Paul Tesar, professor of genetics and genome sciences, School of Medicine


Regeneration of myelin in the brain, shown in blue, after ASO drug treatment

A team led by Case Western Reserve University medical researchers has developed a potential treatment method for Pelizaeus-Merzbacher disease (PMD), a fatal neurological disorder that produces severe movement, motor and cognitive dysfunction in children. It results from genetic mutations that prevent the body from properly making myelin, the protective insulation around nerve cells.

Using mouse models, the researchers identified and validated a new treatment target—a toxic protein resulting from the genetic mutation. Next, they successfully used a family of drugs known as ASOs (antisense oligonucleotides) to target the ribonucleic acid (RNA) strands that created the abnormal protein to stop its production. This treatment reduced PMD’s hallmark symptoms and extended lifespan, establishing the clinical potential of this approach.

By demonstrating effective delivery of the ASOs to myelin-producing cells in the nervous system, researchers raised the prospect for using this method to treat other myelin disorders that result from dysfunction within these cells, including multiple sclerosis (MS).

Their research was published online July 1 in the journal Nature.

“The pre-clinical results were profound. PMD mouse models that typically die within a few weeks of birth were able to live a full lifespan after treatment,” said Paul Tesar, principal investigator on the research, a professor in the Department of Genetics and Genome Sciences at the School of Medicine and the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics. “Our results open the door for the development of the first treatment for PMD as well as a new therapeutic approach for other myelin disorders.”

Study co-authors include an interdisciplinary team of researchers from the medical school, Ionis Pharmaceuticals Inc., a Carlsbad, California-based pioneer developer of RNA-targeted therapies, and Cleveland Clinic. First author Matthew Elitt worked in Tesar’s lab as a Case Western Reserve medical and graduate student.

PMD attacks the young

PMD is a rare, genetic condition involving the brain and spinal cord that primarily affects boys. Symptoms can appear in early infancy and begin with jerky eye movements and abnormal head movements. Over time, children develop severe muscle weakness and stiffness, cognitive dysfunction, difficulty walking and fail to reach developmental milestones such as speaking. The disease shortens life-expectancy, and people with the most severe cases die in childhood.

The disease results from errors in a gene called proteolipid protein 1 (PLP1). Normally, this gene produces proteolipid protein (PLP) a major component of myelin, which wraps and insulates nerve fibers to allow proper transmission of electrical signals in the nervous system. But a faulty PLP1 gene produces toxic proteins that kill myelin producing cells and prevent myelin from developing and functioning properly—resulting in the severe neurological dysfunction in PMD patients.

PMD impacts a few thousand people around the world. So far, no therapy has lessened symptoms or extended lifespans.

For nearly a decade, Tesar and his team have worked to better understand and develop new therapies for myelin disorders. They have had a series of successes, and their myelin-regenerating drugs for MS are now in commercial development.

Latest research

In the current laboratory work, the researchers found that suppressing mutant PLP1 and its toxic protein restored myelin-producing cells, produced functioning myelin, reduced disease symptoms and extended lifespans.

After validating that PLP1 was their therapeutic target, the researchers pursued pre-clinical treatment options. They knew mutations in the PLP1 gene produced faulty RNA strands that, in turn, created the toxic PLP protein.

So they teamed with Ionis Pharmaceuticals, a leader in RNA-targeted therapeutics and pioneer of ASOs. These short strings of chemically modified DNA can be designed to bind to a specific RNA target and block production of its protein product.

And that’s exactly what happened in their studies. The result was improved myelin and locomotion, and substantial extension of lifespan. “ASOs provided an opportunity to cut the disease-causing protein off at its source,” Elitt said.

The successful clinical use of ASOs is relatively new, yet recent developments seem promising. In 2016, the U.S. Food and Drug Administration approved the first ASO drug for a neurological disorder, spinal muscular atrophy. The drug, Spinraza, was developed by Ionis and commercialized by Biogen Inc. More ASO therapies are in development, and clinical trials and hold promise for addressing many neurological diseases that as of now have no effective treatment options.

Tesar said that ongoing and planned experiments in his laboratory will help guide future clinical development of ASO therapy for PMD. For example, researchers want to understand more about how well the treatment works after the onset of symptoms, how long it lasts, how often treatment needs to be given and whether it might be effective for all PMD patients, regardless of their specific form of the disease.

“While important research questions remain, I’m cautiously optimistic about the prospect for this method to move into clinical development and trials for PMD patients,” Tesar said. “I truly hope our work can make a difference for PMD patients and families.”

Case Western Reserve University-led team develops new approach to treat certain neurological diseases

by DAVID NIELD

We already know that our brains have a waste disposal system that keeps dead and toxic neurons from clogging up our biological pathways. Now, scientists have managed to capture a video of the process for the first time, in laboratory tests on mice.

There’s still a lot we don’t know about how dead neurons are cleared out, and how the brain reacts to them, so the new research could be a significant step forward in figuring some of that out – even if we’ve not yet confirmed that human brains work in the exact same way.

“This is the first time the process has ever been seen in a live mammalian brain,” says neurologist Jaime Grutzendler from the Yale School of Medicine in Connecticut.

Further down the line, these findings might even inform treatments for age-related brain decline and neurological disorders – once we know more about how brain clean-up is supposed to work, scientists can better diagnose what happens when something goes wrong.

The team focussed in on the glial cells responsible for doing the clean-up work in the brain; they used a technique called 2Phatal to target a single brain cell for apoptosis (cell death) in a mouse and then followed the route of glial cells using fluorescent markers.

“Rather than hitting the brain with a hammer and causing thousands of deaths, inducing a single cell to die allows us to study what is happening right after the cells start to die and watch the many other cells involved,” says Grutzendler.

“This was not possible before. We are able to show with great clarity what exactly is going on and understand the process.”

Three types of glial cells – microglia, astrocytes, and NG2 cells – were shown to be involved in a highly coordinated cell removal process, which removed both the dead neuron and any connecting pathways to the rest of the brain. The researchers observed one microglia engulf the neuron body and its main branches (dendrites), while astrocytes targeted smaller connecting dendrites for removal. They suspect NG2 may help prevent the dead cell debris from spreading.

The researchers also demonstrated that if one type of glial cell missed the dead neuron for whatever reason, other types of cells would take over their role in the waste removal process – suggesting some sort of communication is occurring between the glial cells.

Another interesting finding from the research was that older mouse brains were less efficient at clearing out dead neural cells, even though the garbage removal cells seemed to be just as aware that a dying cell was there.

This is a good opportunity for future research, and could give experts insight into how older brains start to fail in various ways, as the garbage disposal service starts to slow down or even breaks.

New treatments might one day be developed that can take over this clearing process on the brain’s behalf – not just in elderly people, but also those who have suffered trauma to the head, for example.

“Cell death is very common in diseases of the brain,” says neurologist Eyiyemisi Damisah, from the Yale School of Medicine.

“Understanding the process might yield insights on how to address cell death in an injured brain from head trauma to stroke and other conditions.”

The research has been published in Science Advances.

https://www.sciencealert.com/for-the-first-time-scientists-capture-video-of-brains-clearing-out-dead-neurons

Cleveland Bachs!

Posted: July 1, 2020 in Uncategorized
Tags: ,

For the past few weeks, I’ve been traveling around my adopted home of Cleveland playing the Prelude to Bach’s First Cello Suite. Music may not be able to solve the world’s problems, but I believe it can, as Lincoln said, “bind up the nation’s wounds.”

“With malice toward none; with charity for all; with firmness in the right, as God gives us to see the right, let us strive on to finish the work we are in; to bind up the nation’s wounds…to do all which may achieve and cherish a just and a lasting peace among ourselves, and with all nations.”

Abraham Lincoln, Second Inaugural Address

Special thanks to Katarina Davies for her help with this project. Also, thanks to Grace Gill and Jennifer Woloschyn Harrell.


A yellow-rumped leaf-eared mouse (Phyllotis xanthopygus), perched on a researcher’s glove, at high-altitude on the slopes of Llullaillaco volcano. This species dwells at higher elevations than any other mammal.

BY DOUGLAS MAIN

Last summer, scientists reported finding the world’s highest-dwelling mammal, a yellow-rumped leaf-eared mouse, which was seen scampering among the upper reaches of Llullaillaco, the world’s highest historically active volcano, straddling Argentina and Chile.

It’s incredible that anything could live that high, at 20,340 feet—there is no vegetation, and seemingly nothing to eat. Here, at the edge of the Atacama Desert, there is little rain, and temperatures sometimes plunge below minus 75 degrees Fahrenheit.

“It’s hard to overstate how hostile an environment it is,” says Jay Storz, a biologist at the University of Nebraska, Lincoln, and a National Geographic Explorer.

Intrigued by the discovery, Storz organized an expedition to the volcano in February specifically to search for rodents. And rodents he found. In fact, he encountered another yellow-rumped mouse even higher than previously sighted, atop the very summit of Llullaillaco, at 22,110 feet—breaking the record announced just last year.

The research, described in a study published this week on bioRxiv, where papers can be seen before peer review, is the beginning of a scientific quest to understand how these animals adapt to and survive such grueling conditions. The results could help us better understand how other creatures adapt to extremes, and could even have medical applications for humans coping with low levels of oxygen, for example due to disease, exertion, or altitude sickness.

Most of the mice, which belong to four different species, were caught using small traps during the expedition in February, so the animals could be further studied. But on the summit of Llullaillaco, Storz caught the mouse by hand, just as he was arriving. It was a lucky break, as you can only stay on the summit for a few minutes, due to low oxygen conditions and the possibility of violent storms.

“Nobody expected mice to be living that high,” Storz says. “And it turns out they get as high as you can possibly get.” Storz’s climbing companion, professional mountaineer Mario Perez-Mamani, captured the moment on video.

Mighty mouse

The yellow-rumped leaf-eared mouse (Phyllotis xanthopygus), is a known species that lives in the foothills and mountains of the Andes, and also can be found as low as sea level.

That means the mouse has an unprecedented elevation range of more than 22,000 feet. “That wide of a range is extraordinary,” says Scott Steppan, a mouse expert and biology professor at Florida State University. “No other species does that.”

On the February expedition, Storz and colleagues also found a Lima leaf-eared mouse (Phyllotis limatus) at 16,633 feet, far surpassing the known record for this species. The other two encountered species were found near or at their previously known altitudinal maximum.

In all, the expedition suggests “we’ve probably underestimated the altitude limits and physiological capabilities of lots of animals, just because the summits of the world’s highest peaks are relatively unexplored by biologists,” Storz says.

It all started in 2013, when American climbers Matt Farson, an emergency medicine doctor, and anthropologist Thomas Bowen spotted what was later assumed to be as a yellow-rumped leaf-eared mouse on the volcano. A later 2016 expedition, including Steven Schmidt from the University of Colorado, Boulder, found another mouse in the same location and collected a DNA sample near its burrow, confirming that is was a Phyllotis xanthopygus, which was announced in late June 2019 at the annual meeting of the American Society of Mammalogists in Washington D.C.

Added intrigue

Large-eared pikas, the previous record-holder, have been observed at 20,100 feet. There have also been sightings of yaks and blue-sheep around 20,000 feet, but this is outside of their known habitable zone. In this case of the leaf-eared mice, these individuals are thought to be part of established populations.

The finding adds intrigue to Llullaillaco, which is home to the world’s highest archeological site, a cache of nearly perfectly-preserved Inca mummies, discovered in 1999 by National Geographic Explorer Johan Reinhard. Reinhard also noted rodents at high elevations, though he at the time assumed they followed the climbers and survived off their food. Llullaillaco also has one of the world’s highest-elevation lakes, and resilient, almost otherworldly microbes.

The discovery raises many questions. How do the mice survive at such high elevations, where it is incredibly cold and there is less than half the oxygen found at sea level? And what do they eat?

The animals might eat bits of detritus that are blown up by the wind, but these don’t seem very substantial, says Storz, who studies deer mice, which also span from sea level to elevations above 14,000 feet; they are basically the North American equivalent of leaf-eared mice, he says.

These animals are able to survive at high altitude through “a whole suite of physiological changes,” such as slower muscle metabolism and a specialized cardiovascular system. (Related: Humans ‘domesticated’ mice 15,000 years ago.)

To be continued

Storz plans a return visit to better understand their ability to withstand such extreme lifestyles. Specifically, he plans to put live mice in metabolic chambers to measure their VO2 max, an indicator of oxygen consumption, and to perform other tests. The work has received funding from the National Geographic Society and the U.S. National Institutes of Health, as better understanding adaptations to high altitude life is “potentially relevant in treating a number of human diseases that relate to… problems with oxygen delivery and oxygen utilization,” he says.

These include heart disease and lung conditions including emphysema or chronic obstructive pulmonary disease. The results could also aid doctors in treating altitude sickness and coping with life at high altitude or elsewhere where there are low levels of oxygen.

The finding is “completely unexpected, and one, therefore, that deserves critical research on this animal as well as focused field research in other similar areas around the globe to parallel cases, like the Himalayas,” says James Patton, an emeritus professor at the University of California, Berkeley, who wasn’t involved in the research.

Patton marvels that a mouse could survive here, and is excited to hear more about how this is possible. “Amazing, to put it lightly.”

https://www.nationalgeographic.com/animals/2020/03/mouse-found-atop-volcano-highest-altitude-mammal/?cmpid=org=ngp::mc=crm-email::src=ngp::cmp=IPW2020::add=IPW2020&rid=6379E47F895218E12B545C82AF588C85

We, in the United States and many other Western nations, more often think of children as sources of extra work than as sources of help. We often think that trying to get our children to help us at home or elsewhere would be more effort than it would be worth. We also tend to think that the only way to get children to help is to pressure them, through punishment or bribery, which, for good reasons, we may be loath to do. We ourselves generally think of work as something that people naturally don’t want to do, and we pass that view on to our children, who then pass it on to their children.

But researchers have found strong evidence that very young children innately want to help, and if allowed to do so will continue helping, voluntarily, through the rest of childhood and into adulthood. Here is some of that evidence.

Evidence of Toddlers’ Instinct to Help

In a classic research study, conducted more than 35 years ago, Harriet Rheingold (1982) observed children ages 18, 24, and 30 months interacting with their parent (mother in some cases, father in others) as the parent went about doing routine housework, such as folding laundry, dusting, sweeping the floor, clearing dishes off the table, and putting away items scattered on the floor. For the sake of the study, each parent was asked to work relatively slowly and allow their child to help if the child wanted, but not to ask the child to help or direct the child’s help through verbal instructions. The result was that all of these young children—80 in all—voluntarily helped do the work. Most of them helped with more than half of the tasks that the parent undertook, and some even began tasks before the parent got to them. Moreover, in Rheingold’s words, “The children carried out their efforts with quick and energetic movement, excited vocal intonations, animated facial expressions, and with delight in the finished task.”

Many other studies have confirmed this apparently universal desire of toddlers to help. A common procedure is to bring the little child into the laboratory, allow him or her to play with toys in one part of the room, and then create a condition in which the experimenter needs help in another part of the room. For example, the experimenter might “accidentally” drop something onto the floor, over a barrier and try but fail to reach it. The child, who is on the other side of the barrier from the experimenter, can help by picking the object up and handing it over the barrier to the experimenter. The key question is: Does the child come over and help without being asked? The answer is yes, in almost every case. All the experimenter has to do is draw attention to the fact, through a grunt and attempts to reach, that she is trying to get the object. Even infants as young as 14 months have been found regularly to help in these situations (Warneken & Tomasello, 2009). They see what the experimenter is trying to do, infer what she needs, and then, on their own initiative, satisfy that need.

This helping behavior is not done for some expected reward. In fact, Felix Warneken and Michael Tomasello (2008) found that giving a reward for helping reduces subsequent helping. In one experiment, they allowed 20-month-old children to help an experimenter in a variety of ways and either rewarded the child (with an opportunity to play with an attractive toy) or not. Then they tested the children with more opportunities to help, where no reward was offered. The result was that those who had been previously rewarded for helping were now much less likely to help than were those who had not been rewarded. Only 53% of the children in the previously rewarded condition helped, in this test, compared with 89% in the unrewarded condition.

This finding is evidence that children are intrinsically motivated rather than extrinsically motivated to help—that is, they help because they want to be helpful, not because they expect to get something for it. Much other research has shown that rewards tend to undermine intrinsic motivation. For example, in one classic study, children who were rewarded for drawing a picture subsequently engaged in much less drawing than children who had not been rewarded for drawing (Lepper, Greene, & Nisbett, 1973). Rewards apparently change people’s attitudes about a previously enjoyed activity, from something that one does for its own sake to something that one does primarily to get a reward. This occurs for adults as well as for children (Deci, Koestner & Ryan, 1999).

We parents, in our culture, tend to make two mistakes regarding our little children’s desires to help. First, we brush their offers to help aside, because we are in a rush to get things done and we believe (often correctly) that the toddler’s “help” will slow us down or the toddler won’t do it right and we’ll have to do it over again. Second, if we do actually want help from the child, we offer some sort of deal, some reward, for doing it. In the first case, we present the message to the child that he or she is not capable of helping; and in the second case, we present the message that helping is something a person will do only if they get something in return.

Cross-Cultural Evidence that Toddlers Who Are Allowed to Help Become Truly Helpful Later in Childhood

Researchers studying various Indigenous communities and Indigenous-heritage communities (communities not far removed from Indigenous ways) have found that parents in those communities respond positively to the desires of their toddlers to help, even when the “help” slows them down, because they believe that this pleases the child and helps the child learn to become a truly valuable helper. The research also shows that, by the time they are about 5 or 6 years old, children in those communities are very effective, willing helpers. Actually, “helper” is not even the right word here. A better word is “partner,” because they act as if the family’s work is as much their responsibility as it is their parents’.

Illustrations of this can be found, for example, in a study in which researchers interviewed mothers of 6- to 8-year-olds in Guadalajara, Mexico (Alcala, Rogoff, Mejia-Arauz, Coppens, & Dexter, 2014). Nineteen of the mothers were from an Indigenous-heritage community, still rather closely linked to their Native American roots, and the other 14 were from a more cosmopolitan, Westernized urban community. All of the children attended school, but the parents in the Indigenous-heritage community had much less schooling than did those in the cosmopolitan community. The research revealed great differences in ways that the two sets of parents described their children’s contributions to household tasks. According to the parents’ reports, 74% of the children in the Indigenous-heritage community regularly took initiative in family household work, without being asked, compared with none of the children in the cosmopolitan community. For illustration, here are quotes from two of the Indigenous-heritage mothers describing their children’s activities:

“There are days when she comes home and says: ‘Mom, I’m going to help you do everything.’ Then she picks up the entire house, voluntarily. Or sometimes, when I’m not done cleaning the house, she tells me, ‘Mom you’ve come home really tired, let’s start cleaning the house.’ And then she turns the radio on and tells me, ‘You do one thing, and I’ll do something else,’ and I clean the kitchen and she picks up the rooms.”
“Everybody knows what they need to do, and without having to ask her, she tells me, ‘Mommy I just got home from school, I’m going to visit my grandma, but before I go, I’m going to finish my work,’ and she finishes and then she goes.”
In contrast, the cosmopolitan mothers reported very little voluntary helping from their children and seemed to denigrate what little help a child did offer. Here, for example, is a quotation from one of these mothers: “I’ll walk into the bathroom and everything is all soapy, and she says to me ‘I’m just cleaning.’ I tell her, ‘You know what? It’s better that you don’t clean anything for me because I’m going to slip and fall in here.’”

All in all, the Indigenous-heritage mothers described their children as capable, autonomous, self-initiating, willing partners while the cosmopolitan mothers described their children as subordinates who generally helped only begrudgingly and needed to be told what to do. In the researchers’ words, “Most mothers in the Indigenous-heritage community (87%) reported that their children planned and chose their ‘free-time’ activities (work, unstructured play, homework, religious classes, and visiting relatives and friends), compared with only two mothers (16%) in the cosmopolitan community.” Indeed, other studies, involving first-hand observations of the children in their homes, confirm these parents’ reports. To many people in our culture, it may seem counterintuitive that children who were most free to choose their own activities, least directed by their parents, were the children who contributed most to the family’s welfare.

In some other essays in this blog (e.g.: https://www.psychologytoday.com/us/blog/freedom-learn/200808/children-educate-themselves-iii-wisdom-hunter-gatherers) I’ve described children’s natural drive to learn by observing others around them and then trying out for themselves the activities they observe. Cross-cultural researcher Barbara Rogoff has described this mode of self-directed education as Learning by Observing and Pitching In, or LOPI (Rogoff, Mejia-Arauz, & Correa Chavez, 2015). Helping with housework is just one example of LOPI.

A How-To Summary

In sum, the research I’ve described here suggests that, if you want your child to be a partner with you in taking responsibility for the family work, you should do the following:

Assume it is the family work, and not just your work, which means not only that you are not the only person responsible to get it done but also that you must relinquish some of the control over how it is done. If you want it done exactly your way, you will either have to do it yourself or hire someone to do it.

Assume that your toddler’s attempts to help are genuine and that, if you take the time to let the toddler help, with perhaps just a bit of cheerful guidance, he or she will eventually become good at it.

Avoid demanding help, or bargaining for it, or rewarding it, or micromanaging it, as all of that undermines the child’s intrinsic motivation to help. A smile of pleasure and a pleasant “thank you” is good. That’s what your child wants, just as you want that from your child. Your child is helping in part to reinforce his or her bond with you.

Realize that your child is growing in very positive ways by helping. The helping is good not just for you, but also for your child. He or she acquires valued skills and feelings of personal empowerment, self-worth, and belonging by contributing to the family welfare. At the same time, when allowed to help, the child’s inborn altruism is nourished, not quashed.

https://www.psychologytoday.com/us/blog/freedom-learn/201809/toddlers-want-help-and-we-should-let-them

Fluorsecence microscopy image of human epithelial cells form the colon and infected with the novel coronovirus shows production of filopodia (white) extending our from the cell surface and containing viral particlea.

Most of us have already absorbed the idea that the coronavirus does some weird and sinister things to the human body that are unlike most other respiratory viruses known to man. But now a new study finds yet another unsettling thing that the virus appears to do to help spread from cell to cell.

A new study by an international team led by UC San Francisco finds that cells infected with SARS-CoV-2 quickly begin to grow new arms or dendrites — referred to clinically as filopodia — which are themselves studded with fresh virus particles. These filopodia then seek to reach into and through the walls of neighboring cells, thereby infecting them. And this appears to be a second mode that the virus has for replicating and spreading itself in the body.

As the LA Times reports via the study, up until now, researchers believed that this virus spread itself like most other viruses, by docking itself onto healthy cells, invading, and then turning those cells into copying machines. A team in UCSF’s Quantitative Biosciences Institute led by systems biologist Nevan Krogan launched a project in February to rapidly identify existing drugs and compounds that might treat or slow the spread of the coronavirus. They published initial findings in late April pointing to 10 existing drugs and experimental compounds that showed promise in lab settings when it came to targeting the human proteins this virus most needs to survive.

The latest study is an extension of that work, and Krogan is one of the lead authors of the paper published today in the journal Nature. The important new finding, Krogan and the team hope, will lead to some rapid study of several existing cancer treatments that themselves inhibit the growth of filopedia — thereby shutting down this second means that the virus is using to invade cells.

“It’s just so sinister that the virus uses other mechanisms to infect other cells before it kills the cell,” Krogan says, speaking to the LA Times.

Krogan says that while other viruses — including HIV and the family of viruses that cause smallpox — also use filopedia as mechanisms of spreading infection, the way this virus so rapidly prompts the growth of these tentacles is highly unusual. And the shape of them, branching off the cell and each other like trees, is also apparently strange. Other infectious diseases like HIV don’t cause these kinds of prolific, mutant growths.

Expanding the earlier list of promising drugs, the latest study points to seven cancer drugs already in use that could prove effective against COVID-19. Those include a drug already being used to treat acute myeloid leukemia called Xospata (generic name: gilteritinib); the experimental drug Silmitasertib, which is being studied as a treatment for bile duct cancer and one form of childhood brain cancer; and ralimetinib, another cancer drug which was developed by Eli Lilly to treat multiple forms of cancer.

“We’ve tested a number of these kinase inhibitors and some are better than remdesivir,” Krogan says, via the Milwaukee Journal-Sentinel.

Another experimental drug called Dinaciclib was found by the research team to stop the virus’s assault on a family of kinases called CDKs, which are responsible for cell growth and dealing with DNA damage.

Other infectious disease researchers are just waking up to the revelations of the paper, but most reactions seem fairly excited. While much research is being done on shutting down virus proteins, Krogan’s field of study, called proteomics, instead focuses on the less-likely-to-mutate human proteins involved in helping the virus do its dirty work.

“This paper shows just how completely the virus is able to rewire all of the signals going on inside the cell,” says University of Wisconsin-Madison medical professor Andrew Mehle to the Journal-Sentinel. “That’s really remarkable and it’s something that occurs very rapidly (as soon as two hours after cells are infected).”

And Lynne Cassimeris, a professor of biological sciences at Lehigh University, calls the latest findings “an amazing leap.” “We know that the virus has to be manipulating these human proteins,” Cassimeris says. “Now we have a list of what is changing over time.”

While Krogan’s lab at UCSF got this research off the ground just as the pandemic was emerging in February, there were 70 authors listed on the latest paper, with Krogan as the lead. The work was also done by scientists at Mt. Sinai Hospital in New York, Rocky Mountain Labs in Montana, the Pasteur Institute in Paris, and the University of Freiburg in Germany

https://sfist.com/2020/06/26/ucsf-researchers-discover-how-coronavirus-makes-zombies-of-human-cells-causes-them-to-sprout/

Thanks to Kebmodee for bringing this to the It’s Interesting community.

By Ryan Prior

Every morning, Dr. David Fajgenbaum takes three life-saving pills. He wakes up his 21-month-old daughter Amelia to help feed her. He usually grabs some Greek yogurt to eat quickly before sitting down in his home office.

Then he spends most of the next 14 hours leading dozens of fellow researchers and volunteers in a systematic review of all the drugs that physicians and researchers have used so far to treat Covid-19. His team has already pored over more than 8,000 papers on how to treat coronavirus patients.

The 35-year-old associate professor at the University of Pennsylvania Perelman School of Medicine leads the school’s Center for Cytokine Storm Treatment & Laboratory. For the last few years, he has dedicated his life to studying Castleman disease, a rare condition that nearly claimed his life.

Against epic odds, he found a drug that saved his own life six years ago, by creating a collaborative method for organizing medical research that could be applicable to thousands of human diseases.

But after seeing how the same types of flares of immune-signaling cells, called cytokine storms, kill both Castleman and Covid-19 patients alike, his lab has devoted nearly all of its resources to aiding doctors fighting the pandemic.

During a cytokine storm, the body’s overactive immune response begins to attack its own cells rather than just the virus. When that inflammatory response occurs in Covid-19 patients, cytokines are often the culprit for the severe lung damage, organ failure, blood clots or pneumonia that kills them.

Having personal experience tamping down his own cytokine responses gives him a unique insight.
“I’m alive because of a repurposed drug,” he said.

Now, repurposing old drugs to fight similar symptoms caused by a novel virus has become a global imperative.


Researchers from Fajgenbaum’s lab gather in a video call to discuss Covid-19 treatment data.

A global repository for Covid-19 treatment data

Researchers working with his lab have reviewed published data on more than 150 drugs doctors around the world have to treat nearly 50,000 patients diagnosed with Covid-19. They’ve made their analysis public in a database called the Covid-19 Registry of Off-label & New Agents (or CORONA for short).

It’s a central repository of all available data in scientific journals on all the therapies used so far to curb the pandemic. This information can help doctors treat patients and tell researchers how to build clinical trials.

The team’s process resembles that of the coordination Fajgenbaum used as a medical student to discover that he could repurpose Sirolimus, an immunosuppressant drug approved for kidney transplant patients, to prevent his body from producing deadly flares of immune-signaling cells called cytokines.

The 13 members of Fajgenbaum’s lab recruited dozens of other scientific colleagues to join their coronavirus effort. And what this group is finding has ramifications for scientists globally.

Based on their database, the team published the first systematic review of Covid-19 treatments in the journal Infectious Diseases and Therapy in May.

In that first analysis of the data, the team reviewed 2,706 journal articles published on the topic between December 1, 2019, and March 27, 2020. Just 155 studies met the team’s criteria for being included in the meta-review based on standards such as the size of the cohort, the nature of the study and the end points researchers chose for concluding their inquiries.

“It’s frustrating because we all want a drug that works for everyone,” he said. But that isn’t happening because the coronavirus affects people in ways that are much more complex.

They’re sorting through oceans of data

The first key thing to consider, Fajgenbaum said, was the huge variety of Covid-19 patient experiences. It’s hard to zero in on one particular therapy because there can be such significant differences in the timing of when the drug is administered, how severely Covid-19 strikes a given individual and the stage at which the disease has progressed.

Any change in one of those variables can render an otherwise effective drug impotent. But with massive amounts of patients, the clinical data was bearing out a few noticeable themes, he said.

First, the Covid-19 patients with more severe cytokine storms were more likely to need drugs targeted toward suppressing the immune system. Those with less severe cytokine storms were likely to benefit from an immune-boosting drug.

Outside of drugs designed to boost or suppress the immune system, another major category is antiviral therapies. Various antivirals hit the “viral cascade,” Fajgenbaum said. Some work by stopping the virus from infecting cells, others by halting replication within cells. Other antivirals act in between cells and the virus.

Keeping the database is a huge undertaking, given how stunning the pace of global scientific progress and collaboration has been in the face of the disease’s human toll.

“We set the really ambitious goal of just getting this started,” Fajgenbaum said.

In the three months since the cutoff date for their first paper, the team has reviewed more than 5,000 additional papers published by scientists around the world.

One of their biggest challenges has been fitting the puzzle pieces of the different studies. With each study designed differently, one data set can’t necessarily be grafted neatly onto another. That’s especially tricky when most people diagnosed with Covid-19 eventually get better anyway. It’s hard to parse out if a particular drug was effective and saved lives.

The goal of the CORONA database isn’t to find a wonder drug per se, but to help design better clinical trials that can establish a real cause-and-effect relationship between a drug agent and an individual’s survival.

In the war against the coronavirus, Fajgenbaum hopes CORONA aims to help light the way so the heavy artillery on the front lines can better know what to shoot at Covid-19.

“It’s hard to fight a war if you’re not keeping track of what weapons are being used against the enemy,” he said.


Shown here is one of the researchers’ computer screens as they review Covid-19 treatment data while on a video call. The left side shows a spreadsheet where they tabulate data from the studies. The right side shows the study they’re currently analyzing.

They’re collaborating with FDA analysts

Fajgenbaum’s CORONA database dovetails with ongoing work at the US Food and Drug Administration. For years, the agency has been developing an app called CURE ID, a platform designed to help health care providers capture novel uses of already approved drugs.

The app launched in December with two goals in mind: The first was to help advise physicians searching for new treatment ideas, prescription guidelines and emergency use advisories for drugs across hundreds of diseases. The agency’s second aim was to build a structure by which health providers in the trenches could quickly input anonymized information about their patients so that other doctors around the world could quickly see whether they had been successful using an off-label drug.

The app was ready just in time for the pandemic, and Fajgenbaum gave the keynote speech at its launch.

“It’s really been a terrific collaboration,” said a health policy analyst with the FDA. “His life follows very much the model we hope to use.”

Now that he and his team are working on the coronavirus, the urgency of their partnership has strengthened.

“Nobody wants to go to a database with no data in it,” the analyst said. “Rather than reinventing the wheel, he was kind enough to provide all his data.”

And while the CORONA database project is primarily intended to aid researchers, it’s tapping into major currents in health economics that explain weak points in the way the public and private sector develop therapies together.

“Covid-19 illustrates a market failure in how we build vaccines,” said Amitabh Chandra, a health economist with joint appointments as a professor at the Harvard Kennedy School and Harvard Business School. “We haven’t given firms the correct incentives to make vaccines before a pandemic. Vaccines are very hard to test before the pandemic hits.”

There aren’t old vaccines sitting on a shelf waiting to be dusted off to save the world from the coronavirus. But there are hundreds of FDA-approved drugs at your local pharmacy that can save lives immediately.

When teaching classes, Chandra uses a 2017 New York Times story profiling Fajgenbaum to illustrate the value of drug repurposing and motivate his students to think boldly about how to create economic incentives to cure diseases, particularly when a “invisible medicine” might be right under your nose.

“There’s no substitute for a good story to get people motivated,” he said.
Many drugs are beginning to stand out.

The combination of antivirals lopinavir and ritonavir is the Covid-19 treatment protocol with the most number of studies published so far. As of mid-June, the team had looked at papers on that drug pairing involving more than 4,500 patients.

Next, corticosteroids have shown particular promise, making appearances in studies with another 4,000 patients. At the cellular level, antivirals work for a variety of reasons, each with its own specialty in attacking the virus at different points in its life cycle. Corticosteroids are different, however.

“Steroids tend to act the same, with replicating cortisol,” Fajgenbaum said.

He feels particularly elated about a recent United Kingdom-based study on the steroid dexamethasone. The study garnered headlines for its result showing that a low-dose 10-day regimen of the drug could reduce the risk of death by a third among hospitalized patients requiring ventilation.

In their spreadsheets, the numbers around dexamethasone were like a beacon.
“We built CORONA to help uncover something like dexamethasone,” he said. “It’s a cheap repurposed drug that’s been around for 60 years. This is what it’s all about.”

Studies need rigor

Because Covid-19 is so new, many of the studies are observational or anecdotal. These types of studies obviously matter as scientists are building a foundation of knowledge.

But the best insights come from running double-blind placebo-controlled studies. One shortfall is that many of the published studies just don’t have the level of rigor to inform larger-scale scientific decision-making.

“There are a lot of biases in these observational studies,” Fajgenbaum said.
One drug, the anti-malarial drug hydroxychloroquine, has famously received a lot of boosterism from US President Donald Trump. But in the published studies available for Fajgenbaum’s team to review, the drug hasn’t outperformed others.

Two French studies on hydroxychloroquine drew red flags for the University of Pennsylvania-based team because of the clinical end point the researchers chose: the time when the coronavirus cleared the body. It can be problematic to base an argument for a drug’s success only on that particular metric, because it leaves out crucial details from a person’s longer-term experience following infection.

“‘Virally cured’ is a challenging term,” Fajgenbaum said. “We don’t know if they’re discharged how they fared after leaving the hospital.”

On top of that, the reviewers were skeptical because the virus took a long time to leave the patients’ bodies, which they refer to as “a high time to viral clearance.”

That indicator that could suggest the drug was slow to take effect, or that other factors, including the patient’s own immune system, played a larger role in expelling the pathogen.

Know how to sort through the data

With dozens of people working full time to sort through thousands of studies, it’s obviously impossible for a single frontline health provider to keep abreast of all there is to know about Covid-19 while also treating patients at the same time.

It’s even harder for the average person following the story in the news, especially if you’re not equipped with a graduate degree in statistical analysis.

“Covid threw the world in flux,” said Sheila Pierson, associate director for clinical research at the CSTL. A biostatistician originally hired to study Castleman disease, she’s accepted the new mission along with her colleagues.

“There’s a lot of great science being done,” she explained. With that pace of innovation, it’s incredibly difficult for the average person to stay up to date, so the CORONA database helps everyone with a little extra scientific literacy amid headlines about new treatments that induce a form of intellectual whiplash.

“You should rely on multiple news sources,” Pierson said, in order to sort through what may appear to be conflated messages about whether a certain drug works or not for a certain group of people.

“It’s difficult when you’re only looking at one person’s view of a drug,” she said. “Look for a different write-up and a different view.”

He’s repeating the same methods that saved his life

As of June 27, Fajgenbaum has lived free of Castleman’s cytokine storms for 77.72 months. His last Castleman relapse ended on January 5, 2014. He’s a living experiment, and in his personal accounting he won’t round up to the next full month. Each new day is a precious moment with a daughter he feared he’d never meet.

The doctor and researcher remains immune compromised and won’t take risks with the coronavirus.
He hasn’t set foot in a building other than his home since March 13. And his life still relies on siltuximab and chemotherapy infusions administered monthly through a chest port.

“I’m reminded every time I touch the port in my chest of the cytokine storms I had,” he said. “I want so badly to solve (Covid-19) the way I did with Castleman. I have the same sense of urgency.”

Castleman disease nearly killed Fajgenbaum five times in his 20s while he was working his way through University of Pennsylvania’s Perelman School of Medicine and then earning an MBA at the University of Pennsylvania’s Wharton School.

Each time, the deadly disease triggered cytokine storms that led to multiple organ failure.

But the young man created a global organization to rally doctors, scientists and patients toward finding a cure. With intense study and brilliant partners, he zeroed in on an already available immunosupressant that could be repurposed to save his life.

Last year he published his memoir, “Chasing My Cure,” detailing a journey in which at one point a priest was brought to his hospital room to give his last rites.

Fajgenbaum’s story reads likes the teaser for a hit Netflix series. But if it were a show, all of that is really just season one. Because, spoiler alert — then a global pandemic hit.

A year ago you might have thought what the writers threw at him in a second season might be a bit unrealistic. But this project is the obvious next step.

“I see myself bringing our experiences with Castleman now over to the global fight against corona,” he said.

https://www.cnn.com/2020/06/27/health/coronavirus-treatment-fajgenbaum-drug-review-scn-wellness/index.html


Microscopy image of a section through one brain hemisphere of a 101 day- old ARHGAP11B-transgenic marmoset fetus. Cell nuclei are visualized by DAPI (white). Arrows indicate a sulcus and a gyrus. Credit: Heide et al. / MPI-CBG

The expansion of the human brain during evolution, specifically of the neocortex, is linked to cognitive abilities such as reasoning and language. A certain gene called ARHGAP11B that is only found in humans triggers brain stem cells to form more stem cells, a prerequisite for a bigger brain. Past studies have shown that ARHGAP11B, when expressed in mice and ferrets to unphysiologically high levels, causes an expanded neocortex, but its relevance for primate evolution has been unclear.

Researchers at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, together with colleagues at the Central Institute for Experimental Animals (CIEA) in Kawasaki and the Keio University in Tokyo, both located in Japan, now show that this human-specific gene, when expressed to physiological levels, causes an enlarged neocortex in the common marmoset, a New World monkey. This suggests that the ARHGAP11B gene may have caused neocortex expansion during human evolution. The researchers published their findings in the journal Science.

The human neocortex, the evolutionarily youngest part of the cerebral cortex, is about three times bigger than that of the closest human relatives, chimpanzees, and its folding into wrinkles increased during evolution to fit inside the restricted space of the skull. A key question for scientists is how the human neocortex became so big. In a 2015 study, the research group of Wieland Huttner, a founding director of the MPI-CBG, found that under the influence of the human-specific gene ARHGAP11B, mouse embryos produced many more neural progenitor cells and could even undergo folding of their normally unfolded neocortex. The results suggested that the gene ARHGAP11B plays a key role in the evolutionary expansion of the human neocortex.

The rise of the human-specific gene

The human-specific gene ARHGAP11B arose through a partial duplication of the ubiquitous gene ARHGAP11A approximately five million years ago along the evolutionary lineage leading to Neanderthals, Denisovans, and present-day humans, and after this lineage had segregated from that leading to the chimpanzee. In a follow-up study in 2016, the research group of Wieland Huttner uncovered a surprising reason why the ARHGAP11B protein contains a sequence of 47 amino acids that is human-specific, not found in the ARHGAP11A protein, and essential for ARHGAP11B’s ability to increase brain stem cells.

Specifically, a single C-to-G base substitution found in the ARHGAP11B gene leads to the loss of 55 nucleotides from the ARHGAP11B messenger RNA, which causes a shift in the reading frame resulting in the human-specific, functionally critical 47 amino acid sequence. This base substitution probably happened much later than when this gene arose about 5 million years ago, anytime between 1.5 million and 500,000 years ago. Such point mutations are not rare, but in the case of ARHGAP11B its advantages of forming a bigger brain seem to have immediately influenced human evolution.


Wildtype (normal) and ARHGAP11B-transgenic fetal (101 days) marmoset brains. Yellow lines, boundaries of cerebral cortex; white lines, developing cerebellum; arrowheads, folds. Scale bars, 1 mm. Credit: Heide et al. / MPI-CBG

The gene’s effect in monkeys

However, it has been unclear until now if the human-specific gene ARHGAP11B would also cause an enlarged neocortex in non-human primates. To investigate this, the researchers in the group of Wieland Huttner teamed up with Erika Sasaki at the Central Institute for Experimental Animals (CIEA) in Kawasaki and Hideyuki Okano at the Keio University in Tokyo, both located in Japan, who had pioneered the development of a technology to generate transgenic non-human primates. The first author of the study, postdoc Michael Heide, traveled to Japan to work with the colleagues directly on-site.

They generated transgenic common marmosets, a New World monkey, that expressed the human-specific gene ARHGAP11B, which they normally do not have, in the developing neocortex. Japan has similarly high ethical standards and regulations regarding animal research and animal welfare as Germany does. The brains of 101-day-old common marmoset fetuses (50 days before the normal birth date) were obtained in Japan and exported to the MPI-CBG in Dresden for detailed analysis.

Michael Heide explains: “We found indeed that the neocortex of the common marmoset brain was enlarged and the brain surface folded. Its cortical plate was also thicker than normal. Furthermore, we could see increased numbers of basal radial glia progenitors in the outer subventricular zone and increased numbers of upper-layer neurons, the neuron type that increases in primate evolution.” The researchers had now functional evidence that ARHGAP11B causes an expansion of the primate neocortex.

Ethical consideration

Wieland Huttner, who led the study, adds: “We confined our analyses to marmoset fetuses, because we anticipated that the expression of this human-specific gene would affect the neocortex development in the marmoset. In light of potential unforeseeable consequences with regard to postnatal brain function, we considered it a prerequisite—and mandatory from an ethical point of view—to first determine the effects of ARHGAP11B on the development of fetal marmoset neocortex.”

The researchers conclude that these results suggest that the human-specific ARHGAP11B gene may have caused neocortex expansion in the course of human evolution.

More information: “Human-specific ARHGAP11B increases size and folding of primate neocortex in the fetal marmoset” Science (2020). science.sciencemag.org/cgi/doi … 1126/science.abb2401

https://medicalxpress.com/news/2020-06-human-brain-size-gene-triggers.html

by Ruth Williams

By activating a particular pattern of nerve endings in the brain’s olfactory bulb, researchers can make mice smell a non-existent odor, according to a paper published June 18 in Science. Manipulating these activity patterns reveals which aspects are important for odor recognition.

“This study is a beautiful example of the use of synthetic stimuli . . . to probe the workings of the brain in a way that is just not possible currently with natural stimuli,” neuroscientist Venkatesh Murthy of Harvard University who was not involved with the study writes in an email to The Scientist.

A fundamental goal of neuroscience is to understand how a stimulus—a sight, sound, taste, touch, or smell—is interpreted, or perceived, by the brain. While a large number of studies have shown the various ways in which such stimuli activate brain cells, very little is understood about what these activations actually contribute to perception.

In the case of smell, for example, it is well-known that odorous molecules traveling up the nose bind to receptors on cells that then transmit signals along their axons to bundles of nerve endings—glomeruli—in a brain area called the olfactory bulb. A single molecule can cause a whole array of different glomeruli to fire in quick succession, explains neurobiologist Kevin Franks of Duke University who also did not participate in the research. And because these activity patterns “have many different spatial and temporal features,” he says, “it is difficult to know which of those features is actually most relevant [for perception].”

To find out, neuroscientist Dmitry Rinberg of New York University and colleagues bypassed the nose entirely. “The clever part of their approach is to gain direct control of these neurons with light, rather than by sending odors up the animal’s nose,” Caltech neurobiologist Markus Meister, who was not involved in the work, writes in an email to The Scientist.

The team used mice genetically engineered to produce light-sensitive ion channels in their olfactory bulb cells. They then used precisely focused lasers to activate a specific pattern of glomeruli in the region of the bulb closest to the top of the animal’s head, through a surgically implanted window in the skull. The mice were trained to associate this activation pattern with a reward—water, delivered via a lick-tube. The same mice did not associate random activation patterns with the reward, suggesting they had learned to distinguish the reward-associated pattern, or synthetic smell, from others.

Although the activation patterns were not based on any particular odors, they were designed to be as life-like as possible. For example, the glomeruli were activated one after the other within the space of 300 milliseconds from the time at which the mouse sniffed—detected by a sensor. “But, I’ll be honest with you, I have no idea if it stinks [or] it is pleasant” for the mouse, Rinberg says.

Once the mice were thoroughly trained, the team made methodical alterations to the activity pattern—changing the order in which the glomeruli were activated, switching out individual activation sites for alternatives, and changing the timing of the activation relative to the sniff. They tried “hundreds of different combinations,” Rinberg says. He likened it to altering the notes in a tune. “If you change the notes, or the timing of the notes, does the song remain the same?” he asks. That is, would the mice still be able to recognize the induced scent?

From these experiments, a general picture emerged: alterations to the earliest-activated regions caused the most significant impairment to the animal’s ability to recognize the scent. “What they showed is that, even though an odor will [induce] a very complex pattern of activity, really it is just the earliest inputs, the first few glomeruli that are activated that are really important for perception,” says Franks.

Rinberg says he thinks these early glomeruli most likely represent the receptors to which an odorant binds most strongly.

With these insights into the importance of glomeruli firing times for scent recognition, “the obvious next question,” says Franks, is to go deeper into the brain to where the olfactory bulb neurons project and ask, “ How does the cortex make sense of this?”

E. Chong et al., “Manipulating synthetic optogenetic odors reveals the coding logic of olfactory perception,” Science, 368:eaba2357, 2020.

https://www.the-scientist.com/news-opinion/researchers-make-mice-smell-odors-that-arent-really-there-67643?utm_campaign=TS_DAILY%20NEWSLETTER_2020&utm_medium=email&_hsmi=89854591&_hsenc=p2ANqtz–BMhsu532UL56qwtB0yErPYlgoFTIZWsNouvTV9pnT1ikTw6CvyIPyun3rPGdciV29we7ugRVWYc1uuBDh5CN_F-0FzA&utm_content=89854591&utm_source=hs_email


Oleh Hornykiewicz in his Vienna office in 2009 He helped identify low dopamine levels as a cause of Parkinson’s disease, a finding that led to an effective treatment.

Oleh Hornykiewicz, a Polish-born pharmacologist whose breakthrough research on Parkinson’s disease has spared millions of patients the tremors and other physical impairments it can cause, died on May 27 in Vienna. He was 93.

His death was confirmed by his longtime colleague, Professor Stephen J. Kish of the University of Toronto, where Professor Hornykiewicz (pronounced whor-nee-KEE-eh-vitch) taught from 1967 until his retirement in 1992.

Professor Hornykiewicz was among several scientists who were considered instrumental in first identifying a deficiency of the neurotransmitter dopamine as a cause of Parkinson’s disease, and then in perfecting its treatment with L-dopa, an amino acid found in fava beans.

The Nobel laureate Dr. Arvid Carlsson and his colleagues had earlier shown that dopamine played a role in motor function. Drawing on that research, Professor Hornykiewicz and his assistant, Herbert Ehringer, discovered in 1960 that the brains of patients who had died of Parkinson’s had very low levels of dopamine.

He persuaded another one of his collaborators, the neurologist Walther Birkmayer, to inject Parkinson’s patients with L-dopa, the precursor of dopamine, which could cross the barrier between blood vessels and the brain and be converted into dopamine by enzymes in the body, thus replenishing those depleted levels. The treatment alleviated symptoms of the disease, and patients who had been bedridden started walking.

The initial results of this research were published in 1961 and presented at a meeting of the Medical Society of Vienna. The “L-dopa Miracle,” as it was called, inspired Dr. Oliver Sacks’s memoir “Awakenings” (1973) and the fictionalized movie of the same name in 1990.
As a therapy for Parkinson’s, L-dopa was further refined by other scientists, including George C. Cotzias and Melvin D. Yahr. But it was Professor Hornykiewicz, defying colleagues who had argued that post-mortem brain studies were worthless, who is credited with the critical breakthroughs.

His findings spurred the establishment of human brain tissue banks, research into dopamine and treatments of other diseases caused by low levels of neurotransmitters.

“Today, it is generally agreed that the initiation of the treatment of Parkinson’s disease with L-dopa represented one of the triumphs of pharmacology of our time,” Professor Hornykiewicz wrote in “The History of Neuroscience in Autobiography, Volume IV” (2004). “This provided, apart from the benefit to the patients, a stimulus for analogous studies of many other brain disorders, both neurological and psychiatric.”

He received several distinguished awards, including the Wolf Prize in Medicine in 1979 and the Ludwig Wittgenstein Prize of the Austrian Research Foundation in 1993.

In 2000, when Dr. Carlsson, of Sweden, and others were awarded the Nobel Prize in Physiology or Medicine for discovering dopamine and “allowing for the development of drugs for the disease,” as the Nobel committee wrote, more than 200 scientists signed a petition protesting that the prize had not also been awarded to Professor Hornykiewicz.

Oleh Hornykiewicz was born on Nov. 17, 1926, in the village of Sychow, near Lviv, in what was then southeastern Poland and is now western Ukraine. His was a fourth-generation family of Eastern Orthodox Catholic priests. His father, Theophil Hornykiewicz, ministered to the village’s several dozen parishioners and taught religion; his mother, Anna (Sas-Jaworsky) Hornykiewicz, managed the affairs of the village’s 300-year-old wooden church.

When the Soviet Union invaded in 1939, the family fled to Austria, his mother’s ancestral home, with whatever belongings they could carry. Oleh knew no German but learned it by reading Hitler’s “Mein Kampf,” which was readily available in Vienna. He suffered from tuberculosis and, when the war ended, decided to follow his eldest brother and become a doctor.

He received his medical degree from the University of Vienna in 1951 and began his academic and research career in its pharmacology department. He held a British Council Research Scholarship at the University of Oxford from 1956 to 1958. Beginning in 1967, he headed the psychopharmacology department at the Clarke Institute of Psychiatry in Toronto (now the Center for Addiction and Mental Health), where he established the Human Brain Laboratory in 1978.

He was named a full professor of pharmacology and psychiatry at the University of Toronto in 1973 and, in 1976, appointed to head the newly-founded Institute of Biochemical Pharmacology of the University of Vienna. He held both posts concurrently.

He is survived by his daughter, Maria Hentosz; three sons, Nicholas, Stephen and Joseph; six grandchildren; and one great-grandchild. His wife, Christina (Prus-Jablonowski) Hornykiewicz, had died.

“He was a pharmacologist, biochemist and neurologist who wanted to find out how the brain works and how dopamine was involved,” Professor Kish said. “And he wanted to be known also as a philosopher.”

Despite being snubbed by the Nobel committee, Professor Hornykiewicz was philosophical about what he had accomplished and the degree to which it had been credited.

“I am surprised to see that I have achieved everything I could have wished for,” he wrote in 2004. “The support and recognition I received for my work, I have accepted with gratitude, as a charming reminder to do more and better.”

Professor Kish, who heads the Human Brain Laboratory at the University of Toronto’s Centre for Addiction and Mental Health, said L-dopa, or Levodopa, as it is also called, is today “the mainstay treatment for Parkinson’s disease — no drug is more efficacious.”

“Hornykiewicz,” he added, “reminds us that before L-dopa, persons with Parkinson’s disease were bedridden, crowding chronic hospital wards, and the doctors were powerless to do anything. His discovery changed all that —- it was a miracle.”

Oleh Hornykiewicz, Who Discovered Parkinson’s Treatment, Dies at 93