not involved in the study. However, big questions remain, including what these glycoRNAs do and how they form. For instance, its unclear exactly how the RNAs and glycans are physically connected to one another, she notes, and without that information, shes not quite convinced that the binding happens enzymatically.

Flynn and Bertozzi suggest that the RNAs are glycosylated much in the same way proteins are, and that it even requires some of the same proteins. As noted in the original preprint, when they inhibited key enzymes involved in glycosylation, glycoRNAs disappeared in a dose-dependent manner. Similarly, cell lines engineered to have errors in protein glycosylation produced very little glycoRNA. But for RNAs to be glycosylated by the same pathway as proteins would be weird, Kiessling says, noting that multiple glycosylation steps only proceed after a check for proper protein folding. Its hard for me to imagine exactly how that would occur with RNA.

The researchers were even able to detect glycoRNAs in liver and spleen cells extracted from live mice, suggesting that glycoRNAs are everywhere.

Fairhurst says she also wants to know more about the synthesis pathway. She has lots of other questions, too, which she says is a good sign. A really good, exciting paper leaves a lot more questions than it does answers, she notes.

While the 2019 preprint raised many of these questions, some are unique to the new data presented in the Cell version. Perhaps the biggest addition to the work was the discovery of where these glycoRNAs spend their timestuck on the outsides of cells, explains Flynn. The team demonstrated this by briefly exposing some ManNAz-labeled HeLa cells toan enzyme that can cleave sialic acid glycans from the cell surface. If the glycoRNAs were on the outside, they would be cut off, and the total amount of glycoRNAs remaining would drop. And thats exactly what they found: the glycoRNA signal started to decrease after as little as 20 minutes of incubation with the sialidase and was reduced by more than 50 percent after an hour, which the team suggests means that more than half of a cells glycoRNAs are stuck on its outer membrane.

The researchers further probed the hypothesis of extracellular localization by labeling living cells with an antibody that binds to double-stranded RNA. About one-fifth of a culture of HeLa cells were positive for antibody staining, and the label was sensitive to RNase treatment, further supporting the idea that glycoRNAs are indeed present on the outer cell membrane. That opens up a lot of ideas, and a lot of possibilities, functionally and mechanistically, for what they could be doing, says Flynn.

One of those possibilities is that glycoRNAs are involved in cell-to-cell signaling, especially in an immune context, as thats a known function of membrane glycolipids and glycoproteins. Bertozzi had already been investigating the ligands of Siglecs, a group of sugar-binding receptors that modulate immune reactions, so the team decided to see if any of them bound to glycoRNAs. They first treated HeLa cells with different Siglecs to show that the receptors bound normally, then treated the cells with RNase. Lo and behold, the binding of Siglec-11 and Siglec-14 dropped precipitously, suggesting that their ligands were cleaved from the surface by the RNA-cutting enzyme.

Bertozzi says the experiment indicated glycoRNAs are ligands for Siglec-11 and Siglec-14, and if so, theyd be the first identified for Siglec-11.

As a receptor family, [Siglecs have] kind of been ignored, notes Fairhurst, so the fact that these glycoRNAs can interact with them is very exciting, she says. My immediate desire is to see whether they are associated with diseases, particularly in SLE, she adds.

Lan Lin, an RNA biologist at the University of Pennsylvania and the Childrens Hospital of Philadelphia, says she found the 2019 preprint so interesting that she applied for and received a pilot grant from the Frontiers in Congenital Disorders of Glycosylation (CDG) Consortium to study the roles glycoRNAs may play in CDG, a group of rare congenital conditions arising from mutations in protein glycosylation pathways. Because RNA glycosylation may be related to protein glycosylation, she tells The Scientist, it was only rational or reasonable for [my colleagues and I] to hypothesize that . . . some of these patients might have differences in the glycoRNA in their system, and therefore, CDG conditions could be used to examine the potential functions of glycoRNAs.

So far, she says, her team hasnt detected any consistent differences in glycoRNAs between the cells of healthy controls and CDG patients. She says that may be because differences are more qualitative than quantitative, such as alterations to the sugars themselves or the subset of RNAs that are glycosylated. Alternatively, she notes, the new data in the 2021 Cell paper may provide an explanation: the membrane localization of glycoRNAs wasnt in the preprint, so maybe we are looking in the wrong place, she muses.

Its also possible that new methods are needed to detect glycoRNA differences between cells. She points out that a major limitation of the study is that the ManNAz labeling method cant readily be applied to preserved human tissue samples or blood samples.

Fairhurst says shed like to see more work in primary cell cultures rather than immortalized ones, especially leukocyte subtypes, where one might expect pronounced differences if the RNAs have a role in immunity. For example, she says shed like to see whether, in people with conditions like SLE, different cell types have fewer or more glycoRNAs, though obviously, those experiments are really challenging.

Seeing these big milestones is amazing

Anna-Marie Fairhurst, Agency for Science, Technology and Research in Singapore

Still, she says, seeing these big milestones is amazing.

Kiessling says she thinks glycoRNAs could be really important in the field of glycobiology. Her lab focuses on how carbohydrate-binding proteins can read glycans on the surfaces of cells, she explains, so these glycoRNAs could be a new kind of information to read. Lin points out that the findings are especially impactful for RNA researchers, as they suggest a whole new kind of post-transcriptional modification in need of investigation. Because glycoRNA sits at the intersection of glycobiology, immunology, and RNA biology, says Bertozzi, Ryans discovery has brought together these disparate worlds.

Flynn and Bertozzi say theyre hoping to start answering some of the many questions that remain, including how the glycans attach to RNAs and how and where that happens. The most exciting part, they say, will be the investigations into what glycoRNAs do.

R. Flynn et al., Small RNAs are modified with N-glycans and displayed on the surface of living cells,Cell, doi:10.1016/j.cell.2021.04.023, 2021.

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Penn researchers find a way through the labyrinth keeping CAR-T from solid tumors – Endpoints News

Posted: December 7, 2020 at 4:56 pm

Blood vessels are supposed to act like trees, pumping in oxygen tissues need to grow and immune cells required to clear out pathogens. But in tumors, the forest can go a bit haywire. Vessels grow prodigiously and bulge and twist at abrupt points, making it difficult to even tell whats a vein and whats an artery. It starts to look less like a forest and more like a gnarled root floor. A disorganized labyrinth, one oncologist has called it.

For cancer, chaos is a virtue. That gnarled root floor insulates solid tumors from immune cells and, in recent years, has flustered drug developers best attempts at developing therapies meant to rev up the immune system and direct it toward the tumors.

Researchers at the University of Pennsylvania, however, think they may have stumbled onto a solution, a way of whipping the blood vessels back into proper shape. If it works, experts say, it could pave the way for CAR-T treatments that attack solid tumors and potentially improve the effectiveness for more traditional approaches, such as radiation and chemotherapy.

Its a really novel and potentially important approach, Patrick Wen, a neuro-oncologist at Dana-Farber who was not involved in the work, told Endpoints News. They really did good work. This is a very different way of improving immunotherapy.

Yi Fan, a radiation oncologist at Penns School of Medicine, has been working for the last few years to understand why the labyrinth appears in the first place. Researchers had previously circled in on the so-called growth factors that stimulate blood vessel formation. Attempts to block these factors, though, disappointed; Avastin, an antibody against the factor VEGF, became a blockbuster but has continually failed to improve survival on a range of malignancies.

Scientists would have to go more fundamental. In a pair of 2018 papers, Fan showed that part of the problem is a process called endothelial cell transformation. Cells lining the blood vessels around the tumor acquire stem cell-like properties that allow them to reproduce and expand rapidly, as stem cells do.

Theres a genetic reprogramming, Fan told Endpoints. Theyll become really aggressive.

But how did that reprogramming happen? If Fan could pin down the pathway, he figured he could then devise a way to block it. He started knocking out kinases the cellular engines that can drive epigenetic change, or reprogramming one by one in endothelial cells isolated from patients with an aggressive brain cancer called glioblastoma. Out of 518, 35 prevented transformation and one did so particularly well: PAK4.

Then they injected tumors into mice, some who had PAK4 and some who had the kinase genetically removed: Eighty percent of the mice who had PAK4 removed lived for 60 days, while all of the wild-type mice died within 40. Fans team also showed that T cells infiltrated the tumors more easily in the PAK4-less mice.

It was a fortuitous finding: Drug companies had developed several PAK inhibitors a decade ago, when kinase inhibitors were the flashiest thing in pharma. Many had been abandoned, but Karyopharm had recently brought a PAK4 blocker into Phase I.

To see whether drug developers could exploit this finding, Fan and his team removed T cells from mice and developed a CAR-T therapy to attack the tumors.

They gave mice three different regimens. The CAR-T therapy on its own failed to reduce tumor size, apparently unable to reach through the vessels. The Karyopharm drug also had little effect on its own. But combined, they managed to reduce tumor size by 80% after five days. They published the results in Nature Cancer this week.

It is a really eye-opening result, Fan said. I think we see something really dramatic.

That, of course, is just in mice, but Fan already has strong supporting evidence for PAK4s role in cancer. Last December, while Fan was still completing his experiment, Nature Cancer published a paper from Antoni Ribas UCLA lab suggesting that PAK4 inhibitors can help T cells infiltrate around various solid tumors. They showed that the same Karyopharm inhibitor could boost the effects of PD-1 inhibitors in mice, allowing activated T cells to better reach tumors.

That work has already translated into the clinic; weeks after it came out, Karyopharm added an arm to their Phase I study of the drug that will look at the PAK4 inhibitor in combination with the PD-1 blocker Opdivo.

Ribas said that Fans work is compelling and helps confirm the role of PAK4, but he said a CAR-T therapy would face a much longer path to the clinic. Its simply much easier to combine an approved drug with an experimental one than to devise a new CAR-T therapy, mix it with the unapproved inhibitor (and all the other things, such as bone marrow-clearing chemotherapy, CAR-T recipients receive) and then deduce what effect each is having.

It will a take a while, Ribas told Endpoints. But I hope this is right and its developed clinically.

There are also other unresolved obstacles for CAR-T in solid tumors, Wen said. Developers still struggle to find targets that wont also send the super-charged T cells after healthy tissue. And tangled blood vessels are just one of several mechanisms tumors have of defending themselves. They can, for example, turn tumor-eating immune cells into tumor-defending ones.

Still, Wen said, in the short term, the approach offered a path toward boosting the efficacy of radiation, chemotherapy and other small molecule drugs. Although Fan focused on glioblastoma, researchers agreed PAK4 likely plays the same vessel-warping role in many other solid tumors.

Theres a lot of things you could look at, he said.

In a January review, Jessica Fessler and Thomas Gajewski at the University of Chicago said Ribas paper pointed towards a path for improving PD-1 and overcoming resistance in some tumors. But they also raised questions about the Karyopharm drug, noting that it hits other proteins besides PAK4. That could mean other mechanisms are also at play and that the drug could affect other tissues in humans.

Ribas agreed that Karyopharms drug might not be the perfect molecule but said others could be on their way. He serves as a scientific advisor to Arcus, the Terry Rosen startup that is now working on developing its own PAK4 inhibitor.

If they can develop a very selective PAK4 inhibitor, he said, it may be a more direct way of testing the role of PAK4.

Tests with that drug, in turn, could help clear up a biological mystery that emerged out of Fans and Ribas papers. Although both investigators zeroed in on PAK4, each of them suggested very different mechanisms by which PAK4 kept immune cells out of the tumor. Ribas suggested it directly suppresses T cells, while Fan found it led to those transformations inside the blood vessels near the tumor.

Kinases are versatile proteins and both researchers said its possible that PAK4 is doing both. Its also possible, they said, that one is more important than the other, or simply that one of them is just wrong.

When you start with completely new biology, its hard to get it right the first time, Ribas said.

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‘Benjamin Button’ discovery could reverse ageing process – Queensland Times

Posted: at 4:56 pm

A world-first light bulb moment discovery by a modest Queensland scientist could deliver the ultimate gift in modern science - a way to reverse the ageing process.

On a lab bench at the University of Queensland, Professor Justin Cooper-White, a chemical engineer, is working on an incredible project that will one day help peel back the years and allow older people to live a more youthful, active life and ultimately look younger.

This Benjamin Button-effect is just one of the areas of regenerative science that will change the world of healthcare.

"It's fantastical to think that a 70 year old will suddenly have the youth of a 20 year old that's not going to happen but there is very real evidence that it will be possible to slow ageing and revert cells in the body that are "frustrated" due to age into more calm cells that will allow easier movement, better breathing and faster healing," Prof Cooper-White said.

Professor Justin Cooper-White at UQs Robotic Stem Cell Engineering Facility.

"I can't say that people will look younger but it's possible. When a person is active and living life to the full they generally look better. The focus is not necessarily about prolonging life span, it's more about prolonging health span. Our work is not a silver bullet, exercise and nutrition will all play a part," he said.

Prof Cooper-White made the discovery that body tissues are not just elastic and solid but also work a bit like a liquid and now his team is investigating how the viscoelasticity of bodies change over time and ways to reverse the process.

"Viscoelasticity describes the way materials, like our skin, muscles, bones or even our organs, respond to being 'stressed', through pushing, pulling or shearing, the forces that our tissues experience in everyday life," he said.

"All tissues in the body are viscoelastic - it is an intrinsic property of them. We age because our body gets less viscoelastic. This is something we are focusing on now. Maybe it's just because I am getting older. As we age, daily ailments cause inflammation. Inflammation in one area is carried around the whole body by our blood vessels, causing the extracellular matrix of all our tissues to become stiff and corrupted, or 'fibrotic'. This corrupts the stem cell 'niches', the homes of stem cells that live next to our blood vessels," he said.

"We're investigating what happens when those tissues become less viscoelastic and how we might reverse that," Professor Cooper-White said.

Professor Cooper-White says allowing people to live full lives into old age would be a good investment.

Since the scientist and his team from UQ's Australian Institute for Bioengineering and Nanotechnology (AIBN) unit first flagged the importance of viscoelasticity on stem cell behaviours in 2011, researchers around the world have been working to confirm those findings and probe other related mechanical properties of cells, building an in-depth body of knowledge that can be used to inform biological, medical and engineering research.

"We have been working on the ageing area for the last four or five years and making progress," the professor said.

Late this year Prof Cooper-White joined the world's top tissue engineering experts from Stanford University, Harvard University and University of Pennsylvania to review the works investigating viscoelasticity.

The latest research in their field was published in the prestigious scientific journal Nature.

"There is a lot of work to be done and I would estimate we are talking at least a couple of decades before therapeutics would even be available. We would have to look at trials in small animals, larger animals and then human trials. But this is very important science. We are looking at a future where Australia will have a very high percentage of older people. It would make sense for more investment to be put into allowing older people to live life to the full and have a long health span. Doesn't that make more sense that putting all the money into programs to look after people after they end up decrepit?" the chemical engineer said.

"This has not come to the public eye as much as I would have expected it to, given how important it is," the professor said.

Brad Pitt in a scene from The Curious Case of Benjamin Button. Picture: AP Photo

It is predicted that almost one quarter of Australians will be over 65 by June 2050 and other countries will have an even bigger aged population.

"We are not talking about offering the fountain of life but regenerative science is a key area of research for the future. It's exciting what we have found so far," Prof Cooper-White said. Leading them into work in engineering of healthy ageing with stem cells, the team at UQ works on artificially creating new tissue like recreating breast tissue for women who have had a mastectomy. It was this work into body tissues that lead to the professor's world stopping discovery in regenerative medicine.

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The story of mRNA: From a loose idea to a tool that may help curb Covid – STAT

Posted: November 11, 2020 at 1:57 pm

ANDOVER, Mass. The liquid that many hope could help end the Covid-19 pandemic is stored in a nondescript metal tank in a manufacturing complex owned by Pfizer, one of the worlds biggest drug companies. There is nothing remarkable about the container, which could fit in a walk-in closet, except that its contents could end up in the worlds first authorized Covid-19 vaccine.

Pfizer, a 171-year-old Fortune 500 powerhouse, has made a billion-dollar bet on that dream. So has a brash, young rival just 23 miles away in Cambridge, Mass. Moderna, a 10-year-old biotech company with billions in market valuation but no approved products, is racing forward with a vaccine of its own. Its new sprawling drug-making facility nearby is hiring workers at a fast clip in the hopes of making history and a lot of money.

In many ways, the companies and their leaders couldnt be more different. Pfizer, working with a little-known German biotech called BioNTech, has taken pains for much of the year to manage expectations. Moderna has made nearly as much news for its stream of upbeat press releases, executives stock sales, and spectacular rounds of funding as for its science.


Each is well-aware of the other in the race to be first.

But what the companies share may be bigger than their differences: Both are banking on a genetic technology that has long held huge promise but has so far run into biological roadblocks. It is called synthetic messenger RNA, an ingenious variation on the natural substance that directs protein production in cells throughout the body. Its prospects have swung billions of dollars on the stock market, made and imperiled scientific careers, and fueled hopes that it could be a breakthrough that allows society to return to normalcy after months living in fear.


Both companies have been frequently name-checked by President Trump. Pfizer reported strong, but preliminary, data on Monday, and Moderna is expected to follow suit soon with a glimpse of its data. Both firms hope these preliminary results will allow an emergency deployment of their vaccines millions of doses likely targeted to frontline medical workers and others most at risk of Covid-19.

There are about a dozen experimental vaccines in late-stage clinical trials globally, but the ones being tested by Pfizer and Moderna are the only two that rely on messenger RNA.

For decades, scientists have dreamed about the seemingly endless possibilities of custom-made messenger RNA, or mRNA.

Researchers understood its role as a recipe book for the bodys trillions of cells, but their efforts to expand the menu have come in fits and starts. The concept: By making precise tweaks to synthetic mRNA and injecting people with it, any cell in the body could be transformed into an on-demand drug factory.

But turning scientific promise into medical reality has been more difficult than many assumed. Although relatively easy and quick to produce compared to traditional vaccine-making, no mRNA vaccine or drug has ever won approval.

Even now, as Moderna and Pfizer test their vaccines on roughly 74,000 volunteers in pivotal vaccine studies, many experts question whether the technology is ready for prime time.

I worry about innovation at the expense of practicality, Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine and an authority on vaccines, said recently. The U.S. governments Operation Warp Speed program, which has underwritten the development of Modernas vaccine and pledged to buy Pfizers vaccine if it works, is weighted toward technology platforms that have never made it to licensure before.

Whether mRNA vaccines succeed or not, their path from a gleam in a scientists eye to the brink of government approval has been a tale of personal perseverance, eureka moments in the lab, soaring expectations and an unprecedented flow of cash into the biotech industry.

It is a story that began three decades ago, with a little-known scientist who refused to quit.

Before messenger RNA was a multibillion-dollar idea, it was a scientific backwater. And for the Hungarian-born scientist behind a key mRNA discovery, it was a career dead-end.

Katalin Karik spent the 1990s collecting rejections. Her work, attempting to harness the power of mRNA to fight disease, was too far-fetched for government grants, corporate funding, and even support from her own colleagues.

It all made sense on paper. In the natural world, the body relies on millions of tiny proteins to keep itself alive and healthy, and it uses mRNA to tell cells which proteins to make. If you could design your own mRNA, you could, in theory, hijack that process and create any protein you might desire antibodies to vaccinate against infection, enzymes to reverse a rare disease, or growth agents to mend damaged heart tissue.

In 1990, researchers at the University of Wisconsin managed to make it work in mice. Karik wanted to go further.

The problem, she knew, was that synthetic RNA was notoriously vulnerable to the bodys natural defenses, meaning it would likely be destroyed before reaching its target cells. And, worse, the resulting biological havoc might stir up an immune response that could make the therapy a health risk for some patients.

It was a real obstacle, and still may be, but Karik was convinced it was one she could work around. Few shared her confidence.

Every night I was working: grant, grant, grant, Karik remembered, referring to her efforts to obtain funding. And it came back always no, no, no.

By 1995, after six years on the faculty at the University of Pennsylvania, Karik got demoted. She had been on the path to full professorship, but with no money coming in to support her work on mRNA, her bosses saw no point in pressing on.

She was back to the lower rungs of the scientific academy.

Usually, at that point, people just say goodbye and leave because its so horrible, Karik said.

Theres no opportune time for demotion, but 1995 had already been uncommonly difficult. Karik had recently endured a cancer scare, and her husband was stuck in Hungary sorting out a visa issue. Now the work to which shed devoted countless hours was slipping through her fingers.

I thought of going somewhere else, or doing something else, Karik said. I also thought maybe Im not good enough, not smart enough. I tried to imagine: Everything is here, and I just have to do better experiments.

In time, those better experiments came together. After a decade of trial and error, Karik and her longtime collaborator at Penn Drew Weissman, an immunologist with a medical degree and Ph.D. from Boston University discovered a remedy for mRNAs Achilles heel.

The stumbling block, as Kariks many grant rejections pointed out, was that injecting synthetic mRNA typically led to that vexing immune response; the body sensed a chemical intruder, and went to war. The solution, Karik and Weissman discovered, was the biological equivalent of swapping out a tire.

Every strand of mRNA is made up of four molecular building blocks called nucleosides. But in its altered, synthetic form, one of those building blocks, like a misaligned wheel on a car, was throwing everything off by signaling the immune system. So Karik and Weissman simply subbed it out for a slightly tweaked version, creating a hybrid mRNA that could sneak its way into cells without alerting the bodys defenses.

That was a key discovery, said Norbert Pardi, an assistant professor of medicine at Penn and frequent collaborator. Karik and Weissman figured out that if you incorporate modified nucleosides into mRNA, you can kill two birds with one stone.

That discovery, described in a series of scientific papers starting in 2005, largely flew under the radar at first, said Weissman, but it offered absolution to the mRNA researchers who had kept the faith during the technologys lean years. And it was the starter pistol for the vaccine sprint to come.

And even though the studies by Karik and Weissman went unnoticed by some, they caught the attention of two key scientists one in the United States, another abroad who would later help found Moderna and Pfizers future partner, BioNTech.

Derrick Rossi, a native of Toronto who rooted for the Maple Leafs and sported a soul patch, was a 39-year-old postdoctoral fellow in stem cell biology at Stanford University in 2005 when he read the first paper. Not only did he recognize it as groundbreaking, he now says Karik and Weissman deserve the Nobel Prize in chemistry.

If anyone asks me whom to vote for some day down the line, I would put them front and center, he said. That fundamental discovery is going to go into medicines that help the world.

But Rossi didnt have vaccines on his mind when he set out to build on their findings in 2007 as a new assistant professor at Harvard Medical School running his own lab.

He wondered whether modified messenger RNA might hold the key to obtaining something else researchers desperately wanted: a new source of embryonic stem cells.

In a feat of biological alchemy, embryonic stem cells can turn into any type of cell in the body. That gives them the potential to treat a dizzying array of conditions, from Parkinsons disease to spinal cord injuries.

But using those cells for research had created an ethical firestorm because they are harvested from discarded embryos.

Rossi thought he might be able to sidestep the controversy. He would use modified messenger molecules to reprogram adult cells so that they acted like embryonic stem cells.

He asked a postdoctoral fellow in his lab to explore the idea. In 2009, after more than a year of work, the postdoc waved Rossi over to a microscope. Rossi peered through the lens and saw something extraordinary: a plate full of the very cells he had hoped to create.

Rossi excitedly informed his colleague Timothy Springer, another professor at Harvard Medical School and a biotech entrepreneur. Recognizing the commercial potential, Springer contacted Robert Langer, the prolific inventor and biomedical engineering professor at the Massachusetts Institute of Technology.

On a May afternoon in 2010, Rossi and Springer visited Langer at his laboratory in Cambridge. What happened at the two-hour meeting and in the days that followed has become the stuff of legend and an ego-bruising squabble.

Langer is a towering figure in biotechnology and an expert on drug-delivery technology. At least 400 drug and medical device companies have licensed his patents. His office walls display many of his 250 major awards, including the Charles Stark Draper Prize, considered the equivalent of the Nobel Prize for engineers.

As he listened to Rossi describe his use of modified mRNA, Langer recalled, he realized the young professor had discovered something far bigger than a novel way to create stem cells. Cloaking mRNA so it could slip into cells to produce proteins had a staggering number of applications, Langer thought, and might even save millions of lives.

I think you can do a lot better than that, Langer recalled telling Rossi, referring to stem cells. I think you could make new drugs, new vaccines everything.

Langer could barely contain his excitement when he got home to his wife.

This could be the most successful company in history, he remembered telling her, even though no company existed yet.

Three days later Rossi made another presentation, to the leaders of Flagship Ventures. Founded and run by Noubar Afeyan, a swaggering entrepreneur, the Cambridge venture capital firm has created dozens of biotech startups. Afeyan had the same enthusiastic reaction as Langer, saying in a 2015 article in Nature that Rossis innovation was intriguing instantaneously.

Within several months, Rossi, Langer, Afeyan, and another physician-researcher at Harvard formed the firm Moderna a new word combining modified and RNA.

Springer was the first investor to pledge money, Rossi said. In a 2012 Moderna news release, Afeyan said the firms promise rivals that of the earliest biotechnology companies over 30 years ago adding an entirely new drug category to the pharmaceutical arsenal.

But although Moderna has made each of the founders hundreds of millions of dollars even before the company had produced a single product Rossis account is marked by bitterness. In interviews with the Globe in October, he accused Langer and Afeyan of propagating a condescending myth that he didnt understand his discoverys full potential until they pointed it out to him.

Its total malarkey, said Rossi, who ended his affiliation with Moderna in 2014. Im embarrassed for them. Everybody in the know actually just shakes their heads.

Rossi said that the slide decks he used in his presentation to Flagship noted that his discovery could lead to new medicines. Thats the thing Noubar has used to turn Flagship into a big company, and he says it was totally his idea, Rossi said.

Afeyan, the chair of Moderna, recently credited Rossi with advancing the work of the Penn scientists. But, he said, that only spurred Afeyan and Langer to ask the question, Could you think of a code molecule that helps you make anything you want within the body?

Langer, for his part, told STAT and the Globe that Rossi made an important finding but had focused almost entirely on the stem cell thing.

Despite the squabbling that followed the birth of Moderna, other scientists also saw messenger RNA as potentially revolutionary.

In Mainz, Germany, situated on the left bank of the Rhine, another new company was being formed by a married team of researchers who would also see the vast potential for the technology, though vaccines for infectious diseases werent on top of their list then.

A native of Turkey, Ugur Sahin moved to Germany after his father got a job at a Ford factory in Cologne. His wife, zlem Treci had, as a child, followed her father, a surgeon, on his rounds at a Catholic hospital. She and Sahin are physicians who met in 1990 working at a hospital in Saarland.

The couple have long been interested in immunotherapy, which harnesses the immune system to fight cancer and has become one of the most exciting innovations in medicine in recent decades. In particular, they were tantalized by the possibility of creating personalized vaccines that teach the immune system to eliminate cancer cells.

Both see themselves as scientists first and foremost. But they are also formidable entrepreneurs. After they co-founded another biotech, the couple persuaded twin brothers who had invested in that firm, Thomas and Andreas Strungmann, to spin out a new company that would develop cancer vaccines that relied on mRNA.

That became BioNTech, another blended name, derived from Biopharmaceutical New Technologies. Its U.S. headquarters is in Cambridge. Sahin is the CEO, Treci the chief medical officer.

We are one of the leaders in messenger RNA, but we dont consider ourselves a messenger RNA company, said Sahin, also a professor at the Mainz University Medical Center. We consider ourselves an immunotherapy company.

Like Moderna, BioNTech licensed technology developed by the Pennsylvania scientist whose work was long ignored, Karik, and her collaborator, Weissman. In fact, in 2013, the company hired Karik as senior vice president to help oversee its mRNA work.

But in their early years, the two biotechs operated in very different ways.

In 2011, Moderna hired the CEO who would personify its brash approach to the business of biotech.

Stphane Bancel was a rising star in the life sciences, a chemical engineer with a Harvard MBA who was known as a businessman, not a scientist. At just 34, he became CEO of the French diagnostics firm BioMrieux in 2007 but was wooed away to Moderna four years later by Afeyan.

Moderna made a splash in 2012 with the announcement that it had raised $40 million from venture capitalists despite being years away from testing its science in humans. Four months later, the British pharmaceutical giant AstraZeneca agreed to pay Moderna a staggering $240 million for the rights to dozens of mRNA drugs that did not yet exist.

The biotech had no scientific publications to its name and hadnt shared a shred of data publicly. Yet it somehow convinced investors and multinational drug makers that its scientific findings and expertise were destined to change the world. Under Bancels leadership, Moderna would raise more than $1 billion in investments and partnership funds over the next five years.

Modernas promise and the more than $2 billion it raised before going public in 2018 hinged on creating a fleet of mRNA medicines that could be safely dosed over and over. But behind the scenes the companys scientists were running into a familiar problem. In animal studies, the ideal dose of their leading mRNA therapy was triggering dangerous immune reactions the kind for which Karik had improvised a major workaround under some conditions but a lower dose had proved too weak to show any benefits.

Moderna had to pivot. If repeated doses of mRNA were too toxic to test in human beings, the company would have to rely on something that takes only one or two injections to show an effect. Gradually, biotechs self-proclaimed disruptor became a vaccines company, putting its experimental drugs on the back burner and talking up the potential of a field long considered a loss-leader by the drug industry.

Meanwhile BioNTech has often acted like the anti-Moderna, garnering far less attention.

In part, that was by design, said Sahin. For the first five years, the firm operated in what Sahin called submarine mode, issuing no news releases, and focusing on scientific research, much of it originating in his university lab. Unlike Moderna, the firm has published its research from the start, including about 150 scientific papers in just the past eight years.

In 2013, the firm began disclosing its ambitions to transform the treatment of cancer and soon announced a series of eight partnerships with major drug makers. BioNTech has 13 compounds in clinical trials for a variety of illnesses but, like Moderna, has yet to get a product approved.

When BioNTech went public last October, it raised $150 million, and closed with a market value of $3.4 billion less than half of Modernas when it went public in 2018.

Despite his role as CEO, Sahin has largely maintained the air of an academic. He still uses his university email address and rides a 20-year-old mountain bicycle from his home to the office because he doesnt have a drivers license.

Then, late last year, the world changed.

Shortly before midnight, on Dec. 30, the International Society for Infectious Diseases, a Massachusetts-based nonprofit, posted an alarming report online. A number of people in Wuhan, a city of more than 11 million people in central China, had been diagnosed with unexplained pneumonia.

Chinese researchers soon identified 41 hospitalized patients with the disease. Most had visited the Wuhan South China Seafood Market. Vendors sold live wild animals, from bamboo rats to ostriches, in crowded stalls. That raised concerns that the virus might have leaped from an animal, possibly a bat, to humans.

After isolating the virus from patients, Chinese scientists on Jan. 10 posted online its genetic sequence. Because companies that work with messenger RNA dont need the virus itself to create a vaccine, just a computer that tells scientists what chemicals to put together and in what order, researchers at Moderna, BioNTech, and other companies got to work.

A pandemic loomed. The companies focus on vaccines could not have been more fortuitous.

Moderna and BioNTech each designed a tiny snip of genetic code that could be deployed into cells to stimulate a coronavirus immune response. The two vaccines differ in their chemical structures, how the substances are made, and how they deliver mRNA into cells. Both vaccines require two shots a few weeks apart.

The biotechs were competing against dozens of other groups that employed varying vaccine-making approaches, including the traditional, more time-consuming method of using an inactivated virus to produce an immune response.

Moderna was especially well-positioned for this moment.

Forty-two days after the genetic code was released, Modernas CEO Bancel opened an email on Feb. 24 on his cellphone and smiled, as he recalled to the Globe. Up popped a photograph of a box placed inside a refrigerated truck at the Norwood plant and bound for the National Institute of Allergy and Infectious Diseases in Bethesda, Md. The package held a few hundred vials, each containing the experimental vaccine.

Moderna was the first drug maker to deliver a potential vaccine for clinical trials. Soon, its vaccine became the first to undergo testing on humans, in a small early-stage trial. And on July 28, it became the first to start getting tested in a late-stage trial in a scene that reflected the firms receptiveness to press coverage.

The first volunteer to get a shot in Modernas late-stage trial was a television anchor at the CNN affiliate in Savannah, Ga., a move that raised eyebrows at rival vaccine makers.

Along with those achievements, Moderna has repeatedly stirred controversy.

On May 18, Moderna issued a press release trumpeting positive interim clinical data. The firm said its vaccine had generated neutralizing antibodies in the first eight volunteers in the early-phase study, a tiny sample.

But Moderna didnt provide any backup data, making it hard to assess how encouraging the results were. Nonetheless, Modernas share price rose 20% that day.

Some top Moderna executives also drew criticism for selling shares worth millions, including Bancel and the firms chief medical officer, Tal Zaks.

In addition, some critics have said the government has given Moderna a sweetheart deal by bankrolling the costs for developing the vaccine and pledging to buy at least 100 million doses, all for $2.48 billion.

That works out to roughly $25 a dose, which Moderna acknowledges includes a profit.

In contrast, the government has pledged more than $1 billion to Johnson & Johnson to manufacture and provide at least 100 million doses of its vaccine, which uses different technology than mRNA. But J&J, which collaborated with Beth Israel Deaconess Medical Centers Center for Virology and Vaccine Research and is also in a late-stage trial, has promised not to profit off sales of the vaccine during the pandemic.

Over in Germany, Sahin, the head of BioNTech, said a Lancet article in January about the outbreak in Wuhan, an international hub, galvanized him.

We understood that this would become a pandemic, he said.

The next day, he met with his leadership team.

I told them that we have to deal with a pandemic which is coming to Germany, Sahin recalled.

He also realized he needed a strong partner to manufacture the vaccine and thought of Pfizer. The two companies had worked together before to try to develop mRNA influenza vaccines. In March, he called Pfizers top vaccine expert, Kathrin Jansen.

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The story of mRNA: From a loose idea to a tool that may help curb Covid - STAT

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Dr. Andreas Sauerbrey: The right orthopaedic diagnosis is essential to proper care – Sky Hi News

Posted: September 12, 2020 at 9:53 pm

Dr. Andreas Sauerbrey believes the most important factor in getting efficient and correct orthopaedic treatment is having the right diagnosis.

You need to come to a specialist who can give you the options for that diagnosis, he said.

Dr. Sauerbrey, who specializes in shoulder and upper-extremity surgery, sports medicine, and joint restoration at Steamboat Orthopaedic and Spine Institute (SOSI), is proud of the access the institute provides to so many fellowship-trained surgeons. This extra level of training and experience provides the community with orthopaedic care that is truly world class.

When you come to see us, youll get the right diagnosis, but it doesnt mean you have to have surgery, he said.

Shoulder, elbow and hand

Dr. Sauerbrey is fellowship trained in shoulder and elbow surgery from the University of Pennsylvania and in hand surgery from Thomas Jefferson University in Philadelphia. He also holds a Sports Medicine Specialty Certificate.

Dr. Sauerbrey is particularly skilled in shoulder arthroscopy and reconstruction, and biologic treatments such as platelet-rich plasma (PRP) and growth factors.

For the past 20 years, Dr. Sauerbrey has performed 300 to 400 shoulder surgeries annually. He does just about every orthopaedic procedure, including knee and hip replacements, but about 60% of his work focuses on shoulders.

People have options within our practice, he said. If they dont come see me, they should see one of my partners. Theres really no reason to go out of town.

A progressive approach

Dr. Sauerbrey has been performing PRP injections since 2008. Hes particularly enthusiastic about how biomedicine has evolved in orthopaedic medicine during that time.

The biggest changes in orthopaedic medicine have been in biologics its just blown up in the last 10 years, he said.

Dr. Sauerbrey works with some of the most advanced orthopaedic companies to deliver the latest methods and treatments, which include PRP and stem cells.

The companies we use are very progressive, surgeon-driven, constantly innovating, he says. Its remarkable how much is out there, and SOSI offers it all.

PRP, the most popular injection, releases growth factors that trick the body into creating a healing response. Dr. Sauerbrey says he frequently does PRP injections in knees, shoulders and elbows. While its not going to fix mechanical injuries (such as an ACL tear), PRP, when used in the right context, can relieve pain and improve mobility.

My intention is to bring state-of-the-art medicine to Steamboat in an efficient and affordable way, he said. Together, we ensure the latest, most innovative technology available for both operative and non-operative procedures. We believe patients and their families should have the best care possible at all times.

Destined for orthopaedics

Dr. Sauerbreys brain was always mechanically oriented, so its no surprise he chose a medical field that would allow him to practice that skill on the human body.

Being good with your hands you either have it or you dont, he said. For me, it probably goes back to the days of wrenching on cars with my dad.

One of the first major decisions that medical students make about their future careers is whether they will become surgeons. For Sauerbrey, that happened by his second year of medical school. Having a mother who worked as an orthopaedic nurse for 20 years and getting the mechanical practice he did while working with his father, Sauerbrey was practically destined to become an orthopaedic surgeon.

I knew I had to do procedures, he said. Once you decide that, it eliminates half the field of potential specialties.

Community driven

With a belief that good health care should never be hard to find, Dr. Sauerbrey has committed himself to building an orthopaedic practice that puts the community first. Most of the SOSI physicians have been practicing in Yampa Valley for many years, and thats a testament to their high quality of care.

You cannot survive in a community like this if youre not doing a good job its not going to happen, he says. Youre operating on your friends and neighbors, and you have to be comfortable with that.

With an extremely active and motivated population that demands to be fixed back up so that they can return to their beloved outdoor activities, theres a real motivation to help patients get through their injuries and come out stronger on the other side.

We fix people so they can go back to what they love, Dr. Sauerbrey said. Were accountable socially here in Steamboat.

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T cells, B cells and the range of the human bodys immune response A simple decoder – ThePrint

Posted: August 10, 2020 at 8:49 pm

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New Delhi: Human immunity and its components have never been the topic of such breathless discussion for such a long time. But then, there has never been a time like the Covid-19 pandemic.

Between serological surveys (that check the level of antibodies against the SARS-CoV-2 virus in blood), rapid antigen tests (that test for the part of the virus that kickstarts immune mechanisms) and the quest for vaccines, the immune system is very much in.

That is also why lymphocytes (a class of white blood cells), especially the ones known as T-cells are the flavour of the season. They are probably the single most important component of the immune system; though given the perfectly synchronised working of the defence mechanism of the body, it may be a little unfair to designate any one as more important than the another.

T-cells play a plethora of roles in immunity as killer cells that can attack an infected cell and kill it along with the infecting agent, and as suppressor cells that modulate the level of functioning of other lymphocytes. They also have a starring role in the production of antibodies, a function performed by the other variant of lymphocytes called the B cells.

Latest research in Nature shows that presence of T-cells from earlier encounters with coronaviruses could have an important role to play in the bodys immune response, and therefore, a better understanding of it is crucial for the development of a vaccine.

The published data discussed here indicate that patients with severe COVID-19 can have either insufficient or excessive T cell responses. It is possible, therefore, that disease might occur in different patients at either end of this immune response spectrum, in one case from virus-mediated pathology and in the other case from T cell-driven immunopathology.

However, it is unclear why some patients respond too little and some patients too much, and whether the strength of the T cell response in the peripheral blood reflects the T cell response intensity in the respiratory tract and other SARS-CoV-2-infected organs, wrote the researchers from the University of Pennsylvania. They called for more research on the topic.

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Turns out, antibodies may or may not last, but T-cells are the new superheroes with the potential to possibly save the planet.

Also read: T Cells the unsung immune warriors that takeover after coronavirus antibodies wane

Immunity is of two kinds innate and acquired.

The defence mechanisms that the body is born with is known an innate immunity. This includes something as simple as the ability of the skin to prevent inner, more vulnerable tissues, from coming in contact with the external environment.

Acquired immunity, as the name suggests, is something that develops over time through exposure to pathogens or disease causing agents like virus and bacteria. Acquired immunity kicks in either through antibodies (this is known as humoral immunity) or through cells programmed to destroy invading organisms by causing the dissolution of the very cells that have been infected.

White blood cells (WBC) play a crucial role in immunity. There are five different kinds of WBCs eosinophil, basophil, neutrophil, monocyte and lymphocyte. Among these, the most important are lymphocytes, which include the T lymphocytes and the B lymphocytes. However, the others also have important roles to play as supporting cast. For the present discussion, we are concentrating on lymphocytes.

Also read: Immunity boosters are a myth why you shouldnt believe claims that promise to fight Covid

Structurally, under a microscope, very little differentiates a T-lymphocyte from a B lymphocyte. Both varieties are formed in the bone marrow from stem cells, get trained in different organs and then lodge themselves in the lymph nodes from where they are deployed when the occasion arises.

The training is important. It teaches the cells not to start attacking the bodys own cells. T-cells get trained antenatally (during pregnancy) and for some time after that in the thymus, a small gland present between the lungs only till puberty. B cells are trained in the foetal liver and bone marrow.

When a pathogen invades, specific chemicals unique to it (often proteins or complex carbohydrates) activate the bodys immune system. This activator, which is a unique feature of the invading pathogen, is the antigen. This is what the rapid antigen test looks for.

When an antigen has been detected, the T-cells troop out of the lymph node in an activated form and travel to the affected areas to take on the infection. The activated cells, called the Killer T cells, attach themselves to the membrane of the infected cell and with help of cytotoxic chemicals, kill the cell and destroy the invader with it. This is cell-mediated immunity. It is the basis of what happens when transplanted organs are rejected.

The thymus training teaches T-cells to ignore the antigens that are present within the body and not attack them. When that lesson is forgotten, because of genetic or environmental reasons, an autoimmune disorder is triggered.

Antigens set in motion a different pathway in the B lymphocytes. These enlarge and start duplicating very rapidly to form many clones, all of which, on maturity, start producing antibodies. The whole process happens very fast.

Antibodies are protein molecules that are present in the plasma, the matrix of the blood in which the cells float. Not all T-cells though turn into cytotoxic killers. Some become what are known as helper T cells, to go and further activate B lymphocytes to produce antibodies. In fact, without these helper cells, the antibody output is not quite sufficient to combat the invading particle.

Antibodies can directly kill the invader using a number of different mechanisms at their disposal. They can also activate a set of proteins present in the blood plasma that in turn can attack the invader using their own pathways.

Once the infection has been tackled, some of the B lymphocytes are tucked away with information about how this was done. These are memory cells that remain dormant until the next invasion happens. These ensure that when an infection recurs, the response is expedited, magnified and is longer lasting. This is the principle behind vaccination to teach the body to identify and combat a pathogen so that when a future infection happens, the response is stronger.

Also read:An Oxford immunologist breaks down how the universitys vaccine works against Covid-19

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Are very long-lived trees immortal and what can they teach humans? – ABC News

Posted: at 8:49 pm

While humans are all too familiar with the ravages of getting older, many trees seem to handle ageing a lot better.

Certain trees can live for thousands of years and appear to be immortal.

But not everyone is convinced these old timers can escape death due to old age.

Regardless, could humans with their relatively puny lifespans have something to learn from these ancient trees? Some scientists think so.

Establishing how old the oldest living tree is depends a bit on which plants are in the running for the title.

You could argue that Australia's Wollemi pine, which has been cloning itself for more than 60 million years, deserves the title. But that's kind of cheating because this involves multiple stems growing from the one rootstock.

This is why the oldest tree in the world is generally regarded as a single-stemmed bristlecone pine called Pinus longaeva.

This species can live to around 5,000 years and does well where most other plants cannot even grow in rocky, dry, high-altitude areas in the United States.

What's amazing is that scientists have not so far been able to show that getting older directly affects the health of such millennial trees, plant biologist Sergi Munne-Bosch from the University of Barcelona says.

It's because of this, some have suggested these trees are essentially immortal.

But in a recent article, Professor Munne-Bosch argues that it's likely even ancient trees could die from old age assuming something else doesn't kill them first.

He emphasises that there's a difference between ageing, which is about how long an organism has lived, and age-related deterioration, which is referred to as senescence.

"Just because we can't track senescence in long-lived trees doesn't mean they are immortal."

Professor Munne-Bosch points to recent research on centuries-old Ginkgo biloba trees that found no evidence of senescence.

The study was the first to look for evidence of age-related changes in cells of the cambium, a layer just beneath the bark that contains cells that can produce new tissue throughout the plant's life.

It confirmed the long-lived trees, which in this case were up to 667 years old, were just as healthy as younger ones says Professor Munne-Bosch.

"They grow very well, they produce seeds, they produce flowers, so they are healthy."

He points out that even though a 667-year-old tree seems old when compared to a human, it is relatively young for a ginkgo.

"This species can live for more than two millennia."

Professor Munne-Bosch argues that the ginkgo researchers' data shows that older trees had thinner vascular tissue and that this hints at possible age-related deterioration that would be more obvious in even older trees.

Yet despite this deterioration, he says these trees are more likely to die from insects, disease, fire, drought or loggers, than old age.

"For a species that can live for millennia, aging is not really a problem in evolutionary terms because they are much more likely to die of something else."

The problem is there are so few of these long-lived trees that it's hard to get the data to know for certain whether they can die of old age.

"We cannot prove it either way," Professor Munne-Bosch says, adding that age-related deterioration is likely to happen in these trees at such a different pace compared to in humans.

"For a Ginkgo biloba, six centuries is not as physiologically relevant as it is to us."

Brenda Casper, a professor of biology at the University of Pennsylvania says it's not clear that the changes found in the older Ginkgo biloba trees were necessarily detrimental to the tree.

But she agrees the low number of millennial trees makes it hard to study their longevity.

"It's difficult to find statistical evidence for senescence."

Even if there were enough trees, she says some of the age-related deterioration may be hard to detect, or we may not know what to look for.

"It's not just internal physiology per se but it's the interaction of the tree with its environment."

For example, she says it would be hard to measure whether age had made a tree more susceptible to disease, or less structurally sound so it's more likely to fall over in a windstorm.

Even if the jury is out on whether millennial trees are immortal, some experts say their longevity could be inspirational for medical research.

Professor Munne-Bosch says such trees can draw on a bag of tricks to help them "postpone death".

First is having a simple body plan with modular-like branches and roots. This means they can compartmentalise any damaged or dead roots or branches and work around them.

"They can lose part of leaves or roots and continue to be healthy..

And he says although 95 per cent of the trunk of a tree might be dead, the living cambium just beneath the bark is "one of the secrets of longevity" in trees.

Millennial trees have used the combination of these features to their best advantage and Professor Munne-Bosch says these tricks are providing a model for scientists researching the negative effects of ageing.

"Imagine if we could regenerate our lungs or circulatory system every year, we would be much healthier than we are."

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Professor of biomedical engineering at the University of New South Wales, Melissa Knothe Tate is one researcher who is inspired by millennial trees.

"They have units and if one unit breaks you can replace it with another unit."

Only a small percentage of an individual long-lived tree may be alive, but she argues it's all about survival of the cells that are able to regenerate the tree.

"Those that survive best, survive longest."

"Millennial trees are the best survivors because they've seen a lot."

While a tree and a human might seem worlds apart, Professor Knothe Tate sees the similarities, pointing to the role of stem cells in maintaining bones in humans.

She says cells add new layers to bone, like tree rings, to increase girth and when bone is injured, stem cells quickly help repair it.

"We're constantly renewing our bones and trees do something similar."

Professor Knothe Tate says she is using stem cells and new biomaterials that emulate tree cambium, to create replacement tissue in the lab, and has several patents for the work.

"I think about plants a lot when I'm up in the mountains and amongst the trees."

Professor Knothe Tate, who draws on her training in philosophy, biology and mechanical engineering for her work, sees other similarities that can inspire research.

For example, she likens the human brain to the network of roots and branches that helps a tree remain resilient if one part is damaged, another part can sometimes take up the slack.

"As parts of the brain are injured or die, it's remarkable what functionality we can retain,

"If we knew which of the brain's networks were essential for certain functions, we may be able to grow them."

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Professor Knothe Tate also set up a science education project for girls that explores the parallels between the biomechanics of trees and bones. It was inspired by her observation of how huge trees sway like a blade of grass in the wind.

She has high hopes for the potential of regenerative medicine research that draws on knowledge from other disciplines like plant biology to extend human life.

"We can then start to think about making ourselves immortal."

Plant biologist Professor Munne-Bosch is also enthusiastic.

"The future of medicine is very similar to what has evolved in millennial trees."

But while regenerating tissues will help humans live much longer, he doubts we will ever be immortal.

"It won't be forever, because we are more likely to die of something else, whether it be an accident or a pandemic."

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