Can Lost Neurons Be Replaced?

Neurons

The human brain is a biological wonder with considerable skills. Regeneration, unfortunately, isn?t one of them.

Save for one tiny V shaped region within the hippocampus, the human brain?s ability to rebuild itself is limited. When neurons die, there?s no backup reserve of cells to replace them. Brain trauma such as a blow to the head, a stroke, or neurodegeneration can be brutally final. You?re not getting lost neurons back.

An obvious solution is to supply a broken brain with additional neurons, like swapping a broken stick of RAM with a new one. But a single neuron forms thousands of intricate connections to others near and far, and often these connections are established early in development.

Can a foreign transplant really assimilate into mature neuronal networks after injury and automatically repair broken circuitry? According to a new study recently published in Nature, the answer is a promising yes.

In mice with brain lesions, a German team showed that within two months of transplantation, foreign embryonic neurons matured and fully incorporated into an existing network within the hosts? visual brain region.

Amazingly, the adoptee neurons were nearly indistinguishable from the brain?s native ones and they carried the right information, established functional input and output circuitries, and performed the functions of the damaged neurons.

“To date, this is the most comprehensive study of the circuit integration of transplanted neurons into the adult brain, and the only study so far to follow the integration of individual cells throughout their life span in the new host,” says study author Susanna Falkner, a PhD student at the Max Planck Institute of Neurobiology to Singularity Hub.

It?s a tour de force demonstration of brain plasticity that gives hope to cell transplantation therapies for devastating brain disorders like traumatic brain injury, Parkinson?s and Alzheimer?s disease.

Cell transplantation studies are nothing new, but almost all previous studies used infant animals rather than adults as hosts.

“Early postnatal brains are still developing and thus are much more plastic and receptive for grafts,” explains Falkner.

Although a handful of attempts at grafting stem cells into adult mice brains have been published, so far no one has convincingly demonstrated that the grafts could mature and function in a foreign brain.

To start off, the team used a powerful laser to precisely damage a small bit of brain tissue within a mouse?s visual cortex.

The scientists picked the brain region with care. “We know so much about the functions of the nerve cells in this region and the connections between them that we can readily assess whether the implanted nerve cells actually perform the tasks normally carried out by the network, ” explains study author Dr. Mark H?bener.

They then isolated immature neurons from the outermost layer of mice embryos and labeled them with a fluorescent protein tag. Under the microscope, these tags light up in brilliant reds and greens, which makes the transplanted cells easily distinguishable from the host?s native neurons. Using a long, thin needle, the embryonic neurons were then injected straight into the damaged mouse cortex.

The team next carefully crafted a “cranial window” by removing parts of the skull above the injection site and fitting it with a clear glass panel. This way, scientists were able to observe individual neurons for long periods of time through the window without harming the delicate cortex or risking infection.

Over the course of just a month, the transplanted neurons sprouted long, tortuous branches characteristic of cortical neurons. Tiny mushroom shaped structures called spines popped up on the neurons? output wires (dendrites), a process often seen in normal brain development. Since synapses grow on these bulbous spines, this suggested that the transplants were actively forming connections with other neurons in the brain.

One month after transplantation, the team mapped the newly added neurons? connections of which brain regions they projected to and which regions they received information from. Not only was the wiring exquisitely accurate, with some extending across the entire brain, the strengths of those connections were also similar to those formed by the laser ablated neurons.

“The very fact that the cells survived and continued to develop was very encouraging,” says H?bener. “But things got really exciting when we took a closer look at the electrical activity of the transplanted cells.”

Neurons from a part of the visual cortex called V1 are very picky about what sorts of stimuli they respond to. For example, a neuron may only fire when it detects black and white lines presented at a 45 degree angle, but not at any other angles. This is called tuning, which develops early in life. Promiscuous V1 neurons are bad news without selective activation, they pump noise into the circuit.

By 15 weeks after transplantation, the new neurons adopted the functional quirks of V1 neurons, consistently responding more strongly towards certain line orientations than others. They remained fully functional for the entire year long duration of the study.

“These findings demonstrate that the implanted nerve cells have integrated with high precision into a neuronal network into which, under normal conditions, new nerve cells would never have been incorporated,” explains lead author Dr. Magdalena Gotz at the Ludwig Maximilians University in Munich, Germany.

So what does this mean for repairing a degenerating human brain?

“This proof of principle study shows that?the lesioned adult brain is still capable of integrating new building blocks,” says Falkner. “Neuronal replacement therapies may be realistic, at least at times when a sufficient part of the pre-existing neuronal network is still available.”

Cell replacement therapy has been tried in Parkinson?s disease for at least two decades, but with mixed results. Impure sources of donor cells, pre-implant processing, suboptimal grafting procedures and side effects could all contribute, explains Falker.

Then there?s the issue that real world brain injuries aren?t so sterile and precise. A whack to the head, for example, can trigger inflammatory and other signals that turn the brain into a hostile environment unreceptive to neuron implants.

But the team is hopeful that their regime can help in those situations as well.

“We are doing this now in more realistic models, in models of traumatic and ischemic brain injury and all I can say is that it looks pretty good,” says Gotz.

Supply is also a problem isolating neurons from aborted fetuses isn?t a practical solution but recent advances in cell reprogramming could be a readily available answer.

Scientists can already directly turn skin cells into neurons, for example. Other groups have also shown that glia cells the other major cell type in the brain can shed their identity and transform into neurons under the right conditions. Then there are iPSCs, in which a patient?s skin cell is deprogrammed into stem cells and further developed into neurons.

It?s becoming more possible to get defined mixtures of cells to match the afflicted cell type in the diseased brain, says Falkner.

“Once neurons die, there is, at the moment, no real therapy to make these neurons come back. Surely, at some point in the future, these approaches will be used in the clinic,” says Gotz.

How Anti-Aging Can Save the Economy

Global Increase in Aging Population

The human race is now going through the biggest macroeconomic change in history. This change has two faces. First, life expectancies have nearly doubled in the West since the beginning of the 20th century. This change is even more rapid in formerly undeveloped regions as they catch up to Western technologies.

The other aspect is falling birth rates, which seem correlated to longer life spans. Fertility rates (births per woman) have fallen below replacement rates globally for the first time ever. And in many developed countries, fertility rates are alarmingly low.

A fertility rate of at least 2.1 children per woman is needed for native population stability in the West. It can be 2.5 or more where infant mortality is higher.

Japan and Germany are now at about 1.4 children per woman and falling. Singapore, Greece, and Spain are at about 1.3 births per woman. Within decades, whole nations will be at 1 birth per woman.

This means the next generation will be half the size of the last.

Every generation, from now on, will be smaller than the last. For economists and demographers, this problem is represented by the old-age dependency ratio (OADR).
The OADR refers to the number of people in a society who contribute to the economy compared to those who depend on transfer payments of some kind. Most social programs for the aged as well as pension plans were developed when the OADR was much healthier.

As life spans have lengthened, the OADR has deteriorated. There are two reasons for this. Longer lives mean that more people are moving to the dependent column of the balance sheet. At the same time, falling birth rates have reduced the number of workers in the contributor column.

In 1950, there were about 17 workers in America for every retired person. Today, there are less than three contributors to each retired dependent. This ratio continues to worsen simply because people are living longer and birth rates are falling.

In the US today, politicians say that the economy is doing fine. But if that were true, we?d be running budget surpluses. Instead, the US government is borrowing nearly 30 cents of every dollar spent. Transfer payments to the elderly now account for about 30% of federal spending. The roughly $20 trillion dollar national debt continues to grow, and unfunded liabilities are 10 to 20 times that amount (depending on who?s doing the math).

Former head of the Federal Reserve Allen Greenspan has long been known as an optimist. He?s held the view that market forces are robust enough to counter political recklessness. But recently, Greenspan admitted that he has lost his positive outlook. The reason, in his words, is that ?we have a 9% annual rate of increase in entitlements, which is mandated by law. It has got nothing to do with the economy. It has got to do with age and health and the like.?

Our current economic woes aren?t rooted in traditional economic policies. The problem is ?age and health and the like.? In other words, it?s the OADR.

Increasing the number of people on the contributor side of the balance sheet won?t solve the problem. Japan, Germany, Italy, and the Scandanavian countries have spent billions trying to increase birth rates. And they?ve failed. Even if they succeeded, it wouldn?t help in time. It takes decades for newborns to enter the work force.

The best way to prevent the demise of Western economies and the eventual Greek-style collapse of social programs and pension plans is longer life and health spans. If more people can remain healthy and work or invest longer, it would produce the economic growth we need to fund the innovation that will usher in an unparalleled era of prosperity.

Politicians and unions claim that voters won?t accept an increase in retirement ages, but Americans are already working longer than ever before. In fact, the evidence shows that most people would work longer and save more to pay their own way if they could.

According to a study by Zoya Financial, almost two-thirds of Americans have to retire earlier than planned. This is largely due to problems with their health or that of their spouse.

Anti-aging strategies and biotechnologies aren?t just needed from the point of view of the individual. They are, quite literally, the only way to save modern economies from the unintended consequences of increased life spans? the collapsing OADR.

The mainstream scientific community is starting to accept that we must move from a model of disease treatment to anti-aging. Effective anti-aging therapeutics are in labs right now and will greatly increase health spans and working careers, saving Western economies and cultures from ruin in the process.

Bureaucratic and political inertia, though, is slowing the approval and adoption of these life and economy-saving solutions. The establishment will eventually come around, but only kicking and screaming.

Hence the world truly needs more medical professionals, and patients who can spread the word that the old model of treating diseases is obsolete, inhumane, and fiscally suicidal.

~ Written by Patrick Cox

Regenerating Damaged Nerves

Spinal Cord

Injuries to the spinal cord often cause paralysis and other permanent disabilities because severed nerve fibers do not regrow on their own. During the past few years a number of paralyzed patients have experienced remarkable improvement as a result of Stem Cell Therapy. When their own stem cells or those extracted from cord blood were injected into the spinal column they went straight to the damaged nerves and helped them regenerate. One limitation is that the treatment must be given as soon as possible after the injury. When the same injections were given to patients who had been paralyzed for a year or more they were rarely successful. During the first few months after a spinal injury the nerves lose their ability to regenerate even with the introduction of new stem cells.

Now, scientists of the German Center for Neurodegenerative Diseases (DZNE) have succeeded in releasing a molecular brake that prevents the regeneration of nerve connections. Treatment of mice with Pregabalin, a drug that acts upon the growth inhibiting mechanism, caused damaged nerve connections to regenerate. Researchers led by neurobiologist Frank Bradke report on these findings in the journal Neuron.

Human nerve cells are interconnected in a network that extends to all parts of the body. In this way control signals are transmitted from head to toe, while sensory inputs flow in the opposite direction. For this to happen, impulses are passed from neuron to neuron, not unlike a relay race. Damages to this wiring system can have drastic consequences particularly if they affect the brain or the spinal cord. This is because the cells of the central nervous system are connected by long projections. When severed, these projections, which are called axons, are unable to regrow.

Neural pathways that have been injured can only regenerate if new connections arise between the affected cells. In a sense, the neurons have to stretch out their arms, i.e. the axons have to grow. In fact, this happens in the early stages of embryonic development. However, this ability disappears in the adult. Can it be reactivated? This was the question Professor Bradke and co-workers asked themselves. “We started from the hypothesis that neurons actively down-regulate their growth program once they have reached other cells, so that they don’t overshoot the mark. This means, there should be a braking mechanism that is triggered as soon as a neuron connects to others,” says Dr. Andrea Tedeschi, a member of the Bradke Lab and first author of the current publication.

In mice and cell cultures, the scientists started an extensive search for genes that regulate the growth of neurons. “That was like looking for the proverbial needle in the haystack. There are hundreds of active genes in every nerve cell, depending on its stage of development. To analyze the large data set we heavily relied on bioinformatics. To this end, we cooperated closely with colleagues at the University of Bonn,” says Bradke. “Ultimately, we were able to identify a promising candidate. This gene, known as Cacna2d2, plays an important role in synapse formation and function, in other words in bridging the final gap between nerve cells.” During further experiments, the researchers modified the gene’s activity, e.g. by deactivating it. In this way, they were able to prove that Cacna2d2 does actually influence axonal growth and the regeneration of nerve fibers.

Cacna2d2 encodes the blueprint of a protein that is part of a larger molecular complex. The protein anchors ion channels in the cell membrane that regulate the flow of calcium particles into the cell. Calcium levels affect cellular processes such as the release of neurotransmitters. These ion channels are therefore essential for the communication between neurons.

In further investigations, the researchers used Pregabalin (PGB), a drug that had long been known to bind to the molecular anchors of calcium channels. Over a period of several weeks, they administered PGB to mice with spinal cord injuries. As it turned out, this treatment caused new nerve connections to grow.

“Our study shows that synapse formation acts as a powerful switch that restrains axonal growth. A clinically-relevant drug can manipulate this effect,” says Bradke. In fact, PGB is already being used to treat lesions of the spinal cord, albeit it is applied as a pain killer and relatively late after the injury has occurred. “PGB might have a regenerative effect in patients, if it is given soon enough. In the long term this could lead to a new treatment approach. However, we don’t know yet.”

In previous studies, the DZNE researchers showed that certain cancer drugs can also cause damaged nerve connections to regrow. The main protagonists in this process are the microtubules, long protein complexes that stabilize the cell body. When the microtubules grow, axons do as well. Is there a connection between the different findings? “We don’t know whether these mechanisms are independent or whether they are somehow related,” says Bradke. “This is something we want to examine more closely in the future.”

Hyperelastic Bone – Regeneration Breakthrough

Stem Cell Clinics Map

A Northwestern Engineering research team has developed a 3-D printable ink that produces a synthetic bone implant that rapidly induces bone regeneration and growth. This hyperelastic “bone” material, whose shape can be easily customized, one day could be especially useful for the treatment of bone.

Bone implantation surgery is never an easy process, but it is particularly painful and complicated for children. With both adults and children, often times bone is harvested from elsewhere in the body to replace the missing bone, which can lead to other complications and pain. Metallic implants are sometimes used, but this is not a permanent fix for growing children.

“Adults have more options when it comes to implants,” said Ramille N. Shah, who led the research. “Pediatric patients do not. If you give them a permanent implant, you have to do more surgeries in the future as they grow. They might face years of difficulty.”

Shah and her team aim to change the nature of bone implants, and they particularly want to help pediatric patients. Shah is an assistant professor of materials science and engineering in Northwestern’s McCormick School of Engineering and of surgery in the Northwestern University Feinberg School of Medicine.

The new study, evaluating the material with human stem cells and within animal models, was published online September 28 by the journal Science Translational Medicine. Adam E. Jakus, a postdoctoral fellow in Shah’s laboratory, is the paper’s first author.

Shah’s 3-D printed biomaterial is a mix of hydroxyapatite (a calcium mineral found naturally in human bone) and a biocompatible, biodegradable polymer that is used in many medical applications, including sutures. Shah’s hyperelastic “bone” material shows great promise in in vivo animal models; this success lies in the printed structure’s unique properties. It’s majority hydroxyapatite yet hyperelastic, robust and porous at the nano, micro and macro levels.

“Porosity is huge when it comes to tissue regeneration, because you want cells and blood vessels to infiltrate the scaffold,” Shah said. “Our 3-D structure has different levels of porosity that is advantageous for its physical and biological properties.”

While hydroxyapatite has been proven to induce bone regeneration, it is also notoriously tricky to work with. Clinical products that use hydroxyapatite or other calcium phosphate ceramics are hard and brittle. To compensate for that, previous researchers created structures composed mostly of polymers, but this shields the activity of the bioceramic. Shah’s bone biomaterial, however, is 90 percent by weight percent hydroxyapatite and just 10 percent by weight percent polymer and still maintains its elasticity because of the way its structure is designed and printed. The high concentration of hydroxyapatite creates an environment that induces rapid bone regeneration.

“Cells can sense the hydroxyapatite and respond to its bioactivity,” Shah said. “When you put stem cells on our scaffolds, they turn into bone cells and start to up-regulate their expression of bone specific genes. This is in the absence of any other osteo-inducing substances. It’s just the interaction between the cells and the material itself.”

That’s not to say that other substances couldn’t be combined into the ink. Because the 3-D printing process is performed at room temperature, Shah’s team was able to incorporate other elements, such as antibiotics, into the ink.

“We can incorporate antibiotics to reduce the possibility of infection after surgery,” Shah said. “We also can combine the ink with different types of growth factors, if needed, to further enhance regeneration. It’s really a multi-functional material.”

One of the biggest advantages, however, is that the end product can be customized to the patient. In traditional bone transplant surgeries, the bone — after it’s taken from another part of the body — has to be shaped and molded to exactly fit the area where it is needed. Physicians would be able to scan the patient’s body and 3-D print a personalized product using Shah’s synthetic material. Alternatively, due to its mechanical properties, the biomaterial can also be easily trimmed and cut to size and shape during a procedure. Not only is this faster, but alsoless painful compared to using autograft material.

Shah imagines that hospitals may one day have 3-D printers, where they can print customized implants while the patient waits.

“The turnaround time for an implant that’s specialized for a customer could be within 24 hours,” Shah said. “That could change the world of craniofacial and orthopaedic surgery, and, I hope, will improve patient outcomes.”

Reference: 1.A. E. Jakus, A. L. Rutz, S. W. Jordan, A. Kannan, S. M. Mitchell, C. Yun, K. D. Koube, S. C. Yoo, H. E. Whiteley, C.-P. Richter, R. D. Galiano, W. K. Hsu, S. R. Stock, E. L. Hsu, R. N. Shah. Hyperelastic “bone”: A highly versatile, growth factor-free, osteoregenerative, scalable, and surgically friendly biomaterial. Science Translational Medicine, 2016; 8 (358): 358ra127 DOI: 10.1126/scitranslmed.aaf7704

Stem Cell Clinics in the United States

Stem Cell Clinics Map

There are now more than 500 stem cell clinics in the United States and the FDA has been holding hearings to decide if they should be closed down or much more strictly regulated. The move comes at an awkward time because research on stem cell treatments is just starting to bear fruit. Tantalizing results from a series of small studies suggest injections with certain types of stem cells may be effective treatments for conditions such as stroke and multiple sclerosis. Also thousands of patients have been able to avoid joint surgery after receiving injections with stem cells and platelet rich plasma. Since Medical Doctors in Stem Cell Clinics generally use cells they?ve isolated from a patient?s own fat, and because those cells are considered only ?minimally manipulated,? the FDA has not regulated the treatments as it would a traditional pharmaceutical.

Patients who want immediate treatment for their conditions and Doctors who perform these treatments say the FDA is being pressured into taking a tough line by academics and pharmaceutical giants who want to control, and profit from, the stem cell industry.

?The problem is, if we do well, it hurts their business plan,? said Dr. Mark Berman, a plastic surgeon in Beverly Hills, California.

Back in 2002, Dr. Berman cofounded a chain of clinics called the Cell Surgical Network. He says he and other physicians in the network have conducted some 5,000 stem cell treatments including on himself and his wife for conditions such as arthritis and hip, back and joint pain. He called the draft regulations arbitrary and hypocritical.

The fight over regulation comes at a time when leading stem cell researchers, after years of disappointing results, are increasingly excited about new studies showing the cells appear to be safe and may be effective in treating a variety of crippling diseases, including macular degeneration and Parkinson?s.

?It?s a very exciting time,? said Sally Temple, a stem cell researcher at the Neural Stem Cell Institute in Rensselaer, N.Y. ?We?re going to see many treatments for diseases that are currently untreatable.?

The results researchers are so excited about are only possible because of decades of tedious work to establish safety protocols, test concepts and learn how to grow, produce, and manipulate stem cells, she said.

?It?s hard to have people understand how long this whole process takes,? said Temple, who also serves as president of the International Society of Stem Cell Research. ?You would not believe what we have to do in my lab to prepare cells properly.?

Stem cells can be extracted from a number of different tissues. They?re highly flexible and can turn into other kinds of cells ? heart cells, say, or retinal cells. That ability lets them act as a kind of internal repair system.

Stem cells extracted from bone marrow have long been used to treat cancer, and blood and immune disorders. Now a variety of types of stem cells are being tested in a slew of other applications.

For example, a team at Stanford and the University of Pittsburgh announced in June in the journal Stroke that they had restored mobility in some stroke patients by injecting a particular kind of modified stem cell directly into their brains. Most stroke patients don?t improve much after six months, but some who received the treatment gained mobility a year or more after their strokes. Some who had been confined to wheelchairs even began to walk.

Dr. Gary Steinberg, a neurosurgeon at Stanford and the study?s lead author, said he thought the cells might be helping by secreting factors that led to the regeneration or reactivation of patient?s cells. ?We didn?t imagine we could restore neurologic function in these chronic stroke patients with severe disability,? said Steinberg.

The study just 18 patients; so Dr. Steinberg is recruiting 156 more for an additional study.

In another promising effort, a team from the University of Southern California announced they had restored some mobility in a 21-year-old man, Kris Boesen, who had become paralyzed from the neck down after a car accident this spring.

The team, led by USC neurosurgeon and bioengineer Dr. Charles Liu, injected 10 million specialized cells created from embryonic stem cells directly into the patient?s spine.

To be sure, it?s unclear whether, or how much, the treatment helped; the patient may also have recovered spontaneously. But whatever the mechanism, the improvement was dramatic: Three months after the treatment, the patient was feeding himself, hugging his family, and using his cell phone.

?The first thing he did when he could use his hands was text his girlfriend,? Liu said.

This patient was one of five enrolled in a multicenter clinical trial using cells that support nervous system functioning created from embryonic cells by Asterias Biotherapeutics, which plans to release results from several other patients Wednesday at an International Spinal Cord Society meeting in Vienna.

?If it bears out, it?s going to be huge,? Liu said. ?This was the difference between someone using his hands or not.?