From Harvard Gazette: “Disinfecting your hands with ‘magic’”

Harvard University

From Harvard Gazette

January 23, 2020
Alvin Powell
Photos by Kris Snibbe/Harvard Staff Photographer

Nanostructures can provide an alternative for hand hygiene that is airless and waterless. “… this is like magic. You don’t see; you don’t feel; you don’t smell; but your hands are sanitized,” says Associate Professor of Aerosol Physics Philip Demokritou.

Harvard Chan Center for Nanotechnology and Nanotoxicology looks to improve on soap and water.

Nanosafety researchers at the Harvard T.H. Chan School of Public Health have developed a new intervention to fight infectious disease by more effectively disinfecting the air around us, our food, our hands, and whatever else harbors the microbes that make us sick. The researchers, from the School’s Center for Nanotechnology and Nanotoxicology, were led by Associate Professor of Aerosol Physics Philip Demokritou, the center’s director, and first author Runze Huang, a postdoctoral fellow there. They used a nano-enabled platform developed at the center to create and deliver tiny, aerosolized water nonodroplets containing non-toxic, nature-inspired disinfectants wherever desired. Demokritou talked to the Gazette about the invention and its application on hand hygiene, which was described recently in the journal ACS Sustainable Chemistry and Engineering.

Q&A
Philip Demokritou

GAZETTE: Give us a quick overview of the problem you’re trying to solve.

DEMOKRITOU: If you go back to the ’60s and the invention of many antibiotics, we thought that the chapter on infectious diseases would be closed. Of course, 60 years later, we now know that’s not true. Infectious diseases are still emerging. Microorganisms are smarter than we thought and evolving new strains. It’s a constant battle. And when I talk about infectious diseases, I’m mainly talking about airborne and foodborne diseases: For example, flu and tuberculosis are airborne diseases, respiratory diseases, which cause millions of deaths a year. Foodborne diseases also kill 500,000 people annually and cost our economy billions of dollars.

GAZETTE: Diarrheal diseases are big killers of kids, too.

DEMOKRITOU: It’s a big problem, especially in developing countries with fragmented health care systems.

GAZETTE: What’s wrong with how we sanitize our hands?

DEMOKRITOU: We hear all the time that you have to wash your hands. It’s a primary measure to reduce infectious diseases. More recently, we’re also using antiseptics. Alcohol is OK, but we are also using other chemicals like triclosan and chlorhexadine. There’s research linking these chemicals to the increase in antimicrobial resistance, among other drawbacks. In addition, some people are sensitive to frequent washes and rubbing with chemicals. That’s where new approaches come into play. So, within the last four or five years, we’ve been trying to develop nanotechnology-based interventions to fight infectious diseases.

Harvard Chan School’s Associate Professor Philip Demokritou (right) with research associate Nachiket Vaze (center) and postdoc fellow Runze Huang.

GAZETTE: So the technology involved here — the engineered water nanostructures — is a couple of years old. What’s new is the application?

DEMOKRITOU: We have the tools to make these engineered nanomaterials and, in this particular case, we can take water and turn it into an engineered water nanoparticle, which carries its deadly payload, primarily nontoxic, nature-inspired antimicrobials, and kills microorganisms on surfaces and in the air.

It is fairly simple, you need 12 volts DC, and we combine that with electrospray and ionization to turn water into a nanoaerosol, in which these engineered nanostructures are suspended in the air. These water nanoparticles have unique properties because of their small size and also contain reactive oxygen species. These are hydroxyl radicals, peroxides, and are similar to what nature uses in cells to kill pathogens. These nanoparticles, by design, also carry an electric charge, which increases surface energy and reduces evaporation. That means these engineered nanostructures can remain suspended in air for hours. When the charge dissipates, they become water vapor and disappear.

Very recently, we started using these structures as a carrier, and we can now incorporate nature-inspired antimicrobials into their chemical structure. These are not super toxic to humans. For instance, my grandmother in Greece used to disinfect her surfaces with lemon juice — citric acid. Or, in milk — and also found in tears — is another highly potent antimicrobial called lysozyme. Nisin is another nature-inspired antimicrobial that bacteria release when they’re competing with other bacteria. Nature provides us with a ton of nontoxic antimicrobials that, if we can find a way to deliver them in a targeted, precise manner, can do the job. No need to invent new and potentially toxic chemicals. Let’s go to nature’s pharmacy and shop.

When we put these nature-inspired antimicrobials into the engineered water nanostructures, their antimicrobial potency increases dramatically. But we do that without using huge quantities of antimicrobials, about 1 percent or 2 percent by volume. Most of the engineered water nanostructure is still water.

At this point, these engineered structures are carrying antimicrobials and are charged, and we can use the charge to direct them to surfaces by applying a weak electric field. You can also release them into the air — they’re highly mobile — and they can move around and inactivate flu virus, for example.

GAZETTE: How would this work with food?

DEMOKRITOU: This nano-enabled platform can be used as an intervention technology for food safety applications as well. When it comes to disinfecting our food, we’re still using archaic approaches developed in the ’50s. For instance, today we put our fresh produce into chlorine-based solutions, which leave residues that can compromise health. It leaves behind byproducts, which are toxic, and you have to find a way to deal with them as well.

Instead, you can use the water nanoaerosols that contain nanogram levels of an active ingredient — nature-inspired and not toxic — and disinfect our food. Currently, this novel invention is being explored for use — from the farm to the fork — to enhance food safety and quality.

Source: “Inactivation of Hand Hygiene-Related Pathogens Using Engineered Water Nanostructures,” Runze Huang, Nachiket Vaze, Anand Soorneedi, Matthew D. Moore, Yalong Xue, Dhimiter Bello, Philip Demokritou

GAZETTE: So when you use it on food, you would essentially spray the nanoparticles onto a head of lettuce, for example?

DEMOKRITOU: It depends on the application. You can put this technology in your refrigerator, and it will kill microbes on food surfaces and in the air there and improve food safety. It will also increase shelf life, which is linked to spoilage microorganisms. You can also use this technology for air disinfection. The only thing you need is 12-volt DC, which you can power from your computer USB port. Imagine sitting on a train and you generate an invisible shield of these engineered water nanostructures that protects you and minimizes the risk of getting the flu.

GAZETTE: If you’re on the train with a bunch of sick people?

DEMOKRITOU: Exactly, or on an airplane, anywhere you have microorganisms. Most planes recirculate the air, and all it takes is one sick guy — he doesn’t have to be sitting next to you — to get sick. Unfortunately, that’s a big problem. The newer airplanes have filtration to remove some of these pathogens. But this is a very versatile technology that you can pretty much take with you.

GAZETTE: Let’s talk about hand hygiene.

DEMOKRITOU: We know hand hygiene is very important, but in addition to the drawbacks of washing with water or using chemicals, the air dryers commonly used in the bathroom environment can aerosolize microbes and put them back in the air and even back on your hands. So there is room to utilize these engineered water nanostructures and develop an alternative that is airless and waterless — because it uses picogram levels of water, your hands will never get wet.

GAZETTE: So you’re washing your hands, using water. But they don’t get wet?

DEMOKRITOU: Exactly. And it disinfects hands in a matter of 15–20 seconds, as indicated in our recently published study.

GAZETTE: As far as an application goes, do you see something similar to the hand driers we all use at highway rest stops? Only, when you stick your hands in, it doesn’t blow? Do you feel anything at all?

DEMOKRITOU: You don’t feel anything. That’s the problem; this is like magic. You don’t see; you don’t feel; you don’t smell; but your hands are sanitized.

GAZETTE: So how do people know anything’s happened? As humans we want some sort of stimulation.

DEMOKRITOU: We could put a light and music to entertain people, but nobody can see a 25-nanometer particle. We are excited to see that there is interest from industry to pursue commercialization of this technology for hand hygiene. We may soon have an airless, waterless apparatus that can be used across the board, though not necessarily in the bathroom environment. This can be a battery-operated device, it can be placed around airports and other spots where people don’t have time or access to water to wash their hands.

See the full article here .

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Harvard University is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

From UC Riverside: “America’s most widely consumed oil causes genetic changes in the brain”

From UC Riverside

January 17, 2020
Jules L Bernstein
Senior Public Information Officer
(951) 827-4580
jules.bernstein@ucr.edu

news.ucr.edu

New UC Riverside research shows soybean oil not only leads to obesity and diabetes, but could also affect neurological conditions like autism, Alzheimer’s disease, anxiety, and depression.

Used for fast food frying, added to packaged foods, and fed to livestock, soybean oil is by far the most widely produced and consumed edible oil in the U.S., according to the U.S. Department of Agriculture. In all likelihood, it is not healthy for humans.

It certainly is not good for mice. The new study, published this month in the journal Endocrinology, compared mice fed three different diets high in fat: soybean oil, soybean oil modified to be low in linoleic acid, and coconut oil.

Chart depicts consumption of edible oils in the U.S. for 2017/18. (USDA)

The same UCR research team found in 2015 [PLOS ONE] that soybean oil induces obesity, diabetes, insulin resistance, and fatty liver in mice. Then in a 2017 study [Nature Scientific Reports], the same group learned that if soybean oil is engineered to be low in linoleic acid, it induces less obesity and insulin resistance.

However, in the study released this month, researchers did not find any difference between the modified and unmodified soybean oil’s effects on the brain. Specifically, the scientists found pronounced effects of the oil on the hypothalamus, where a number of critical processes take place.

“The hypothalamus regulates body weight via your metabolism, maintains body temperature, is critical for reproduction and physical growth as well as your response to stress,” said Margarita Curras-Collazo, a UCR associate professor of neuroscience and lead author on the study.

Comparison of oxytocin hormone in the hypothalamus of mice fed three different diets. The image on the far right shows very little oxytocin in mice fed a soybean oil diet. (UCR)

The team determined a number of genes in mice fed soybean oil were not functioning correctly. One such gene produces the “love” hormone, oxytocin. In soybean oil-fed mice, levels of oxytocin in the hypothalamus went down.

The research team discovered roughly 100 other genes also affected by the soybean oil diet. They believe this discovery could have ramifications not just for energy metabolism, but also for proper brain function and diseases such as autism or Parkinson’s disease. However, it is important to note there is no proof the oil causes these diseases.

Additionally, the team notes the findings only apply to soybean oil — not to other soy products or to other vegetable oils.

“Do not throw out your tofu, soymilk, edamame, or soy sauce,” said Frances Sladek, a UCR toxicologist and professor of cell biology. “Many soy products only contain small amounts of the oil, and large amounts of healthful compounds such as essential fatty acids and proteins.”

A caveat for readers concerned about their most recent meal is that this study was conducted on mice, and mouse studies do not always translate to the same results in humans.

Also, this study utilized male mice. Because oxytocin is so important for maternal health and promotes mother-child bonding, similar studies need to be performed using female mice.

One additional note on this study — the research team has not yet isolated which chemicals in the oil are responsible for the changes they found in the hypothalamus. But they have ruled out two candidates. It is not linoleic acid, since the modified oil also produced genetic disruptions; nor is it stigmasterol, a cholesterol-like chemical found naturally in soybean oil.

Identifying the compounds responsible for the negative effects is an important area for the team’s future research.

“This could help design healthier dietary oils in the future,” said Poonamjot Deol, an assistant project scientist in Sladek’s laboratory and first author on the study.

“The dogma is that saturated fat is bad and unsaturated fat is good. Soybean oil is a polyunsaturated fat, but the idea that it’s good for you is just not proven,” Sladek said.

Indeed, coconut oil, which contains saturated fats, produced very few changes in the hypothalamic genes.

“If there’s one message I want people to take away, it’s this: reduce consumption of soybean oil,” Deol said about the most recent study.

See the full article here .

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Please help promote STEM in your local schools.

Stem Education Coalition

The University of California, Riverside is one of 10 universities within the prestigious University of California system, and the only UC located in Inland Southern California.

Widely recognized as one of the most ethnically diverse research universities in the nation, UCR’s current enrollment is more than 21,000 students, with a goal of 25,000 students by 2020. The campus is in the midst of a tremendous growth spurt with new and remodeled facilities coming on-line on a regular basis.

We are located approximately 50 miles east of downtown Los Angeles. UCR is also within easy driving distance of dozens of major cultural and recreational sites, as well as desert, mountain and coastal destinations.

From Science News: “Injecting a TB vaccine into the blood, not the skin, boosts its effectiveness”

From Science News

1.1.20
Tara Haelle

The BCG vaccine is notoriously bad at preventing the most common form of tuberculosis.

PET-CT scans of rhesus monkey lungs show spots of TB infection and tissue inflammation (red and orange). Monkeys that received a TB vaccine intravenously (bottom) were better protected than those who received it just under the skin (top). University of Pittsburgh School of Medicine.

Delivering a high dose of a vaccine against tuberculosis intravenously, instead of under the skin, greatly improves the drug’s ability to protect against the deadly disease, a new study finds.

Changing the typical dose and method of administration of the bacille Calmette-Guérin, or BCG, vaccine prevented TB in 90 percent of rhesus monkeys, researchers report online January 1 in Nature.

Most “astonishing” is that six of the 10 monkeys who received the IV vaccine never even developed an initial infection when exposed to TB, says Joel Ernst, an immunologist who specializes in TB at the University of California, San Francisco. Preventing infection, not just disease — called sterilizing immunity — is extremely rare with any TB vaccine, says Ernst, who was not involved in the study. Thwarting that infection means that no bacteria can reactivate to cause a latent or active TB infection.

The BCG vaccine has been around for nearly a century and is the only currently licensed TB vaccine. More than 150 countries, but not the United States, regularly use BCG to protect infants against some forms of TB. But the vaccine often fails to prevent the most common type of tuberculosis infection, in the lungs, in adolescents or adults.

Globally, TB infected 10 million people in 2018. It kills about 1.5 million a year, making it the most lethal infectious disease. Up to 13 million people in the United States have latent TB infection, which induces an immune response but hasn’t progressed to active tuberculosis. An experimental TB vaccine that could help protect people with the latent infection from developing active TB is in the works (SN: 9/25/18).

It’s been difficult to create an effective TB vaccine because the bacteria that cause the disease, Mycobacterium tuberculosis, enter cells, where they’re more protected from antibodies, which primarily attack outside cells. Fighting most intracellular infections requires immune cells called T cells to attack the infected cells, says immunologist Robert Seder of the National Institute of Allergy and Infectious Diseases Vaccine Research Center in Bethesda, Md.

Delivering the BCG vaccine just under the skin causes the body to make some T cells to fight TB. But not enough of these cells are created and get to where they need to be and stay there — the lungs, for example — limiting the vaccine’s effectiveness, says JoAnne Flynn, a microbiologist and immunologist at the University of Pittsburgh’s Center for Vaccine Research.

A malaria infection similarly requires T cells to fight the malaria parasite inside cells, Seder says. After his success with an intravenous malaria vaccine in another trial [Science], researchers wondered: If they injected BCG vaccine directly into the blood, where it could travel throughout the body, would it trigger the creation of enough T cells in the tissues where the cells need to be?

Flynn, Seder and their colleagues tested five BCG formulations in macaques: a standard under-the-skin, or intradermal, human dose; a high dose given under the skin (100 times greater concentration than the human dose); an aerosol high dose administered with a mask; an intravenous high dose; and a combination of high-dose aerosol and standard-dose intradermal. Six months later, the research exposed the five differently vaccinated groups of macaques and a sixth unvaccinated control group to TB.

All of the unvaccinated, standard-dose intradermal and aerosol-vaccinated macaques developed the bacterial infection. The eight macaques that received the intradermal high dose did not have significantly better protection than those that got the standard dose, Flynn says. All but one of those eight developed infection, though two monkeys cleared it several weeks later. In contrast, six of 10 IV-vaccinated macaques never developed a TB infection, and three had fewer than 45 individual TB bacteria in the lungs, a very low amount, and went on to clear the infection.

One possible reason that the vaccine worked better when given intravenously is the high number of T cells induced by the IV vaccine — 100 times as many in those macaques’ airways compared with the intradermal and aerosol groups. Potentially more important is the discovery that the vaccine induced production of tissue-resident memory T cells [Immunity], primed T cells in the tissue itself, not just the blood.

Punam Mangtani, an epidemiologist at the London School of Hygiene and Tropical Medicine, calls the research “a rare and exciting proof-of-concept study.”

Preventing TB in adolescents and adults is crucial, Flynn says, so the major question is whether this approach would be safe and effective in that target population. The only adverse effects seen in the macaques were a temporary, modest increase in inflammation. Ernst says one safety concern is whether intravenous BCG could induce a harmful inflammatory response in people with latent TB infection — about a quarter of the planet’s population. It’s not clear if this vaccine could help or harm those with latent infections, which the researchers plan to test in monkeys. If it could cause harm, screening before vaccination would be necessary.

For now, the next step is to test how low a dose still offers protection, Flynn says. “This study really provides us hope that a truly effective vaccine against TB is on the horizon,” she says. “I’ve been in the field for 30 years, and I feel we are making progress in really starting to understand the disease and vaccines that can prevent infection.”

See the full article here .

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From University of Washington: “Alzheimer’s study shows promise to protect brain from tau”

From University of Washington

December 18, 2019
Bobbi Nodell
bnodell@uw.edu
206.543.7129

Researchers discover impact of MSUT2 gene and binding protein, offering others a starting point for new therapeutics.

MedicalXpress

In the wake of recent disappointments over clinical trials targeting amyloid plaque build-up in Alzheimer’s disease, researchers are focusing more attention on misfolded tau protein, another culprit in brain diseases that cause dementia.

New research published in Science Translational Medicine finds that targeting abnormal tau through the suppression of a gene called MSUT2 (mammalian suppressor of tauopathy 2) shows promise.

Tau, like amyloid protein, is another substance that builds up in Alzheimer’s disease and damages brain cells. However, clinical trials targeting tau have been far less numerous in part because tau-targeted drugs have been hard to find.

In this study, researchers concluded that suppressing MSUT2 might protect people from Alzheimer’s disease as long as the RNA binding protein PolyA Binding Protein Nuclear 1 (PABPN1) is not depleted. MSUT2 and PABPNI normally work together closely to regulate the biology of tau in the brain.

“If you inhibit MSUT2 and don’t affect PABN1, that protects against the effects of tau pathology,” said senior author Brian Kraemer, a research associate professor of medicine in the Division of Gerontology and Geriatric Medicine at the University of Washington School of Medicine. He is also a scientist at the Veterans Affairs Puget Sound Health Care System.

Kraemer said his team sees their role as the person kicking the ball down field to provide other researchers and drug companies an opportunity to move the ball towards the ultimate goal: A treatment or cure for Alzheimer’s disease.

“Pharmaceutical companies have heavily invested in going after amyloid but so far these efforts haven’t moved the needle on dementia treatments,” he said. “I think the field needs to think about targeting amyloid and tau together because both amyloid and tau act together to kill neurons in Alzheimer’s disease.”

Senior author Jeanna Wheeler, a research scientist at the Seattle Institute for Biomedical and Clinical Research and the VA, said what’s novel about the study is the discovery of the role of the MSUT2 gene.

“We discovered MSUT2 originally in a completely unbiased way by looking for anything that could make worms resistant to pathological tau protein. Now we have shown that this gene can also affect tau toxicity in mice, and also that there are differences in MSUT2 in human Alzheimer’s patients,” she said. “If we can use MSUT2 in the future as a drug target, this would be a completely novel approach for treating Alzheimer’s and other related disorders.”

The significance of tau

The study also brings more attention to the role of tau pathology in Alzheimer’s disease.

The healthy human brain contains tens of billions of specialized cells or neurons that process and transmit information. By disrupting communication among these cells, Alzheimer’s disease results in loss of neuron function and cell death.

Previous studies have shown that abnormal tau burden correlates strongly with cognitive decline in Alzheimer’s disease patients, but amyloid does not. Some dementia disorders, such as frontotemporal lobar degeneration, may have only abnormal tau with no amyloid deposits.

“If you could protect the brain from tau alone, you may provide substantial benefit for people with Alzheimer’s disease,” Kraemer said. “Likewise, targeting tau in tangle-only Alzheimer’s disease-related dementia disorders, like frontotemporal lobar degeneration, will almost certainly be beneficial for patients.”

Study went from worms to mice

This study follows previous work by these researchers that showed very similar results using the worm C. elegans. Worms go from egg to adult in three days so it was easier to do experiments on the biology of aging rapidly. Although worms don’t have complex cognitive functions, their movement is affected by tau buildup. Researchers found that they could cure the worm by knocking out the worm sut-2 gene.

The more recent study applied the experiment to mice, whose evolutionary distance to humans is much smaller than the distance between worms and humans.

The researchers knocked out the MSUT2 gene in mice, thereby preventing the formation of the tau tangles that kill off brain cells. This lessened learning and memory problems as well.

While examining autopsy brain samples from Alzheimer’s patients, the researchers found that cases with more severe disease lacked both MSUT2 protein, and its partner protein, PABPN1. This finding suggests that neurons that lose the MSUT2 -PABPN1 protein partnership may simply die during a patient’s life.

Moreover, mice lacking MSUT2 but possessing a normal complement of PABPN1 were strongly protected against abnormal tau and the resulting brain degeneration. Therefore, the researchers concluded that the key to helping people with abnormal tau buildup is blocking MSUT2 while preserving PABPN1 activity.

The study was funded by the Department of Veterans Affairs and the National Institute on Aging ( grant nos. 101BX002619,101BX007080,RF1AG055474,R01NS064131,P01AG017856,P50AG05136). Research involved investigators from the University of Washington’s School of Medicine Alzheimer’s Disease Research Center, University of Pennsylvania Center for Neurodegenerative Disease, and Michigan State University.

See the full article here .

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The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.
So what defines us —the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

From The New York Times: “Crisis Looms in Antibiotics as Drug Makers Go Bankrupt”

From The New York Times

Dec. 25, 2019
Andrew Jacobs

At a time when germs are growing more resistant to common antibiotics, many companies that are developing new versions of the drugs are hemorrhaging money and going out of business, gravely undermining efforts to contain the spread of deadly, drug-resistant bacteria.

Antibiotic start-ups like Achaogen and Aradigm have gone belly up in recent months, pharmaceutical behemoths like Novartis and Allergan have abandoned the sector and many of the remaining American antibiotic companies are teetering toward insolvency. One of the biggest developers of antibiotics, Melinta Therapeutics, recently warned regulators it was running out of cash.

Experts say the grim financial outlook for the few companies still committed to antibiotic research is driving away investors and threatening to strangle the development of new lifesaving drugs at a time when they are urgently needed.

“This is a crisis that should alarm everyone,” said Dr. Helen Boucher, an infectious disease specialist at Tufts Medical Center and a member of the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria.

The problem is straightforward: The companies that have invested billions to develop the drugs have not found a way to make money selling them. Most antibiotics are prescribed for just days or weeks — unlike medicines for chronic conditions like diabetes or rheumatoid arthritis that have been blockbusters — and many hospitals have been unwilling to pay high prices for the new therapies. Political gridlock in Congress has thwarted legislative efforts to address the problem.

The challenges facing antibiotic makers come at time when many of the drugs designed to vanquish infections are becoming ineffective against bacteria and fungi, as overuse of the decades-old drugs has spurred them to develop defenses against the medicines.

Drug-resistant infections now kill 35,000 people in the United States each year and sicken 2.8 million, according a report from the Centers for Disease Control and Prevention released last month. Without new therapies, the United Nations says the global death toll could soar to 10 million by 2050.

The newest antibiotics have proved effective at tackling some of the most stubborn and deadly germs, including anthrax, bacterial pneumonia, E. coli and multidrug-resistant skin infections.

The experience of the biotech company Achaogen, is a case in point. It spent 15 years and a billion dollars to win Food and Drug Administration approval for Zemdri, a drug for hard-to-treat urinary tract infections. In July, the World Health Organization added Zemdri to its list of essential new medicines.

By then, however, there was no one left at Achaogen to celebrate.

This past spring, with its stock price hovering near zero and executives unable to raise the hundreds of millions of dollars needed to market the drug and do additional clinical studies, the company sold off lab equipment and fired its remaining scientists. In April, the company declared bankruptcy.

Public health experts say the crisis calls for government intervention. Among the ideas that have wide backing are increased reimbursements for new antibiotics, federal funding to stockpile drugs effective against resistant germs and financial incentives that would offer much needed aid to start-ups and lure back the pharmaceutical giants. Despite bipartisan support, legislation aimed at addressing the problem has languished in Congress.

“If this doesn’t get fixed in the next six to 12 months, the last of the Mohicans will go broke and investors won’t return to the market for another decade or two,” said Chen Yu, a health care venture capitalist who has invested in the field.

The former offices of Achaogen in South San Francisco. The company sold off the last of its lab equipment and fired its remaining scientists this past spring. Credit Brian L. Frank for The New York Times

First Big Pharma fled the field, and now start-ups are going belly up, threatening to stifle the development of new drugs.

Dr. Ryan Cirz, a microbiologist and a co-founder of Achaogen, a company whose drug, Zemdri, showed promise in treating U.T.I.s.Credit Brian L. Frank for The New York Times

The industry faces another challenge: After years of being bombarded with warnings against profligate use of antibiotics, doctors have become reluctant to prescribe the newest medications, limiting the ability of companies to recoup the investment spent to discover the compounds and win regulatory approval. And in their drive to save money, many hospital pharmacies will dispense cheaper generics even when a newer drug is far superior.

“You’d never tell a cancer patient ‘Why don’t you try a 1950s drug first and if doesn’t work, we’ll move on to one from the 1980s,” said Kevin Outterson, the executive director of CARB-X, a government-funded nonprofit that provides grants to companies working on antimicrobial resistance. “We do this with antibiotics and it’s really having an adverse effect on patients and the marketplace.”

Many of the new drugs are not cheap, at least when compared to older generics that can cost a few dollars a pill. A typical course of Xerava, a newly approved antibiotic that targets multi-drug resistant infections, can cost as much as $2,000.

“Unlike expensive new cancer drugs that extend survival by three-to-six months, antibiotics like ours truly save a patient’s life,” said Larry Edwards, chief executive of the company that makes Xerva, Tetraphase Pharmaceuticals. “It’s frustrating.”

Tetraphase, based in Watertown, Mass., has struggled to get hospitals to embrace Xerava, which took more than a decade to discover and bring to market, even though the drug can vanquish resistant germs like MRSA and CRE, a resistant bacteria that kills 13,000 people a year.

Tetraphase’s stock price has been hovering around $2, down from nearly $40 a year ago. To trim costs, Mr. Edwards recently shuttered the company’s labs, laid off some 40 scientists and scuttled plans to move forward on three other promising antibiotics.

For Melinta Therapeutics based in Morristown, N.J., the future is even grimmer. Last month, the company’s stock price dropped 45 percent after executives issued a warning about the company’s long-term prospects. Melinta makes four antibiotics, including Baxdela, which recently received F.D.A. approval to treat the kind of drug-resistant pneumonia that often kills hospitalized patients. Jennifer Sanfilippo, Melinta’s interim chief executive, said she was hoping a sale or merger would buy the company more time to raise awareness about the antibiotics’ value among hospital pharmacists and increase sales.

“These drugs are my babies, and they are so urgently needed,” she said.

Coming up with new compounds is no easy feat. Only two new classes of antibiotics have been introduced in the last 20 years — most new drugs are variations on existing ones — and the diminishing financial returns have driven most companies from the market. In the 1980s, there were 18 major pharmaceutical companies developing new antibiotics; today there are three.

“The science is hard, really hard,” said Dr. David Shlaes, a former vice president at Wyeth Pharmaceuticals and a board member of the Global Antibiotic Research and Development Partnership, a nonprofit advocacy organization. “And reducing the number of people who work on it by abandoning antibiotic R & D is not going to get us anywhere.”

A new antibiotic can cost $2.6 billion to develop, he said, and the biggest part of that cost are the failures along the way.

Some of the sector’s biggest players have coalesced around a raft of interventions and incentives that would treat antibiotics as a global good. They include extending the exclusivity for new antibiotics to give companies more time to earn back their investments and creating a program to buy and store critical antibiotics much the way the federal government stockpiles emergency medication for possible pandemics or bioterror threats like anthrax and smallpox.

The DISARM Act, a bill introduced in Congress earlier this year, would direct Medicare to reimburse hospitals for new and critically important antibiotics. The bill has bipartisan support but has yet to advance.

One of its sponsors, Senator Bob Casey, Democrat of Pennsylvania, said some of the reluctance to push it forward stemmed from the political sensitivity over soaring prescription drug prices. “There is some institutional resistance to any legislation that provides financial incentives to drug companies,” he said.

Washington has not entirely been sitting on its hands. Over the past decade, the Biomedical Advanced Research and Development Authority, or BARDA, a federal effort to counter chemical, nuclear and other public health threats, has invested a billion dollars in companies developing promising antimicrobial drugs and diagnostics that can help address antibiotic resistance.

“If we don’t have drugs to combat these multi-drug resistant organisms, then we’re not doing our job to keep Americans safe,” Rick A. Bright, the director of the agency, said.

Dr. Bright has had a firsthand experience with the problem. Two years ago, his thumb became infected after he nicked it while gardening in his backyard. The antibiotic he was prescribed had no effect, nor did six others he was given at the hospital. It turned out he had MRSA.

The infection spread, and doctors scheduled surgery to amputate the thumb. His doctor prescribed one last antibiotic but only after complaining about its cost and warning that Dr. Bright’s insurance might not cover it. Within hours, the infection began to improve and the amputation was canceled.

“If I had gotten the right drug on Day 1, I would have never had to go to the emergency room,” he said.

Achaogen and its 300 employees had held out hope for government intervention, especially given that the company had received $124 million from BARDA to develop Zemdri.

As recently as two years ago, the company had a market capitalization of more than $1 billion and Zemdri was so promising that it became the first antibiotic the F.D.A. designated as a breakthrough therapy, expediting the approval process.

Dr. Ryan Cirz, one of Achaogen’s founders and the vice president of research, recalled the days when venture capitalists took a shine to the company and investors snapped up its stock. “It wasn’t hype,” Dr. Cirz, a microbiologist, said. “This was about saving lives.”

In June, investors at the bankruptcy sale bought out the company’s lab equipment and the rights to Zemdri for a pittance: $16 million. (The buyer, generics drug maker Cipla USA, has continued to manufacture the drug.) Many of Achaogen’s scientists have since found research jobs in more lucrative fields like oncology.

Dr. Cirz lost his life savings, but he said he had bigger concerns. Without effective antibiotics, many common medical procedures could one day become life-threatening.

“This is a problem that can be solved, it’s not that complicated,” he said. “We can deal with the problem now, or we can just sit here and wait until greater numbers of people start dying. That would be a tragedy.”

See the full article here .

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From JHU HUB: “New ultra-miniaturized microendoscope produces higher-quality images at a fraction of the size”

From JHU HUB

12.6.19
Chanapa Tantibanchachai

The lensless scope is the width of a few strands of hair and able to capture images of live neuron activity.

The image above shows imaging results from the study. Images A through C show beads on a slide viewed through a bulk microscope. D through F show the beads as viewed through a conventional, lens-based microendoscope. G through I show the beads as seen by the new lensless microendoscope. These raw images are purposefully scattered, but provide important information about light that can be used in computational reconstruction to create clearer images, shown in J through L. Image credit: Courtesy of Mark Foster

Johns Hopkins engineers have created a new lens-free, ultra-miniaturized endoscope—the width of only a few human hairs—that is capable of producing high-quality images.

Their findings were published today in Science Advances.

“Usually, you have to sacrifice either size or image quality. We’ve been able to achieve both with our microendoscope,” says Mark Foster, an associate professor of electrical and computer engineering at Johns Hopkins University and the study’s corresponding author.

Microendoscopes are designed to examine neurons as they fire in the brains of animal test subjects, and accordingly must be minuscule in scale yet powerful enough to produce a clear image. Most standard microendoscopes are about half a millimeter to a few millimeters in diameter and require larger, more invasive lenses to achieve high-quality imaging. While lensless microendoscopes exist, the optical fiber that scans an area of the brain pixel by pixel frequently bends and loses imaging ability when moved.

In their new study, Foster and colleagues created a lens-free, ultra-miniaturized microendoscope that, compared to a conventional lens-based microendoscope, increases the amount researchers can see and improves image quality. To test their device, they examined beads in different patterns on a slide.

The researchers achieved this by using a coded aperture—a flat grid that randomly blocks light, creating a projection in a known pattern, akin to randomly poking a piece of aluminum foil and letting light through all of the small holes. This creates a messy image, but one that provides a bounty of information about where the light originates, and that information can be computationally reconstructed into a clearer image.

“For thousands of years, the goal has been to make an image as clear as possible,” Foster says. “Now, thanks to computational reconstruction, we can purposefully capture something that looks awful and counterintuitively end up with a clearer final image.”

Additionally, Foster’s team’s microendoscope doesn’t require movement to focus on objects at different depths; they use computational refocusing to determine where the light originated from in three dimensions. This allows their endoscope to be much smaller than traditional versions.

The researchers achieved this by using a coded aperture—a flat grid that randomly blocks light, creating a projection in a known pattern, akin to randomly poking a piece of aluminum foil and letting light through all of the small holes. This creates a messy image, but one that provides a bounty of information about where the light originates, and that information can be computationally reconstructed into a clearer image.

“For thousands of years, the goal has been to make an image as clear as possible,” Foster says. “Now, thanks to computational reconstruction, we can purposefully capture something that looks awful and counterintuitively end up with a clearer final image.”

Additionally, Foster’s team’s microendoscope doesn’t require movement to focus on objects at different depths; they use computational refocusing to determine where the light originated from in three dimensions. This allows their endoscope to be much smaller than traditional versions.

Looking forward, the research team will test their microendoscope with fluorescent labeling procedures, in which active brain neurons are tagged and illuminated, to determine the endoscope’s accuracy in imaging neural activity.

See the full article here .

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About the Hub
We’ve been doing some thinking — quite a bit, actually — about all the things that go on at Johns Hopkins. Discovering the glue that holds the universe together, for example. Or unraveling the mysteries of Alzheimer’s disease. Or studying butterflies in flight to fine-tune the construction of aerial surveillance robots. Heady stuff, and a lot of it.

In fact, Johns Hopkins does so much, in so many places, that it’s hard to wrap your brain around it all. It’s too big, too disparate, too far-flung.

We created the Hub to be the news center for all this diverse, decentralized activity, a place where you can see what’s new, what’s important, what Johns Hopkins is up to that’s worth sharing. It’s where smart people (like you) can learn about all the smart stuff going on here.

At the Hub, you might read about cutting-edge cancer research or deep-trench diving vehicles or bionic arms. About the psychology of hoarders or the delicate work of restoring ancient manuscripts or the mad motor-skills brilliance of a guy who can solve a Rubik’s Cube in under eight seconds.

There’s no telling what you’ll find here because there’s no way of knowing what Johns Hopkins will do next. But when it happens, this is where you’ll find it.

Johns Hopkins niversity opened in 1876, with the inauguration of its first president, Daniel Coit Gilman. “What are we aiming at?” Gilman asked in his installation address. “The encouragement of research … and the advancement of individual scholars, who by their excellence will advance the sciences they pursue, and the society where they dwell.”

The mission laid out by Gilman remains the university’s mission today, summed up in a simple but powerful restatement of Gilman’s own words: “Knowledge for the world.”

What Gilman created was a research university, dedicated to advancing both students’ knowledge and the state of human knowledge through research and scholarship. Gilman believed that teaching and research are interdependent, that success in one depends on success in the other. A modern university, he believed, must do both well. The realization of Gilman’s philosophy at Johns Hopkins, and at other institutions that later attracted Johns Hopkins-trained scholars, revolutionized higher education in America, leading to the research university system as it exists today.

From Lawrence Berkeley National Lab: “News Center Rare Disease Q&A: What Rare Diseases Are and Why That Matters”

From Lawrence Berkeley National Lab

December 3, 2019
Aliyah Kovner
akovner@lbl.gov
510-486-6376

Rare diseases are … rare, right? Not as rare as you might think. As much as 10% of the population is thought to have a “rare disease.” Unfortunately, due to a lack of understanding, many rare diseases remain very difficult to diagnose and treat.

Inspired by the enormous unmet needs of people with rare diseases, a group of scientists from across the globe has teamed up to develop open-access tools and resources for sharing disease characteristics and treatment information. The research is centered around an artificial intelligence-enabled catalog of disease descriptions called Mondo, which, like a Wikipedia for rare diseases, can be added to and improved by the scientific and medical community.

In a recent commentary in Nature Reviews Drug Discovery, the group explained how agreeing on precise definitions of each rare disease can lead to more accurate diagnoses and better treatments. They also shared results from a preliminary analysis that suggests that the number of different rare diseases may be higher than previously estimated.

The project team, led by Melissa Haendel of Oregon Health & Science University, and Tudor Oprea of the University of New Mexico, includes Lawrence Berkeley National Laboratory (Berkeley Lab) researchers Chris Mungall, Nomi Harris, Deepak Unni, and Marcin Joachimiak. We spoke with Chris and Nomi about the project and why they are participating in it.

How do we decide what qualifies as a rare disease?

Nomi: There’s no single definition of “rare disease” because it depends on which region or group you’re talking about. In the U.S., a rare disease is legally defined as one that affects fewer than 200,000 people; in the EU, a rare disease is one that affects fewer than 1 in 2,000 people. Some diseases are rare in some groups but common in others – for example, Tay-Sachs disease is rare in the general population, but much more common in Ashkenazi Jews, and tuberculosis is rare in the U.S. but is one of the top 10 causes of death worldwide.

All of us almost certainly know someone who has a rare disease, though they may be undiagnosed.

How are the current systems or protocols for classifying rare diseases translating into problems in patient care?

Nomi: To diagnose and treat a disease, we need to know how to define and characterize the disease. For common diseases, there are many cases to observe, so we have a pretty good idea of what that disease looks like – what the symptoms are, how to test for it, how to treat it. For rare diseases, there may be only scattered information – maybe one physician in South America has seen a case, and one researcher in China, but they aren’t sharing their information, so we don’t have a complete picture of what that disease looks like. And if we can’t precisely define a disease, then it’s hard to reliably diagnose it, and even harder to treat it optimally.

Our preliminary analysis, included in the commentary, suggests that the number of rare diseases may be higher than we thought – maybe around 10,000 different diseases, rather than the 5,000-7,000 that has previously been estimated. That means that distinct rare diseases (for example, different varieties of thyroid cancer) have probably been lumped together, when there might be different subtypes that benefit from different treatments.

What needs to be done to improve and expedite rare disease research, diagnosis, and treatment?

Chris: As Nomi mentioned, it’s hard to come up with the best treatment for a disease if you’re not even sure what exactly that disease looks like, or if it is confused with a similar disease. To address this, our team is working to catalog the whole landscape of rare diseases. We’re bringing together separate efforts in rare disease research, and developing computational tools to help experts come up with a precise definition for each rare disease. We developed a new artificial intelligence algorithm that helps disambiguate and unify the disease definitions from different databases and reference sources. We call this unified set of disease definitions “Mondo,” from the Italian word for “world,” because it brings together information from all over the world.

To accelerate this important work, we hope that funding and regulatory agencies, patient advocacy groups, and biomedical researchers will join together to support a coordinated effort to build a complete catalog of rare diseases.

How can Berkeley Lab play a role in this effort?

Chris: Berkeley Lab has been at the forefront of efforts to establish standards for representing and sharing biomedical data. My specialty is ontologies, which are like specialized vocabularies for precisely describing a class of things, such as symptoms, diseases, biochemical processes, or even entire ecological systems. One of the most widely used ontologies in biological science, the Gene Ontology, was launched by a team that included several Berkeley Lab researchers. My group has helped to build many other important biomedical ontologies, including Mondo, and we write computational tools to help others build, use, and expand ontologies.

There are many advantages to engaging in this type of work at Berkeley Lab, including the presence of leading researchers in computer science, biology, and other relevant fields, and also a commitment to open science – meaning that anyone in the world is free to not only use the resources we develop, but also to contribute to them. When we’re attacking a big problem like accurately defining all rare diseases, we can use all the help we can get!

Berkeley Lab is a great place to engage in this research, but I also want to recognize the key contributions of our talented Mondo collaborators at Oregon State University, the Jackson Laboratory, the European Bioinformatics Institute, and many others.

What motivated you both, personally, to join this project?

Chris: One of my main areas of research is characterizing and interpreting regions of the genome using ontologies. Many rare diseases are Mendelian, which means the cause of the disease can be traced back to changes within or affecting parts of the genome. Other rare diseases may be environmental, or a mixture of environmental and genetic, and I’m very interested in how the environment influences the health of complex organisms like humans. This led to the creation of Mondo as a way to annotate genomes and environments. My role was developing the algorithms that used different kinds of reasoning to bring together multiple sources of information and organize it coherently.

Nomi: My master’s thesis involved applying artificial intelligence techniques to predict the risk of inheriting genetic disorders. After that, I worked for years on bioinformatics projects that didn’t directly relate to human health. I was excited to have a chance to get back into the medical realm and contribute to a project that we hope will ultimately help to improve the prospects of those with rare diseases.

See the full article here .

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LBNL campus

LBNL Molecular Foundry

Bringing Science Solutions to the World
In the world of science, Lawrence Berkeley National Laboratory (Berkeley Lab) is synonymous with “excellence.” Thirteen Nobel prizes are associated with Berkeley Lab. Seventy Lab scientists are members of the National Academy of Sciences (NAS), one of the highest honors for a scientist in the United States. Thirteen of our scientists have won the National Medal of Science, our nation’s highest award for lifetime achievement in fields of scientific research. Eighteen of our engineers have been elected to the National Academy of Engineering, and three of our scientists have been elected into the Institute of Medicine. In addition, Berkeley Lab has trained thousands of university science and engineering students who are advancing technological innovations across the nation and around the world.

Berkeley Lab is a member of the national laboratory system supported by the U.S. Department of Energy through its Office of Science. It is managed by the University of California (UC) and is charged with conducting unclassified research across a wide range of scientific disciplines. Located on a 202-acre site in the hills above the UC Berkeley campus that offers spectacular views of the San Francisco Bay, Berkeley Lab employs approximately 3,232 scientists, engineers and support staff. The Lab’s total costs for FY 2014 were $785 million. A recent study estimates the Laboratory’s overall economic impact through direct, indirect and induced spending on the nine counties that make up the San Francisco Bay Area to be nearly $700 million annually. The Lab was also responsible for creating 5,600 jobs locally and 12,000 nationally. The overall economic impact on the national economy is estimated at $1.6 billion a year. Technologies developed at Berkeley Lab have generated billions of dollars in revenues, and thousands of jobs. Savings as a result of Berkeley Lab developments in lighting and windows, and other energy-efficient technologies, have also been in the billions of dollars.

Berkeley Lab was founded in 1931 by Ernest Orlando Lawrence, a UC Berkeley physicist who won the 1939 Nobel Prize in physics for his invention of the cyclotron, a circular particle accelerator that opened the door to high-energy physics. It was Lawrence’s belief that scientific research is best done through teams of individuals with different fields of expertise, working together. His teamwork concept is a Berkeley Lab legacy that continues today.

A U.S. Department of Energy National Laboratory Operated by the University of California.

From Penn Today: “These overlooked global diseases take a turn under the microscope”

From Penn Today

December 4, 2019
Katherine Unger Baillie, Writer
Eric Sucar, Photographer

In rural areas of Nigeria, such as this small fishing village in the north, children are at risk of infection with hookworm as well as other parasites. De’Broski Herbert of the School of Veterinary Medicine is embarking on a study of the disease in Nigerian schoolchildren. (Image: De’Broski Herbert)

Most people don’t die from tropical diseases like hookworm, schistosomiasis, or even malaria. But these understudied diseases, often caused by parasites, rob people of health in sometimes insidious ways.

For example, schistosomiasis is a disease caused by a waterborne, snail-transmitted parasite, and it’s the research focus of the School of Veterinary Medicine’s Robert Greenberg.

Schistosomiasis, a disease caused by parasitic flatworms, has long been a research focus for Penn Vet’s Robert Greenberg. (Image: John Donges/Penn Vet)

“It’s not necessarily a death sentence, though there are fatalities” says Greenberg, a research associate professor of pathobiology. “But you get anemia, children get stunted in terms of growth and cognitive abilities. It’s a disease that keeps people in poverty.”

Such diseases, by and large, receive less financial support and, as a result, far less scientific attention than those that more often afflict residents of wealthier nations, such as diabetes and heart disease.

Penn Vet researchers, however, have committed attention to these diseases, which, taken as a whole, affect billions around the globe. Their work benefits from the niche strengths of the school, specifically in immunology and host-pathogen interactions.

“At the Vet School, a third of our funding supports infectious disease research,” says Phillip Scott, vice dean for research and academic resources and a professor of microbiology and immunology in the Department of Pathobiology. “That’s pretty amazing, given that the School is also awarded funding for regenerative medicine, for cancer, and for a variety of other areas.”

That strength is seen in the research portfolios of some of the more senior faculty, such as Christopher Hunter’s work on toxoplasmosis, James “Sparky” Lok’s studies of Strongyloides, Carolina Lopez’s investigations of lung infections, and Bruce Freedman and Ron Harty’s efforts against Ebola and other hemorrhagic viral diseases. It has attracted newer faculty members, like cryptosporidium expert Boris Striepen, to Penn Vet.

Parasitology professor James Lok’s studies of the development and basic biology of parasites, particularly the roundworm
Strongyloides, have implications for finding new drug candidates. Veterinary schools have traditionally been strongholds of parasitology research, and Penn Vet is no exception. (Image: Eric Sucar)

Raising awareness

Penn Vet’s De’Broski Herbert, for example, an associate professor of pathobiology, had held prior positions at Cincinnati Children’s Hospital and the University of California, San Francisco. He had felt called to work on hookworm, a parasite he first learned of growing up in the South from his great-grandmother, who warned him about walking around barefoot because of the risk of contracting the parasite. But at the medical centers where he worked, he shifted gears away from studying the parasite itself, instead focusing on related research in asthma and allergy.

As part of his hookworm research in Nigeria, Herbert (left), speaking with Babatunde Adewale of the Nigerian Institute for Medical Research, hopes to study the impacts of infection on the microbiome, the immune system, and more. (Image: Courtesy of De’Broski Herbert)

“Here, our veterinary students are likely to encounter parasites in their patients, so working directly on the parasite is easier to justify,” Herbert says.

This spring, Herbert traveled to Nigeria where, working with partners at the Nigerian Institute for Medical Research, he launched a study of hookworm in 300 school-aged children in five sites around the northern and central portions of the country.

“The goal is to first establish what the prevalence of the disease really is and draw attention to that,” Herbert says. “And secondly, this is a place where the World Health Organization is going in and doing mass treatments, so I’m also interested in learning something very novel about the association between the microbiome, tissue repair, immune suppression, and metabolism in these children in Nigeria.”

Pairing basic and translational science

Those insights could lead to treatments, but they will also likely shed new light on the basic science of how hookworms affect their host. This pairing of basic and applied work is characteristic of Penn Vet scientists. In Scott’s lab, for instance, which has long pursued studies of the tropical disease leishmaniasis, advances in basic science have unfurled alongside insights that stand to reshape treatment of this parasitic infection which, in its cutaneous form, can cause serious and chronic skin ulcers.

“When I was a postdoc at NIH, there’s something my boss used to say that I still use in my talks,” says Scott. “He said, ‘Leishmaniasis has done more for immunology than immunology has done for leishmaniasis.’ And you could substitute parasitology for leishmaniasis and it would be much the same quote.

The Leishmania parasite (in red), transmitted by a sandfly, can cause painful, disfiguring ulcers. Immunologist Phillip Scott and collaborators including Daniel Beiting have worked to understand the immune response to infection and better tailor treatment for those affected. (Image: Courtesy of Phillip Scott)

“What I think is exciting right now,” he adds, “is that that’s going to change.”

As part of this contribution toward advancements against parasitic disease, Scott has traveled regularly to a leishmaniasis clinic in Brazil to obtain samples for his research and, back at Penn, has paired up with dermatology and microbiome experts such as Elizabeth Grice in the Perelman School of Medicine, and Dan Beiting from Penn Vet’s Center for Host-Microbial Interactions to break new ground.

No vaccine exists for leishmaniasis and current therapies fail a substantial percentage of the time. But recent publications from Scott’s lab have revealed new information about how the disease and existing treatments work and when to predict when they don’t. At the same time, Scott and colleagues’ research into the immunology of the infection has identified ways that FDA-approved drugs could be leveraged to alleviate the most severe forms of leishmaniasis.

New diagnostics

A major hurdle to matching appropriate therapies with neglected disease comes at one of the earliest stages of medical intervention: diagnostics. Researchers at Penn Vet are employing innovative techniques to fill these unmet needs. Robert Greenberg is one who has crossed disciplinary boundaries to do so.

In a partnership between Greenberg and Haim Bau of Penn’s School of Engineering and Applied Science, the scientists are working to craft an improved diagnostic test for schistosomes, which can lead to schistosomiasis, causing anemia, tissue fibrosis and lesions, malnutrition, learning difficulties, and, depending on the parasite species, bladder cancer and heightened HIV risk.

Greenberg has studied the ion channels that govern key biological functions in schistosomes to potentially develop drug targets that paralyze and kill the organisms. And by adapting insights from other researchers about additional parasitic-specific targets, he’s helping Bau train his microfluidic, portable diagnostic system on schistosomes to one day help clinicians make point-of-care diagnoses and issue timely treatment for infected patients.

“The current diagnostics are pretty terrible,” Greenberg says. “We’re looking at some new approaches now that should give us a much earlier, more sensitive, and more specific diagnosis for individual patients that might be able to detect other coinfections simultaneously.”

At Penn Vet’s New Bolton Center, Marie-Eve Fecteau and Ray Sweeney are also taking part in the design of a 21st-century solution to diagnostics of an insidious and challenging disease, in this case, a disease that takes a particular toll on livestock: paratuberculosis, or Johne’s disease. Caused by the bacterium Mycobacterium avium paratuberculosis, the condition affects ruminants such as cows and goats and drastically decreases their weight and milk production.

Infectious diseases take a toll on livestock as well, indirectly impacting human health and livelihoods. Large animal veterinarians Marie-Eve Fecteau and Raymond Sweeney are making progress on a stall-side diagnostic system that could quickly identify calves infected with paratuberculosis, halting the spread of infection. (Image: Louisa Shepard)

“Ruminants are a very important part of survival and livelihood in developing countries,” says Fecteau, an associate professor of food animal medicine and surgery. “Families may rely on only one or two cows to provide for their nutritional needs or income, and if that cow is affected by Johne’s, that’s a serious problem.”

Paratuberculosis has been shown to be endemic in parts of India and elsewhere in Asia and is also a burden for U.S. farms, where 70% of dairy herds test positive for the infection. Separating infected animals from the herd is a key step to stem the spread, but the bacteria have proved difficult to grow in the lab, making diagnosis challenging.

Fecteau and Sweeney, the Mark Whittier & Lila Griswold Allam Professor at Penn Vet, are hoping to change that, working with Beiting and biotechnology firm Biomeme to develop a “lab in a fanny pack,” as they call it: A stall-side diagnostic test that relies on PCR to identify infected animals from stool samples within hours.

“This is the kind of technology that could be extremely valuable for use in areas where sophisticated technology is harder to come by,” says Sweeney.

Stopping disease where it starts

Elsewhere at Penn Vet, researchers are approaching globally significant diseases by focusing on the vector. In the insectary that is part of Michael Povelones’s lab, he and his team test methods to stop disease-transmission cycles within mosquitoes.

The tens of thousands of mosquitoes in Michael Povelones’s insectary enable new insights into how the disease vectors defend themselves against infection. (Image: Rebecca Elias Abboud)

In the work, which relies on disrupting the way that mosquitoes interact with or respond immunologically to the pathogens they pass on, Povelones, an assistant professor of pathobiology, has explored everything from dengue to Zika to heart worm to elephantiasis, and his discoveries have implications for targeting a much longer list of diseases. In a recent study, Povelones and colleagues developed a new model system for studying the transmission of diseases caused by kinetoplastids, a group of parasites that includes the causative agents of Chagas disease and leishmaniasis.

“We think this could be a model for a number of important neglected diseases,” Povelones says.

In the latest of his team’s work finding ways to activate mosquitoes’ immune system to prevent pathogen transmission, they’ve identified a strategy that both blocks heartworm and the parasite that causes elephantiasis.

“These two diseases have very different behavior once they’re in the mosquito, so we’re still figuring out why this seems to work for both,” says Povelones. “But we’re very encouraged that it does.”

Using these types of creative approaches is a common thread across the Vet School, and the researchers’ efforts and successes seem to be multiplying. To continue accelerating progress, the School is developing a plan to harness these strengths, working with existing entities such as the Center for Host-Microbial Interactions internally and cross-school units such as the Institute for Immunology.

“We are a key part of the biomedical community at Penn and bring a valuable veterinary component to the table in confronting diseases of poverty,” says Scott.

See the full article here .

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Academic life at Penn is unparalleled, with 100 countries and every U.S. state represented in one of the Ivy League’s most diverse student bodies. Consistently ranked among the top 10 universities in the country, Penn enrolls 10,000 undergraduate students and welcomes an additional 10,000 students to our world-renowned graduate and professional schools.

Penn’s award-winning educators and scholars encourage students to pursue inquiry and discovery, follow their passions, and address the world’s most challenging problems through an interdisciplinary approach.

From Rutgers University: “Better Biosensor Technology Created for Stem Cells”

Our Great Seal.

From Rutgers University

November 10, 2019

Todd Bates
848-932-0550
todd.bates@rutgers.edu

Rutgers innovation may help guide treatment of Alzheimer’s, Parkinson’s diseases.

This unique biosensing platform consists of an array of ultrathin graphene layers and gold nanostructures. The platform, combined with high-tech imaging (Raman spectroscopy), detects genetic material (RNA) and characterizes different kinds of stem cells with greater reliability, selectivity and sensitivity than today’s biosensors. Image: Letao Yang, KiBum Lee, Jin-Ho Lee and Sy-Tsong (Dean) Chueng

The technology, which features a unique graphene and gold-based platform and high-tech imaging, monitors the fate of stem cells by detecting genetic material (RNA) involved in turning such cells into brain cells (neurons), according to a study in the journal Nano Letters.

Stem cells can become many different types of cells. As a result, stem cell therapy shows promise for regenerative treatment of neurological disorders such as Alzheimer’s, Parkinson’s, stroke and spinal cord injury, with diseased cells needing replacement or repair. But characterizing stem cells and controlling their fate must be resolved before they could be used in treatments. The formation of tumors and uncontrolled transformation of stem cells remain key barriers.

“A critical challenge is ensuring high sensitivity and accuracy in detecting biomarkers – indicators such as modified genes or proteins – within the complex stem cell microenvironment,” said senior author KiBum Lee, a professor in the Department of Chemistry and Chemical Biology in the School of Arts and Sciences at Rutgers University–New Brunswick. “Our technology, which took four years to develop, has demonstrated great potential for analyzing a variety of interactions in stem cells.”

The team’s unique biosensing platform consists of an array of ultrathin graphene layers and gold nanostructures. The platform, combined with high-tech imaging (Raman spectroscopy), detects genes and characterizes different kinds of stem cells with greater reliability, selectivity and sensitivity than today’s biosensors.

The team believes the technology can benefit a range of applications. By developing simple, rapid and accurate sensing platforms, Lee’s group aims to facilitate treatment of neurological disorders through stem cell therapy.

Stem cells may become a renewable source of replacement cells and tissues to treat diseases including macular degeneration, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis and rheumatoid arthritis, according to the National Institutes of Health.

The study’s co-lead authors are Letao Yang and Jin-Ho Lee, postdoctoral researchers in Lee’s group. Rutgers co-authors include doctoral students Christopher Rathnam and Yannan Hou. A scientist at Sogang University in South Korea contributed to the study.

See the full article here .

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Rutgers, The State University of New Jersey, is a leading national research university and the state’s preeminent, comprehensive public institution of higher education. Rutgers is dedicated to teaching that meets the highest standards of excellence; to conducting research that breaks new ground; and to providing services, solutions, and clinical care that help individuals and the local, national, and global communities where they live.

Founded in 1766, Rutgers teaches across the full educational spectrum: preschool to precollege; undergraduate to graduate; postdoctoral fellowships to residencies; and continuing education for professional and personal advancement.

As a ’67 graduate of University college, second in my class, I am proud to be a member of

Alpha Sigma Lamda, National Honor Society of non-tradional students.

From Harvard Gazette: “Why some people are resistant to Alzheimer’s”

Harvard University

From Harvard Gazette

November 4, 2019
MGH News and Public Affairs

Researchers find gene variants that may protect against the disease.

New study provides insights on why some people may be more resistant to Alzheimer’s disease than others. The findings may lead to strategies to delay or prevent the condition.

The study was led by investigators at Harvard-affiliated Massachusetts General Hospital (MGH), in collaboration with the University of Antioquia, Schepens Eye Research Institute of Massachusetts Eye and Ear, and Banner Alzheimer’s Institute.

According to researchers, some people who carry mutations in genes known to cause early onset Alzheimer’s disease do not show signs of the condition until a very old age — much later than expected. Studying these individuals may reveal insights on gene variants that reduce the risk of developing Alzheimer’s disease and other forms of dementia.

In their Nature Medicine study, Yakeel T. Quiroz, a clinical neuropsychologist and neuroimaging researcher at MGH, and her colleagues describe one such patient, from a large extended family with more than 6,000 living members from Colombia, who did not develop mild cognitive impairment until her 70s, nearly three decades after the typical age of onset.

Like her relatives who showed signs of dementia in their 40s, the patient carried the E280A mutation in a gene called Presenilin 1 (PSEN1), which has been shown to cause early onset Alzheimer’s disease. She also had two copies of a gene variation called ChristChurch, named after the New Zealand city where it was first found in the APOE3 gene (APOE3ch). The team was unable to identify any additional family members who had two copies of this variation who also carried the PSEN1 E280A mutation. In an analysis of 117 kindred members, 6 percent had one copy of the APOE3ch mutation, including four PSEN1 E280A mutation carriers who showed signs of mild cognitive impairment at the average age of 45 years.

Imaging tests revealed only minor neurodegeneration in the patient’s brain. Surprisingly, the patient had unusually high brain levels of amyloid beta deposits, a hallmark of Alzheimer’s disease; however, the amount of tau tangles — another hallmark of the disease — was relatively limited.

The investigators suspect that carrying two copies of the APOE3ch variant may postpone the clinical onset of Alzheimer’s disease by limiting tau pathology and neurodegeneration.

“This single case opens a new door for treatments of Alzheimer’s disease, based more on the resistance to Alzheimer’s pathology rather than on the cause of the disease. In other words, not necessarily focusing on reduction of pathology, as it has been done traditionally in the field, but instead promoting resistance even in the face of significant brain pathology,” said Quiroz.

APOE3 is one form of the APOE gene, the major susceptibility gene for late-onset Alzheimer’s. The APOE gene provides instructions for making a protein called apolipoprotein E, which is involved in the metabolism of fats in the body. Experiments revealed that the APOE3ch variant may reduce the ability of apolipoprotein E to bind to certain sugars called heparan sulphate proteoglycans (HSPG), which have been implicated in processes involving amyloid beta and tau proteins.

“This finding suggests that artificially modulating the binding of APOE to HSPG could have potential benefits for the treatment of Alzheimer’s disease, even in the context of high levels of amyloid pathology,” said co–lead author Joseph F. Arboleda-Velasquez of the Schepens Eye Research Institute.

The investigators suspect that carrying two copies of the APOE3ch variant may postpone the clinical onset of Alzheimer’s disease by limiting tau pathology and neurodegeneration.

“This single case opens a new door for treatments of Alzheimer’s disease, based more on the resistance to Alzheimer’s pathology rather than on the cause of the disease. In other words, not necessarily focusing on reduction of pathology, as it has been done traditionally in the field, but instead promoting resistance even in the face of significant brain pathology,” said Quiroz.

APOE3 is one form of the APOE gene, the major susceptibility gene for late-onset Alzheimer’s. The APOE gene provides instructions for making a protein called apolipoprotein E, which is involved in the metabolism of fats in the body. Experiments revealed that the APOE3ch variant may reduce the ability of apolipoprotein E to bind to certain sugars called heparan sulphate proteoglycans (HSPG), which have been implicated in processes involving amyloid beta and tau proteins.

“This finding suggests that artificially modulating the binding of APOE to HSPG could have potential benefits for the treatment of Alzheimer’s disease, even in the context of high levels of amyloid pathology,” said co–lead author Joseph F. Arboleda-Velasquez of the Schepens Eye Research Institute.

See the full article here .

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Harvard University is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.