From Vanderbilt University: “Tiny tweezer developed at Vanderbilt can trap molecules on a nanoscale, creating powerful research capabilities into cancer metastasis, neurodegenerative diseases”

From Vanderbilt University

Aug. 31, 2020
Marissa Shapiro

In 2018, one-half of the Nobel Prize was awarded to Arthur Ashkin, the physicist who developed optical tweezers, the use of a tightly focused laser beam to isolate and move micron-scale objects (the size of red blood cells). Now Justus Ndukaife, assistant professor of electrical engineering at Vanderbilt University, has developed the first-ever opto-thermo-electrohydrodynamic tweezers, optical nanotweezers that can trap and manipulate objects on an even smaller scale.

The article, “Stand-off trapping and manipulation of sub-10 nm objects and biomolecules using opto-thermo-electrohydrodynamic tweezers” was published online in the journal Nature Nanotechnology on August 31, 2020.

The article was authored by Ndukaife and graduate students Chuchuan Hong and Sen Yang, who are conducting research in Ndukaife’s lab.

Micron-scale optical tweezers represent a significant advancement in biological research but are limited in the size of the objects they can work with. This is because the laser beam that acts as the pincer of an optical tweezer can only focus the laser light to a certain diameter (about half the laser’s wavelength). In the case of red light with a wavelength of 700 nanometers, the tweezer can focus on and manipulate only objects with a diameter of approximately 350 nanometers or greater using low power. Of course, size is relative, so while a size of 350 nanometers is extremely small, it leaves out the even smaller molecules such as viruses, which come in at 100 nanometers, or DNA and proteins that measure less than 10 nanometers.

The technique that Ndukaife established with OTET leaves several microns between the laser beam and the molecule it is trapping, another important element of how these new, tiny tweezers work. “We have developed a strategy that enables us to tweeze extremely small objects without exposing them to high-intensity light or heat that can damage a molecule’s function,” Ndukaife said. “The ability to trap and manipulate such small objects gives us the ability to understand the way our DNA and other biological molecules behave in great detail, on a singular level.”

Before OTET, molecules such as extracellular vesicles could only be isolated using high-speed centrifuges. However, the technology’s high cost has inhibited wide adoption. OTET, on the other hand, has the potential to become broadly available to researchers with smaller budgets. The tweezers can also sort objects based on their size, an approach that is important when looking for specific exosomes, extracellular vesicles secreted by cells that can cause cancers to metastasize. Exosomes range in size from 30 to 150 nanometers, and sorting and investigating specific exosomes has typically proven challenging.

Nanotweezer (Justus Ndukaife).

Other applications of OTET that Ndukaife envisions include detecting pathogens by trapping viruses for study and researching proteins that contribute to conditions associated with neurodegenerative diseases such as Alzheimer’s. Both applications could contribute to early detection of disease because the tweezers can effectively capture low levels of molecules, meaning a disease does not have to be full-blown before disease-causing molecules can be researched. OTET can also be combined with other research techniques such as biofluorescence and spectroscopy.

“The sky is the limit when it comes to the applications of OTET,” said Ndukaife, who collaborated with the Center for Technology Transfer and Commercialization to file a patent on this technology. “I am looking forward to seeing how other researchers harness its capabilities in their work.”

The research was funded by National Science Foundation (NSF) grant ECCS-1933109 and Vanderbilt University.

See the full article here .

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Commodore Cornelius Vanderbilt was in his 79th year when he decided to make the gift that founded Vanderbilt University in the spring of 1873.
The $1 million that he gave to endow and build the university was the commodore’s only major philanthropy. Methodist Bishop Holland N. McTyeire of Nashville, husband of Amelia Townsend who was a cousin of the commodore’s young second wife Frank Crawford, went to New York for medical treatment early in 1873 and spent time recovering in the Vanderbilt mansion. He won the commodore’s admiration and support for the project of building a university in the South that would “contribute to strengthening the ties which should exist between all sections of our common country.”

McTyeire chose the site for the campus, supervised the construction of buildings and personally planted many of the trees that today make Vanderbilt a national arboretum. At the outset, the university consisted of one Main Building (now Kirkland Hall), an astronomical observatory and houses for professors. Landon C. Garland was Vanderbilt’s first chancellor, serving from 1875 to 1893. He advised McTyeire in selecting the faculty, arranged the curriculum and set the policies of the university.

For the first 40 years of its existence, Vanderbilt was under the auspices of the Methodist Episcopal Church, South. The Vanderbilt Board of Trust severed its ties with the church in June 1914 as a result of a dispute with the bishops over who would appoint university trustees.

From the outset, Vanderbilt met two definitions of a university: It offered work in the liberal arts and sciences beyond the baccalaureate degree and it embraced several professional schools in addition to its college. James H. Kirkland, the longest serving chancellor in university history (1893-1937), followed Chancellor Garland. He guided Vanderbilt to rebuild after a fire in 1905 that consumed the main building, which was renamed in Kirkland’s honor, and all its contents. He also navigated the university through the separation from the Methodist Church. Notable advances in graduate studies were made under the third chancellor, Oliver Cromwell Carmichael (1937-46). He also created the Joint University Library, brought about by a coalition of Vanderbilt, Peabody College and Scarritt College.

Remarkable continuity has characterized the government of Vanderbilt. The original charter, issued in 1872, was amended in 1873 to make the legal name of the corporation “The Vanderbilt University.” The charter has not been altered since.

The university is self-governing under a Board of Trust that, since the beginning, has elected its own members and officers. The university’s general government is vested in the Board of Trust. The immediate government of the university is committed to the chancellor, who is elected by the Board of Trust.

The original Vanderbilt campus consisted of 75 acres. By 1960, the campus had spread to about 260 acres of land. When George Peabody College for Teachers merged with Vanderbilt in 1979, about 53 acres were added.

Vanderbilt’s student enrollment tended to double itself each 25 years during the first century of the university’s history: 307 in the fall of 1875; 754 in 1900; 1,377 in 1925; 3,529 in 1950; 7,034 in 1975. In the fall of 1999 the enrollment was 10,127.

In the planning of Vanderbilt, the assumption seemed to be that it would be an all-male institution. Yet the board never enacted rules prohibiting women. At least one woman attended Vanderbilt classes every year from 1875 on. Most came to classes by courtesy of professors or as special or irregular (non-degree) students. From 1892 to 1901 women at Vanderbilt gained full legal equality except in one respect — access to dorms. In 1894 the faculty and board allowed women to compete for academic prizes. By 1897, four or five women entered with each freshman class. By 1913 the student body contained 78 women, or just more than 20 percent of the academic enrollment.

National recognition of the university’s status came in 1949 with election of Vanderbilt to membership in the select Association of American Universities. In the 1950s Vanderbilt began to outgrow its provincial roots and to measure its achievements by national standards under the leadership of Chancellor Harvie Branscomb. By its 90th anniversary in 1963, Vanderbilt for the first time ranked in the top 20 private universities in the United States.

Vanderbilt continued to excel in research, and the number of university buildings more than doubled under the leadership of Chancellors Alexander Heard (1963-1982) and Joe B. Wyatt (1982-2000), only the fifth and sixth chancellors in Vanderbilt’s long and distinguished history. Heard added three schools (Blair, the Owen Graduate School of Management and Peabody College) to the seven already existing and constructed three dozen buildings. During Wyatt’s tenure, Vanderbilt acquired or built one-third of the campus buildings and made great strides in diversity, volunteerism and technology.

The university grew and changed significantly under its seventh chancellor, Gordon Gee, who served from 2000 to 2007. Vanderbilt led the country in the rate of growth for academic research funding, which increased to more than $450 million and became one of the most selective undergraduate institutions in the country.

On March 1, 2008, Nicholas S. Zeppos was named Vanderbilt’s eighth chancellor after serving as interim chancellor beginning Aug. 1, 2007. Prior to that, he spent 2002-2008 as Vanderbilt’s provost, overseeing undergraduate, graduate and professional education programs as well as development, alumni relations and research efforts in liberal arts and sciences, engineering, music, education, business, law and divinity. He first came to Vanderbilt in 1987 as an assistant professor in the law school. In his first five years, Zeppos led the university through the most challenging economic times since the Great Depression, while continuing to attract the best students and faculty from across the country and around the world. Vanderbilt got through the economic crisis notably less scathed than many of its peers and began and remained committed to its much-praised enhanced financial aid policy for all undergraduates during the same timespan. The Martha Rivers Ingram Commons for first-year students opened in 2008 and College Halls, the next phase in the residential education system at Vanderbilt, is on track to open in the fall of 2014. During Zeppos’ first five years, Vanderbilt has drawn robust support from federal funding agencies, and the Medical Center entered into agreements with regional hospitals and health care systems in middle and east Tennessee that will bring Vanderbilt care to patients across the state.

Today, Vanderbilt University is a private research university of about 6,500 undergraduates and 5,300 graduate and professional students. The university comprises 10 schools, a public policy center and The Freedom Forum First Amendment Center. Vanderbilt offers undergraduate programs in the liberal arts and sciences, engineering, music, education and human development as well as a full range of graduate and professional degrees. The university is consistently ranked as one of the nation’s top 20 universities by publications such as U.S. News & World Report, with several programs and disciplines ranking in the top 10.

Cutting-edge research and liberal arts, combined with strong ties to a distinguished medical center, creates an invigorating atmosphere where students tailor their education to meet their goals and researchers collaborate to solve complex questions affecting our health, culture and society.

Vanderbilt, an independent, privately supported university, and the separate, non-profit Vanderbilt University Medical Center share a respected name and enjoy close collaboration through education and research. Together, the number of people employed by these two organizations exceeds that of the largest private employer in the Middle Tennessee region.

From The New York Times: “U.S. Will Revive Global Virus-Hunting Effort Ended Last Year”

From The New York Times

Aug. 30, 2020
Donald G. McNeil Jr.
Thomas Kaplan

A federal agency is resurrecting a version of Predict, a scientific network that for a decade watched for new pathogens dangerous to humans. Joe Biden has also vowed to fund the effort.

Some of the Obama-era program’s money supported researchers in China working with bats, which can carry coronaviruses like the one that causes Covid-19. Credit: EcoHealth Alliance.

A worldwide virus-hunting program allowed to expire last year by the Trump administration, just before the coronavirus pandemic broke out, will have a second life — whatever the outcome of the presidential election.

Joseph R. Biden Jr. has promised that, if elected, he will restore the program, called Predict, which searched for dangerous new animal viruses in bat caves, camel pens, wet markets and wildlife-smuggling routes around the globe.

The expiration of Predict just weeks before the advent of the pandemic prompted wide criticism among scientists, who noted that the coronavirus is exactly the sort of catastrophic animal virus the program was designed to head off.

In a speech on Thursday, Kamala Harris, the Democratic vice-presidential candidate, briefly alluded to the controversy as she attacked President Trump ahead of the last night of the Republican National Convention.

“Barack Obama and Joe Biden had a program, called Predict, that tracked emerging diseases in places like China,” she said late in her 20-minute speech. “Trump cut it.”

The government agency that let Predict die last October has quietly created a $100 million program with a similar purpose as Predict, but it has a different name. The new program, set to begin in October, will be called Stop Spillover.

Predict, which was started in 2009 as part of the Obama administration’s Emerging Pandemic Threats program, was inspired by the 2005 H5N1 bird flu scare. Predict was run by the United States Agency for International Development, which is an independent foreign-aid agency overseen by the State Department.

Predict was an odd fit for USAID, experts said. Unlike the Centers for Disease Control and Prevention or the National Institutes of Health, the agency is not normally a home to cutting-edge science.

The American response to pandemics is strangely fragmented. The C.D.C. investigates outbreaks, while the National Institute of Allergy and Infectious Diseases pursues vaccines. Much research into tropical diseases and bioweapons is done by the military, legacies of the Spanish-American War and the Cold War, while the State Department coordinates global campaigns against AIDS.

Some experts have called for a more centralized arrangement, a sort of Pentagon for diseases.

In the public health arena, USAID is home to programs like the President’s Malaria Initiative and campaigns to bring clean drinking water to rural villages. But those programs rely on long-established interventions, like well-drilling, mosquito nets and anti-malaria drugs.

Interviews with former Predict officials and grantees indicate that the program was not actively targeted by the White House in 2019, but that it was allowed to die by cautious administrators who were already under pressure to cut budgets and who feared running afoul of Mr. Trump’s hostility to foreign aid.

Dennis Carroll, Predict’s creator and director, retired from government service when the virus-hunting program was shut down. In an interview on Friday, he said Predict was closed by “risk-averse bureaucrats who were trying to divine what the Trump administration did and didn’t want.”

Dr. Carroll, a fellow at the Bush School of Government and Public Service at Texas A&M in College Station, is now an informal adviser on global health issues to the Biden campaign.

On Friday, a USAID spokeswoman, Pooja Jhunjhunwala, denied that Predict was canceled and said it simply came to the end of its 10-year “life cycle.”

The program was then extended twice for six months, she said — first to finish some analyses, then to help other countries fight Covid-19.

In the early days of the pandemic, Predict became a target of some administration officials because of a grant to the EcoHealth Alliance, a New York-based consultancy employing field veterinarians and wildlife biologists. The alliance had used the grant money to train Chinese scientists at the Wuhan Institute of Virology to catch bats, take fecal and blood samples, and analyze them for viruses.

By then, the Wuhan institute had become the target of rumors that said it had accidentally released the lethal new coronavirus into the world. Those rumors were repeated by national security officials without evidence, and were central to the administration’s efforts to divert blame to China, rather than to Mr. Trump, for the deaths of tens of thousands of Americans from the virus.

(The rumors arose in part because one of the institute’s thousands of stored bat samples contained a virus that was a 96 percent match for SARS-CoV-2. But because coronaviruses mutate slowly, that figure does not describe a close relative. Most evolutionary biologists interpreted the finding to suggest that the two viruses evolved from a common ancestor 40 years ago.)

During its 10-year existence, Predict spent $207 million to train about 5,000 scientists in 30 African and Asian countries, and to build or strengthen 60 laboratories to seek out animal viruses that could endanger humans. Scientists working for Predict collected over 140,000 biological samples and found over 1,000 new viruses, including a new strain of Ebola.

Even after Predict ended, gene-sequencing teams that it trained in Thailand and Nepal were the first to detect Covid-19 in their countries, even before they got test kits from the World Health Organization, said Dr. Jonna Mazet, a veterinarian at the University of California, Davis, who was Predict’s global director.

Both countries rapidly contained the spread of the virus and have kept deaths from it very low, despite having cases early.

Now Predict’s five major grantees have formed a new consortium to apply for the $100 million Stop Spillover grant from USAID. The group includes the One Health Institute at U.C. Davis; the EcoHealth Alliance; the Wildlife Conservation Society, which runs the Bronx Zoo; the Smithsonian Institution, which manages the National Zoo in Washington; and the Center for Infection and Immunity at Columbia University in New York.

“I don’t know who our competitors are, but I’m sure we have some,” said Dr. Christine K. Johnson, associate director of the One Health Institute.

The application process for the Stop Spillover grant was unusually brief, she said. USAID first discussed it with scientists in March as a possible $50 million grant, then doubled the amount and announced on May 1 that applications had to be received by June 1.

Culled chickens suspected of H7N9 infection at a poultry market in Hong Kong in 2014. China-U.S. cooperation helped prevent that outbreak from becoming a pandemic. Credit: Lam Yik Fei/Getty Images.

The request for applications asked for expertise in known threats like the Ebola, Nipah and Lassa viruses, she said, but it also hinted that the work could be broadened to include emerging threats. The agency sought expertise in coronaviruses, filoviruses and other viral “families” that produce novel pathogens.

Dr. Carroll said Friday that he had designed Stop Spillover years ago and intended it as a “companion piece” to Predict that would focus on spotting outbreaks of known pathogens while Predict hunted for still-unknown ones.

Predict, he had hoped, would eventually be folded into the Global Virome Project, a multi-billion-dollar effort to genetically sequence up to 800,000 potentially dangerous viruses discovered in dozens of animal species.

By making Stop Spillover sound like the revival of Predict, Dr. Carroll said, USAID is “trying to create an optic that gets them out of the blowback for ending Predict.”

Although Ms. Jhunjhunwala said Stop Spillover “is not a revival of Predict, nor a follow-on project,” she said it was designed to “implement the scientific gains of Predict to reduce the risk of viral spillover.”

By coincidence, on Thursday the N.I.A.I.D. announced that it would spend $82 million over five years to create 11 “centers” in which American and foreign scientists would collaborate to hunt emerging diseases.

The new network, to be called the Centers for Research in Emerging Infectious Diseases, will focus more on drug and vaccine expertise than on the daring fieldwork sponsored by Predict, which involved jobs like netting bats and birds and sampling gorilla carcasses.

This $82 million grant was in the works years before Predict was eliminated, and it was created in response to the 2014 West African Ebola outbreak and the 2016 Zika epidemic, said Dr. Anthony S. Fauci, the N.I.A.I.D.’s director.

“Yes, it’s like Predict, but it wasn’t the cancellation of Predict that inspired it,” Dr. Fauci said in an interview.

The institutions receiving initial grants were the One Health Institute; the EcoHealth Alliance; the Pasteur Institute in Paris; the Scripps Research Institute in La Jolla, Calif.; the University of Texas Medical Branch in Galveston; the University of Washington in Seattle; Washington University School of Medicine in St. Louis; RTI International in North Carolina; and Duke University in Durham, N.C.

In a statement to The New York Times, Mr. Biden vowed to restore many of the programs cut during the Trump administration, including Predict, that might have given the country more warning of an impending pandemic.

“As president, I will prioritize sustained long-term investments that ensure America is strong, resilient and ready in the face of new pandemic threats,” Mr. Biden said. Of the current crisis, he said: “It did not have to be this bad. That’s the greatest tragedy of all.”

Mr. Biden said he would also strengthen the military’s biological threat-reduction program, whose budget Mr. Trump proposed cutting in February, and would restore the National Security Council’s directorate for global health security and biodefense.

That directorate, established during the Obama administration, was downgraded in 2018 by John Bolton, then Mr. Trump’s national security adviser, and merged into another directorate whose chief mission was to watch out for nuclear threats.

Mr. Bolton eased out the directorate’s widely respected leader, Rear Adm. Tim Ziemer, who long led the President’s Malaria Initiative, begun under President George W. Bush. The Trump administration also sought to cut funding for fighting Ebola just as that disease was re-emerging in central Africa.

Mr. Biden also promised to expand the C.D.C.’s “disease detectives” division and rebuild its office in Beijing.

That division, the Epidemic Intelligence Service, is famous for investigating disease outbreaks, whether of Zika on Yap Island in the South Pacific or of dangerous bacteria in romaine lettuce.

In the two years before the coronavirus crisis broke out in Wuhan, China, the Trump administration cut the size of the C.D.C. staff in Beijing to 14 people from 47, Reuters reported, and transferred home the manager of an Agriculture Department program that monitored diseases in pigs and poultry.

Recent budget cuts have shrunk the number of E.I.S. “detectives” by about 25 percent, said Dr. Thomas R. Frieden, a former C.D.C. director.

The current pandemic “is a once-in-a-lifetime opportunity to strengthen public health,” he said of Mr. Biden’s proposals, and that will require more funding for the World Health Organization, to which Mr. Trump has threatened to cut all U.S. funding.

Admiral Ziemer called Mr. Biden’s proposals “clear and strong” and said he supported “any science that will flush out future threats.” At the same time, he said, he didn’t think it made sense to “get hung up on the N.S.C. organizational chart” or worry about which agency would run which program.

Peter Daszak, president of the EcoHealth Alliance, welcomed Mr. Biden’s plans. “Having eyes and ears on the ground in China protects America,” he said.

In his work, Dr. Daszak said, he had dealt with hunters and wildlife smugglers, and had visited farms where captive bamboo rats, civet cats and porcupines were raised in pens next to chickens and pigs.

Such situations “create a potential for another Covid every 10 years,” he said. “Trying to head that off is a no-brainer. Even Republicans who think about taxpayer dollars can see that.”

See the full article here .

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From University of North Carolina – Chapel Hill: “Algal Blooms Pose Possible Respiratory Threat”

From University of North Carolina – Chapel Hill

July 29, 2020
Megan May

In Pursuit: Algal Blooms Pose Possible Respiratory Threat

Haley Plaas hits the road before sunrise to get an early start on the drive from Morehead City to Edenton, North Carolina. After two hours of farmland views along country backroads, she finally arrives at her destination — a small residential neighborhood on the banks of the Chowan River. Balancing plastic tubs filled with research equipment, she hauls her gear through a backyard. At the edge of the grass, Plaas gets her first view of the water — streaked with the tell-tale bright green hue of a cyanobacterial bloom.

“Nice!” she exclaims. “I know it’s weird to say but this gets me so excited. This is perfect.”

Algal Blooms Return to the Chowan River. 2017 UNCTV

Plaas, a PhD student at the University of North Carolina at Chapel Hill’s Institute for Marine Sciences (IMS), studies the potential respiratory threat caused by harmful algal blooms.

Commonly called blue-green algae — although formed by cyanobacteria rather than algae — these are freshwater blooms that emit toxins. While a green scum on the water’s surface is the most obvious indication, even seemingly clear water can be infected. Quite common in the South where temperatures are warm most of the year, they are found worldwide.

They are also becoming more frequent and severe due to humans. Nutrients like nitrogen and phosphorus from fertilizer, untreated sewage, stormwater runoff, and even air pollution can cause the blooms to grow out of control. In addition, they favor warm water temperatures caused by climate change, as well as increased rainfall bringing more runoff nutrients into waterways from sources like farms and lawns.

“People equals nutrients,” says Hans Paerl, a professor of marine and environmental sciences at IMS. “The more people you pack into a watershed, the more nutrients end up getting generated and discharged.”

Out-of-control growth can be detrimental to aquatic ecosystems in a number of ways. Because they form on the water’s surface, cyanobacteria outcompete desirable aquatic plants by shading them, thereby cutting off the plants’ ability to grow through photosynthesis. Another issue is bioaccumulation — when toxins are magnified in their intensity as they move up the food chain. Additionally, when the blooms die their decomposition can greatly reduce the concentration of dissolved oxygen in the water and kill fish, shellfish, and other aquatic life.

They also pose a danger to human and animal health by producing neurotoxins and liver toxins. Last year, multiple dogs died after swimming, and some evidence points to their deaths being caused by acute liver failure after exposure to a harmful bloom. Exposure over long periods of time can also promote tumor growth and cancer.

While many studies examine intoxication through ingestion or skin contact, Plaas’ work looks at a different angle: aerosol.

Wave action causes air bubbles to become trapped beneath the water’s surface. As these bubbles rise through the water column they collect all sorts of particles, including cyanobacterial cells. The bubbles then burst at the surface, creating a spray of microscopic aerosol that carry these cells into the air — sometimes up to two miles.

Since May, Plaas and a team of community scientists from the Chowan Edenton Environmental Group have collected aerosol and water samples every two weeks from various points along the Chowan River.

Back in the Paerl Lab, Plaas will quantify the amount of toxins emitted to help determine if they pose a public health risk. Currently, no guidelines for aerosolized bloom toxins exist from the United States Environmental Protection Agency, Centers for Disease Control and Prevention, or the World Health Organization.

Plaas is also analyzing how different amounts and ratios of nutrients and water salinity impact cyanobacterial growth.

“If we can figure out what types of nutrients are making these blooms thrive, then we can work backward from that and figure out how to prevent them from getting that concentration of nutrients,” she says.

While they are becoming more frequent, there are a multitude of preventative steps to mitigate these blooms — the most important being reducing nutrient inputs into waterways. The most effective strategy, Paerl says, is using less fertilizer and applying fertilizer in a timely fashion — such as avoiding fertilizing during storm-prone periods like hurricane season.

“You’ll always worry that you haven’t put enough on but, believe me, I’ve been doing this for a long time and you don’t need much,” he says.

Another solution is advanced wastewater treatment that removes phosphorus and nitrogen from discharge, something he says many North Carolina wastewater treatment plants are already doing. Creating artificial wetlands or riparian buffers — essentially, natural vegetation — around agricultural lands and urban areas can capture runoff and remove nutrients before entering waterways or groundwater. Some farmers also rotate crops and grow nitrogen-fixing plants like soybeans to add nitrogen back into the soil naturally instead of through fertilizers.

“We know a lot about how to start controlling blooms but the will has to come to deal with it,” Paerl says. “Given that we are running out of freshwater resources in many places, there’s certainly more pressure to do something about controlling them.”

See the full article here .

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UNC-University of North Carolina-Chapel Hill
Carolina’s vibrant people and programs attest to the University’s long-standing place among leaders in higher education since it was chartered in 1789 and opened its doors for students in 1795 as the nation’s first public university. Situated in the beautiful college town of Chapel Hill, N.C., UNC has earned a reputation as one of the best universities in the world. Carolina prides itself on a strong, diverse student body, academic opportunities not found anywhere else, and a value unmatched by any public university in the nation.

From University of North Carolina – Chapel Hill: “Taking a Bite Out of Meat Allergies”

From University of North Carolina – Chapel Hill

August 14th, 2020
Megan May

Food allergies have long baffled scientists — much is still to be learned about how they develop and why certain people are more susceptible than others. Researchers at UNC may be able to answer some of these questions by studying an unusual food allergy to mammalian meat called alpha-gal syndrome.

Thirteen years ago, research fellow Scott Commins and colleagues at the University of Virginia were attempting to solve an unusual conundrum. People were reporting late-night symptoms ranging from hives to shortness of breath and gastrointestinal issues. The reactions were eventually linked to an allergy to alpha-gal, a molecular sugar found in red meat. Many of the affected reported eating mammalian meat their whole lives without problems. So, why the sudden change?

It wasn’t until some of Commins’ peers also began having reactions — one even needing a trip to the hospital due to anaphylactic shock — that the picture became more clear. Like detectives trying to piece together a case, the researchers sought commonalities among the allergy “victims.” Their answer was surprising: All spent lots of time outdoors.

The team to ask patients if they had a history of tick bites. The answer was a resounding yes.

Now an associate professor in the UNC School of Medicine, Commins continues to piece together this mystery.

An allergy oddity

A study from the Centers for Disease Control and Prevention (CDC) estimates about 34,000 people nationwide have alpha-gal syndrome (AGS). Development of the allergy is strongly linked to the lone star tick in the U.S., and other species of ticks worldwide. Easily identified by a white dot on the back of females, the lone star tick is an aggressive species. Mostly found throughout the eastern U.S., particularly in the South, the tick has become invasive to other regions of the country. While scientists are confident that AGS is acquired through tick bites, the actual way in which it develops is unclear.

In the U.S., the alpha-gal allergy is formed after a bite from the lone star tick. The females, which tend to be more aggressive than males, are easily identified by a white dot on their back.

“The jury is still out. There’s still a lot of research on exactly what is going on,” says Onyinye Iweala, assistant professor in the UNC School of Medicine.

The prevailing idea is the tick contains the alpha-gal sugar in its saliva. When the tick bites, it transfers that alpha-gal into the human and can cause a reaction in the allergic immune system. Humans don’t carry the alpha-gal sugar, which is why reactions can occur. Another possible way of transmission is a tick may feed on an animal like a dog or deer and then a human for its next blood meal. The leftover alpha-gal from the previous mammal may then enter the bloodstream of the human.

The method of acquiring AGS isn’t its only unusual characteristic. Most patients report a delay between exposure and reaction, sometimes hours later. Commins thinks this may be because unlike most food allergies, alpha-gal patients react to a sugar and not a protein. Also, if the person can avoid further tick bites, for many, the allergy will eventually subside.

It may seem simple to avoid red meat, but the difficulty is in unexpected exposures. Some vegetable dishes are cooked with lard or beef broth, cooking surfaces can be cross contaminated, and many processed foods contain animal byproduct. Medicines are also a challenge, as gelatin is frequently used to create pill capsules, cow intestines to produce a common blood thinner, and heart valves from pigs or cattle are used in valve replacement surgery.

“It’s those hidden exposures that often are the ones that trip people up and can lead to accidental reactions,” Commins says.

A clue for other allergies

Understanding more about AGS may help prevent some of those accidental exposures. Commins, Iweala, and their colleagues try to answer fundamental questions by studying both the host and the carrier: What are the chances of developing the allergy from one tick? Does the tick need a blood meal before the bite? Are certain people genetically predisposed to acquiring AGS? What is the basic science behind developing the syndrome?

In 2019, with support from the CDC, Commins began a longitudinal patient study to understand the risk of developing AGS. Over the course of at least five years, researchers will gather surveys and blood samples from patients to learn more. Commins has also been named the leading AGS expert for the U.S. Department of Health and Human Services national tick-borne disease working group, where he will help develop public health recommendations for disease prevention, treatment, and research.

Earlier this year, Iweala received a $1 million grant from the National Institutes of Health to study at cellular and gene expression of the allergy’s development. The idea of studying a topic with so many unknowns may seem daunting for some, but Iweala finds it invigorating. It provides endless areas of exploration, she says.

“There’s a lot about food allergy that we just don’t understand,” says Iweala. “And I think if we can figure that out with something as bizarre as alpha-gal allergy, we might get tools and strategies that we can then apply to conventional food allergies and even other illnesses.”

See the full article here .

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Please help promote STEM in your local schools.

Stem Education Coalition

UNC-University of North Carolina-Chapel Hill
Carolina’s vibrant people and programs attest to the University’s long-standing place among leaders in higher education since it was chartered in 1789 and opened its doors for students in 1795 as the nation’s first public university. Situated in the beautiful college town of Chapel Hill, N.C., UNC has earned a reputation as one of the best universities in the world. Carolina prides itself on a strong, diverse student body, academic opportunities not found anywhere else, and a value unmatched by any public university in the nation.

From SLAC National Accelerator Lab: “SLAC scientists invent low-cost emergency ventilator and share the design for free”

From SLAC National Accelerator Lab

August 13, 2020
Manuel Gnida
mgnida@slac.stanford.edu
(650) 926-2632

The technology could save the lives of COVID-19 patients when more advanced ventilators are too expensive or not available.

Researchers at the Department of Energy’s SLAC National Accelerator Laboratory have invented an emergency ventilator that could help save the lives of patients suffering from COVID-19, the disease caused by novel coronavirus SARS-CoV-2.

Using standard parts that cost less than $400, the ventilator could be an affordable option when more sophisticated technology is not available, in short supply or too expensive.

“We wanted to build the simplest device that could be effective,” said Martin Breidenbach, professor emeritus of particle physics and astrophysics at SLAC and Stanford University, who led the project and hosted the initial studies in his home workshop. “Our acute shortage ventilator is exactly that, and we now want to get it into use as quickly as possible.”

Sander Breur from SLAC’s EXO neutrino research group, describes the acute shortage ventilator project. (Alberto Gamazo/Olivier Bonin/SLAC National Accelerator Laboratory.)

While SLAC and Stanford do not produce or distribute this ventilator, they are offering the technology at no cost to others who want to build the ventilator and deploy it after having obtained regulatory approvals. The scientists described the device in a recent paper posted to the medRxiv preprint server.

A fancy version of the simplest technology

Ventilators provide air to patients who can’t breathe sufficiently on their own – a common problem for those severely affected by COVID-19.

A ventilator’s operating principle is simple: It compresses oxygen-rich air and pushes it through tubes into a patient’s lungs, expanding them and helping the patient take up oxygen. The lungs contract on their own, pushing the air back out. Then the cycle starts over.

In the simplest version, doctors squeeze a self-inflating bag by hand to pump air into the lungs. High-end automated versions compress the air in other ways and use complex electronics to control pressure, volume, air flow and other parameters.

SLAC’s emergency ventilator is based on a simple model, but it adds a mechanism that automatically squeezes the self-inflating bag. The system also incorporates modern, inexpensive electronic pressure sensors and microcomputers with sophisticated software that precisely controls the squeeze. The microcomputers also drive a small control panel, and operators can control the system with that or with a laptop computer. The rest is standard hospital parts.

Christina Ignarra, a research associate working on SLAC’s LUX-ZEPLIN dark matter project team, helped build the acute shortage ventilator. (Jacqueline Orrell/SLAC National Accelerator Laboratory.)

Other groups have developed emergency ventilators in recent months, often by simplifying fancier machines. “Our invention stands out for the opposite approach: We made a fancier version of the simplest ventilator design,” said SLAC project scientist Christina Ignarra, who helped build the device.

The simple design allowed the team to develop, build and test the device in about four months. It also made the ventilator very inexpensive ­– less than $400 per unit, compared to $20,000 or more for a professional-grade system with field support.

“These qualities should make the ventilator particularly helpful for mid- and low-income countries, where medical resources are scarce,” said Michael Bressack, a Bay Area pediatrician and ICU doctor, who has been on several medical missions in Asia, Africa and South America.

A team of physicists and doctors

Bressack actually started the project. In March, he had just returned from a mission in Bangladesh when COVID-19 hospitalizations were skyrocketing in New York and potential shortages of life-saving ventilators were a big concern. He started talking to his physicist friend, Breidenbach, to see if scientists and engineers at SLAC could lend their technical expertise to develop an affordable emergency solution.

The project quickly took off. Bressack pulled in respiratory therapists and ventilator experts, and Breidenbach brought in several of his colleagues, including Dan Akerib and Tom Shutt, co-leaders of the lab’s contributions to the LUX-ZEPLIN (LZ) dark matter experiment.

SLAC’s acute shortage ventilator project started in the home workshop of Martin Breidenbach, professor emeritus of particle physics and astrophysics at SLAC and Stanford. (Jacqueline Orrell/SLAC National Accelerator Laboratory.)

Ignarra, who also works on LZ, said, “We quickly realized that the project was right up our alley. In our experiment, we work with tubes and valves to carefully control the flow of high-purity gases. So, in a way, building a ventilator was not that much different. And it was extremely gratifying to jump in and do something that might directly help in the coronavirus situation.”

To jumpstart the project without lab access due to the Bay Area’s shelter-in-place order, Breidenbach began building several prototypes in his home workshop. He used materials around the shop, ventilator parts bought out of pocket from high-tech distributors, and other components dropped off by team members at his home. He tested what he had built with a Michigan Instruments Lung Simulator that simulates the behavior of sick and healthy human lungs. With additional support from the DOE and Stanford, the project quickly expanded and the team set up four more prototypes at SLAC once the scientists were allowed to go back to the lab.

They also took the ventilator to the VA Palo Alto Health Care System for more advanced tests. In particular, they wanted to make sure their device fulfilled requirements from the Association for the Advancement of Medical Instrumentation for simplified ventilator designs.

SLAC’s acute shortage ventilator is tested at the VA Palo Alto Health Care System. (Sander Breur/SLAC National Accelerator Laboratory.)

Available at no cost

The tests were successful, and the team is now giving their invention away for free. This is about saving lives, not about making money, they said.

“We’re soliciting proposals from companies that are willing to take the technology beyond the lab and deploy it in the field,” said Evan Elder from Stanford’s Office of Technology Licensing (OTL), who is helping with getting the word out. “When we find corporate partners that are a good fit, we’ll be offering royalty-free licenses for at least a year.” Based on the state of the pandemic, this approach will then be reevaluated.

To find out more about the project or contact the ventilator team, please visit https://www.slac-asv.net/ or Stanford OTL’s techfinder website.

Part of the project was supported by the DOE Office of Science through the National Virtual Biotechnology Laboratory, a consortium of DOE national laboratories focused on response to COVID-19, with funding provided by the Coronavirus CARES Act.

See the full article here .

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Please help promote STEM in your local schools.

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SLAC National Accelerator Lab

SLAC/LCLS

SLAC/LCLS II projected view

SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.

SSRL and LCLS are DOE Office of Science user facilities.

From SLAC National Accelerator Lab: Updated to add images- “SLAC’s upgraded X-ray laser facility produces first light”

From SLAC National Accelerator Lab

July 17, 2020

Marking the beginning of the LCLS-II era, the first phase of the major upgrade comes online.

Just over a decade ago in April 2009, the world’s first hard X-ray free-electron laser (XFEL) produced its first light at the US Department of Energy’s SLAC National Accelerator Laboratory. The Linac Coherent Light Source (LCLS) generated X-ray pulses a billion times brighter than anything that had come before. Since then, its performance has enabled fundamental new insights in a number of scientific fields, from creating “molecular movies” of chemistry in action to studying the structure and motion of proteins for new generations of pharmaceuticals and replicating the processes that create “diamond rain” within giant planets in our solar system.

The next major step in this field was set in motion in 2013, launching the LCLS-II upgrade project to increase the X-ray laser’s power by thousands of times, producing a million pulses per second compared to 120 per second today. This upgrade is due to be completed within the next two years.

Today the first phase of the upgrade came into operation, producing an X-ray beam for the first time using one critical element of the newly installed equipment.

“The LCLS-II project represents the combined effort of five national laboratories from across the US, along with many colleagues from the university community and DOE,” said SLAC Director Chi-Chang Kao. “Today’s success reflects the tremendous value of ongoing partnerships and collaboration that enable us to build unique world-leading tools and capabilities.”

XFELs work in a two-step process. First, they accelerate a powerful electron beam to nearly the speed of light. They then pass this beam through an exquisitely tuned series of magnets within a device known as an undulator, which converts the electron energy into intense bursts of X-rays. The bursts are just millionths of a billionth of a second long – so short that they can capture the birth of a chemical bond and produce images with atomic resolution. The LCLS-II project will transform both elements of the facility – by installing an entirely new accelerator that uses cryogenic superconducting technology to achieve the unprecedented repetition rates, along with undulators that can provide exquisite control of the X-ray beam.

Powerful and precise

Over the past 18 months, the original LCLS undulator system (above) was removed and replaced with two totally new systems that offer dramatic new capabilities (below). (Andy Freeberg/Alberto Gamazo/SLAC National Accelerator Laboratory)

This video shows how a sequence of carefully designed springs works to counteract the magnetic forces in powerful magnetic devices known as hard X-ray undulator segments. The spring force must exactly match the manetic force in these segments to keep them aligned within millionths of an inch. These segments contain more than 500 magnets and are about 13 feet long. A chain of 32 of these undulator segments will be used at SLAC National Accelerator Laboratory’s LCLS-II X-ray laser to produce X-rays from a powerful electron beam. The video also shows an undulator segment undergoing magnet measurements at Berkeley Lab. (Credits: Matthaeus Leitner and Marilyn Sargent/Berkeley Lab)

The new undulators were designed and prototyped by DOE’s Argonne National Laboratory and built by Lawrence Berkeley National Laboratory, and have been installed at SLAC over the past year. Today, the first of these systems demonstrated its performance in readiness for the experimental campaigns ahead. Scientists in the SLAC Accelerator Control Room were able to direct the electron beam from the existing LCLS accelerator through the array of magnets in the new “hard X-ray” undulator. Over the course of just a few hours, they produced the first sign of X-rays, and then precisely tuned the configuration to achieve full X-ray laser performance.

“Reaching the first light is a milestone we all have been looking forward to,” said Henrik von der Lippe, Engineering Division director at Berkeley Lab. “This milestone shows how all the hard work and collaboration has resulted in a scientific facility that will enable new science.”

He added, “Berkeley Lab’s contribution of the hard X-ray undulator design and fabrication used our experience from providing undulators to science facilities and our longstanding strength in mechanical design. It is rewarding to see the fruits from years of dedicated Engineering Division teams delivering devices that meet all expectations.”

Images of one of the 21 segments in the soft X-ray undulator (left) and one of the 32 segments in the hard X-ray undulator (right). Each undulator segment is 3.4 meters long. (SLAC National Accelerator Laboratory)

The scientific impact of the new undulators will be significant. One major advance is that the separation between the magnets can be changed on demand, allowing the wavelength of the emitted X-rays to be tuned to match the needs of experiments. Researchers can use this to pinpoint the behavior of selected atoms in a molecule, which among other things will enhance our ability to track the flow and storage of energy for advanced solar power applications.

The undulator demonstrated today is optimized for the hard X-ray regime, and will be able to double the peak X-ray energy LCLS can generate. This will provide much higher precision insights into how materials respond to extreme stress at the atomic level and into the emergence of novel quantum phenomena.

An overlay of LCLS showing the undulator hall, the Front End Enclosure and experimental hall. (SLAC National Accelerator Laboratory)

Next steps

Beyond the undulators lies the Front End Enclosure, or FEE, which contains an array of optics, diagnostics and tuning devices that prepare the X-rays for specific experiments. These include the world’s flattest, smoothest mirrors that are a meter in length but vary in height by only an atom’s width across their surface. Over the next few weeks, these optics will be tested in preparation for more than 80 experiments to be conducted by researchers from around the world over the next six months.

“Today marks the start of the LCLS-II era for X-ray science,” said LCLS Director Mike Dunne. “Our immediate task will be to use this new undulator to investigate the inner workings of the SARS-CoV-2 virus. Then the next couple of years will see an amazing transformation of our facility. Next up will be the soft X-ray undulator, optimized for studying how energy flows between atoms and molecules, and thus the inner workings of novel energy technologies. Beyond this will be the new superconducting accelerator that will increase our X-ray power by many thousands of times. The future is bright, as we like to say in the X-ray laser world.”

See the full article here .

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Please help promote STEM in your local schools.

Stem Education Coalition

SLAC National Accelerator Lab

SLAC/LCLS

SLAC/LCLS II projected view

SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.

SSRL and LCLS are DOE Office of Science user facilities.

From Lawrence Berkeley National Lab: “Scaling Up Science During a Global-Scale Emergency”

From Lawrence Berkeley National Lab

July 7, 2020
Aliyah Kovner
akovner@lbl.gov
510-486-5375

Berkeley Lab’s biomanufacturing experts are helping biotech companies ramp up production of new COVID-19 testing and treatment technologies.

Showing an inspiring knack for innovation under pressure, the global scientific community has developed promising tests and treatments for COVID-19 in the span of just a few months. But moving medical technologies from conception to deployment at such an unprecedented rate comes with a multitude of hurdles, one of which is the obvious challenge of scale. How do companies turn a handful of prototypes or a few flasks of drug-secreting cells into a mass-produced product ready for market?

This is the primary focus for process engineer scientists at the Advanced Biofuels and Bioproducts Process Development Unit (ABPDU) at Lawrence Berkeley National Laboratory (Berkeley Lab). The ABPDU was founded to serve as a resource of equipment and expertise for companies or institutions that are using biological processes to generate exciting and potentially revolutionary products. Since opening their doors in 2012, the unit has collaborated with more than 62 groups to accelerate the development of sustainable biofuels, smart materials, innovative foods, and next-generation medicines.

Eager to apply their biomanufacturing know-how to the current crisis, ABPDU teams have been working during the shelter-in-place orders to help two companies scale-up production of new technologies that could aid in ending the pandemic.

Rapid, portable test kits using CRISPR

Although diagnostic testing for COVID-19 is becoming increasingly accessible, the test kits currently in use at hospitals, clinics, and walk-in centers around the world have many limitations. To detect the presence of coronavirus (SARS-CoV-2) from nasal and throat swabs, most of these kits have to be analyzed in centralized laboratories, with trained personnel and sophisticated equipment. Hoping to shift the paradigm, Argentina-based startup Caspr Biotech is developing a streamlined testing approach based on the increasingly powerful CRISPR gene editing system.

“The company has recently shown how well their system works, and its potential is pretty big,” said project lead and ABPDU principal investigator Eric Sundstrom. “The limiting factor for them at this time is the production of the CRISPR Cas-12 enzyme system. Our role here is to work in parallel with them and design an approach for scaled-up production of the protein, so that they have enough for more widespread clinical testing. Then, hopefully, we can help transfer the technology to a manufacturer who can produce it at the commercial scale.”

Like many biological products and medicines, Caspr’s proprietary Cas-12 enzyme is produced by specially engineered microbes through fermentation. The enzyme works as a detection system because it binds to a specific sequence of DNA – in this case it is engineered to target part of the SARS-CoV-2 genome – and then chops the DNA at that location. After cleaving the viral DNA, the Cas-12 enzyme will start to indiscriminately chop up any DNA that it encounters, so each test kit contains special DNA fragments that are bound with fluorescent proteins. This way, if the Cas-12 enzymes encounter the target viral DNA sequence in the blood sample added to the kit, the fluorescent molecules will be freed, and therefore activated, producing a light-based signal that indicates the individual is positive for a COVID-19 infection.

The company’s CRISPR Cas-12 enzyme is capable of seeking out very low levels of coronavirus DNA and has negligible rates of binding to other DNA sequences, according to as-of-yet unpublished evaluations of the system using samples collected from COVID-19 patients in the U.S. and other countries. These properties make the test highly sensitive and specific; meaning that the test results should have very few false negatives and no false positives. Furthermore, the kit analyzing equipment is small, portable, and can process a sample in less than 40 minutes. Current tests take several hours.

When Caspr approached the ABPDU for scale-up help in early April, they were already in the midst of validation testing (a step necessary for approval by regulatory agencies such as the Food and Drug Administration [FDA]) yet were only able to produce tiny batches of their enzyme at a time. “The company was at the smallest scale when they came to ABPDU, so working on this project has been an excellent opportunity for our team to rapidly dissect a challenge and build new processes,” said Laura Fernandez, a Berkeley Lab process engineer at the ABPDU.

Fernandez and senior process engineer Jan-Philip Prahl first scaled Caspr’s fermentation process up to their highly automated 250-milliliter bioreactor system, then successfully designed a fermentation protocol for 10-liter bioreactors. The insights generated by the 10-liter run will allow the company to further scale to commercial volumes, which are typically hundreds or thousands of liters. Two other team members are now developing a process for purifying the protein from the other molecules made by the fermenting microbes.

“We found that ABPDU is the ideal partner for the optimization of the fermentation at the initial scale of 10 liters and for helping us with the tech transfer process to larger industrial players to continue the production,” said Caspr co-founder and CEO Franco Goytia. “We are submitting to the FDA for Emergency Use Authorization in the next few weeks, while in parallel scaling up our production capacity to hopefully make our solution widely available in the U.S. and the rest of the world in the second half of 2020.”

A faster approach for antibody production

The co-founder and CEO of Swiftscale Biologics, a San Francisco-based startup, reached out to the ABPDU in early March for help scaling up their rapid neutralizing antibody development and manufacturing platform. Neutralizing antibodies are proteins produced by immune cells that allow the body to detect and combat pathogens. They work by binding to specific features on the outside of virus particles, thereby inhibiting the virus’ ability to infect cells or tagging it for destruction by specialized engulfing immune cells.

Antibody infusions – of either survivor-donated blood plasma or antibodies produced through biomanufacturing – are frequently used to treat infectious diseases in cases where the patient’s immune system is struggling, and evidence from across the world shows that donated plasma is currently the most effective treatment for COVID-19. But unfortunately, there is not nearly enough donated plasma to treat all patients in need, and lab-grown copies of SARS-CoV-2 antibodies are still being developed and tested in clinical trials.

Ethan Oksen (left) and Jan-Philip Prahl (right) set up the disc stack centrifuge as they work on the Swiftscale antibody platform. (Credit: Marilyn Sargent/Berkeley Lab)

Showing an inspiring knack for innovation under pressure, the global scientific community has developed promising tests and treatments for COVID-19 in the span of just a few months. But moving medical technologies from conception to deployment at such an unprecedented rate comes with a multitude of hurdles, one of which is the obvious challenge of scale. How do companies turn a handful of prototypes or a few flasks of drug-secreting cells into a mass-produced product ready for market?

This is the primary focus for process engineer scientists at the Advanced Biofuels and Bioproducts Process Development Unit (ABPDU) at Lawrence Berkeley National Laboratory (Berkeley Lab). The ABPDU was founded to serve as a resource of equipment and expertise for companies or institutions that are using biological processes to generate exciting and potentially revolutionary products. Since opening their doors in 2012, the unit has collaborated with more than 62 groups to accelerate the development of sustainable biofuels, smart materials, innovative foods, and next-generation medicines.

Eager to apply their biomanufacturing know-how to the current crisis, ABPDU teams have been working during the shelter-in-place orders to help two companies scale-up production of new technologies that could aid in ending the pandemic.
Rapid, portable test kits using CRISPR

Although diagnostic testing for COVID-19 is becoming increasingly accessible, the test kits currently in use at hospitals, clinics, and walk-in centers around the world have many limitations. To detect the presence of coronavirus (SARS-CoV-2) from nasal and throat swabs, most of these kits have to be analyzed in centralized laboratories, with trained personnel and sophisticated equipment. Hoping to shift the paradigm, Argentina-based startup Caspr Biotech is developing a streamlined testing approach based on the increasingly powerful CRISPR gene editing system.

“The company has recently shown how well their system works, and its potential is pretty big,” said project lead and ABPDU principal investigator Eric Sundstrom. “The limiting factor for them at this time is the production of the CRISPR Cas-12 enzyme system. Our role here is to work in parallel with them and design an approach for scaled-up production of the protein, so that they have enough for more widespread clinical testing. Then, hopefully, we can help transfer the technology to a manufacturer who can produce it at the commercial scale.”

Like many biological products and medicines, Caspr’s proprietary Cas-12 enzyme is produced by specially engineered microbes through fermentation. The enzyme works as a detection system because it binds to a specific sequence of DNA – in this case it is engineered to target part of the SARS-CoV-2 genome – and then chops the DNA at that location. After cleaving the viral DNA, the Cas-12 enzyme will start to indiscriminately chop up any DNA that it encounters, so each test kit contains special DNA fragments that are bound with fluorescent proteins. This way, if the Cas-12 enzymes encounter the target viral DNA sequence in the blood sample added to the kit, the fluorescent molecules will be freed, and therefore activated, producing a light-based signal that indicates the individual is positive for a COVID-19 infection.

The company’s CRISPR Cas-12 enzyme is capable of seeking out very low levels of coronavirus DNA and has negligible rates of binding to other DNA sequences, according to as-of-yet unpublished evaluations of the system using samples collected from COVID-19 patients in the U.S. and other countries. These properties make the test highly sensitive and specific; meaning that the test results should have very few false negatives and no false positives. Furthermore, the kit analyzing equipment is small, portable, and can process a sample in less than 40 minutes. Current tests take several hours.

When Caspr approached the ABPDU for scale-up help in early April, they were already in the midst of validation testing (a step necessary for approval by regulatory agencies such as the Food and Drug Administration [FDA]) yet were only able to produce tiny batches of their enzyme at a time. “The company was at the smallest scale when they came to ABPDU, so working on this project has been an excellent opportunity for our team to rapidly dissect a challenge and build new processes,” said Laura Fernandez, a Berkeley Lab process engineer at the ABPDU.

Fernandez and senior process engineer Jan-Philip Prahl first scaled Caspr’s fermentation process up to their highly automated 250-milliliter bioreactor system, then successfully designed a fermentation protocol for 10-liter bioreactors. The insights generated by the 10-liter run will allow the company to further scale to commercial volumes, which are typically hundreds or thousands of liters. Two other team members are now developing a process for purifying the protein from the other molecules made by the fermenting microbes.

“We found that ABPDU is the ideal partner for the optimization of the fermentation at the initial scale of 10 liters and for helping us with the tech transfer process to larger industrial players to continue the production,” said Caspr co-founder and CEO Franco Goytia. “We are submitting to the FDA for Emergency Use Authorization in the next few weeks, while in parallel scaling up our production capacity to hopefully make our solution widely available in the U.S. and the rest of the world in the second half of 2020.”
A faster approach for antibody production

The co-founder and CEO of Swiftscale Biologics, a San Francisco-based startup, reached out to the ABPDU in early March for help scaling up their rapid neutralizing antibody development and manufacturing platform. Neutralizing antibodies are proteins produced by immune cells that allow the body to detect and combat pathogens. They work by binding to specific features on the outside of virus particles, thereby inhibiting the virus’ ability to infect cells or tagging it for destruction by specialized engulfing immune cells.

Antibody infusions – of either survivor-donated blood plasma or antibodies produced through biomanufacturing – are frequently used to treat infectious diseases in cases where the patient’s immune system is struggling, and evidence from across the world shows that donated plasma is currently the most effective treatment for COVID-19. But unfortunately, there is not nearly enough donated plasma to treat all patients in need, and lab-grown copies of SARS-CoV-2 antibodies are still being developed and tested in clinical trials.
Ethan Oksen and Jan-Philip Prahl work on the Swiftscale antibody platform.

Ethan Oksen (left) and Jan-Philip Prahl (right) set up the disc stack centrifuge as they work on the Swiftscale antibody platform. (Credit: Marilyn Sargent/Berkeley Lab)

“Traditional manufacturing processes for biologics are too time-consuming to meet the needs of the current outbreak,” said Swiftscale CEO David Mace. “To meet this urgent need, Swiftscale is building a platform that can produce these life-saving therapies in a fraction of that time. We can then leverage this platform to accelerate the work of our partners who are developing promising biologics.”

Akash Narani, principal process engineer at ABPDU and lead on the team collaborating with Swiftscale, explained that the company is using a “cell-free” approach that expedites the screening and development of antibodies and then leverages specially engineered microbes that can produce active therapeutic antibodies with previously unachievable productivity. This approach is less costly and time-consuming to develop and scale compared with the standard way to produce antibodies for human medicines and diagnostics, which relies on cultured mammalian cells.

“Swiftscale is envisioning a new way to develop and manufacture biologics. Cell-free technology is still relatively new, but if done right, they can lead to rapid prototyping [identification of the most effective antibodies] and rapid production,” said Narani.

Asun Oka (right) and Chang Dou work on the floor centrifuge for the Swiftscale Biologics collaboration. (Credit: Marilyn Sargent/Berkeley Lab)

Narani and his colleagues began hands-on work at the ABPDU on May 18. Their role is to design and test an efficient process to take Swiftscale’s 250-mililiter fermentations, performed in collaboration with Culture Biosciences, up to 300 liters – a 1,000-fold increase in production volume. Adding to the challenge, the company is still continually optimizing the parts of the production process that come before and after the fermentation stage.

“The scale-up production is a crucial step in the research process and I’m glad we could contribute to such important work and that our efforts are helping research to move quickly,” said Carolina Araujo-Barcelos, an ABPDU fermentation researcher.

Ethan Oksen, a senior research associate, added: “We hope that Swiftscale can apply the insights and data we generated to move quickly to production scale, where they can generate neutralizing antibodies for clinical trials.”

This work also included the efforts of Berkeley Lab researchers Gregory Bontemps, Shawn Chang, Chang Dou, Asun Oka, Isaac Wolf, and Jipeng Yan. The COVID-19 research performed at the ABPDU is supported by Caspr Biotech and Swiftscale Biologics. ABPDU is funded by the Department of Energy’s Bioenergy Technologies Office (BETO).

See the full article here .

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Please help promote STEM in your local schools.

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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 University of Minnesota: “Researchers Use Brain Imaging to Demonstrate Weaker Neural Suppression for Those With Autism”

From University of Minnesota

May 29, 2020
Kelly Glynn

According to the National Autism Association, people with autism spectrum disorder (ASD) may experience sensory hypersensitivity. A University of Minnesota Medical School researcher recently published an article in Nature Communications that illustrates why that may be true by showing the differences in visual motion perception in ASD are accompanied by weaker neural suppression in the visual cortex of the brain.

While experts in neuroscience and psychiatry recognize that differences in sensory functioning are common among people with ASD, it is not currently understood what is happening differently in the brain on a neural level to cause the variations in sensory perception.

Using functional MRI and visual tasks, lead author Michael-Paul Schallmo, PhD, assistant professor in the Department of Psychiatry at the U of M Medical School, and a team of researchers at the University of Washington found:

-People with ASD show enhanced perception of large moving stimuli compared to neuro-typical individuals;
-Brain responses to these visual stimuli are different among young adults with ASD compared to neuro-typical individuals. In particular, brain responses in visual cortex show less neural suppression in ASD;
-A computational model can describe the difference in brain responses.

“Our work suggests that there may be differences in how people with ASD focus their attention on objects in the visual world that could explain the difference in neural responses we are seeing and may be linked to symptoms like sensory hypersensitivity,” Schallmo said.

Schallmo is currently working with collaborators at the U of M on a follow-up study of visual and cognitive functioning in youth with ASD, Tourette syndrome, attention deficit hyperactivity disorder and obsessive-compulsive disorder. Having a better understanding of how these different disorders affect brain function could lead to new screenings to better identify kids who are at risk for ASD and related conditions. It may also help scientists to find new targets for studies seeking to improve treatments for sensory symptoms in these disorders.

This research was supported by the National Institutes of Health.

See the full article here .

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Please help promote STEM in your local schools.

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The University of Minnesota, Twin Cities (often referred to as the U of M, UMN, Minnesota, or simply the U) is a public research university in Minneapolis and Saint Paul, MN. The Twin Cities campus comprises locations in Minneapolis and St. Paul approximately 3 miles (4.8 km) apart, and the St. Paul location is in neighboring Falcon Heights. The Twin Cities campus is the oldest and largest in the University of Minnesota system and has the sixth-largest main campus student body in the United States, with 51,327 students in 2019-20. It is the flagship institution of the University of Minnesota System, and is organized into 19 colleges, schools, and other major academic units.

The University was included in a list of Public Ivy universities in 2001. Legislation passed in 1851 to develop the university, and the first college classes were held in 1867. The university is categorized as a Doctoral University – Highest Research Activity (R1) in the Carnegie Classification of Institutions of Higher Education. Minnesota is a member of the Association of American Universities and is ranked 14th in research activity, with $881 million in research and development expenditures in the fiscal year ending June 30, 2015.

University of Minnesota faculty, alumni, and researchers have won 26 Nobel Prizes and three Pulitzer Prizes. Notable University of Minnesota alumni include two vice presidents of the United States, Hubert Humphrey and Walter Mondale.

From University of New South Wales: “Colour of cells a ‘thermometer’ for molecular imbalance, study finds”

From University of New South Wales

13 May 2020
Sherry Landow
UNSW Media & Content
02 9385 9555
s.landow@unsw.edu.au

Non-invasive colour analysis of cells could one day be used in diagnostics, a proof-of-concept study has shown.

Professor Ewa Goldys and her team used an adapted microscope to capture detailed maps of cells and tissues via a series of photographs. Image: Supplied.

An imbalance of unstable molecular species called ‘free radicals’ will change the colour of cells – and a new imaging technique could one day allow scientists to detect and decode this colour without needing to take samples from the body, a new study by UNSW Sydney researchers has found. The paper was published online yesterday in Redox Biology.

“In our study of cell cultures and tissues in the lab, we found that colour is like a thermometer for oxidative stress,” says UNSW Engineering Professor Ewa Goldys, lead author of the study and Deputy Director of the ARC Centre of Excellence for Nanoscale Biophotonics.

Oxidative stress is caused by an overabundance of free radicals, which can cause damage to cells, DNA and proteins if left unchecked. Poor diet, alcohol consumption and obesity are some factors that can lead to the overproduction of free radicals.

Our body has a natural system for balancing these free radicals with antioxidants, but too many free radicals will make it harder for the body to repair damaged cells. Oxidative stress can cause chronic inflammation and is linked to many diseases, such as heart disease, diabetes and cancer.

“Oxidative stress isn’t disease-specific, but its restoration to healthy levels is an excellent measure of how well a therapeutic approach is working,” says Prof Goldys.

Despite the important role of oxidative stress to our health, it is often overlooked in medical diagnostics. This is largely because it’s difficult to measure on cells ‘in-vivo’ – within the body.

Current methods for testing oxidative stress involve extracting cells from the body and testing their response in a lab. While some cells can be easily removed, such as blood, this method isn’t an option for other parts of the body.

To solve this problem, Prof Goldys and her team adapted a standard fluorescent microscope – a microscope that detects natural fluorescent emissions from cells – to test whether cell and tissue colour is impacted by oxidative stress. They also developed a UV-free version of this technology for instances when UV is too dangerous to use, like in ophthalmology and reproductive health.

The microscopic camera works by emitting bursts of low-level LED light at various wavelengths onto cells and tissues. The light is absorbed by fluorescent molecules, which then emit their own light in response.

This fluorescent light allows the researchers to capture detailed maps of cells and tissues via a series of photographs. The microscope then decodes what the colours mean at a molecular level.

“The microscope has a device that precisely captures the colours in the cells,” explains Prof Goldys.

“We then use a big data approach to digitally ‘unmix’ the colour into its molecular components – red, green and blue, for example.”

The team developed a way to quantify each colour component by assigning it with a value. Once these values are tallied, scientists can measure oxidisation levels without need for cell extraction and analytical procedures.

“Once you have numbers, you can test all sorts of things,” says Prof Goldys, who was awarded a prestigious Eureka Award in 2016 for her discovery that the colours of cells and tissues can be subtle indicators of health and disease.

While their adapted microscope is not yet on the market, Prof Goldys is undertaking steps to begin the clinical trial in two years’ time. First, she will conduct an animal study, then seek TGA approval for the adapted microscope to be used in human studies, before starting a human trial in a selected disease condition.

If these steps are successful, the adapted microscope could become a common tool used in medical practices and scientific research.

In the meantime, Prof Goldys is excited about her next project, which will focus on how this technology can help monitor eye disease – particularly glaucoma.

Alongside researchers including UNSW Scientia Fellow Dr Nicole Carnt, the team are developing a bespoke camera that will photograph the back of the eye via the pupil. This camera will help ophthalmologists measure the oxidative stress of cells and tissues in the retina.

“The findings could change how we monitor and treat eye diseases,” says Prof Goldys.

“Early detection could hopefully help medical staff and patients slow disease progression.”

See the full article here .

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From University of Washington: “Sleep difficulties in the first year of life linked to altered brain development in infants who later develop autism”

From University of Washington

May 7, 2020
Kim Eckart

An 8-month-old boy wears an EEG cap to measure brain activity during a visit to the UW Autism Center.Kiyomi Taguchi/U. of Washington

Studying baby brains at UW Autism Center

Infants spend most of their first year of life asleep. Those hours are prime time for brain development, when neural connections form and sensory memories are encoded.

But when sleep is disrupted, as occurs more often among children with autism, brain development may be affected, too. New research led by the University of Washington finds that sleep problems in a baby’s first 12 months may not only precede an autism diagnosis, but also may be associated with altered growth trajectory in a key part of the brain, the hippocampus.

In a study published May 7 in the American Journal of Psychiatry, researchers report that in a sample of more than 400 6- to 12-month-old infants, those who were later diagnosed with autism were more likely to have had difficulty falling asleep. This sleep difficulty was associated with altered growth trajectories in the hippocampus.

“The hippocampus is critical for learning and memory, and changes in the size of the hippocampus have been associated with poor sleep in adults and older children. However, this is the first study we are aware of to find an association in infants as young as 6 months of age,” said lead author Kate MacDuffie, a postdoctoral researcher at the UW Autism Center.

As many as 80% of children with autism spectrum disorder have sleep problems, said Annette Estes, director of the UW Autism Center and senior author on the study. But much of the existing research, on infants with siblings who have autism, as well as the interventions designed to improve outcomes for children with autism, focus on behavior and cognition. With sleep such a critical need for children — and their parents — the researchers involved in the multicenter Infant Brain Imaging Study Network, or IBIS Network, believed there was more to be examined.

“In our clinical experience, parents have a lot of concerns about their children’s sleep, and in our work on early autism intervention, we observed that sleep problems were holding children and families back,” said Estes, who is also a UW professor of speech and hearing sciences.

Researchers launched the study, Estes said, because they had questions about how sleep and autism were related. Do sleep problems exacerbate the symptoms of autism? Or is it the other way around — that autism symptoms lead to sleep problems? Or something different altogether?

“It could be that altered sleep is part-and-parcel of autism for some children. One clue is that behavioral interventions to improve sleep don’t work for all children with autism, even when their parents are doing everything just right. This suggests that there may be a biological component to sleep problems for some children with autism,” Estes said.

To consider links among sleep, brain development and autism, researchers at the IBIS Network looked at MRI scans of 432 infants, surveyed parents about sleep patterns, and measured cognitive functioning using a standardized assessment. Researchers at four institutions — the UW, University of North Carolina at Chapel Hill, Washington University in St. Louis and the Children’s Hospital of Philadelphia — evaluated the children at 6, 12 and 24 months of age and surveyed parents about their child’s sleep, all as part of a longer questionnaire covering infant behavior. Sleep-specific questions addressed how long it took for the child to fall asleep or to fall back asleep if awakened in the middle of the night, for example.

At the outset of the study, infants were classified according to their risk for developing autism: Those who were at higher risk of developing autism — about two-thirds of the study sample — had an older sibling who had already been diagnosed. Infant siblings of children with autism have a 20 percent chance of developing autism spectrum disorder — a much higher risk than children in the general population.

A 2017 study by the IBIS Network found that infants who had an autistic older sibling and who also showed expanded cortical surface area at 6 and 12 months of age were more likely to be diagnosed with autism compared with infants without those indicators.

In the current study, 127 of the 432 infants were identified as “low risk” at the time the MRI scans were taken because they had no family history of autism. They later evaluated all the participants at 24 months of age to determine whether they had developed autism. Of the roughly 300 children originally considered “high familial risk,” 71 were diagnosed with autism spectrum disorder at that age.

Those results allowed researchers to re-examine previously collected longitudinal brain scans and behavioral data and identify some patterns. Problems with sleep were more common among the infants later diagnosed with autism spectrum disorder, as were larger hippocampi. No other subcortical brain structures were affected, including the amygdala, which is responsible for certain emotions and aspects of memory, or the thalamus, a signal transmitter from the spinal cord to the cerebral cortex.

The UW-led sleep study is the first to show links between hippocampal growth and sleep problems in infants who are later diagnosed with autism.

Other studies have found that “overgrowth” in different brain structures among infants who go on to develop those larger structures has been associated, at different stages of development, with social, language and behavioral aspects of autism.

While the UW sleep study found a pattern of larger hippocampal volume, and more frequent sleep problems, among infants who went on to be diagnosed with autism, what isn’t yet known is whether there is a causal relationship. Studying a broader range of sleep patterns in this population or of the hippocampus in particular may help determine why sleep difficulties are so prevalent and how they impact early development in children with autism spectrum disorder.

“Our findings are just the beginning — they place a spotlight on a certain period of development and a particular brain structure but leave many open questions to be explored in future research,” MacDuffie said.

A focus on early assessment and diagnosis prompted the UW Autism Center to establish an infant clinic in 2017. The clinic provides evaluations for infants and toddlers, along with psychologists and behavior analysts to create a treatment plan with clinic- and home-based activities — just as would happen with older children.

The UW Autism Center has evaluated sleep issues as part of both long-term research studies and in the clinical setting, as part of behavioral intervention.

“If kids aren’t sleeping, parents aren’t sleeping, and that means sleep problems are an important focus for research and treatment,” said MacDuffie.

The authors note that while parents reported more sleep difficulties among infants who developed autism compared to those who did not, the differences were very subtle and only observed when looking at group averages across hundreds of infants. Sleep patterns in the first years of life change rapidly as infants transition from sleeping around the clock to a more adult-like sleep/wake cycle. Until further research is completed, Estes said, it is not possible to interpret challenges with sleep as an early sign of increased risk for autism.

The study was funded by the National Institutes of Health, Autism Speaks and the Simons Foundation. Dr. Stephen Dager, professor of radiology at the UW School of Medicine and Tanya St. John, research scientist at the UW Autism Center, were co-authors. Additional co-authors, all at IBIS Network institutions, were Mark Shen, Martin Styner, Sun Hyung Kim and Dr. Joseph Piven at the University of North Carolina at Chapel Hill; Sarah Paterson, now at the James S. McDonnell Foundation; Juhi Pandey at the Children’s Hospital of Philadelphia; Jed Elison and Jason Wolff at the University of Minnesota; Meghan Swanson at the University of Texas at Dallas; Kelly Botteron at Washington University in St. Louis; and Dr. Lonnie Zwaigenbaum at the University of Alberta.

See the full article here .

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