Category Archives: Cell Medicine

A research team from the University of Missouri School of Medicine has recently used CRISPR to edit a genetic mutation that contributes to Duchenne muscular dystrophy (DMD). This rare and debilitating genetic disorder is characterized by loss of muscle mass and physical impairment. By using this powerful gene-editing technology, these MU School of Medicine researchers have successfully treated mouse models of the disease. This work was published this summer in the journal Molecular Therapy.

Those with DMD possess a specific mutation that hinders the production of the dystrophin protein, which contributes to the structural integrity of muscle tissue. In the absence of this protein, the muscle cells weaken and eventually die. Pediatric patients with the condition often lose their ability to walk and can even lose the function of muscles that are essential for respiration and heart contractions.

Research has shown that CRISPR can be used to edit out the mutation that causes the early death of muscle cells in an animal model, explained senior author Dongsheng Duan, PhD, Margaret Proctor Mulligan Professor in Medical Research in the Department of Molecular Microbiology and Immunology at the MU School of Medicine. However, there is a major concern of relapse because these gene-edited muscle cells wear out over time. If we can correct the mutation in muscle stem cells, then cells regenerated from the edited stem cells will no longer carry the mutation. A one-time treatment of the muscle stem cells with CRISPR could result in continuous dystrophin expression in regenerated muscle cells.

Working alongside other researchers from MU, the National Center for Advancing Translational Sciences, Johns Hopkins School of Medicine and Duke University, Duan aimed to genetically modify muscle stem cells in mice. These scientists first edited the gene using an adeno-associated virus known as AAV9. Being this specific viral strain was recently approved by the FDA in treating spinal muscular atrophy, the researchers saw it as a viable candidate in treating DMD.

We transplanted AAV9 treated muscle into an immune-deficient mouse, said lead author Michael Nance, an MD-PhD program student in Duans lab. The transplanted muscle died first then regenerated from its stem cells. If the stem cells were successfully edited, the regenerated muscle cells should also carry the edited gene.

Upon analyzing the regenerated muscle tissue, the researchers found that its cells contained the edited gene, supporting their reasoning. The team then tested whether the muscle stem cells in mice with DMD could be genetically edited using CRISPR. These findings also supported their hypothesis, with the stem cells in the diseased tissue sustaining these edits and the regenerated cells successfully producing dystrophin.

This finding suggests that CRISPR gene editing may provide a method for lifelong correction of the genetic mutation in DMD and potentially other muscle diseases, explained Duan. Our research shows that CRISPR can be used to effectively edit the stem cells responsible for muscle regeneration. The ability to treat the stem cells that are responsible for maintaining muscle growth may pave the way for a one-time treatment that can provide a source of gene-edited cells throughout a patients life.

Duan and colleagues hope that future research will help this stem cell CRISPR therapy become a revolutionary treatment for children with DMD.

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Editing Muscle Stem Cells with CRISPR Treats Mouse Model of Muscular Dystrophy - DocWire News

Super Sentinel Cells Show an Unprecedented 80% Success Rate in Curing Cancer

LONG BEACH, CA, Sept. 19, 2019 /PRNewswire/ - INTELLiSTEM Technologies, an international company revolutionizing stem cell medicine, today announced that they have created genetically engineered Super Sentinel Cells (SSC's) to effectively target cancer cells. The SSC's are showing an unprecedented 80% success rate in animal models. The current success rate for existing cancer treatments is 20-40%.

"This is a true eureka moment! Our genetically engineered ethical stem cells are designed to find cancer cells hiding in the body and signal the immune system to kick in and destroy them. Remarkably, their level of success in targeting and destroying cancer cells is unprecedented at 80%," explains Dr. Riam Shammaa MD, Founder and CEO of INTELLiSTEM.

"We could see practical cures for specific cancers in as little as 5 years," added Shammaa.

See animated video of SSC's here high resolution Images also available.

Shammaa chose the annual SoCalBio Council conference to unveil their cancer breakthrough because it brings together the best of local and international researchers working on the cutting edge of biotechnology. He is also presenting at the conference on September 19th.

Q&A:

i) Why has no one else thought of this treatment before?

Dr. Shammaa speculates that this may be due to the traditional 'silo' nature of cancer research. Often treatments are fully researched and tested by medical professionals in one discipline only. Dr. Shammaa's team combined the promising technology of stem cells with the science of immunology to form INTELLiSTEM. This fast-tracked the development of Super Sentinel Cells.

ii) How does the treatment work?

Cancer cells are very good at hiding from the immune system. Essentially, the Super Sentinel Cells show the immune system where the cancer cells are hiding in a host and allow the immune system to kick in and attack/kill them.

iii) What Cancers could this effectively treat?

Super Sentinel Cells have the capacity to target any cancer due to their ability to learn the signals and antigens of each cancer. Due to the massive task at hand and to accelerate the progression of multiple cancer cures Dr. Shammaa is looking to collaborate with experts/labs across the world to develop treatments for different cancers. The SSC's are expected to be effective on Lung Cancer, Melanoma, Prostate Cancer and Lymphoma.

iv) How much does this cost?

Dr. Shammaa expects the SSC treatments to be available for $30k-$50k USD, this is significantly less than current treatments such as CAR T that run from $350k - $500k USD.

v) How many treatments are required?

Animal models are showing that 80% of the tested animals survive after one treatment compared to 20% using available drugs and 0% without treatment, but Shammaa believes that 100% can be achieved with a second injection/treatment of Super Sentinel Cells.

vi) What stage is the research at?

INTELLiSTEM has finalized all testing of safety and efficacy of the technology as required by the FDA and Health Canada. They are now preparing to file for the first clinical trial in humans in the next 12 months!

viii) What's next?

INTELLiSTEM is now moving to human trials and to accelerate targeting of multiple cancers. INTELLiSTEM is seeking to partner with experts and laboratories to target multiple cancers using SSCs.

"We are telling our story now to hit the ground running and let our peers and the world know that we've reached a major milestone in cancer research," added Shammaa. "Our vision is to have ourSuper Sentinel Cells in every hospital, available for everyone. Every time a patient gets diagnosed with cancer, the doctors in that hospital take a biopsy of that cancer and "incubate" it with Super Sentinel Cells and then inject SSC's into the patient to treat their cancer, we call this approach, off-the-shelf personalized medicine." said Shammaa

"We will do everything we can to make this technology available to everyone as fast as possible," said Shammaa. "With international support, we really could be looking at practical cancer treatments in the next five years."

View original content:http://www.prnewswire.com/news-releases/cancer-killing-breakthrough-being-proudly-announced-at-socalbio-conference-300921799.html

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Cancer Killing Breakthrough Being Proudly Announced At Socalbio Conference - Yahoo Finance

In an ideal world, we could eat whatever we want, exercise as little as wed like and somehow magically lose weight and gain muscle mass. Pure fantasy, youd think, other than for those blessed by the gods with incredible metabolisms.

Not so, according to Dr. Ana Mihalcea of AM Medical. In fact, a way of achieving such an outcome already exists, in the form of peptides. These short-chain amino acids are now being used to treat everything from Alzheimers to autoimmune diseases and yes, they can help people lose weight and improve health, even while consuming a high-fat diet. The peptides are an integral part of this practice because they are so profound in what we can access and do, says Mihalcea.

The field of peptide therapy is exploding. Of the 7,000 existing peptides, currently 60 are FDA-approved, but more are under review. Peptides act like a key in a lock, allowing them access to many levels of cellular function. Whats so exciting is that we now have a way to tell the cell to rejuvenate itself in very specific ways, says Mihalcea.

Regular cells produce energy, using nicotinamide adenine dinucleotide (NAD) to power metabolism by enabling the mitochondria to convert the food we eat into the energy our body needs. NAD helps produce cellular energy, but as we age, our levels of NAD decline, leaving us at risk for a host of health problems. Some people take NAD as a supplement, Mihalcea notes, but there are peptides that increase the biosynthesis of NAD, so your cells are producing more of it to create more energy.Increased energy means increased health and function.

Peptide therapy has many applications. One form known as Mots-C has been shown to improve insulin resistance and increase the bodys ability to use sugar to produce energy by accessing mitochondrial DNA. People lose weight and gain energy, says Mihalcea. Mots-C has also been linked to healthy longevity.

Anti-aging is a hot topic in peptide therapy, especially after researchers made a significant discovery. It always appeared that you can reverse the age of a cell up to a certain point, but if its been old for a long time, the cell is locked into that aging process, Mihalcea explains. The more of these old cells you have, the faster you age because those cells are signaling inflammation. Now with peptides, we have ways to unlock those aging cells and put them back into reversible states. This can be applied to all chronic diseases because they all work the same way through inflammation.

Researchers at the University of Washington recently developed a peptide called Dihexa that causes neurons to grow like a tree, reversing the loss of neurons and shrinkage of synapses and dendrites which occur with Alzheimers disease. Its called the wonder drug of neurology, Mihalcea says. Its used in treatment of Alzheimers and Parkinsons disease.

And then theres CJC1295 with Ipamorelin, which causes weight loss and muscle mass gain, Weight loss is key for overall disease prevention, Mihalcea maintains. Basically, metabolism rules your health, she says. If there are problems with obesity and diabetes, you are more at risk. Its been shown that if your blood sugar is above 85, which is still considered in the normal range, your risk of heart disease already goes up by 40 percent. Weve had cases of people on CJC1295 with Ipamorelin, who have gained eight pounds of muscle mass but lost 12 pounds of body fat in one month.

Peptides can even help to regrow cartilage for those struggling with osteoarthritis. Peptide AOD 9604 has been shown to reduce pain and swelling, says Mihalcea. If you inject it into a knee, there have been clinical trials where its been very effective for osteoarthritis treatment. Our patients can function better, and they feel better.

Although AM Medical has been open for just three months, already shes seen results in patients using peptide therapy, including cognitive improvement and weight loss. People have lost 20 pounds in six to eight weeks, she says. Theres also an improvement in energy to get through the day. Ive had a lot of people tell me, I remember what it feels like to get back to having energy to do things. Thats really wonderful.

Mihalcea encourages anyone who wants to learn more to check out AM Medicals YouTube channel, where she goes into peptide therapy in depth. I think this is an exciting new health care field, she says. Its important for people to understand that there are more options. Theres no such thing as the impossible anymore. The research is so progressive and so rapid in all these areas that the future of medicine is unfolding now.

Learn more at the AM Medical website or by calling 360-960-8538.

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Peptide Therapy at AM Medical: The Future of Medicine is Now - ThurstonTalk

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To survive chemotherapy, some cancer cells eat their neighboring tumor cells, a new study shows.

The findings suggest that this act of cannibalism gives the cancer cells the energy they need to stay alive and initiate tumor relapse after the course of treatment is completed.

Chemotherapy drugs such as doxorubicin damage cancer cells DNA to kill them, but cells that survive initial treatment can soon give rise to relapsed tumors. This is a particular problem in breast cancers that retain a normal copy of a gene called TP53. Instead of dying in response to chemotherapy-induced DNA damage, these cancer cells generally just stop proliferating and enter a dormant but metabolically active state known as senescence.

In addition to surviving chemotherapy, these senescent cancer cells produce large amounts of inflammatory molecules and other factors that can promote the tumors regrowth. Chemotherapy-treated breast cancer patients with normal TP53 genes are therefore prone to relapse and have poor survival rates.

Understanding the properties of these senescent cancer cells that allow their survival after chemotherapy treatment is extremely important, says Crystal A. Tonnessen-Murray, a postdoctoral research fellow in James G. Jacksons laboratory at the Tulane University School of Medicine.

Researchers discovered that, after exposure to doxorubicin or other chemotherapy drugs, breast cancer cells that become senescent frequently engulf neighboring cancer cells. They observed this surprising behavior not only in cancer cells grown in the lab, but also in tumors growing in mice. Lung and bone cancer cells are also capable of engulfing their neighbors after becoming senescent, the researchers discovered.

As reported in the Journal of Cell Biology, senescent cancer cells activate a group of genes that are normally active in white blood cells that engulf invading microbes or cellular debris. After eating their neighbors, senescent cancer cells digested them by delivering them to lysosomes, acidic cellular structures that are also highly active in senescent cells.

Senescent cancer cells that engulfed a neighboring cell survived in culture for longer than senescent cancer cells that didnt. The researchers suspect that consuming their neighbors may provide senescent cancer cells with the energy and materials they need to survive and produce the factors that drive tumor relapse.

Inhibiting this process may provide new therapeutic opportunities, because we know that it is the breast cancer patients with tumors that undergo TP53-mediated senescence in response to chemotherapy that have poor response and poor survival rates, Jackson says.

Source: Tulane University

Original Study DOI: 10.1083/jcb.201904051

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Some cancer cells turn cannibal to survive chemotherapy - Futurity: Research News

Using optogenetic techniques, which relied on laser light to activate the cancer cells in mice implanted with human gliomas, the researchers demonstrated that increasing electrical signals into the tumors caused more tumor growth. Proliferation of the tumors was largely prevented when glioma cells expressed a gene that blocked transmission of the electrical signals.

Existing drugs that block electrical currents also reduced growth of high-grade gliomas, the research found. A seizure medication called perampanel, which blocks activity of neurotransmitter receptors on the receiving end of a synapse, reduced proliferation of pediatric gliomas implanted into mice by 50%. Meclofenamate, a drug that blocks the action of gap junctions, resulted in a similar decrease in tumor proliferation.

Monjes team plans to continue investigating whether blocking electrical signaling within tumors could help people with high-grade gliomas. Its a really hopeful new direction, and as a clinician Im quite excited about it, she said.

Other Stanford co-authors of the paper are staff scientist Wade Morishita, PhD; postdoctoral scholars Anna Geraghty, PhD, Marlene Arzt, MD, and Kathryn Taylor, PhD; graduate student Shawn Gillespie; medical student Lydia Tam; staff scientist Cedric Espenel, PhD; research assistants Anitha Ponnuswami, Lijun Ni and Pamelyn Woo; Hannes Vogel, MD, professor of pathology and of pediatrics; and Robert Malenka, MD, PhD, professor of psychiatry and behavioral sciences.

Monje is a member of Stanford Bio-X, the Stanford Institute for Stem Cell Biology and Regenerative Medicine, the Stanford Maternal & Child Health Research Institute, the Stanford Cancer Institute and the Wu Tsai Neurosciences Institute at Stanford.

Scientists from Massachusetts General Hospital, Harvard Medical School, the Massachusetts Institute of Technology, Johns Hopkins University, the University of Michigan and the University of California-San Francisco also contributed to the research.

The research was funded by the National Institutes of Health (grant DP1 NS111132), the National Institute of Neurological Disorders and Stroke (grant NINDS R01NS092597), the National Cancer Institute (grant F31CA200273), the Michael Mosier Defeat DIPG Foundation, the ChadTough Foundation, the V Foundation, Ians Friends Foundation, the Department of Defense, the Mckenna Claire Foundation, Alexs Lemonade Stand Foundation, The Cure Starts Now Foundation and DIPG Collaborative, the Lyla Nsouli Foundation, Unravel Pediatric Cancer, the California Institute for Regenerative Medicine, the Joey Fabus Childhood Cancer Foundation, the N8 Foundation, the Sam Jeffers Foundation, Cancer Research UK, the Virginia and D.K. Ludwig Fund for Cancer Research, and the Stanford Maternal & Child Health Research Institutes Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases.

Stanfords Department of Neurology and Neurological Sciences also supported the work.

A second paper showing similar findings by another team of researchers was published simultaneously in Nature.

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Brain tumors form synapses with healthy neurons, Stanford-led study finds - Stanford Medical Center Report

An international team of scientists from Gero Discovery LLC, the Institute of Biomedical Research of Salamanca, and Nanosyn, Inc. has found a potential drug that may prevent neuronal death through glucose metabolism modification in stressed neurons. The positive results obtained in mice are promising for future use in humans. The new drug could be advantageous in neurological conditions ranging from amyotrophic lateral sclerosis, Alzheimers and Huntingtons diseases, to traumatic brain injury and ischemic stroke. The results have been published in the Scientific Reports Journal.Brain injuries and neurological disorders are among the most significant causes of death worldwide. According to WHO, stroke is the second most common cause of mortality, and more than a third of people who have survived a stroke will have a severe disability.What is more, as the population ages, millions more people are at risk of developing Alzheimers or Parkinsons diseases in the near future. However, there are no efficient drugs for major neurodegenerative diseases. It is thus critically important to understand the biology of these diseases and to identify new drugs capable of improving quality of life, survival, and, in the best-case scenario, curing the disease completely.

In most tissues in the body, glycolysis is considered an essential metabolic pathway for cell survival since it meets the cells energy needs in case of intensive energy consumption. However, in brain tissue, the situation is quite different - individual cell types show distinct glucose metabolism patterns. In neurons, only a small portion of glucose is consumed via the glycolysis pathway. At the same time, astrocytes provide nutrients to neurons and utilize glycolysis to metabolize glucose. These differences are mostly due to a specialized protein called PFKFB3, which is normally absent in neurons and is active in astrocytes. In the case of certain neurological diseases, stroke being one of them, the amount of active PFKFB3 increases in neurons, which is highly stressful for these cells and leads to cell death.

An international team of researchers led by Peter Fedichev, a scientist and biotech entrepreneur from Gero Discovery, and professor Juan P. Bolaos from the University of Salamanca, suggested and further confirmed in in vivo experiments that a small molecule, an inhibitor of PFKFB3, may prevent cell death in the case of ischemia injury. In experiments using mouse cell cultures, it was shown that the PFKFB3 inhibitor protected neurons from the amyloid-beta peptide, the main component of the amyloid plaques found in the brains of Alzheimers disease patients. Subsequent in vivo testing showed that inhibition of PFKFB3 improves motor coordination of mice after stroke and reduced brain infarct volume.

Bolaos commented, Excitotoxicity is a hallmark of various neurological diseases, stroke being one of them. Our group has previously established a link between this pathological condition and high activity of PFKFB3 enzyme in neurons, which leads to severe oxidative stress and neuronal death.

We are glad that our hypothesis that pharmacological inhibition of PFKFB3 can be beneficial in an excitotoxicity-related condition, such as stroke, was confirmed. I would like to note that in our work, we used a known molecule to demonstrate that PFKFB3 blockage has a therapeutic effect. But we have also performed the same experiments with other proprietary small molecule designed in our company and showed that it had a similar effect. There is, of course, still much work to do. We are currently investigating the efficacy of our compounds in models of orphan excitotoxicity-related neurological diseases. We have already obtained good safety results in mice and believe that we will be successful in our future investigations said Olga Burmistrova, director of preclinical development in Gero Discovery.

The Gero Discovery team is planning to proceed with preclinical trials and to move into clinical trials soon. These promising results bring hope to dozens of millions of patients suffering from life-threatening neurological diseases. We have started communicating with potential investors and co-development partners and invite interested parties to collaborate on the further development of this breakthrough medicine through the preclinical and early clinical stage said Maksim Kholin, the Gero Discovery Co-Founder and Business Development Director.

Reference:http://dx.doi.org/10.1038/s41598-019-48196-z

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Glycolysis Inhibitor Could Prevent Cell Death and Excitotoxic Brain Disease - Technology Networks

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The CRISPR gene editing technique may provide the means for lifelong correction of the genetic mutation responsible for Duchenne muscular dystrophy, a new study with mice shows.

Duchenne muscular dystrophy (DMD), a rare but devastating genetic disorder, causes muscle loss and physical impairment. Children with DMD have a gene mutation that interrupts the production of a protein known as dystrophin. Without it, muscle cells weaken and eventually die. Many children lose the ability to walk, and muscles essential for breathing and heart function ultimately stop working.

Research has shown that CRISPR can be used to edit out the mutation that causes the early death of muscle cells in an animal model, says Dongsheng Duan, professor in medical research in the molecular microbiology and immunology department at the University of Missouri School of Medicine and senior author of the paper in Molecular Therapy.

However, there is a major concern of relapse because these gene-edited muscle cells wear out over time. If we can correct the mutation in muscle stem cells, then cells regenerated from the edited stem cells will no longer carry the mutation. A one-time treatment of the muscle stem cells with CRISPR could result in continuous dystrophin expression in regenerated muscle cells.

For the study, researchers explored whether they could efficiently edit muscle stem cells from mice. They first delivered the gene editing tools to normal mouse muscle through AAV9, a virus that the US Food and Drug Administration recently approved to treat spinal muscular atrophy.

We transplanted AAV9 treated muscle into an immune-deficient mouse, says lead author Michael Nance, a MD-PhD program student in Duans lab. The transplanted muscle died first then regenerated from its stem cells. If the stem cells were successfully edited, the regenerated muscle cells should also carry the edited gene.

The researchers reasoning was correctthey found abundant edited cells in the regenerated muscle. They then tested if they could use CRISPR to edit muscle stem cells in a mouse model of DMD. Similar to what they found in normal muscle, the stem cells in the diseased muscle were also edited. Cells regenerated from these edited cells successfully produced dystrophin.

This finding suggests that CRISPR gene editing may provide a method for lifelong correction of the genetic mutation in DMD and potentially other muscle diseases, Duan says.

Our research shows that CRISPR can be used to effectively edit the stem cells responsible for muscle regeneration. The ability to treat the stem cells that are responsible for maintaining muscle growth may pave the way for a one-time treatment that can provide a source of gene-edited cells throughout a patients life.

With more study, the researchers hope this stem cell-targeted CRISPR approach may one day lead to long-lasting therapies for children with DMD.

Additional coauthors are from the University of Missouri, the National Center for Advancing Translational Sciences, Johns Hopkins School of Medicine, and Duke University. The National Institutes of Health, the Department of Defense, the Jackson Freel DMD Research Fund, Hope for Javier, and the Intramural Research Program of the National Center for Advancing Translational Sciences funded the work.

Source: University of Missouri

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CRISPR fix in mice may lead to muscular dystrophy therapy - Futurity: Research News

Ancient Greek philosopher Aristotle made what may be the first known attempt to define life. He said that something is alive if it grows, is animated and nourishes itself. A more recent definition suggests the important characteristics being the capacity for growth, reproduction, functional activity and continual change preceding death.

There are other attempts, but they all fail in some way. Both of these definitions, for example, would consider fire to be alive and mules, which are born sterile, not to be alive. All that said, most of us have an instinctive understanding of what it means to be alive. If you see a bug or a bird or even an amoeba, you are certain it possesses life.

None of this, however, tells us anything about how life first started or whence it came. Again, there are countless thoughts about this, such as life resulting from a stroke of lightning zapping just the right elements at the right time. Some believe radiation was the instigator, and some suggest that early life forms arrived on Earth aboard rocks from outer space. No one knows for sure.

However, there is research that shows the possibility of creating the basic building blocks of life, amino acids and proteins, from basic inorganic compounds by simulating the conditions that must have prevailed at Earths beginning. And research in cell biology has established some remarkably likely facts about how we became human.

Its all about cells?

A cell is the smallest functional unit of every living thing; we are made from trillions of them. The cell has a jelly-like liquid called cytoplasm enclosed in a membrane. Within the cytoplasm are structures with functions similar to our organs, and they are called organelles, or little organs, with names like mitochondria, lysosomes and others. With these, the cell can perform for itself all the same functions that we need for life: respiration, reproduction, waste removal, energy conversion and more.

Some cells have an organelle called the nucleus inside the membrane, as well. These are called eukaryotes, meaning to have a true (eu) nucleus (kary). A nucleus is important, as it contains most of the cells genes that are part of its DNA molecules; DNA is packaged in the form of chromosomes in order to fit into the nucleus. Other cells are called prokaryotes, meaning to exist before (pro) a nucleus occurs; bacteria are prokaryotes. They, too, have DNA, but its located directly in the cytoplasm.

The organelles are like computer programs, apps, in that they can perform specific functions, but they have to be started by a brain. The important fact is that cells are intelligent, and their brain is the cell membrane. The membrane includes tens of thousands of IMPs (integral membrane proteins) that receive and send signals from and to their environment, directing the organelles to do their thing and so create the complex behavior of a living cell.

A brief timeline

Earth was created about 41/2 billion years ago, but it wasnt until 3.8 billion years ago that single-cell prokaryotes appeared. That is, the bacteria have been here a seriously long time.

The eukaryotes evolved from prokaryotes, appearing about 21/2 billion years ago, and the kind of life forms we experience today are only about 600 million years old. There were no mammals until about 200 million years ago, and we, Homo sapiens, have been around for a mere 200,000 years. So, what happened to get from the first eukaryotes to us?

Community building

For the first 3 billion years that there was life on Earth, it consisted of independent single cells, monads. They were bacteria, they were algae, they were protozoans and some fungi. It was long thought that they were solitary.

Research has shown, however, that the signals they use to organize their own physiology can be released into their environment, creating a kind of long-distance communication. For example, amoebas consuming food release a particular molecule that informs other amoebas of a supply of food to which many are then drawn. Other signal molecules like hormones were in use by these single-cell critters, as well.

As time passed, monads learned to increase the number of IMPs in their membrane and started to assemble themselves into close-knit cellular communities for survival. As the size and complexity of these multicellular communities grew, they became highly organized and parceled out specific functions to specialized groups of cells: forming body tissues and organs, building nervous and immune systems, etc. And so there evolved the complex organisms we recognize as plants and animals.

As the more complex animals evolved, there were specialized cells that became responsible for monitoring and regulating the flow of signaling among other cells. This central information processor became the brain that controls the overall interaction and behavior of all the cells in the body. We commonly believe that our mind is the same as our brain and is located our head. However, neuroscientist and pharmacologist Candace Perts elegant experiments showed that the mind is distributed throughout the body.

We as humans, and, in fact, all mammals and some others, are an advanced stage of this kind of community organization. Of special interest is the development of a region of the brain called the prefrontal cortex. In this, we find the capacity for thinking, planning and decision-making, as well as the seat of self-consciousness.

And so ...

Cellular communities continue to evolve, giving new perspectives on what it means to be alive.

Bob Keller maintains a holistic practice in Newburyport. He offers medical massage therapy for pain relief, as well as psychological counseling, dream work and spiritual direction. Many patients call him Dr. Bob and accuse him of doing miracles, but he is not a medical doctor nor a divinity. His expertise is medical massage therapy, understanding this miracle we call the human being. He can be reached at 978-465-5111 or rk2name@gmail.com.

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Making Sense of Medicine: The meaning of life | Lifestyles - The Daily News of Newburyport

Several recent studies in high-profile journals reported to have genetically engineered neurons to become responsive to magnetic fields. In doing so, the authors could remotely control the activity of particular neurons in the brain, and even animal behaviorpromising huge advances in neuroscientific research and speculation for applications even in medicine. We envision a new age of magnetogenetics is coming, one 2015 study read.

But now, two independent teams of scientists bring those results into question. In studies recently posted as preprints to bioRxiv,the researchers couldnt replicate those earlier findings.

Both studies . . . appear quite meticulously executed from a biological standpointmultiple tests were performed across multiple biological testbeds, writes Polina Anikeeva, a materials and cognitive scientist at MIT, to The Scientist in an email. I applaud the authors for investing their valuable time and resources into trying to reproduce the results of their colleagues.

Being able to use small-scale magnetic fields to control cells or entire organisms would have enormous potential for research and medical therapies. It would be a less invasive method than optogenetics, which requires the insertion of optical fibers to transmit light pulses to specific groups of neurons, and would provide a more rapid means of inducing neural activity than chemogenetics, which sparks biochemical reactions that can take several seconds to stimulate neurons.

In a 2016 study in Nature, geneticist Jeffrey Friedman from Rockefeller University and colleagues reported to have stimulated neural activity in glucose-sensing neurons in the mouse hypothalamus. Those neurons fired when the animals were exposed to a magnetic field, causing blood glucose concentrations to rise and insulin levels to fall. Ultimately, the mice ate more.

What I find most impressive about these reports . . . is just the level of care and effort that has gone into this.

Markus Meister, Caltech

The researchers did so by genetically engineering a construct to be expressed specifically in those neurons. The introduced sequences coded for the iron-based blood cell protein ferritin coupled to the TRPV1 membrane channel, a temperature-sensitive protein that allows positively charged ions such as calcium to enter cells. Stimulation of ferritins iron through a magnetic field was thought to prompt TRPV1 to open, although the precise mechanism is unclear.

In a different 2016 study in Nature Neuroscience,neuroscientist Ali Gler of the University of Virginia and colleagues used a similar construct they named Magnetothis time coupling ferritin to the TRPV4 membrane protein, sensitive to mechanical forces as well as temperature changes. Expressing this in dopamine-receptor neurons in the mouse striatum caused the rodents to preferentially spend time in a magnetized area of their cage.

The year prior, researchers of Tsinghua University in Beijing had expressed the gene for a different iron proteinmembrane channel construct, dubbed MAR, in specific sensory neurons of the nematode worm Caenorhabditis elegans. Applying a magnetic field resulted in changes to the worms movement, they reported in Science Bulletin. All three research groups presented multiple lines of evidence to back up their claims, such as electrophysiologic techniques to monitor the activity of individual neurons in brain slices and in vitro calcium imaging assays, in addition to the behavioral studies.

The studies received a mix reception from the scientific community. Some, like Boston neuroscientist Steve Ramirez, were enthusiastic, calling the work badass on Twitter, while others were skeptical, critiquing the findings in journals and on blogs. That latter includes Markus Meister, a physicist-turned neuroscientist at Caltech, who says hes aware of several research groups that had difficulties replicating some of the findingsspurring some to conduct lengthy, systematic investigations of the function of these constructs.

The new replication studies used a range of methods to investigate whether the constructs work as described in earlier research. In one study, neurophysiologist Tansu Celikel of Radboud University in the Netherlands and his colleagues focused their research on the Magneto construct used in Glers study.

Like Glers group, they used a virus to deliver DNA encoding Magneto to neurons in the mouse cortex and waited two weeks for the cells there to express the construct. Using permanently implanted microelectrodes, they recorded cortical neural activity as they exposed the animals to a magnetic field. The stimulus didnt change the rate of action potentials in those neurons, they observed, and the same was true for in vitro experiments. We argue that the utility of Magneto to control neural activity in vivo is not warranted, the authors write in the preprint.

In the second study, neuroscientist Julius Zhu of the University of Virginia and his team conducted a systematic investigation of all three constructs that had been used in previous studies: Magneto, the TRPV1-ferritin complex developed by the Rockefeller group, and the MAR construct. (Gler, who is also at Virginia provided some materials for the experiments, but the two labs did not collaborate.)

Were anxious to understand what the basis for the differences between his results and ours are.

Jeffrey Friedman, Rockefeller University

Similar to Celikels findings, they observed that magnetic fields did not induce an electrical current in Magneto-expressing mouse hippocampal cells in culture, when the construct was delivered either with a plasmid or a virus. They did note, however, that both Magneto-expressing neurons as well as control cells that lacked the construct frequently displayed spontaneous changes in current that sometimes triggered the cells to fire an action potential. Based on this, they suggest that Glers reportedly magnetically triggered action potentials are likely to represent mismatched spontaneous firings.

The team appears to have had difficulties getting the construct expressed in cells at all. They used a plasmid encoding the Magneto construct to express it human kidney cells in culture, and made electrophysiological recordings of the cells. Neither a magnetic field nor the addition of a protein that stimulates TRPV4 elicited significant electrical currents in the cells. Interestingly, they did observe a current when they repeated these experiments with kidney cells that expressed the wildtype, unaltered version of the gene for TRPV4 expressed separately with ferritins gene. Together with other observations, this suggested that Magneto doesnt form a functional ion channel or incorporate into the plasma membrane, the authors suggest. The construct lacks a portion of the TRPV4 protein considered necessary for its placement in cellular membranes, the researchers note.

In testing the other constructs, Zhus group used viruses to express MAR in neurons from cultured rat hippocampal slices, and the TRPV1-ferritin construct in hypothalamic neurons in intact mouse brains. Again, electrophysiologic recordings did not detect a change in action potentials in any of the genetically modified cells when they were exposed to a magnetic field, although the cells did exhibit frequent spontaneous action potentials. Together, these results support the theoretical conclusion that Magneto, [MAR] and [the ferritin-TRPV1 construct] are incapable of controlling neuronal activity by producing magnetically-evoked action potentials, they write in the preprint. The senior authors of both studies both declined to comment out of concern it would interfere with the publication of their research in a peer-reviewed journal.

What I find most impressive about these reports . . . is just the level of care and effort that has gone into this, remarks Meister. Neither he nor Anikeeva are surprised by the new findings; both have previously critiqued earlier studies. By now, if it worked as advertised, you would expect a small industry of people doing this and using it for all kinds of purposes, Meister says.

Neither have a good alternative explanation for the observations reported in earlier studies. Meister suggests it may boil down to human error, while Anikeeva speculates that tethering ferritin, a relatively bulky protein, to TRPV proteins might possibly make the channels leaky and lower the threshold for action potential firing.

Gler, who developed the Magneto construct, points out several differences between his study and the two preprints that may account for the contradictory results. The groups used different viruses to introduce the constructs to cells, and for the most part, didnt allow as much time for them to be expressed in neurons as Glers group did, which may be why they didnt achieve full presentation in the cellular membranes. For some experiments, they also didnt verify that the viruses were actually expressing the constructs before they introduced them into cells, he adds. Some batches will not work, and you have to systematically make sure that your tools are up to par, he tells The Scientist.

We acknowledge that the system we have developed is a little finnicky in that it requires a lot of optimization to get it to work, he adds. I think that is where the setback is: everybody wants to have something that works immediately. Magnetogenetics techniques will take some time to refine until they are reliable, he says.

Friedman, the senior author of the Nature study, is similarly puzzled why Zhus team couldnt replicate his findings. We take the Zhu paper seriously and . . . were anxious to understand what the basis for the differences between his results and ours are, he says. Zhus team expressed the construct indiscriminately into all neurons in the hypothalamus rather than selectively in a subset of cells, as Friedman did. Some hypothalamic neurons are more easily excitable than others, he explains. Its possible that by restricting the cells we were recording from, we may have gotten a cell type that . . . seems to be more rather than less responsive.

Friedman stresses that his team did multiple experiments as part of their study to ensure that they werent mistakenly attributing spontaneous neural activity to a magnetic effect. For instance, in the same Nature study they repeated their experiments with an altered version of the TRPV1 channel that acts as a chloride channel rather than a calcium channel. Whereas calcium influx would excite a neuron, chloride flux would inhibit it, Friedman explains. We get opposite effects when we use the inhibitory version of the construct instead of the activating one, he says. We wouldnt see that if it was spontaneous activity.

Both Gler and Friedman note there are three additional studies that report having successfully used similar genetic techniques to excite neurons under magnetic fields. In 2017, a team of researchers engineered a construct made of the genes for ferritin and the heat-sensitive channelseither TRPV1 or TRPV4into neural crest cells of chick embryos, claiming to have stimulated the neurons with electromagnetic fields. In 2018, another group combined the TRPV1-ferritin construct with a protein involved in cell migration, and showed that human kidney cells expressing the introduced genes had an unusual migration pattern when under a magnetic field. And earlier this year, a third set of researchers replicated Glers findings by expressing a TRPV4-ferritin construct in a human kidney cell line to better understand its function, also observing a response to magnetic stimulation.

Its not quite clear how these constructs might work. One possibility is that magnetic fields cause the iron atoms in the ferritin to flip periodically, generating heat that causes the temperature-sensitive TRPV1 channel to open. Another option is that the stimulated ferritin would tug open the central pore of the membrane channels. The group that was able to replicate Glers results in kidney cells suggested that the magnetic sensitivity of the TRPV4 channel has more to do with thermal energy than with mechanical force.

Meister has argued that these proposed mechanisms conflict with basic laws of physics, on the grounds that ferritin doesnt have the characteristics necessary to prompt a mechanical stimulus under a magnetic field. In several back-of-the-envelope calculations outlined in his 2016 eLife paper, Meister shows that magnetic interactions between ferritin and a magnetic field would be between five and ten orders of magnitude too weak to generate the mechanical force to cause a membrane channel to open.

The core of ferritin consists not of a truly magnetic substance, but ferrihydrite, which is only weakly paramagnetic at room temperature. This means that the molecule requires a more powerful magnetic field to induce a magnetic momentthat is, to align all iron atoms with the magnetic fieldthan those used in previous studies. Even if the iron ferritin was truly magnetic, the forces would still be too small to account for the proposed mechanisms, notes Anikeeva, who made similar arguments in a separate eLife paper.

Those biophysical arguments could be overcome if physicist Mladen Barbic of the Howard Hughes Medical Institutes Janelia research campus is right. Earlier this year in eLifehe proposed several new alternative mechanisms whereby magnetic stimulation of ferritin could open an ion channel. One, for instance, is based on the Einstein-de-Haas effect, by which iron oxide particles would rotate under a magnetic field, producing energy which could perhaps cause the ion channel to open. Other groups are exploring the possibility of a chemical mechanism through the release of free iron, Friedman says. I think all these are on the table, he says.

The lure of a non-invasive method to control neural activity has kept scholars in pursuit of a reliable method of magnetogenetics, including those that arent based on ferritin. For instance, Anikeevas group has shown that its possible to open TRPV1 and stimulate neuronal activity with synthetic nanoparticles made of the iron oxide magnetite. The particles are known to dissipate heat, and that opens the channels, she explains. However, these particles cant be genetically expressed because they are synthetic. Rather, they have to be injected into the brain.

Another route is to look at organisms in nature that have already evolved systems that respond to magnetic fields. Magnetotactic bacteria, for instance, produce particles similar to the ones Annikeeva synthesized in her lab, she writes. Scientists could also examine the mechanisms that migratory organisms such as pigeons, butterflies, and fish use to sense magnetic fields to navigate, she suggests.

What may help speed these efforts along, and help untangle the controversies around magnetogenetics, is better communication between physics and neuroscience, Anikeeva notes. There should be more interaction between physical and biological sciences, especially in the context of training of both biologists and engineers in each others disciplines and vocabularies.

Katarina Zimmeris a New Yorkbased freelance journalist. Find her on Twitter@katarinazimmer.

Continued here:
Two Studies Fail to Replicate Magnetogenetics Research - The Scientist

The news that Formula One legend Michael Schumacher was moved to a hospital in Paris last week for pioneering stem cell therapy has provoked a fever of hope and speculation among fans that his condition could be improved.

After suffering devastating head injuries in a ski accident almost six years ago, Schumacher was placed in a coma for six months and has been receiving treatment at his home in Switzerland. He has not been seen in public since the accident.

His privacy is closely guarded and, while it is understood he cannot walk or stand, and, according to former Ferrari manager, Jean Todt, he may still have trouble communicating, nothing has been confirmed officially.

No wonder then that fans have been so excited to hear Schumacher is now under the care of world-renowned cardiac surgeon Philippe Menasch, described as a "pioneer in cell surgery" at the Georges-Pompidou hospital in Paris.

READ MORE:* Schumacher 'conscious' after treatment*Corinna Schumacher provides rare update*Schumacher 'struggles' to communicate*Mick Schumacher trying to emulate his dad

Stem cells are cells that can differentiate or change into other types of cell, opening the possibility of replacing damaged cells with healthy ones. Scientists have been looking into their use since the Sixties, most successfully so far in cases of cancers of the blood or bone marrow. More than 26,000 patients are treated with blood stem cells in Europe each year.

And since the Eighties, skin stem cells have been used to grow skin grafts for patients with life-threatening burns; most recently, a new stem cell-based treatment to repair damage to the cornea (the surface of the eye) after an injury like a chemical burn, has received conditional approval in Europe.

But their flexibility offers hope for lots of illnesses and conditions including heart disease, MS and macular degeneration and clinical trials are progressing in all these areas. Chronic spinal cord injury is being researched with some promise, thanks to the Christopher & Dana Reeve Foundation, set up after actor Christopher Reeve was paralysed in a riding accident.

Crucially, for cases such as Schumacher, stem cells are also being explored for neurodegenerative diseases like Parkinson's and Alzheimer's and traumatic brain injuries like the one he suffered in a skiing accident in December 2013.

Head injuries are difficult to treat as brain damage cannot be undone and each case is different. Asked for comment by The Daily Telegraph, the hospital responded that they could neither confirm nor deny the presence of Schumacher.

However, if he is under the care of Menasch, it is likely he will have had stem cells delivered by an IV to the area of the body where it is felt they could work best - whether that is his head or heart.

CHRISTOPHE ENA/AP

Paris' Georges-Pompidou Hospital, where Michael Schumacher is reportedly a patient.

In a recent interview online, Menasch explained that stem cell treatment for cardiac conditions - his particular area of expertise - is in its infancy. "Nobody really knows how stem cells are working," he said. "They do not permanently transplant into the myocardium [the muscular tissue of the heart] - after a couple of days or weeks, they just disappear.

"But you still may have a functional benefit as during their transient stay in the heart," he explains in the Future Tech podcast, "as the cells release molecules into the tissue. The hypothesis is that the repair comes from the heart itself, stimulated by these molecules."

Should the stem cells have been intended for Schumacher's brain injury, research suggests that the treatment has potential. A University of Plymouth study published in the journal Cell Reports in June found that neural stem cells could be used to "wake up" and produce new neurons (nerve cells) and surrounding glial cells in the brain.

The research is in its infancy, says lead author Dr Claudia Barros, from the Institute of Translational and Stratified Medicine at the University of Plymouth, who acknowledges there is still a long way to go until such findings can be translated into human treatments.

"We are working to expand our findings, to bring us closer to the day when human neural stem cells can be controlled and efficiently used to facilitate brain damage repair, or even prevent brain cancer growth that is fuelled by stem-like cells," she says.

A Chinese study published last month in the journal Frontiers in Cellular Neuroscience examined the current state of progress into the effects of stem cell therapy on traumatic brain injury. But the researchers from Zhejiang University, Hangzhou warned much more work was needed: "Although a large number of basic studies have confirmed that stem cells have good effect in the craniocerebral injury," they said, "the safety of stem cells, the route of injection, the time of injection and the specific mechanism are all factors that affect the clinical application of stem cells, and are the important research point in the future study."

PREMA TEAM

Mick Schumacher doesn't mind the comparisons with his seven-time F1 champion father Michael.

In the UK, some applications of stem cell medicine are already available privately, although tightly controlled by the Human Tissue Authority and not in the brain.

Simon Checkley, CEO at the Regenerative Clinic in Brighton, explains: "It is possible to get stem cells from sources outside your body, like the umbilical cord or Wharton's jelly [the vitreous humour in the eyeball], but in the UK we can only take stem cells from our own bodies.

"It is possible to get them donated, but it is safer to use your own."

In some countries, stem cells can then be manipulated in a laboratory but that is illegal in the UK, says Checkley. "There is a concern with cultured stem cells which have been bred in a Petri dish that they may keep proliferating after you transplant them into a body. That, having triggered their growth, you can't stop it and no one knows what might happen."

At the Regenerative Clinic, stem cells are taken from adipose fat, where they are plentiful, and then injected back into the area to be treated - mostly arthritic joints.

"We are seeing fantastic results," Checkley says, "with reduced pain and improved mobility for 80 per cent of patients." He is considering a clinical trial which could see the treatment pass through the National Institute for Health and Care Excellence (NICE) and become available on the NHS.

The therapy is still only four years old, he emphasises. "We have treated 1000 patients so far and around the world, it's about 40,000. We need longer-term studies."

LUCA BRUNO/AP

Michael Schumacher has not been seen in public since suffering a serious brain injury in a skiing accident nearly six years ago.

This type of stem cell treatment is also offered in the UK for post-menopause vaginal atrophy and stress incontinence, Checkley says, plus the genital skin condition lichen sclerosis. In all these cases, he says, the mechanism is the same: the stem cells are not replicating dead or dying cells but acting as signalling devices, alerting the body that this is an area where healing is needed.

For stem cells to work in more complex conditions, they would need to be manipulated, Checkley says. In cases of brain injury or disease, that would mean altering stem cells so that they could be targeted more precisely. But he believes the role would be similar: "The idea is they would go to the area of greatest damage and signal the body to regrow tissue there."

Cost would be a huge factor, he points out. A treatment for arthritis costs about 6000 (NZ$11,700) at the Regenerative Clinic but an IV-led treatment for brain injury with manipulated stem cells could cost up to 50,000 (NZ$98,000). But then what price recovery from a traumatic brain injury? Full recovery thanks to stem cells would be a prize beyond value.

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Reported stem cell treatment could give hope to Michael Schumacher - Stuff.co.nz