Tuesday, September 27, 2011

Brain Implants are Coming: Can They Repair Stroke Damage?

Recent research on rats at Tel Aviv University is offering hope that we may soon have access to brain implants which could help to bypass damaged areas of brain, and allow relatively normal functioning after stroke and other types of brain damage.
Matti Mintz of Tel Aviv University in Israel and his colleagues have created a synthetic cerebellum which can receive sensory inputs from the brainstem - a region that acts as a conduit for neuronal information from the rest of the body. Their device can interpret these inputs, and send a signal to a different region of the brainstem that prompts motor neurons to execute the appropriate movement.

"It's proof of concept that we can record information from the brain, analyse it in a way similar to the biological network, and return it to the brain," says Mintz, who presented the work this month at the Strategies for Engineered Negligible Senescence meeting in Cambridge, UK.

...The team analysed brainstem signals feeding into a real cerebellum and the output it generated in response. They then used this information to generate a synthetic version on a chip that sits outside the skull and is wired into the brain using electrodes.

To test the chip, they anaesthetised a rat and disabled its cerebellum before hooking up their synthetic version. They then tried to teach the anaesthetised animal a conditioned motor reflex - a blink - by combining an auditory tone with a puff of air on the eye, until the animal blinked on hearing the tone alone. They first tried this without the chip connected, and found the rat was unable to learn the motor reflex. But once the artificial cerebellum was connected, the rat behaved as a normal animal would, learning to connect the sound with the need to blink.

...The next step is to model larger areas of the cerebellum that can learn a sequence of movements and test the chip in a conscious animal - a much greater challenge. "This is very demanding because of the decrease of [neural] signal quality due to artefacts caused by movement," says Robert Prueckl of Guger Technologies in Graz, Austria, who is working with Mintz. He thinks this can be achieved, though, by developing improved software to tune out noise and better techniques for implanting the electrodes. Ultimately, the goal is to build chips that can replicate complex areas of the brain _NewScientist
Yes, the implant used by the researchers was only able to substitute for a small part of the cerebellum -- which is only one part of the brain. Still, it is a start. The challenge is to enlarge and consolidate this understanding of the motor system. Then we can move beyond these early victories to the far more complex and difficult challenges of substituting for more complex signaling that occurs in the cortical and subcortical tissues.

And yet it would be best not to underestimate this achievement. The cerebellum helps to control and coordinate body movement, which is a very important function of being human. Those who have lost the ability to initiate, control, coordinate, and terminate basic movements, understand how important the motor system is to quality of life.

Cyborg brain part replacement is not the end goal, of course. We really want to re-grow any damaged brain parts or nerve connections which have been lost. But cyborg replacements will be an important bridge between where we are now and where we would like to go.

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Thursday, September 15, 2011

IPS Stem Cells Are Looking More Promising for Regenerative Medicine

George Church is a professor of genetics at Harvard Medical School. He is becoming more and more deeply involved in the field of regenerative medicine, using induced pluripotent stem cells (IPS). Church was interviewed recently on how he sees the field of IPS regenerative medicine progressing.
A pioneer in developing DNA sequencing technologies, and in researching everything from epigenetics and microbiomics to synthetic biology, Church has co-founded or advises over 20 companies. He also has launched the Personalized Genome Project with a goal of sequencing the complete genomes of 100,000 volunteers.

When I asked Church what he was most excited about right now, he answered without hesitation: "I'm thinking a lot about using regeneration as the key to treatments and keeping people healthy."

TR: You mean regeneration using stem cells?

Church: Yes, induced pluripotent stem (IPS) cells (see, "Growing Heart Cells Just for You"). This is where I'm putting almost all of my chips these days, because it combines many of my interests--genomics, sequencing, epigenetics, synthetic biology, stem cells. I don't think people have fully appreciated how quickly adult stem cells and sequencing and synthetic biology have progressed. They have progressed by orders of magnitude since we got IPS. Before that, they basically weren't working.

Is this because IPS cells are relatively easy to create and to engineer?

You can use them to reprogram genomes--not sequence them, but to reprogram them genetically and epigenetically. In other words you make the minimum changes it takes to get them where you want them to be genetically and epigenetically and then you program the cells into tissues.

What do you mean?

Let's use stem cells in bone marrow as an example. They are easy to use and to get to work when you implant them in bone marrow. You might one day have three choices. You can have bone marrow from someone else that is matched to you, or that is from you, or bone marrow that is matched to you and comes to you, but is better than you. This better bone marrow might be [engineered to be] resistant to one virus, or to all viruses. It could have a bunch of alleles that you picked out of super centenarians, alleles that you have reason to believe are at least harmless and possibly helpful. So now you have choice, a patient who can take a good bone marrow that he might reject and you'll be on immunosuppressants your whole life. Or you might use your own, or your own that might fix the cancer, or your own enhanced bone marrow. And you will be able to do that for almost every stem cell population. Some of them are a little bit harder to replace, though.

Does IPS really work to accomplish this regeneration?

We have good evidence that you can create an entire mouse from IPS cells.

Has this been done?

This has been done. They have used IPS cells to grow a mouse, and they made IPS cells from that mouse. They're totipotent [able to make an entire organism], not merely pluripotent. We haven't done this for humans for obvious ethical reasons, but we will do it. As far as I know the mice have done fine.

But haven't there been some problems with mutations occurring with IPS-generated tissue?

We have a recent paper in Nature that shows that when you make human induced pluripotent stem cells you actually do get mutations in coding regions at a slightly elevated level. But I think this is temporary. We're going to use this information as an assay to make the process work better, to correct problems. You will be able to use this to improve the quality of gene therapy because that's been the problem with gene therapy the last ten years.

How far are we from testing that in humans?

Almost everything I've described has been done in rodents, so we're talking about years, not decades. It's shorter than the Human Genome Project [which took 13 years], not less expensive, but definitely shorter. _TechnologyReview
Scientists at the University of Toronto have recently made a breakthrough in the control of IPS cells' pluripotency:
Scientists have found a control switch that regulates stem cell “pluripotency,” the capacity of stem cells to develop into any type of cell in the human body. The discovery reveals that pluripotency is regulated by a single event in a process called alternative splicing.

Alternative splicing allows one gene to generate many different genetic messages and protein products. The researchers found that in genetic messages of a gene called FOXP1, the switch was active in embryonic stem cells but silent in “adult” cells—those that had become the specialized cells that comprise organs and perform functions.

“It opens the field to the fact that alternative splicing plays a really important role in stem cell pluripotency,” said Prof. Benjamin Blencowe, principal investigator on the study and a Professor in the University of Toronto’s Departments of Molecular Genetics and Banting and Best Department of Medical Research. “We’re beginning to see an entirely new landscape of regulation, which will be crucial to our understanding of how to produce more effective pluripotent stem cells for therapeutic and research applications.”

The findings were published in the current online edition of the scientific journal Cell. _Source
These are some fascinating developments, which will eventually lead to advanced therapies for diseases which are currently untreatable, such as cancers and end stage degenerative diseases of the heart, lungs, liver, kidneys, and brain.

The ability to grow replacement organs from stem cells is already being proven in animals. The ability to regenerate a badly degenerated organ in situ, using stem cells, is also being proven. According to George Church, stem cells are also the best method for making genetic improvements to organs and organisms.

BioHeart's clinical stem cell trials in Mexico

ThermoGenesis an early commercial entrant into the human stem cell regenerative medicine industry

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Friday, September 02, 2011

Molecular Circuits Learn to Trigger Targeted Cancer Cell Death


An international team of researchers has learned to use micro-RNA circuits to trigger targeted cell death in HeLa cells, widely used cultured cervical cancer cells, orginally taken from a woman who died long ago. Although it is too late for this information to help Henrietta Lacks, it is possible that this approach -- or something like it -- may be used to trigger the large-scale suicide of a wide range of cancer cells eventually.
Xie has developed a genetic “logic circuit” that prompts cells to kill themselves if the levels of five molecules match those of a cancer cell. Yaakov Benenson, who led the study, says, “In the long term, the circuits’ role is to act like miniature surgeons that can identify and destroy cancer cells.” That is a very long way off, but the study is a promising step in the right direction.

Xie worked with HeLa cells, a common line of cervical cancer cells taken from a tobacco farmer called Henrietta Lacks in 1951. Since then, they have become one of the most important tools in modern medicine. Xie identified five small molecules called microRNAs that act as a signature for HeLa cells, separating them from healthy ones. Two of the microRNAs are unusually common in HeLa; three are unusually rare.

Next, Xie created five genetic switches that would only flip if their respective microRNAs were found at the right levels. The switches control a gene called Bax, an executioner that compels a cell to kill itself. If the circuit is introduced into a cell that carries the molecular signature of HeLa, all five switches flip, Bax is roused into action, and the cell automatically self-destructs.

Xie rigged his circuit so that Bax could be restrained by each of the three microRNAs found at low levels in HeLa cells. The gene would only activate if all three molecules were largely absent; any one of them could stay the executioner’s hand. Meanwhile, the two microRNAs that are common in HeLa actually lift restraints on Bax, by blocking genes that keep it in check. Again, the circuit needs high levels of both of these molecules. If either is absent, Bax is held back.

This clever set up means that all five switches must to be flipped before the executioner carries out it bloody work. The cell only dies if it meets every one of five conditions. And Xie found that his circuit worked in practice. It activated Bax at far higher levels in HeLa cells and selectively killed them while leaving other lineages of laboratory cells unharmed. _Discover

Article abstract from Science

More from ArsTechnica

More from ETH Zurich via Nanowerk

Al Fin research oncologists and molecular biologists feel that Benenson's approach is more than a bit awkward and prone to breaking down. But he is working at a level of gene regulation which should prove relatively safe, as it moves closer to clinical research. And he is working at a level of complexity which should prove fertile for learning more about the molecular networks of cancer.

Expect some fascinating developments to come from this line of research.


Thursday, September 01, 2011

Why Do Old Brains Prefer Young Blood?

A paper published today in Nature finds that when younger mice are exposed to the blood of older mice, their brain cells behave more like those found in aging brains, and vice versa. The researchers who carried out the work also uncovered chemical signals in aged blood that can dampen the growth of new brain cells, suggesting that the decline in brain function with age could be caused in part by blood-borne factors rather than an intrinsic failure of brain cells. _TechnologyReview
Many things change in the human body as we age. Our cells lose their ability to repair incidental damage, and produce less and less energy for our ever-less efficient muscles. We produce lower levels of hormones which help us, and higher levels of chemicals that cause inflammation and cellular damage.

It has been found that young blood can reverse certain signs of aging in the circulatory systems of old mice. Now there is evidence that young blood can help rejuvenate old brains.
To arrive at the discovery, the researchers studied pairs of old and young mice that were literally joined at the hip. They used a technique called parabiosis, in which two mice are surgically joined together along the flank, which causes them to develop a shared circulatory system. The technique has been used to study the development of the blood system, and more recently has been used to investigate the effects of age by joining old and young mice.

Lead author Tony Wyss-Coray, a neuroscientist at Stanford University, says that five weeks after creating these May-December pairings, "we found striking effects both on the young and old brains." The young mice had a reduction in the production of new neurons (neurogenesis), an increase in brain inflammation, and less activity in synapses connecting neurons.

The older mice, in contrast, had an increase in new neurons, less inflammation, and greater activity at synapses. "You could almost call this a rejuvenation effect," Wyss-Coray says.

...To see whether the effect could influence behavior, they injected, in separate experiments, young mice with plasma from older mice and vice versa, and found that old plasma impaired the younger animals' ability to perform learning and memory tasks, whereas young plasma improved the abilities of older mice.

Blood cells from one mouse cannot travel into the brain of the other because of the blood-brain barrier, so the team concluded that free-floating molecules in the blood, capable of passing through, must be responsible for the effects. By comparing more than 60 chemokines—chemical messengers secreted by cells that circulate in the blood—the researchers identified several associated with the detrimental effect of old blood. Administering one of these chemicals, called CCL11, to young mice dampened neurogenesis and impaired learning and memory. CCL11 has been studied for its role in allergies and asthma, but it's not clear how it influences neurons. _TechnologyReview
Does this mean that those of us who wish to stay young will have to prey on our young like vampires, sucking their life's blood for our own sustenance? No. For we are learning how to take our old cells and make them young again, in vitro -- in the test tube. The goal is to do the same thing, only better, and in vivo.

Such cellular rejuvenation treatments are likely to excellent stopgap methods of anti-aging, with significant -- but limited -- effects. The lifespans we live will be lived as younger, more vital monkey-men. And that is worth a very great deal.

But if we wish to live significantly longer lives, at significantly higher levels of awareness, intellect, and invention, we will need to go deeper than cellular replacement and humoral replacement therapies of this type.


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