Entries in Neurodegenerative Disorders (4)

Thursday
Jul072016

YOUNG BLOOD REJUVENATES OUR CELLS

 

 

IT SOUNDS like the dark plot of a vampire movie – Young blood rejuvenates our cells. In October 2014, people with Alzheimer’s disease started to be injected with the blood of young people in the hope that it will reverse some of the damage caused by that condition. But holds promise for individuals suffering for a wide range issues that have impacted their body and effected the quality of their life style. Just imagine the implications of reversing Traumatic Brain Injuries, Parkinson’s, MS, ALS, Repairing Damaged Organs, Surgical Healing, Aging of Skin, Muscle and Vascular Development.

In the first human trial of the effects of young blood, at Stanford University, infusions of blood plasma from young people are being given to older people. The preliminary results have surprised the research team, since it appears that young blood rejuvenates all of the cells within the recipients’ bodies are showing marked improvement.

 

The scientists behind the experiment have evidence on their side that young blood rejuvenates. Work in animals has shown that a transfusion of young mouse blood can improve cognition and the health of several organs in older mice. It could even make those animals look younger. The ramifications for the cosmetics and pharmaceutical industries could be huge, if the same thing happens in people.

The study was published in Nature Medicine in 2014. Immediately, emails flooded in to Wyss-Coray’s inbox. Alzheimer’s patients wanted infusions of young blood. So did numerous aged billionaires interested in the potential that young blood rejuvenates. One, who flies around in a jet with his name emblazoned on the side, invited Wyss-Coray to an Oscars after-party this year. (He didn’t go.) Another correspondent wrote with a more disturbing offer: he said he could provide blood from children of whatever age the scientists required. Wyss-Coray was appalled. “That was creepy,” he said.

But it wasn’t until spring 2012 that plans to form a company emerged. Nikolich, an entrepreneur and neuroscientist at Stanford, had flown to Hong Kong to visit the family of Chen Din-hwa, a Chinese billionaire known as the King of Cotton Yarn. Three years earlier, Chen had died, aged 89, with Alzheimer’s disease. His grandson told Nikolich that towards the end of his life, Chen barely recognised his own family. Then he had a plasma transfusion for an unrelated condition, which seemed to have a spectacular effect. His mind was clearer and he was suddenly cogent. His grandson indicated that Alzheimer’s disease seem to historical effect the male of the family often at an early age.

Nikolich told them about Wyss-Coray’s research and the potential for plasma-based therapies that revitalised the ageing brain. Before long, the conversation turned to starting a company. The family invested a year later. The money got Alkahest established and ready to launch the first human trial of young plasma.

Alkahest’s ultimate goal – to identify the key proteins in plasma that rejuvenate or age human tissues and then manufacture a product that uses them – could take 10 to 15 years. In the near term, the company has another strategy. Earlier this year, the Spanish blood products firm,Grifols, pledged $37.5m for a 45% stake in Alkahest. With another $12.5m, the company will bankroll more research in exchange for rights to Alkahest’s first products. Over the next two years, Alkahest will take human plasma and divide it into fractions that are rich in different proteins. Each fraction will then be tested in mice to see if they boost brain function. Any that do will be swiftly introduced into human trials and developed into the first generation of products.

The Alkahest trial is small. Sha, a specialist in behavioral neurology, can enroll only 18 people aged 50 to 90 with mild to moderate Alzheimer’s disease. Each receives a unit of young human plasma or saline once a week for four weeks. They have the next six weeks off, then have four more weeks of infusions. Those who had plasma first time around get saline and vice versa. The process is blinded, so neither the patients, nor their carers, nor Sha herself, know who is receiving what. Throughout the trial, doctors will look for cognitive improvements. Only at the end of the trial, as soon as October this year, will Sha analyse the findings.

If patients improve with infusions of young plasma, scientists will be ecstatic. But the finding, indicating that young blood rejuvenates, would need to be replicated, ideally at other hospitals, and in more patients, in order to convince researchers. If any benefits stand the test of time, the studies will move on, to tease out the best doses and ages at which to give plasma, how patients’ brains change, and whether improvements make a real difference to the life of someone who can no longer recognize their own family.

Then there is safety. Toying with the ageing process might backfire. Rando is concerned that pumping pro-youthful proteins into people for years could end up giving them cancer. Wyss-Coray agrees it is a worry, but points out that long-term growth hormone therapy appears to be safe. “We just don’t know yet whether or not it will be a problem,” he said.

Rando is more upbeat about infusing patients with pro-youthful proteins for short periods. An elderly person having surgery might get an infusion to help them heal like a teenager. “Let’s say it works. If you can target tissues and improve wound healing in older people, that would be a feasible approach. It would not be about making 90-year-olds younger, or having people live to 150. It’s about healthy living, not longer living,” he said.

In the first human trial of the effects of young blood, at Stanford University, infusions of blood plasma from young people are being given to older people. The preliminary results have surprised the research team, since it appears that all of the cells within the recipients’ bodies are showing marked improvement.

In some countries, there is already a legal market for blood plasma. In the wake of the BSE crisis of the 1990s, plasma donations are not used in the UK. But in the US, donors can make $200 a month (plus loyalty points) from plasma donations. The fresh plasma is separated from the blood, and the red blood cells returned to the bloodstream, in a sitting that lasts 90 minutes. The plasma is used in medical procedures, to treat coagulation disorders and immune deficiencies. The business is completely legitimate, but if young blood rejuvenates our cells is proved to have anti-ageing effects, the risk of backstreet operators setting up will soar. When I asked Wyss-Coray if the prospect worried him, he looked serious. “Absolutely,” he said. “There are always going to be nutcases.”

These are worst-case scenarios. The Stanford trial may find that simply injecting young plasma into old people has little or no effect. Wyss-Coray confesses that he suspects as much. He believes that rejuvenating older people might take a more potent brew than natural plasma. He has in mind a concentrated blend of 10 or 20 pro-youthful factors from young blood, mixed with antibodies that neutralise the effects of ageing factors found in old blood.

“As we get older, we have fewer stem cells and newly born neurons in our brains, and our learning and memory are affected,” says Villeda. “It’s not ddementia it’s just the natural degeneration associated with age.”

 

Amy Wagers emphasizes that no one has convincingly shown that young blood lengthens lives, and there is no promise that it will. Still, she says that young blood, or factors from it, may hold promise for helping elderly people to heal after surgery, or treating diseases of ageing.

Young mice blood has been studied to cause repair of age related damage such as cardiac hypertrophy, muscle dysfunction, demyelination processes and brain vasculature system in old mice. The mouse is the most common model organism for preclinical studies even though it has not proven particularly reliable at predicting the outcome of studies in humans.

Wyss-Coray one of the authors of the study mentioned in the question is a part of board of directors of a biotechnology start-up named Alkahest to explore the therapeutic implications of the mice findings in humans. The young mice blood treatment has been shown to have effects in old mice neural dysfunctions such as

1. Cardiac hypertrophy: Loffredo et.al. have concluded that treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging in 2013.

2. Muscle dysfunction: GDF11 systemically regulates muscle aging and may be therapeutically useful for reversing age-related skeletal muscle and stem cell dysfunction per conclusions of Sinha M et.al. in 2014.

3. Reversal of demyelination processes: Ruckh JM et.al. in 2012 concluded that enhanced remyelinating (Remyelination is a term for the re-generation of the nerve’s myelin sheath, damaged in many diseases) activity requires both youthful monocytes and other factors, and that remyelination-enhancing therapies targeting endogenous cells can be effective throughout life.

4. Improvement of brain vasculature system: Katsimpardi L et.al. in 2014 concluded that GDF11 alone can improve the cerebral vasculature and enhance neurogenesis. Studies in mice and Xenopus suggest that this protein is involved in mesodermal formation and neurogenesis during embryonic development. Research shows that there could be multiple forms of GDF11

Sources:

http://www.nature.com/news/ageing-research-blood-to-blood-1.16762

http://randolab.stanford.edu/

http://glennlaboratories.stanford.edu/

http://www.nature.com/news/blood-hormone-restores-youthful-hearts-to-old-mice-1.12971

http://www.bizjournals.com/sanfrancisco/print-edition/2014/01/31/conboy-uc-berkeley-aging-research.html

http://www.bizjournals.com/sanfrancisco/blog/biotech/2014/05/young-blood-stanford-researchers-hope-plasma.html

http://www.bizjournals.com/sanfrancisco/print-edition/2014/01/31/aging-calico-levinson-buck-institute.html

http://www.nytimes.com/2014/05/05/science/young-blood-may-hold-key-to-reversing-aging.html?_r=0

https://www.ucsf.edu/news/2014/01/122211/blood-work-scientists-uncover-surprising-new-tools-rejuvenate-brain

https://www.newscientist.com/article/mg22329831-400-young-blood-to-be-used-in-ultimate-rejuvenation-trial/

http://www.theguardian.com/science/2015/aug/04/can-we-reverse-ageing-process-young-blood-older-people

 

PD Dr. med. Rainer Arendt
FMH Cardiology, Internal Medicine
Regenerative Medicine 

SWISS  PREVENTION  CLINIC
Klausstrasse 10
CH-8008 ZURICH
T +41 43 336 7260
M +41 78 825 0803
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rainer.arendt@swisspreventionclinic.ch

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Thursday
Jul072016

Can we reverse the ageing process by putting young blood into older people?

A series of experiments has produced incredible results by giving young blood to old mice. Now the findings are being tested on humans. Ian Sample meets the scientists whose research could transform our lives

On an August morning in 2008, Tony Wyss-Coray sat in a conference room at the Veterans Affairs hospital in Palo Alto, California, waiting for his lab’s weekly meeting to begin. Wyss-Coray, a professor of neurology at Stanford University, was leading a young group of researchers who studied ageing and neurodegeneration. As a rule, the gatherings were forgettable affairs – the incremental nature of scientific progress does not lend itself to big surprises. But a lab member scheduled to speak that day had taken on a radical project, and he had new results to share.

Saul Villeda, an ebullient PhD student with slick black hair and a goatee, had spent the past year engrossed in research that called to mind the speculative medical science of the middle ages. He was investigating whether the old and frail could be rejuvenated by infusions of blood from the young. The hypothesis was not as absurd as it might sound.

Villeda’s work took skill. A mouse brain is the size of a peanut. To remove one for inspection is not difficult, but Villeda then had to cut each brain into wafers 1/25th of a millimetre thick using a cryomicrotome, a machine that resembles a benchtop deli slicer. Villeda took multiple slivers from about 40 mice and then stained them with a dye that binds to newborn neurons. Under a microscope the baby brain cells stand out like little brown trees.

The day before the lab meeting, Villeda and his colleague Kurt Lucin arrived early for work. With a small paintbrush, Villeda swept each brain slice, one after another, onto a microscope slide, and counted the tiny brown tree shapes. It took hours: he had about 200 slivers to inspect, from old and young mice. After totting up the newborn neurons in each section, he tapped the number into a statistics program. He finished after 10pm.

Though it was late, Villeda made Lucin stay with him to crunch the numbers. “It had been such a long experiment. I thought, if it doesn’t work, he’s here. We can go and grab a drink,” Villeda told me recently. He clicked a button on the screen marked “analyse”. The statistics program took all the data and calculated the average number of newborn neurons in the brains of each group of mice. A moment later, bar charts popped up on the screen.

Villeda got three hours’ sleep that night. The next morning, he stood up at the lab meeting and revealed to his colleagues what young blood did to the ageing brain. “There was a palpable electricity in the room,” Wyss-Coray recalled. “I remember seeing the images for the first time and saying, ‘Wow.’” Old mice that received young blood experienced a burst of brain cell growth in the hippocampus. They had three to four times as many newborn neurons as their counterparts. But that was not all: old blood had the opposite effect on the brains of young mice, stalling the birth of new neurons and leaving them looking old before their time.

 

Old mice that received young blood experienced a burst of brain cell growth in the hippocampus

 

The other scientists in the room were stunned. Some were sceptical. Could it be real? “This could be big,” said Wyss-Coray. “If an old mouse starts to make more neurons when you give it young blood? That is amazing.”

Since that meeting seven years ago, research on this topic has moved on dramatically. It has led some to speculate that in young blood might lie an antidote to the ravages of old age. But the apparent rejuvenating properties of young blood must be treated with healthy scepticism. The hopes they raise rest solely on mouse studies. No beneficial effects have ever been proven in humans. Then again, no one has ever looked.

That is about to change. In October 2014, Wyss-Coray launched the first human trial of young blood. At Stanford School of Medicine, infusions of blood plasma from young people are being given to older people with Alzheimer’s disease. The results are expected at the end of the year. It is the greatest test yet for the medical potential of young blood.

* * *

For much of history, people sought to halt ageing to achieve immortality – or at least to live for hundreds of years. These days, scientists tend to have more modest aims. In wealthy nations, basic healthcare and medical advances have driven up lifespan for the past century. Five years from now, for the first time in human history, there will be more over-60s than children under five years old. In 2050, two billion people will be 60 or older, nearly double the number today.

Behind that statistic lies a serious problem. People are living longer, but they are not necessarily living better. The old struggle with chronic conditions, often many at once: cancer, respiratory disease, heart disease, diabetes, arthritis, osteoporosis, dementia.

Blood plasma.

 

 

In the first human trial of the effects of young blood, at Stanford University, infusions of blood plasma from young people are being given to older people. Photograph: Ralf Hirschberger/dpa/Corbis

Medical researchers tend to tackle these diseases separately. After all, the illnesses are distinct: cancer arises from mutated DNA; heart disease from clogged up blood vessels; dementia from damaged brain cells. The biological processes that underpin the pathologies vary enormously. Each, then, needs its own treatment. Yet some researchers take another view: the greatest driver of disease in old age is old age itself. So why not invent treatments for ageing?

The idea has caught on, though it is still far from mainstream. Google’s secretive Calico operation, founded in 2013, is putting hundreds of millions of dollars into anti-ageing researchCraig Venter, the genetics entrepreneur, has launched a company called Human Longevity to find the genes that lead to long life. Meanwhile, scientists have asked the US Food and Drug Administration to approve trials of well-known drugs, such as the diabetes treatment, metformin, in the hope of uncovering anti-ageing effects.

 

People are living longer, but they are not necessarily living better. The old struggle with chronic conditions

 

Scientists may never halt the process entirely: ageing is an opaque and complex mingle of molecular pathways. But they might learn how to stop changes that underpin the worst chronic diseases. They want to extend healthspan, not lifespan. The stakes are enormous. Over the next decade, the cost of dementia care in Britain alone will rise to £24bn, a 60% increase on the cost in 2007. Last year, the World Health Organisation called the rise in chronic illness due to the greying population a major public health challenge.

Wyss-Coray is not the first person to wonder whether the answer to the problem of ageing might lie in human blood. One of the first physicians to propose blood transfusions to rejuvenate older people was Andreas Libavius, a German doctor and alchemist. In 1615 he proposed connecting the arteries of an old man to those of a young man. He had high hopes for the procedure. “The hot and spirituous blood of the young man will pour into the old one as if it were from a fountain of youth, and all of his weakness will be dispelled,” he claimed, in an account told in the Textbook of Bloodbanking and Transfusion Medicine by Sally Rudmann. It is unclear how it turned out; there is no record of the transfusion happening.

 

The fledgling years of the Royal Society, founded in London in 1660, witnessed some of the earliest experiments in blood transfusion. When Robert Boyle, one of the society’s founders, compiled a wishlist of scientific projects, the top entry was “The prolongation of life”. That might be achieved, he hoped, by replacing old blood with new.

Progress in science takes more than hope. With no knowledge of blood groups or coagulation factors, the early transfusion experiments were deadly. Before long, the procedure was banned, first in France, and then England. The pope endorsed the bans in 1679, and transfusion all but ceased for a century. When advances in medicine allowed its return, the emphasis was on healing the sick, not helping the aged.

It is 400 years since Libavius proposed that young blood could rejuvenate older people. At the time, the idea was radical and dangerous. Even though modern science has made blood transfusions safe, blood remains a mysterious fluid: it ferries more than 700 proteins and other substances around our bodies; many are known, but what they do is less clear. Wyss-Coray suspects that among them are factors that orchestrate the ageing process. If scientists can understand how they work, the ageing process might be laid bare. It could be slowed down, or perhaps even reversed.

* * *

When Wyss-Coray was in his 20s and 30s, he did not much care about ageing. “You have no understanding of what the problems are,” he recently told me, in his soft Swiss-German accent. Sitting in his office at the Veterans Affairs hospital, surrounded by books on immunology and biology, Wyss-Coray was fashionably unshaven, with a crop of blonde hair and lively blue eyes framed by dark rimmed glasses. “Now I see that the brain starts to slow down. I’m not as quick any more at grasping things, or remembering faces. I used to see a person for a few minutes and I’d remember their face. I couldn’t understand how they’d not remember who I was. And now it happens to me. It annoys the crap out of me.”

For Wyss-Coray, ageing has become much more than a personal bugbear. In 2014, the prestigious US journal, Science, named his work on young blood one of its breakthroughs of the year. He is regularly invited to give talks at conferences and the world’s top universities; in January, he spoke at the World Economic Forum in Davos. “In almost every talk I give, people make comments or jokes about vampires.” He slumped back in his chair and groaned. Another question also crops up: “I have people asking me, ‘Are you taking young blood?’” He assured me that he was not, and screwed up his face in horror, but it’s easy to see why they ask; he looks much younger than his 50 years.

Tony Wyss-Coray.

 Tony Wyss-Coray is a professor of neurology at Stanford university Photograph: Tony Wyss-Coray

Wyss-Coray was the first in his family to go to university. From the start, he set his sights on a career in the US. In 1993, he began as a postdoctoral fellow at the well-regarded Scripps Research Institute in La Jolla, California, studying HIV-related dementia. The work led to Alzheimer’s research, focusing on how the immune system played a role in the disease. In 2002, he joined Stanford University’s medical school, where he remains a faculty member.

Much of Wyss-Coray’s research on Alzheimer’s used mice that were genetically modified to develop the disease. This kind of experimentation has major limitations. Alzheimer’s mice mimic the forms of disease that run in families because of specific mutations, but they cannot tell us much about the origins of the sporadic forms of Alzheimer’s, which account for 99% of human cases. “People always joke: if you’re a mouse and you have Alzheimer’s, we can cure you, no problem,” Wyss-Coray told me. For humans, however, nothing so far has worked.

Frustrated by the limitations of his experiments, Wyss-Coray looked for better ways to understand how the disease first arose in humans. Brain scans and cognitive tests were out – neither revealed anything about disease at the molecular level. Nor would it make sense to study the brains of the dead, as scientists had traditionally done: the subtle neurological changes that lead to Alzheimer’s are set in motion two or three decades before patients are diagnosed, which meant old brains told you how bad the rot got, but not how the rot got started.

Wyss-Coray wondered if blood might hold the answer. Human blood travels 96,000 kilometres along the arteries, veins and capillaries of the circulatory system. It circulates through every organ. What if blood picked up information as it streamed around the body? What if its molecular makeup reflected the state of the brain, as it aged and changed with disease?

He assembled an international team of two dozen scientists to test the idea. They analysed blood plasma from more than 200 Alzheimer’s patients, and compared the profiles with those from healthy people. The findings, published in 2007, made headlines around the world. By measuring the levels of certain proteins in plasma, Wyss-Coray’s team believed they had found an accurate way to diagnose Alzheimer’s years before it began to take its toll. Wyss-Coray set up Satoris, a private company, to commercialise the research.

The study was too good to be true. Wyss-Coray’s later efforts to develop the test showed it was unreliable. In the course of this work, however, he had come across something intriguing. He noticed that in healthy people, the levels of certain proteins in blood fell with age. By 20 years old, most had already dropped steeply. Meanwhile, the levels of other proteins ramped up. Some doubled or tripled in old age. What the changes meant, no one knew.

* * *

One floor up from Wyss-Coray’s lab is the office of Thomas Rando, a neurologist and deputy director of the Stanford Center on Longevity. On his desk sits a small display of chemistry lab glassware and dozens of miniature figurines of the New York Giants. It was Rando who hired Wyss-Coray in 2002. “Tony is incredibly creative,” Rando told me. “He thinks about neuroscience in the context of the whole organism, as opposed to someone who has tunnel vision of the brain.”

In 2005, Rando oversaw a series of important experiments that would become closely intertwined with Wyss-Coray’s work. The question Rando wanted to investigate centred on stem cells. The body’s tissues need stem cells to remain healthy and in good working order, but in older people, stem cells stop doing their job – this is why wounds heal so much slower as we age. Rando wondered whether stem cells failed in old animals because they no longer got the right signals. What if something in young blood turned them back on again? Perhaps he could make older people heal as fast as young ones.

Rando’s experiments involved an unsettling but remarkable procedure in which mice were cut along the flanks and sewn together, wound-on-wound. This procedure, pioneered by the 19th-century French physiologist Paul Bert, is known as parabiosis. Bert’s work on conjoined rats demonstrated that, once their wounds had healed, the animals developed a single, shared circulatory system.

For a long time, experiments involving parabiosis were gruesome. In 1956, Clive McCay, an American gerontologist at Cornell University who was pursuing a similar line of research to Wyss-Coray, described his own attempts to conjoin rats in the Bulletin of the New York Academy of Medicine. “If the two rats are not adjusted to each other,” he wrote, “one will chew the head of the other until it is destroyed.” Grim though it was, McCay’s work hinted that young blood might have rejuvenating properties.

Though other scientists took up McCay’s experiments and got similarly encouraging results, the work was effectively abandoned in the 1970s. Not knowing what to make of their findings, researchers moved on to other projects. Only when parabiosis was resurrected at Stanford did scientists start to make sense of the anti-ageing effects.

 

Parabiosis is different today: ethics committees are strict and the surgical procedure has improved. The animals are genetically matched, so there is no risk of immune rejection. Once they have recovered from the operation, paired animals tend to eat normally and to make nests together. But the procedure is still disturbing – it would be a stretch to call the animals happy.

Scientists in Rando’s lab joined old and young mice for five weeks and looked at how well they repaired little tears in muscle tissue. The young blood activated stem cells in the old mice that swiftly regenerated their damaged muscles. The young mice, however, fared worse for their exposure to old blood. Their stem cells became sluggish, and their tissues healed more slowly. Rando saw hints of another effect too, but needed more evidence before he could publish: the old mice had begun to grow new brain cells.

The results led Wyss-Coray and Rando to collaborate. The kinds of proteins Wyss-Coray had seen rise and fall in blood were known to have effects on biological processes. What if they had driven the changes Rando had seen in muscle? Might they similarly revitalise the brain? Rather than being mere signatures of age, the proteins might be chemical cues for the ageing process itself.

Saul Villeda

 

 

Saul Villeda carried out the early research on the restorative properties of young blood. Photograph: Saul Villeda

Wyss-Coray asked his PhD student Saul Villeda to investigate. Villeda grew up in Pasadena on the outskirts of Los Angeles. His parents had immigrated illegally from Guatemala in the 1970s, and took jobs in factories, or as janitors. They became legal residents when Saul was a boy. Villeda had not planned on being a scientist when he went to college at the University of California in LA. But he enjoyed physiology classes: “I instantly fell in love with research,” he told me. “The idea that you were investigating something completely new and that you could come up with your own experiments to figure things out was amazing.” When he told his parents he wanted to be a university scientist, they didn’t really know what he meant. “I took them to my undergraduate lab to show them what a scientist looked like,” he said. “I think that really helped them understand.”

After Villeda presented his work on conjoined mice to Wyss-Coray at the lab meeting in August 2008, he went on to look at proteins in old and young blood. He found that the old mice, like old humans, had high levels of a protein called CCL11 in their blood. If you injected CCL11 into young mice, their learning and memory declined. The protein hampered the growth of new neurons. The young mice struggled to remember the location of a hidden platform in a water maze, and took longer to recognise a place where they had received a small but unpleasant electric shock. Villeda published the landmark research in 2011.

But the study failed to answer a major question: could proteins in young blood restore the mental capacities that old animals lost? Testing this was by no means easy. A mouse’s wits can be examined in a water maze, but two mice sewn together? It would be impossible to know how much one had led the other. Wyss-Coray believed that rather than experimenting with conjoined mice, the only option was to take blood from young mice, strip out the blood cells, and inject the plasma into old ones. This, too, was difficult. One mouse yields about 200 microlitres of plasma, the yellowish fluid that contains all the proteins. That is enough for two injections into another mouse. For an experiment that requires 10 injections into 10 old mice, you need to siphon the blood from 50 young mice.

Villeda was reluctant to do the experiment. He didn’t think it would work. But he changed his mind when he performed electrical measurements on slices of brain tissue and found that exposure to young blood strengthened the connections between neurons that had weakened in old mice. He went ahead with the plasma injections. Each mouse had one injection every three days for 24 days. The plasma came from three-month-old mice, the equivalent of human beings in their 20s, and went into 18-month-old mice, the equivalent of a human in their 60s.

The results were dramatic. Old mice given young plasma jabs aced the water-maze test, and quickly remembered the cage where they had earlier received an electric shock. They performed like mice half their age. “That time, I showed Tony the data one-on-one,” Villeda told me. “I was freaking out. I said: ‘I have to see this again.’”

Not everyone was impressed. The journal Nature rejected the study in 2012; its reviewers felt the work was not a big enough leap forward. So Wyss-Coray and Villeda sent it along to a sister publication, Nature Medicine. The editors there wanted to know precisely how young blood helped old mice. Villeda, who had just opened his own lab at the University of California in San Francisco, said he would find out.

A microscopic view of a plasma cell inside a blood vessel.

 

A microscopic view of a plasma cell inside a blood vessel. Photograph: Alamy

Villeda looked at how young blood altered the way genes are expressed in old mice. He noticed a stark difference among genes that help neural connections strengthen and weaken, a process crucial for learning and memory. In normal ageing, the genes that control this “synaptic plasticity” become less active. Young plasma jabs ramped the gene activity back up again.

From the pattern of genes affected, Villeda traced the mechanism back to a master regulator in the brain, a protein known as CREB, which behaves like a switch that turns on many genes at once, and is instrumental in memory and learning from birth. To confirm young plasma was working through CREB, Villeda’s PhD student Kristopher Plambeck designed a virus that turned the master regulator off. When they injected the virus into old mice, young plasma had a much reduced effect on their brains. The animals performed better, but only slightly. It showed that young plasma worked through CREB, though not exclusively.

The study was published in Nature Medicine in 2014. Immediately, emails flooded in to Wyss-Coray’s inbox. Alzheimer’s patients wanted infusions of young blood. So did numerous aged billionaires. One, who flies around in a jet with his name emblazoned on the side, invited Wyss-Coray to an Oscars after-party this year. (He didn’t go.) Another correspondent wrote with a more disturbing offer: he said he could provide blood from children of whatever age the scientists required. Wyss-Coray was appalled. “That was creepy,” he said. 

Wyss-Coray and Villeda were not the only scientists making headway in this area. Two members of the team behind Rando’s 2005 paper on stem cells had moved to the University of California, Berkeley, where they found that oxytocin, often called the love hormone, rejuvenated old muscle tissue. Another, Amy Wagers, had begun working at Harvard. She showed that when given young plasma, old mice regained their stamina. On a treadmill, the treated mice ran for an hour on average, compared with only 35 minutes for untreated ones.

Wagers picked out one factor, known as GDF11, as a rejuvenating protein in young blood. In Villeda’s most recent paper, published in July 2015, he found a second factor, B2M, which peaks in the blood of old mice, as it does in old humans: when injected into young mice, B2M impairs their memories.

The studies all point in one direction. Among the hundreds of substances found in blood are proteins that keep tissues youthful, and proteins that make them more aged. Wyss-Coray has a hypothesis: when we are born, our blood is awash with proteins that help our tissues grow and heal. In adulthood, the levels of these proteins plummet. The tissues that secrete them might produce less because they get old and wear out, or the levels might be suppressed by an active genetic programme. Either way, as these pro-youthful proteins vanish from the blood, tissues around the body start to deteriorate. The body responds by releasing pro-inflammatory proteins, which build up in the blood, causing chronic inflammation that damages cells and accelerates ageing.

“This opens an entirely new field. It tells us that the age of an organism, or an organ like the brain, is not written in stone. It is malleable. You can move it in one direction or the other,” says Wyss-Coray. “It’s almost mythological that something in young organisms can maintain youthfulness, and it’s probably true.”

* * *

As a business proposition, the transfusion of young blood raises all kinds of fears. It raises the spectre of a macabre black market, where teenagers bleed for the highest bidder, and young children go missing from the streets. Then there is the danger of unscrupulous dealers selling fake plasma, or plasma unsafe for human infusion. The fears are not unfounded: health has become one of the most lucrative sectors for criminals and con artists.

Havocscope, an online database, tracks the latest prices of all manner of black market goods and services. For $600 you can buy an AK-47 in Europe. A rhino-horn dagger will cost you $14,000. The services of a group of former military snipers? That will be $800,000. The list includes human organs too, mostly lungs, kidneys and livers. Today, a healthy seller can expect about $5,000 for their kidney. The organ broker who handles the deal can make a hefty profit, selling it on for $150,000 to a wealthy patient who needs a transplant.

In some countries, there is already a legal market for blood plasma. In the wake of the BSE crisis of the 1990s, plasma donations are not used in the UK. But in the US, donors can make $200 a month (plus loyalty points) from plasma donations. The fresh plasma is separated from the blood, and the red blood cells returned to the bloodstream, in a sitting that lasts 90 minutes. The plasma is used in medical procedures, to treat coagulation disorders and immune deficiencies. The business is completely legitimate, but if young plasma is proved to have anti-ageing effects, the risk of backstreet operators setting up will soar. When I asked Wyss-Coray if the prospect worried him, he looked serious. “Absolutely,” he said. “There are always going to be nutcases.”

 

The transfusion of young blood raises the spectre of a macabre black market where teenagers bleed for the highest bidder

 

These are worst-case scenarios. The Stanford trial may find that simply injecting young plasma into old people has little or no effect. Wyss-Coray confesses that he suspects as much. He believes that rejuvenating older people might take a more potent brew than natural plasma. He has in mind a concentrated blend of 10 or 20 pro-youthful factors from young blood, mixed with antibodies that neutralise the effects of ageing factors found in old blood.

In January 2014, Wyss-Coray set up Alkahest, a company that aims to separate plasma into its constituent parts, and combine them into a potent, rejuvenating cocktail. In Silicon Valley, scientists frequently launch start-up companies on the back of early-stage research – an alignment of the commercial and the scientific that some researchers still frown upon.  Sergio Della Sala, a professor of human cognitive neuroscience at the University of Edinburgh, warns that creating a business before the science is done can raise a conflict of interest. “Science should first understand then sell,” he said. “We should always be skeptical when these two factors are reversed.”

Wyss-Coray formed Alkahest with Karoly Nikolich, an entrepreneur and neuroscientist at Stanford, who immigrated to the US from Hungary in the 1970s. I met Nikolich at his office in Menlo Park in February. He has thin hair, a full grey moustache and a mind filled with stories. Sat at a table on the sun-drenched roof terrace, Nikolich, handed me an Alkahest business card. The company logo is a blue droplet. Inside it is a golden disc.

Karoly Nikolich.

 Karoly Nikolich, co-founder with Tony Wyss-Coray of Alkahest, the company trying to identify the key proteins in plasma that rejuvenate or age human tissues. Photograph: Karoly Nikolich

Nikolich got to know Wyss-Coray in 2005. He had taken on the job of executive director of the Neuroscience Institute at Stanford University and over the years, Nikolich kept tabs on Wyss-Coray’s progress – from the Alzheimer’s blood test to the rejuvenating properties of young blood. But it wasn’t until spring 2012 that plans to form a company emerged. Nikolich had flown to Hong Kong to visit the family of Chen Din-hwa, a Chinese billionaire known as the King of Cotton Yarn. Three years earlier, Chen had died, aged 89, with Alzheimer’s disease. His grandson told Nikolich that towards the end of his life, Chen barely recognised his own family. Then he had a plasma transfusion for an unrelated condition, which seemed to have a spectacular effect. His mind was clearer. He was suddenly cogent.

Nikolich told them about Wyss-Coray’s research and the potential for plasma-based therapies that revitalised the ageing brain. Before long, the conversation turned to starting a company. The family invested a year later. The money got Alkahest established and ready to launch the first human trial of young plasma.

Alkahest’s ultimate goal – to identify the key proteins in plasma that rejuvenate or age human tissues and then manufacture a product that uses them – could take 10 to 15 years. In the near term, the company has another strategy. Earlier this year, the Spanish blood products firm, Grifols, pledged $37.5m for a 45% stake in Alkahest. With another $12.5m, the company will bankroll more research in exchange for rights to Alkahest’s first products. Over the next two years, Alkahest will take human plasma and divide it into fractions that are rich in different proteins. Each fraction will then be tested in mice to see if they boost brain function. Any that do will be swiftly introduced into human trials and developed into the first generation of products.

And what then? One enormous obstacle for hopes of plasma therapy is the limited supply. In a rough extrapolation from the mouse studies, Nikolich estimates that the globe’s entire plasma supply would be sufficient for only half a million of the world’s 15 million Alzheimer’s patients. “That means big questions about who gets treatment and who does not,” he said.

* * *

A short drive from the Palo Alto Veterans Affairs hospital is Stanford University’s School of Medicine, where the Alkahest trial is running. The woman in charge of the trial is Sharon Sha, a specialist in behavioural neurology who spends much of her time with patients who have Alzheimer’s. When I visited in February, Sha, a cheery woman with dark shoulder-length hair, was running late for a meeting in her third-floor office. But she was delayed for good reason: she had been infusing young plasma into an Alzheimer’s patient enrolled on the trial – a procedure that cannot be rushed.

The Alkahest trial is small. Sha can enrol only 18 people aged 50 to 90 with mild to moderate Alzheimer’s disease. Each receives a unit of young human plasma or saline once a week for four weeks. They have the next six weeks off, then have four more weeks of infusions. Those who had plasma first time around get saline and vice versa. The process is blinded, so neither the patients, nor their carers, nor Sha herself, know who is receiving what. Throughout the trial, doctors will look for cognitive improvements. Only at the end of the trial, as soon as October this year, will Sha analyse the findings.

Sharon Sha.

 

Sharon Sha is in charge of the blood plasma trial at Stanford University’s School of Medicine. Photograph: Sharon Sha

Big questions lie ahead. Even if none of the patients benefit from young plasma, the research is far from finished. The plasma for the trial comes from donors under 30, and it may not be potent enough. The patients on the trial have dementia already, and may be too far gone to rescue.

Earlier this year, John Hardy of University College London, who is the most cited Alzheimer’s researcher in Britain, saw Wyss-Coray’s latest data at a meeting in London. “It’s really interesting work,” he told me. “It’s woken everybody up.” Nonetheless, Hardy is cautious; he suspects that young plasma will be less effective in people than in mice, because people live so much longer, and in far more varied environments. But, he said: “I would guess this will still point us towards pathways involved in ageing more generally.”

If patients improve with infusions of young plasma, scientists will be ecstatic. But the finding would need to be replicated, ideally at other hospitals, and in more patients, in order to convince researchers. If any benefits stand the test of time, the studies will move on, to tease out the best doses and ages at which to give plasma, how patients’ brains change, and whether improvements make a real difference to the life of someone who can no longer recognise their own family.

Then there is safety. Toying with the ageing process might backfire. Rando is concerned that pumping pro-youthful proteins into people for years could end up giving them cancer. Wyss-Coray agrees it is a worry, but points out that long-term growth hormone therapy appears to be safe. “We just don’t know yet whether or not it will be a problem,” he said.

Rando is more upbeat about infusing patients with pro-youthful proteins for short periods. An elderly person having surgery might get an infusion to help them heal like a teenager. “Let’s say it works. If you can target tissues and improve wound healing in older people, that would be a feasible approach. It would not be about making 90-year-olds younger, or having people live to 150. It’s about healthy living, not longer living,” he said.

In the 20 years that Wyss-Coray has lived in the US, his attitude to ageing has swung from disinterest to fascination. Why does a mouse live for three years and a human for 80? He sees its effects on a personal level too. He gets frustrated when a word fails to come as quickly as it once did, but knows how much worse it must be for people noticing the early signs of dementia: their words and memories slipping away into the gloom.

The carers of the patients enrolled in the young-blood trial keep journals to record how well the patients are doing. Among their pages may be signs of hope, that perhaps in the days after an infusion, a patient does a little bit better. “If it actually works? That would be huge. Every patient would want it,” Wyss-Coray said. He smiled. “I’d probably have to turn off my email and go somewhere else.”

 

PD Dr. med. Rainer Arendt
FMH Cardiology, Internal Medicine
Regenerative Medicine 

SWISS  PREVENTION  CLINIC
Klausstrasse 10
CH-8008 ZURICH
T +41 43 336 7260
M +41 78 825 0803
F +41 43 336 7261

rainer.arendt@swisspreventionclinic.ch

www.swisspreventionclinic.ch
www.patientcircle.org

 

Thursday
Jul072016

How young blood might reverse aging. Yes, really

Based on Tony Wyss-Coray’s TED lecture of Aug. 2015

 

 

The famous Fountain of Youth. If you drink its water or you bathe in it, you will get health and youth. Every culture, every civilization has dreamed of finding eternal youth. There are people like Alexander the Great or Ponce De León, the explorer, who spent much of their life chasing the Fountain of Youth. They didn't find it. But what if there was something to it? What if there was something to this Fountain of Youth?

I will share an absolutely amazing development in aging research that could revolutionize the way we think about aging and how we may treat age-related diseases in the future. It started with experiments that showed, in a recent number of studies about growing, that animals -- old mice -- that share a blood supply with young mice can get rejuvenated. What Tom Rando, a stem-cell researcher, reported in 2007, was that old muscle from a mouse can be rejuvenated if it's exposed to young blood through common circulation. This was reproduced by Amy Wagers at Harvard a few years later, and others then showed that similar rejuvenating effects could be observed in the pancreas, the liver and the heart. But what I'm most excited about, and several other labs as well, is that this may even apply to the brain.

So, what we found is that an old mouse exposed to a young environment in this model called parabiosis, shows a younger brain -- and a brain that functions better. And I repeat: an old mouse that gets young blood through shared circulation looks younger and functions younger in its brain. So when we get older -- we can look at different aspects of human cognition, and you can see on this slide here, we can look at reasoning, verbal ability and so forth. And up to around age 50 or 60, these functions are all intact, and as I look at the young audience here in the room, we're all still fine.

But it's scary to see how all these curves go south. And as we get older, diseases such as Alzheimer's and others may develop. We know that with age, the connections between neurons -- the way neurons talk to each other, the synapses -- they start to deteriorate; neurons die, the brain starts to shrink, and there's an increased susceptibility for these neurodegenerative diseases.

One big problem we have -- to try to understand how this really works at a very molecular mechanistic level -- is that we can't study the brains in detail, in living people. We can do cognitive tests, we can do imaging --all kinds of sophisticated testing. But we usually have to wait until the person dies to get the brain and look at how it really changed through age or in a disease. This is what neuropathologists do, for example. So, how about we think of the brain as being part of the larger organism. Could we potentially understand more about what happens in the brain at the molecular level if we see the brain as part of the entire body? So if the body ages or gets sick, does that affect the brain? And vice versa: as the brain gets older, does that influence the rest of the body? And what connects all the different tissues in the body is blood. Blood is the tissue that not only carries cells that transport oxygen, for example, the red blood cells, or fights infectious diseases, but it also carries messenger molecules, hormone-like factors that transport information from one cell to another, from one tissue to another, including the brain. So if we look at how the blood changes in disease or age, can we learn something about the brain? We know that as we get older, the blood changes as well, so these hormone-like factors change as we get older. And by and large, factors that we know are required for the development of tissues, for the maintenance of tissues -- they start to decrease as we get older, while factors involved in repair, in injury and in inflammation -- they increase as we get older.

So there's this unbalance of good and bad factors, if you will. And to illustrate what we can do potentially with that, I want to talk you through an experiment that we did. We had almost 300 blood samples from healthy human beings 20 to 89 years of age, and we measured over 100 of these communication factors, these hormone-like proteins that transport information between tissues. And what we noticed first is that between the youngest and the oldest group, about half the factors changed significantly. So our body lives in a very different environment as we get older, when it comes to these factors. And using statistical or bioinformatics programs, we could try to discover those factors that best predict age -- in a way, back-calculate the relative age of a person. And the way this looks is shown in this graph. So, on the one axis you see the actual age a person lived, the chronological age. So, how many years they lived.

And then we take these top factors that I showed you, and we calculate their relative age, their biological age. And what you see is that there is a pretty good correlation, so we can pretty well predict the relative age of a person. But what's really exciting are the outliers, as they so often are in life. You can see here, the person I highlighted with the green dot is about 70 years of age but seems to have a biological age, if what we're doing here is really true, of only about 45. So is this a person that actually looks much younger than their age? But more importantly: Is this a person who is maybe at a reduced risk to develop an age-related disease and will have a long life -- will live to 100 or more? On the other hand, the person here, highlighted with the red dot, is not even 40, but has a biological age of 65. Is this a person at an increased risk of developing an age-related disease? So in our lab, we're trying to understand these factors better, and many other groups are trying to understand, what are the true aging factors, and can we learn something about them to possibly predict age-related diseases?

So what I've shown you so far is simply correlational, right? You can just say, "Well, these factors change with age," but you don't really know if they do something about aging. So what I'm going to show you now is very remarkable and it suggests that these factors can actually modulate the age of a tissue. And that's where we come back to this model called parabiosis.

 

So, parabiosis is done in mice by surgically connecting the two mice together, and that leads then to a shared blood system, where we can now ask, "How does the old brain get influenced by exposure to the young blood?" And for this purpose, we use young mice that are an equivalency of 20-year-old people, and old mice that are roughly 65 years old in human years.

What we found is quite remarkable. We find there are more neural stem cells that make new neurons in these old brains. There's an increased activity of the synapses, the connections between neurons. There are more genes expressed that are known to be involved in the formation of new memories. And there's less of this bad inflammation. But we observed that there are no cells entering the brains of these animals. So when we connect them, there are actually no cells going into the old brain, in this model. Instead, we've reasoned, then, that it must be the soluble factors, so we could collect simply the soluble fraction of blood which is called plasma, and inject either young plasma or old plasma into these mice, and we could reproduce these rejuvenating effects, but what we could also do now is we could do memory tests with mice.

As mice get older, like us humans, they have memory problems. It's just harder to detect them, but I'll show you in a minute how we do that. But we wanted to take this one step further, one step closer to potentially being relevant to humans. What I'm showing you now are unpublished studies, where we used human plasma, young human plasma, and as a control, saline, and injected it into old mice, and asked, can we again rejuvenate these old mice? Can we make them smarter?

And to do this, we used a test. It's called a Barnes maze. This is a big table that has lots of holes in it, and there are guide marks around it, and there's a bright light, as on this stage here. The mice hate this and they try to escape, and find the single hole that you see pointed at with an arrow, where a tube is mounted underneath where they can escape and feel comfortable in a dark hole. So we teach them, over several days, to find this space on these cues in the space, and you can compare this for humans, to finding your car in a parking lot after a busy day of shopping.

So, let's look at an old mouse here. This is an old mouse that has memory problems, as you'll notice in a moment. It just looks into every hole, but it didn't form this spacial map that would remind it where it was in the previous trial or the last day. In stark contrast, this mouse here is a sibling of the same age, but it was treated with young human plasma for three weeks, with small injections every three days. And as you noticed, it almost looks around, "Where am I?" -- and then walks straight to that hole and escapes. So, it could remember where that hole was.

So by all means, this old mouse seems to be rejuvenated -- it functions more like a younger mouse. And it also suggests that there is something not only in young mouse plasma, but in young human plasma that has the capacity to help this old brain. So to summarize, we find the old mouse, and its brain in particular, are malleable. They're not set in stone; we can actually change them. It can be rejuvenated. Young blood factors can reverse aging, and what I didn't show you -- in this model, the young mouse actually suffers from exposure to the old. So there are old-blood factors that can accelerate aging. And most importantly, humans may have similar factors, because we can take young human blood and have a similar effect. Old human blood, I didn't show you, does not have this effect; it does not make the mice younger.

So, is this magic transferable to humans? We're running a small clinical study at Stanford, where we treat Alzheimer's patients with mild disease with a pint of plasma from young volunteers, 20-year-olds, and do this once a week for four weeks, and then we look at their brains with imaging. We test them cognitively, and we ask their caregivers for daily activities of living. What we hope is that there are some signs of improvement from this treatment. And if that's the case, that could give us hope that what I showed you works in mice might also work in humans.

Now, I don't think we will live forever. But maybe we discovered that the Fountain of Youth is actually within us, and it has just dried out. And if we can turn it back on a little bit, maybe we can find the factors that are mediating these effects, we can produce these factors synthetically and we can treat diseases of aging, such as Alzheimer's disease or other dementias.



PD Dr. med. Rainer Arendt
FMH Cardiology, Internal Medicine
Regenerative Medicine 

SWISS  PREVENTION  CLINIC
Klausstrasse 10
CH-8008 ZURICH
T +41 43 336 7260
M +41 78 825 0803
F +41 43 336 7261

rainer.arendt@swisspreventionclinic.ch

www.swisspreventionclinic.ch
www.patientcircle.org

Monday
Jun292015

Can the Bacteria in Your Gut Explain Your Mood?

The Dolder Grand
Health & Rejuvenation

PD Dr. Rainer Arendt
Internal Medicine & Cardiology FMH
Prevention & Regenerative Medicine


We offer gut microbiome exchange (transplantation) as novel opportunity in prevention and treatment of various and so far difficult to treat ailments (auto-immune diseases, metabolic disorders, neuro-psychiatric diseases and addictions, cardiovascular disease, endocrine disorders and infertility, cancer).

 

It is the rich array of microbiota in our intestines that makes us the human beings we are and preserves our health.

 

Since 2007, when scientists announced plans for a Human Microbiome Project to catalog the micro-organisms living in our body, the profound appreciation for the influence of such organisms has grown rapidly with each passing year. Bacteria in the gut produce vitamins and break down our food; their presence or absence has been linked to obesity, inflammatory bowel disease and the toxic side effects of prescription drugs. Biologists now believe that much of what makes us human depends on microbial activity. The two million unique bacterial genes found in each human microbiome can make the 23,000 genes in our cells seem paltry, almost negligible, by comparison. ‘‘It has enormous implications for the sense of self,’’ Tom Insel, the director of the National Institute of Mental Health, told me. ‘‘We are, at least from the standpoint of DNA, more microbial than human. That’s a phenomenal insight and one that we have to take seriously when we think about human development.’’

Given the extent to which bacteria are now understood to influence human physiology, it is hardly surprising that scientists have turned their attention to how bacteria might affect the brain. Micro-organisms in our gut secrete a profound number of chemicals, and researchers have found that among those chemicals are the same substances used by our neurons to communicate and regulate mood, like dopamine, serotonin and gamma-aminobutyric acid (GABA). These, in turn, appear to play a function in intestinal disorders, which coincide with high levels of major depression and anxiety. Last year, for example, a group in Norway examined feces from 55 people and found certain bacteria were more likely to be associated with depressive patients.

Anxiety, depression and several pediatric disorders, including autism and hyperactivity, have been linked with gastrointestinal abnormalities. Microbial transplants can be performed safely, it is not invasive brain surgery, and that is the point: Changing a patient’s bacteria can be done, altering his genes is still far away.

When Mark Lyte from the Texas Tech University Health Sciences Center campus in Abilene, Tex., as one of the first, began his work on the link between microbes and the brain three decades ago, it was dismissed as a curiosity. By contrast, last September, the National Institute of Mental Health awarded four grants worth up to $1 million each to spur new research on the gut microbiome’s role in mental disorders, affirming the legitimacy of a field that had long struggled to attract serious scientific credibility. Lyte and one of his longtime colleagues, Christopher Coe, at the Harlow primate lab, received one of the four. ‘‘What Mark proposed going back almost 25 years now has come to fruition,’’ Coe told me. ‘‘Now what we’re struggling to do is to figure out the logic of it.’’ It seems plausible that we might use microbes to diagnose neurodevelopmental disorders, treat mental illnesses and perhaps even fix them in the brain.

In 2011, a team of researchers at University College Cork, in Ireland, and McMaster University, in Ontario, published a study in Proceedings of the National Academy of Science that has become one of the best-known experiments linking bacteria in the gut to the brain. Laboratory mice were dropped into tall, cylindrical columns of water in what is known as a forced-swim test, which measures over six minutes how long the mice swim before they realize that they can neither touch the bottom nor climb out, and instead collapse into a forlorn float. Researchers use the amount of time a mouse floats as a way to measure what they call ‘‘behavioral despair.’’ (Antidepressant drugs, like Zoloft and Prozac, were initially tested using this forced-swim test.)

For several weeks, the team, led by John Cryan, the neuroscientist who designed the study, fed a small group of healthy rodents a broth infused with Lactobacillus rhamnosus, a common bacterium that is found in humans and also used to ferment milk into probiotic yogurt. Lactobacilli are one of the dominant organisms babies ingest as they pass through the birth canal. Recent studies have shown that mice stressed during pregnancy pass on lowered levels of the bacterium to their pups. This type of bacteria is known to release immense quantities of GABA; as an inhibitory neurotransmitter, GABA calms nervous activity, which explains why the most common anti-anxiety drugs, like Valium and Xanax, work by targeting GABA receptors.

Cryan found that the mice that had been fed the bacteria-laden broth kept swimming longer and spent less time in a state of immobilized woe. ‘‘They behaved as if they were on Prozac,’’ he said. ‘‘They were more chilled out and more relaxed.’’ The results suggested that the bacteria were somehow altering the neural chemistry of mice.

Until he joined his colleagues at Cork 10 years ago, Cryan thought about microbiology in terms of pathology: the neurological damage created by diseases like syphilis or H.I.V. ‘‘There are certain fields that just don’t seem to interact well,’’ he said. ‘‘Microbiology and neuroscience, as whole disciplines, don’t tend to have had much interaction, largely because the brain is somewhat protected.’’ He was referring to the fact that the brain is anatomically isolated, guarded by a blood-brain barrier that allows nutrients in but keeps out pathogens and inflammation, the immune system’s typical response to germs. Cryan’s study added to the growing evidence that signals from beneficial bacteria nonetheless find a way through the barrier. Somehow — though his 2011 paper could not pinpoint exactly how — micro-organisms in the gut tickle a sensory nerve ending in the fingerlike protrusion lining the intestine and carry that electrical impulse up the vagus nerve and into the deep-brain structures thought to be responsible for elemental emotions like anxiety. Soon after that, Cryan and a co-author, Ted Dinan, published a theory paper in Biological Psychiatry calling these potentially mind-altering microbes ‘‘psychobiotics.’’

It has long been known that much of our supply of neurochemicals — an estimated 50 percent of the dopamine, for example, and a vast majority of the serotonin — originate in the intestine, where these chemical signals regulate appetite, feelings of fullness and digestion. But only in recent years has mainstream psychiatric research given serious consideration to the role microbes might play in creating those chemicals. Lyte’s own interest in the question dates back to his time as a postdoctoral fellow at the University of Pittsburgh in 1985, when he found himself immersed in an emerging field with an unwieldy name: psychoneuroimmunology, or PNI, for short. The central theory, quite controversial at the time, suggested that stress worsened disease by suppressing our immune system.

By 1990, at a lab in Mankato, Minn., Lyte distilled the theory into three words, which he wrote on a chalkboard in his office: Stress->Immune->Disease. In the course of several experiments, he homed in on a paradox. When he dropped an intruder mouse in the cage of an animal that lived alone, the intruder ramped up its immune system — a boost, he suspected, intended to fight off germ-ridden bites or scratches. Surprisingly, though, this did not stop infections. It instead had the opposite effect: Stressed animals got sick. Lyte walked up to the board and scratched a line through the word ‘‘Immune.’’ Stress, he suspected, directly affected the bacterial bugs that caused infections.

To test how micro-organisms reacted to stress, he filled petri plates with a bovine-serum-based medium and laced the dishes with a strain of bacterium. In some, he dropped norepinephrine, a neurochemical that mammals produce when stressed. The next day, he snapped a Polaroid. The results were visible and obvious: The control plates were nearly barren, but those with the norepinephrine bloomed with bacteria that filigreed in frostlike patterns. Bacteria clearly responded to stress.

Then, to see if bacteria could induce stress, Lyte fed white mice a liquid solution of Campylobacter jejuni, a bacterium that can cause food poisoning in humans but generally doesn’t prompt an immune response in mice. To the trained eye, his treated mice were as healthy as the controls. But when he ran them through a plexiglass maze raised several feet above the lab floor, the bacteria-fed mice were less likely to venture out on the high, unprotected ledges of the maze. In human terms, they seemed anxious. Without the bacteria, they walked the narrow, elevated planks.

Each of these results was fascinating, but Lyte had a difficult time finding microbiology journals that would publish either. ‘‘It was so anathema to them,’’ he told me. When the mouse study finally appeared in the journal Physiology & Behavior in 1998, it garnered little attention. And yet as Stephen Collins, a gastroenterologist at McMaster University, told me, those first papers contained the seeds of an entire new field of research. ‘‘Mark showed, quite clearly, in elegant studies that are not often cited, that introducing a pathological bacterium into the gut will cause a change in behavior.’’

Lyte went on to show how stressful conditions for newborn cattle worsened deadly E. coli infections. In another experiment, he fed mice lean ground hamburger that appeared to improve memory and learning — a conceptual proof that by changing diet, he could change gut microbes and change behavior. After accumulating nearly a decade’s worth of evidence, in July 2008, he flew to Washington to present his research. He was a finalist for the National Institutes of Health’s Pioneer Award, a $2.5 million grant for so-called blue-sky biomedical research. Finally, it seemed, his time had come. When he got up to speak, Lyte described a dialogue between the bacterial organ and our central nervous system. At the two-minute mark, a prominent scientist in the audience did a spit take.

‘‘Dr. Lyte,’’ he later asked at a question-and-answer session, ‘‘if what you’re saying is right, then why is it when we give antibiotics to patients to kill bacteria, they are not running around crazy on the wards?’’

Can antibiotics given prior to surgery increase chances of depression after surgery? I know a person who suffered severe depression after...

Lyte knew it was a dismissive question. And when he lost out on the grant, it confirmed to him that the scientific community was still unwilling to imagine that any part of our neural circuitry could be influenced by single-celled organisms. Lyte published his theory in Medical Hypotheses, a low-ranking journal that served as a forum for unconventional ideas. The response, predictably, was underwhelming. ‘‘I had people call me crazy,’’ he said.

But by 2011 — when he published a second theory paper in Bioessays, proposing that probiotic bacteria could be tailored to treat specific psychological diseases — the scientific community had become much more receptive to the idea. A Canadian team, led by Stephen Collins, had demonstrated that antibiotics could be linked to less cautious behavior in mice, and only a few months before Lyte, Sven Pettersson, a microbiologist at the Karolinska Institute in Stockholm, published a landmark paper in Proceedings of the National Academy of Science that showed that mice raised without microbes spent far more time running around outside than healthy mice in a control group; without the microbes, the mice showed less apparent anxiety and were more daring. In Ireland, Cryan published his forced-swim-test study on psychobiotics. There was now a groundswell of new research. In short order, an implausible idea had become a hypothesis in need of serious validation.

Late last year, Sarkis Mazmanian, a microbiologist at the California Institute of Technology, gave a presentation at the Society for Neuroscience, ‘‘Gut Microbes and the Brain: Paradigm Shift in Neuroscience.’’ Someone had inadvertently dropped a question mark from the end, so the speculation appeared to be a definitive statement of fact. But if anyone has a chance of delivering on that promise, it’s Mazmanian, whose research has moved beyond the basic neurochemicals to focus on a broader class of molecules called metabolites: small, equally druglike chemicals that are produced by micro-organisms. Using high-powered computational tools, he also hopes to move beyond the suggestive correlations that have typified psychobiotic research to date, and instead make decisive discoveries about the mechanisms by which microbes affect brain function.

Two years ago, Mazmanian published a study in the journal Cell with Elaine Hsiao, then a graduate student in the lab of Paul Patterson, another author of the study, and now a neuroscientist at Caltech, that made a provocative link between a single molecule and behavior. Their research found that mice exhibiting abnormal communication and repetitive behaviors, like obsessively burying marbles, were mollified when they were given one of two strains of the bacterium Bacteroides fragilis.

The study added to a working hypothesis in the field that microbes don’t just affect the permeability of the barrier around the brain but also influence the intestinal lining, which normally prevents certain bacteria from leaking out and others from getting in. When the intestinal barrier was compromised in his model, normally ‘‘beneficial’’ bacteria and the toxins they produce seeped into the bloodstream and raised the possibility they could slip past the blood-brain barrier. As one of his colleagues, Michael Fischbach, a microbiologist at the University of California, San Francisco, said: ‘‘The scientific community has a way of remaining skeptical until every last arrow has been drawn, until the entire picture is colored in. Other scientists drew the pencil outlines, and Sarkis is filling in a lot of the color.’’

Mazmanian knew the results offered only a provisional explanation for why restrictive diets and antibacterial treatments seemed to help some children with autism: Altering the microbial composition might be changing the permeability of the intestine. ‘‘The larger concept is, and this is pure speculation: Is a disease like autism really a disease of the brain or maybe a disease of the gut or some other aspect of physiology?’’ Mazmanian said. For any disease in which such a link could be proved, he saw a future in drugs derived from these small molecules found inside microbes. In his view, the prescriptive solutions probably involve more than increasing our exposure to environmental microbes in soil, dogs or even fermented foods; he believed there were wholesale failures in the way we shared our microbes and inoculated children with these bacteria. So far, though, the only conclusion he could draw was that disorders once thought to be conditions of the brain might be symptoms of microbial disruptions, and it was the careful defining of these disruptions that promised to be helpful in the coming decades.

The list of potential treatments incubating in labs around the world is startling. Several international groups have found that psychobiotics had subtle yet perceptible effects in healthy volunteers in a battery of brain-scanning and psychological tests. Another team in Arizona recently finished an open trial on fecal transplants in children with autism. (Simultaneously, at least two offshore clinics, in Australia and England, began offering fecal microbiota treatments to treat neurological disorders, like multiple sclerosis.) Mazmanian: ‘‘We’ve reached the stage where there’s a lot of, you know, ‘The microbiome is the cure for everything,’ ’’ he said. ‘‘I have a vested interest if it does. But I’d be shocked if it did.’’

 

Excerpted from Peter Andrey Smith, a reporter living in Brooklyn. He frequently writes about the microbial world.

Reporting for his New York Times' article was supported by the UC Berkeley-11th Hour Food and Farming Journalism Fellowship.

PD Dr. med. Rainer Arendt
FMH Cardiology, Internal Medicine
Regenerative Medicine 

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