It's neuroscience's final frontier. Tiny bubbles will open the blood-brain barrier to sneak drugs into tumours – and we might treat Alzheimer's the same way KULLERVO HYNYNEN is preparing to cross neuroscience's final frontier. In July he will work with a team of doctors in the first attempt to open the blood-brain barrier in humans – the protective layer around blood vessels that shields our most precious organ against threats from the outside world.
If successful, the method would be a huge step in the treatment of pernicious brain diseases such as cancer, Parkinson's and Alzheimer's, by allowing drugs to pass into the brain.
The blood-brain barrier (BBB) keeps toxins in the bloodstream away from the brain. It consists of a tightly packed layer of endothelial cells that wrap around every blood vessel throughout the brain. It prevents viruses, bacteria and any other toxins passing into the brain, while simultaneously ushering in vital molecules such as glucose via specialised transport mechanisms.
The downside of this is that the BBB also completely blocks the vast majority of drugs. Exceptions include some classes of fat and lipid-soluble chemicals, but these aren't much help as such drugs penetrate every cell in the body – resulting in major side effects.
"Opening the barrier is really of huge importance. It is probably the major limitation for innovative drug development for neurosciences," says Bart De Strooper, co-director of the Leuven Institute for Neuroscience and Disease in Belgium.
Hynynen, a medical physicist at Sunnybrook Research Institute in Toronto, Canada, thinks the answer lies in gas-filled microbubbles. These were discovered accidentally in the 1960s when radiologists noticed that tiny bubbles in blood made ultrasound images clearer. More recently, they have been investigated as a way to help treat hard-to-reach cancers.
Hynynen's trial will involve 10 people with a cancerous brain tumour. First, the volunteers will be given a chemotherapy drug that does not usually cross the BBB. They will then receive an injection of microbubbles, which will spread throughout the body, including into the blood vessels that serve the brain.
Next is a treatment called high-intensity focused ultrasound. The volunteers will wear a cap that contains an array of transducers that direct ultrasound waves into their brain. Just as the sun's rays can be focused by a magnifying glass, ultrasound waves can be concentrated inside the body to get the microbubbles to vibrate.
The vibrating bubbles will expand and contract about 200,000 times a second, which will force apart the endothelial cells that form the BBB. The idea is that this will allow the chemotherapy drug in the bloodstream to sneak through the gaps in the barrier and into any nearby tumour cells.
The ultrasound will be on for a maximum of 2 minutes, during which time it will perforate the BBB in nine sites around each volunteer's tumour. To confirm that this happens, the team will inject a fluorescent marker and watch it move from the blood stream into the tumour using fMRI scans.
Shortly after, the volunteers will have surgery to remove the tumour, which will be sampled to compare the concentration of the chemotherapy drug in areas zapped by ultrasound with those that remained unzapped.
The BBB starts to close almost immediately after the ultrasound is turned off, says Hynynen, and should be back to normal about 6 hours later. Although opening up the BBB to drugs also opens it up to unwanted toxins, animal experiments have shown few side effects and no long-term effects on behaviour or health.
"You're not exposing the brain to any more bacteria than you are when you do open brain surgery," says Hynynen. Importantly, the treatment is non-invasive and painless. "Theoretically, the patients could go straight home," says Hynynen.
"Identifying effective – and most importantly safe and reversible – methods for opening the BBB has been a major goal in the development of neurological treatments for many years," says Eleanor Stride who studies drug delivery at the University of Oxford. "This is very exciting news indeed. If the results can be replicated in people this will be a huge step forward for treating a wide range of diseases."
For example, trastuzumab (sold as Herceptin) is an effective treatment for some breast cancers but it cannot cross the BBB to reach tumours that have metastasised and travelled to the brain, so opening the BBB could help. It could also make it feasible to produce highly tailored drugs for a whole spectrum of brain receptors, says De Strooper, meaning potential treatments for conditions such as schizophrenia or clinical depression.
Alzheimer's would be another possible target. In brain tissue grown in a dish, antibodies that cannot easily cross the BBB have been shown to wipe out the protein plaques that are characteristic of Alzheimer's (Experimental Gerontology, doi.org/s79). "We think trials of these antibodies in humans failed because researchers haven't managed to get a high enough dose into the brain," says Hynynen. "So we hope to try these drugs in humans in the future, maybe as soon as a year, depending on how well this first trial goes."
One stumbling block might be what happens to the drugs once they are in the brain, says Matthew Wood at the University of Oxford, as most drugs won't spread between brain cells unaided. This could mean having to open up the BBB throughout the brain for diseases like Alzheimer's, where the damage is widespread, he says.
Hynynen doesn't envisage this being a big problem. "We have disrupted whole hemispheres in animals without any negative consequences," he says. In Alzheimer's you would most likely target areas which had the largest volume of plaques first – where the impact of the disease is greatest – and eventually zap the whole brain over several sessions. "It's a slow-progressing disease so you have lots of time to divide up the brain into sections, open them up one by one and let each section recover before moving on to the next area," he says.
This article appeared in print under the headline "Breaking and entering" and in "newscientist.com".
Cancer has one less place to hide. A drug that stops tumours camouflaging themselves from the immune system appears to significantly boost survival rates in people with a form of lung cancer that is almost incurable unless removed surgically before it spreads. Some people who received the drug have seen their tumours disappear completely.
Lung cancer is the world's most deadly cancer, killing over 4000 people a day worldwide. Only 15 per cent of those diagnosed survive for five years or more, compared with 89 per cent of those with breast cancer.
Many common cancers evade detection by silencing part of the immune system. Rather than targeting tumours by destroying them through radiation or chemotherapy, it might be possible to treat them by finding ways to reactivate the immune system so it will destroy cancer cells itself.
A drug designed to do this, nivolumab, has now been tested in 129 people for whom other treatments had already failed. The group had non-small cell lung cancer (NSCLC) – the most common form of the disease, accounting for 85 per cent of all cases. Participants received either 1, 3, or 10 milligrams of nivolumab per kilogram of bodyweight daily for up to 96 months.
Waking the immune systemOne way that cancer cells evade the immune system is by interacting with a molecule on the surface of white blood cells called PD-1. Nivolumab blocks PD-1 so tumour cells can't interact with it. This reawakens the immune system, allowing it to attack the cancer.
The two-year survival rate of the group on nivolumab was more than double that in a group given standard therapies. "We found 1 in 4 patients alive at two years, compared with 1 in 10 for conventional chemotherapy," says Michael Giordano, head of oncology development at Bristol-Myers Squibb, the company behind nivolumab.
The results were released this week ahead of the annual meeting of the American Society of Clinical Oncology, which opens in Chicago at the end of May. A larger trial of 500 people is now being organised.
A separate trial involving 20 people hinted at why some with lung cancer respond better to nivolumab than others. Those who had a molecule called PD-L1 present in their tumour were significantly more likely to respond than those without it. "This is an important finding, because there's a significant enrichment in the likelihood of a response if patients are PD-L1 positive," says Giordano.
Melanoma Last year, nivolumab was reported to produce dramatic improvements in people with advanced malignant melanoma . The Chicago meeting will hear of new, encouraging results from melanoma trials: of 107 people treated with nivolumab at least three years ago as a last resort, 48 per cent were alive at 2 years, with 41 per cent still alive after three years. "We've gone from zero survival at three years to 40 per cent," says Giordano. "That's very clear evidence of the value of immune-based therapies."
A combination of nivulomab with another immunotherapy drug, called ipilimumab, also developed by Bristol-Myers Squibb, is also working well in kidney cancer that has spread to other organs.
Nivulomab is not the only PD-1 inhibitor being tested against lung cancer. At the Chicago meeting, the drug company Merck will be presenting new resultsof tests of its drug codenamed MK-347, and Roche will be releasing trial dataon how a similar immunotherapy agent, MPDL3280A, has performed in a trial of people with bladder cancer.
"The data from these studies offer additional evidence that immunotherapymay play an increasingly important role in cancer treatment options," says Maggie Callaghan of the Memorial Sloan Kettering Cancer Center in New York, who was not involved in the research.
"The results add to a growing body of evidence that throwing switches of the immune system can have a profound effect on cancer," says Peter Johnson, chief clinician at Cancer Research UK. He points out that cancer cells can out-evolve and defy drugs targeted at particular mutations, but the immune system can co-evolve and keep pace with the cancer. "If your immune system is working properly, it will follow the tumour round the room," he says.
This article appeared in "newscientist.com".
The secret of how salamanders successfully regrow body parts is being unravelled by researchers in a bid to apply it to humans. For the first time, researchers have found that the 'ERK pathway' must be constantly active for salamander cells to be reprogrammed, and hence able to contribute to the regeneration of different body parts.
For the first time, researchers have found that the 'ERK pathway' must be constantly active for salamander cells to be reprogrammed, and hence able to contribute to the regeneration of different body parts.
The team identified a key difference between the activity of this pathway in salamanders and mammals, which helps us to understand why humans can't regrow limbs and sheds light on how regeneration of human cells can be improved.
The study published in Stem Cell Reports today, demonstrates that the ERK pathway is not fully active in mammalian cells, but when forced to be constantly active, gives the cells more potential for reprogramming and regeneration. This could help researchers better understand diseases and design new therapies.
Lead researcher on the study, Dr Max Yun (UCL Institute of Structural and Molecular Biology) said: "While humans have limited regenerative abilities, other organisms, such as the salamander, are able to regenerate an impressive repertoire of complex structures including parts of their hearts, eyes, spinal cord, tails, and they are the only adult vertebrates able to regenerate full limbs.
We're thrilled to have found a critical molecular pathway, the ERK pathway, that determines whether an adult cell is able to be reprogrammed and help the regeneration processes. Manipulating this mechanism could contribute to therapies directed at enhancing regenerative potential of human cells." The ERK pathway is a way for proteins to communicate a signal from the surface of a cell to the nucleus which contains the cell's genetic material. Further research will focus on understanding how this important pathway is regulated during limb regeneration, and which other molecules are involved in the process.
This article appeared in "sciencedaily".
Physicists are using equations to reveal the hidden complexities of the human body. From the beating of our hearts to the proper functioning of our brains, many systems in nature depend on collections of 'oscillators'; perfectly-coordinated, rhythmic systems working together in flux, like the cardiac muscle cells in the heart.
From the beating of our hearts to the proper functioning of our brains, many systems in nature depend on collections of 'oscillators'; perfectly-coordinated, rhythmic systems working together in flux, like the cardiac muscle cells in the heart.
Unless they act together, not much happens. But when they do, powerful changes occur. Cooperation between neurons results in brain waves and cognition, synchronized contractions of cardiac cells cause the whole heart to contract and pump the blood around the body. Lasers would not function without all the atomic oscillators acting in unison. Soldiers even have to break step when they reach a bridge in case oscillations caused by their marching feet cause the bridge to collapse. But sometimes those oscillations go wrong.
Writing in the journal Nature Communications , scientists at Lancaster University report the possibility of "glassy states" and a "super-relaxation" phenomenon, which might appear in the networks of tiny oscillators within the brain, heart and other oscillating entities.
To uncover these phenomena, they took a new approach to the solution of a set of equations proposed by the Japanese scientist Yoshiki Kuramoto in the 1970s. His theory showed it was possible in principle to predict the properties of a system as a whole from a knowledge of how oscillators interacted with each other on an individual basis.
Therefore, by looking at how the microscopic cardiac muscle cells interact we should be able to deduce whether the heart as a whole organ will contract properly and pump the blood round. Similarly, by looking at how the microscopic neurons in the brain interact, we might be able to understand the origins of whole-brain phenomena like thoughts, or dreams, or amnesia, or epileptic fits.
Physicists Dmytro Iatsenko , Professor Peter McClintock, and Professor Aneta Stefanovska, have reported a far more general solution of the Kuramoto equations than anyone has achieved previously, with some quite unexpected results.
One surprise is that the oscillators can form "glassy" states, where they adjust the tempos of their rhythms but otherwise remain uncoordinated with each other, thus giving birth to some kind of "synchronous disorder" rather like the disordered molecular structure of window glass. Furthermore and even more astonishingly, under certain circumstances the oscillators can behave in a totally independent manner despite being tightly coupled together, the phenomenon the authors call "super-relaxation."
These results raise intriguing questions. For example, what does it mean if the neurons of your brain get into a glassy state?
Dmytro Iatsenko, the PhD student who solved the equations, admitted the results posed more questions than they answered.
"It is not fully clear yet what it might mean if, for example, this happened in the human body, but if the neurons in the brain could get into a "glassy state" there might be some strong connection with states of the mind, or possibly with disease."
Lead scientist Professor Aneta Stefanovska said: "With populations of oscillators, the exact moment when something happens is far more important than the strength of the individual event. This new work reveals exotic changes that can happen to large-scale oscillations as a result of alterations in the relationships between the microscopic oscillators. Because oscillations occur in myriads of systems in nature and engineering, these results have broad applicability."
Professor Peter McClintock said: "The outcome of the work opens doors to many new investigations, and will bring enhanced understanding to several seemingly quite different areas of science."
This article appeared in "sciencedaily".
While young children sleep, connections between the left and the right hemispheres of their brain strengthen, which may help brain functions mature, according to a new study by the University of Colorado Boulder.
The research team -- led by Salome Kurth, a postdoctoral researcher, and Monique LeBourgeois, assistant professor in integrative physiology -- used electroencephalograms, or EEGs, to measure the brain activity of eight sleeping children multiple times at the ages of 2, 3 and 5 years.
"Interestingly, during a night of sleep, connections weakened within hemispheres but strengthened between hemispheres," Kurth said.
Scientists have known that the brain changes drastically during early childhood: New connections are formed, others are removed and a fatty layer called "myelin" forms around nerve fibers in the brain. The growth of myelin strengthens the connections by speeding up the transfer of information.
Maturation of nerve fibers leads to improvement in skills such as language, attention and impulse control. But it is still not clear what role sleep plays in the development of such brain connections.
In the new study, appearing online in the journal Brain Sciences, the researchers looked at differences in brain activity during sleep as the children got older and differences in brain activity of each child over a night's sleep. They found that connections in the brain generally became stronger during sleep as the children aged. They also found that the strength of the connections between the left and right hemispheres increased by as much as 20 percent over a night's sleep.
"There are strong indications that sleep and brain maturation are closely related, but at this time, it is not known how sleep leads to changes in brain structure," Kurth said. "I believe inadequate sleep in childhood may affect the maturation of the brain related to the emergence of developmental or mood disorders," Kurth said.
Future studies will be aimed at determining how sleep disruption during childhood may affect brain development and behavior.
This article appeared in "sciencedaily".
Scientists recently documented how migrating bar-headed geese could fly over the Himalayas at an altitude of up to almost 24,000 feet above sea level. The birds accomplish the feat by timing their trips to coincide with the presence of cooler air, in which it's easier to fly and breathe.
High Fliers Floating and flying above us are not only the usual suspects — birds, bats, insects — but countless microscopic creatures as well. The disciplines of aerobiology and aeroecology explore how animals, plants and other organisms live in, move through and interact with the aerosphere — the part of Earth's atmosphere that supports life.
Mutual Attraction Air as an environment can lead to surprising interactions between living and nonliving things. When positively charged insects fly close to a spiderweb, for example, electrostatic charges cause the web to move toward them to actively capture the hapless fliers.
Spreading Spores Fungi don't leave themselves to the whims of the wind when disseminating the spores they use to reproduce: Mushrooms create their own breeze by releasing moisture with the spores. The water cools the air, creating a tiny convection current.
Fast Food An average North American purple martin eats about 20,000 insects each year, with the whole species devouring about 412 billion bugs per year.
Mental Map Observing big brown bats as they repeatedly fly through a room filled with obstacles, researchers have concluded the bats create a mental map that helps them navigate a familiar area.
Wing Nuts Alpine swifts, which soar over Europe and Africa, are truly at home in the aerosphere. Surviving largely on insects, these birds can stay aloft for nearly seven months at a time.
Sky High Bacteria have been found thriving 4 to 6 miles above Earth's surface. The microbes can ride the wind from continent to continent.
Beeline More experienced bumblebees fly farther, faster and straighter when searching for food than naïve ones, which tend to fly in loops as they learn the best search strategy.
This Article appeared in "discovermagazine".
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