Human stem cells successfully cloned for the first time

A working process for cloning stem cells from existing human cells has finally been discovered by a team at Oregon Health & Science University.

These stem cells were created by reprogramming healthy skin cells, a goal that has eluded researchers around the world for years. It’s the first key step in developing medical procedures for replacing dying or injured cells with new ones to stave off disease and age. That could mean growing a new liver, or kidney or heart, in the lab for an organ transplant, or even repairing the brains of those suffering with diseases like Parkinson’s.

The team was led by Shoukhrat Mitalipov from the reproductive and developmental sciences department of the Oregon National Primate Research Centre. He said: “A thorough examination of the stem cells derived through this technique demonstrated their ability to convert just like normal embryonic stem cells into several different cell types, including nerve cells, liver cells and heart cells. Furthermore, because these reprogrammed cells can be generated with nuclear genetic material from a patient, there is no concern of transplant rejection.”

“While there is much work to be done in developing safe and effective stem cell treatments, we believe this is a significant step forward in developing the cells that could be used in regenerative medicine.”

The technique Mitalipov and his team used is called “somatic cell nuclear transfer” — as you can see in the video, it essentially involves sucking out the DNA from an adult cell and inserting it into the empty nucleus of a donor egg. This creates a clone of the original cell, and is in fact the first step in the cloning method used to create animal clones like Dolly the sheep.

However, in its therapeutic mode, the new cells can be grown as replacements for the original type of cell. That objective hasn’t been reached until now as human eggs are extremely fragile compared to many of the animals which we have cloned. That Mitalipov and team have succeeded is down to research on primates, and adapting primate stem cell research to humans.

As a cell divides after fertilisation, it undergoes several transformations as it prepares to split and multiply. The metaphase is the moment just before a cell splits, as the chromosomes align alongside each other in the very centre of the cell so that, when it splits, one goes one way as another goes the other, each taking the full copy of the genetic code. The researchers managed to stall the metaphase while the cell underwent nuclear transfer, effectively giving the new chromosomes time to get settled before the metaphase finished and cell division proceeded.

An added bonus is that the eggs used have not been fertilised, so there won’t be any debates over the ethics of embryonic stem cells as we have seen in the US in the past. While the researchers placed skin cell nuclei into the receptor egg cells, the method is conceivably similar for any other kind of cell.

And, while it may sounds like the first step towards a practical method for cloning humans, the Mitalipov has made it clear that’s not the aim. “Our research is directed toward generating stem cells for use in future treatments to combat disease. While nuclear transfer breakthroughs often lead to a public discussion about the ethics of human cloning, this is not our focus, nor do we believe our findings might be used by others to advance the possibility of human reproductive cloning.”

The research has been published in the journal Cell.

Ketamine Shows Significant Therapeutic Benefit in People with Treatment-Resistant Depression

Patients with treatment-resistant major depression saw dramatic improvement in their illness after treatment with ketamine, an anesthetic, according to the largest ketamine clinical trial to-date led by researchers from the Icahn School of Medicine at Mount Sinai. The antidepressant benefits of ketamine were seen within 24 hours, whereas traditional antidepressants can take days or weeks to demonstrate a reduction in depression.

The research will be discussed at the American Psychiatric Association meeting on Monday, May 20, 2013 at 12:30 pm in the Press Briefing Room at the Moscone Center in San Franscico.

Led by Dan Iosifescu, MD, Associate Professor of Psychiatry at Mount Sinai; Sanjay Mathew, MD, Associate Professor of Psychiatry at Baylor College of Medicine; and James Murrough, MD Assistant Professor of Psychiatry at Mount Sinai, the research team evaluated 72 people with treatment-resistant depression—meaning their depression has failed to respond to two or more medications—who were administered a single intravenous infusion of ketamine for 40 minutes or an active placebo of midazolam, another type of anesthetic without antidepressant properties. Patients were interviewed after 24 hours and again after seven days. After 24 hours, the response rate was 63.8 percent in the ketamine group compared to 28 percent in the placebo group. The response to ketamine was durable after seven days, with a 45.7 percent response in the ketamine group versus 18.2 percent in the placebo group. Both drugs were well tolerated.

“Using midazolam as an active placebo allowed us to independently assess the antidepressant benefit of ketamine, excluding any anesthetic effects,” said Dr. Murrough, who is first author on the new report. “Ketamine continues to show significant promise as a new treatment option for patients with severe and refractory forms of depression.”

Major depression is caused by a breakdown in communication between nerve cells in the brain, a process that is controlled by chemicals called neurotransmitters. Traditional antidepressants such as selective serotonin reuptake inhibitors (SSRIs) influence the activity of the neurotransmitters serotonin and noreprenephrine to reduce depression. In these medicines, response is often significantly delayed and up to 60 percent of people do not respond to treatment, according to the U.S Department of Health and Human Services. Ketamine works differently than traditional antidepressants in that it influences the activity of the glutamine neurotransmitter to help restore the dysfunctional communication between nerve cells in the depressed brain, and much more quickly than traditional antidepressants.

Future studies are needed to investigate the longer term safety and efficacy of a course of ketamine in refractory depression. Dr. Murrough recently published a preliminary report in the journal Biological Psychiatry on the safety and efficacy of ketamine given three times weekly for two weeks in patients with treatment-resistant depression.

“We found that ketamine was safe and well tolerated and that patients who demonstrated a rapid antidepressant effect after starting ketamine were able to maintain the response throughout the course of the study,” Dr. Murrough said. “Larger placebo-controlled studies will be required to more fully determine the safety and efficacy profile of ketamine in depression.”

The potential of ketamine was discovered by Dennis S. Charney, MD, Anne and Joel Ehrenkranz Dean of the Icahn School of Medicine at Mount Sinai, and Executive Vice President for Academic Affairs of The Mount Sinai Medical Center, in collaboration with John H. Krystal, MD, Chair of the Department of Psychiatry at Yale University.

“Major depression is one of the most prevalent and costly illnesses in the world, and yet currently available treatments fall far short of alleviating this burden,” said Dr. Charney. “There is an urgent need for new, fast-acting therapies, and ketamine shows important potential in filling that void.”

Dr. Murrough will present his research on Sunday, May 19, 2013 from 1:00 pm to 3:00 pm in the Moscone exhibit hall at the APA meeting.

Temporal Processing in the Olfactory System: Can We See a Smell?

Sensory processing circuits in the visual and olfactory systems receive input from complex, rapidly changing environments. Although patterns of light and plumes of odor create different distributions of activity in the retina and olfactory bulb, both structures use what appears on the surface similar temporal coding strategies to convey information to higher areas in the brain. We compare temporal coding in the early stages of the olfactory and visual systems, highlighting recent progress in understanding the role of time in olfactory coding during active sensing by behaving animals. We also examine studies that address the divergent circuit mechanisms that generate temporal codes in the two systems, and find that they provide physiological information directly related to functional questions raised by neuroanatomical studies of Ramon y Cajal over a century ago. Consideration of differences in neural activity in sensory systems contributes to generating new approaches to understand signal processing.

For combat veterans suffering from post-traumatic stress disorder, ‘fear circuitry’ in the brain never rests

Chronic trauma can inflict lasting damage to brain regions associated with fear and anxiety. Previous imaging studies of people with post-traumatic stress disorder, or PTSD, have shown that these brain regions can over-or under-react in response to stressful tasks, such as recalling a traumatic event or reacting to a photo of a threatening face. Now, researchers at NYU School of Medicine have explored for the first time what happens in the brains of combat veterans with PTSD in the absence of external triggers.

Their results, published in Neuroscience Letters, and presented today at the annual meeting of the American Psychiatry Association in San Francisco, show that the effects of trauma persist in certain brain regions even when combat veterans are not engaged in cognitive or emotional tasks, and face no immediate external threats. The findings shed light on which areas of the brain provoke traumatic symptoms and represent a critical step toward better diagnostics and treatments for PTSD.

A chronic condition that develops after trauma, PTSD can plague victims with disturbing memories, flashbacks, nightmares and emotional instability. Among the 1.7 million men and women who have served in the wars in Iraq and Afghanistan, an estimated 20% have PTSD. Research shows that suicide risk is higher in veterans with PTSD. Tragically, more soldiers committed suicide in 2012 than the number of soldiers who were killed in combat in Afghanistan that year.

“It is critical to have an objective test to confirm PTSD diagnosis as self reports can be unreliable,” says co-author Charles Marmar, MD, the Lucius N. Littauer Professor of Psychiatry and chair of NYU Langone’s Department of Psychiatry. Dr. Marmar, a nationally recognized expert on trauma and stress among veterans, heads The Steven and Alexandra Cohen Veterans Center for the Study of Post-Traumatic Stress and Traumatic Brain Injury at NYU Langone Medical Center.

The study, led by Xiaodan Yan, a research fellow at NYU School of Medicine, examined “spontaneous” or “resting” brain activity in 104 veterans of combat from the Iraq and Afghanistan wars using functional MRI, which measures blood-oxygen levels in the brain. The researchers found that spontaneous brain activity in the amygdala, a key structure in the brain’s “fear circuitry” that processes fearful and anxious emotions, was significantly higher in the 52 combat veterans with PTSD than in the 52 combat veterans without PTSD. The PTSD group also showed elevated brain activity in the anterior insula, a brain region that regulates sensitivity to pain and negative emotions.

Moreover, the PTSD group had lower activity in the precuneus, a structure tucked between the brain’s two hemispheres that helps integrate information from the past and future, especially when the mind is wandering or disengaged from active thought. Decreased activity in the precuneus correlates with more severe “re-experiencing” symptoms—that is, when victims re-experience trauma over and over again through flashbacks, nightmares and frightening thoughts.

Individuals who drink heavily and smoke may show ‘early aging’ of the brain

• Alcohol treatment interventions work best when patients understand and are actively involved in the process.
• A first-of-its-kind study looks at the interactive effects of smoking status and age on neurocognition in one-month-abstinent alcohol dependent (AD) individuals in treatment.
• Results show that AD individuals who currently smoke have more problems with memory, ability to think quickly and efficiently, and problem-solving skills than those who do not smoke, effects which seem to become greater with increasing age.

Treatment for alcohol use disorders works best if the patient actively understands and incorporates the interventions provided in the clinic. Multiple factors can influence both the type and degree of neurocognitive abnormalities found during early abstinence, including chronic cigarette smoking and increasing age. A new study is the first to look at the interactive effects of smoking status and age on neurocognition in treatment-seeking alcohol dependent (AD) individuals. Findings show that AD individuals who currently smoke show more problems with memory, ability to think quickly and efficiently, and problem-solving skills than those who don’t smoke, effects which seem to become exacerbated with age.

Results will be published in the October 2013 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.

“Several factors – nutrition, exercise, comorbid medical conditions such as hypertension and diabetes, psychiatric conditions such as depressive disorders and post-traumatic stress disorder, and genetic predispositions – may also influence cognitive functioning during early abstinence,” explained Timothy C. Durazzo, assistant professor in the department of radiology and biomedical imaging at the University of California San Francisco, and corresponding author for the study. “We focused on the effects of chronic cigarette smoking and increasing age on cognition because previous research suggested that each has independent, adverse affects on multiple aspects of cognition and brain biology in people with and without alcohol use disorders. This previous research also indicated that the adverse effects of smoking on the brain accumulate over time. Therefore, we predicted that AD, active chronic smokers would show the greatest decline in cognitive abilities with increasing age.”

“The independent and interactive effects of smoking and other drug use on cognitive functioning among individuals with AD are largely unknown,” added Alecia Dager, associate research scientist in the department of psychiatry at Yale University. “This is problematic because many heavy drinkers also smoke. Furthermore, in treatment programs for alcoholism, the issue of smoking may be largely ignored. This study provides evidence of greater cognitive difficulties in alcoholics who also smoke, which could offer important insights for treatment programs. First, individuals with AD who also smoke may have more difficulty remembering, integrating, and implementing treatment strategies. Second, there are clear benefits for thinking skills as a result of quitting both substances.”

Durazzo and his colleagues compared the neurocognitive functioning of four groups of participants, all between the ages of 26 and 71 years of age: never-smoking healthy individuals or “controls” (n=39); and one-month abstinent, treatment-seeking AD individuals, who were never-smokers (n = 30), former-smokers (n = 21) and active-smokers (n = 68). Evaluated cognitive abilities included cognitive efficiency, executive functions, fine motor skills, general intelligence, learning and memory, processing speed, visuospatial functions, and working memory.

“We found that, at one month of abstinence, actively smoking AD [individuals] had greater-than-normal age effects on measures of learning, memory, processing speed, reasoning and problem-solving, and fine motor skills,” said Durazzo. “AD never-smokers and former-smokers showed equivalent changes on all measures with increasing age as the never-smoking controls. These results indicate the combination of alcohol dependence and active chronic smoking was related to an abnormal decline in multiple cognitive functions with increasing age.”

“These results indicate the combined effects of these drugs are especially harmful and become even more apparent in older age,” said Dager. “In general, people show cognitive decline in older age. However, it seems that years of combined alcohol and cigarette use exacerbate this process, contributing to an even greater decline in thinking skills in later years.”

Durazzo agreed. “Chronic cigarette smoking, excessive alcohol consumption, and increasing age are all associated with increased oxidative damage to brain tissue,” he said. “Oxidative damage results from increased levels of free radicals and other compounds that directly injure neurons and other cells that make up the brain. Cigarette smoking and excessive alcohol consumption expose the brain to a tremendous amount of free radicals. We hypothesize that chronic, long-term exposure to cigarette smoke and excessive alcohol consumption interacts with the normal aging process to produce greater neurocognitive decline in the active-smoking AD group.”

Cigarette smoking is a “modifiable health risk” that is directly associated with at least 440,000 deaths every year in the United States, Durazzo noted. “Chronic smoking, and to a lesser extent, alcohol use disorders are also associated with an increased risk for Alzheimer’s disease,” he said. “So, the combination of these modifiable health risks may place an individual at even greater risk for development of Alzheimer’s disease. Given the above, in conjunction with the findings from our cognitive and neuroimaging research, we completely support programs that routinely offer smoking cessation programs to all individuals seeking treatment for alcohol/substance abuse disorders.”

Deep brain stimulation: a fix when the drugs don’t work

Neurological disorders can have a devastating impact on the lives of sufferers and their families.

Symptoms of these disorders differ extensively – from motor dysfunction in Parkinson’s disease, memory loss in Alzheimer’s disease to inescapable cravings in drug addiction.

Drug treatments are often ineffective in these disorders. But what if there was a way to simply switch off a devastating tremor, or boost a fading memory?

Recent advances using Deep Brain Stimulation (DBS) in selective brain regions have provided therapeutic benefits and have allowed those affected by these neurological disorders freedom from their symptoms, in absence of an existing cure.

A pacemaker for the brain

Artificial cardiac pacemakers are typically associated with controlling and resynchronising heartbeats by electrical stimulation of the heart muscle.

In a similar manner, DBS sends electrical impulses to specific parts of the brain that control discrete functions. This stimulation evokes control over the neural activity within these regions.

Prior to switching on the electrical stimulation, electrodes are surgically implanted within precise brain regions to control a specific function.

The neurosurgery is conducted under local anaesthetic to maintain consciousness in the patient. This ensures that the electrode does not damage critical brain regions.

The brain itself has no pain receptors so does not require anaesthetic.

Following recovery from surgery the electrodes are activated and the current calibrated by a neurologist to determine the optimal stimulation parameters.

The patient can then control whether the electrodes are on or off by a remote battery-powered device.

Turning off tremors

Perhaps the most documented success of DBS is in the control of tremors and motor coordination in Parkinson’s disease.

This is caused by the degeneration of neurons in an area of the brain called the substantia nigra. These neurons secrete the neurotransmitter dopamine.

Deterioration of these neurons reduces the amount of dopamine available to be released in a brain area involved in movement, the basal ganglia.

Drug therapy for Parkinson’s disease involves the use of levodopa (L-DOPA), a form of dopamine that can cross the blood brain barrier and then be synthesised into dopamine.

The administration of L-DOPA temporarily reduces the motor symptoms by increasing dopamine concentrations in the brain. However, side effects of this treatment include nausea and disordered movement.

DBS has been shown to provide relief from the motoric symptoms of Parkinson’s disease and essential tremors.

For the treatment of Parkinson’s disease electrodes are implanted into regions of the basal ganglia – the subthalamic nucleus or globus pallidus, to restore control of movement.

These are regions innervated by the deteriorating substantia nigra, therefore the DBS boosts stimulation to these areas.

Patients can then switch on the electrodes, stimulating these brain regions to enhance control of movement and diminish tremors.

Restoring fading memories

Recently, DBS has been used to diminish memory deficits associated with Alzheimer’s disease, a progressive and terminal form of dementia.

The pathologies associated with Alzheimer’s disease involve the formation of amyloid plaques and neurofibrillary tangles within the brain leading to dysfunction and death of neurons.

Brain regions primarily affected include the temporal lobes, containing important memory structures including the hippocampus.

Recent clinical trials with DBS involve the implantation of electrodes within the fornix – a structure connecting the left and right hippocampi together.

By stimulating neural activity within the hippocampi via the fornix, memory deficits associated with Alzheimer’s disease can be improved, enhancing the daily functioning of patients and slowing the progression of cognitive decline.

Deactivating addiction

Another use of DBS is in the treatment of substance abuse and drug addiction. Substance-related addictions constitute the most frequently occurring psychiatric disease category and patients are prone to relapse following rehabilitative treatment.

Persistent drug use leads to long term changes in the brain’s reward system.

Understanding of the reward systems affected in addiction has created a range of treatment options that directly target dysregulated brain circuits in order to normalise functionality.

One of the key reward regions in the brain is the nucleus accumbens and this has been used as a DBS target to control addiction.

Translational animal research has indicated that stimulation of the nucleus accumbens decreases drug seeking in models of addiction. Clinical studies have shown improved abstinence in both heroin addicts and alcoholics.

Studies have extended the use of DBS to potentially restore control of maladaptive eating behaviours such as compulsive binge eating.

In a recent study, binge eating of a high fat food in mice was decreased by DBS of the nucleus accumbens. This is the first study demonstrating that DBS can control maladaptive eating behaviours and may be a potential therapeutic tool in obesity.

Despite its therapeutic use for more than a decade, the neural mechanism of DBS is still not yet fully understood.

The remedial effect is proposed to involve modulation of the dopamine system – and this seems particularly relevant in the context of Parkinson’s disease and addiction.

DBS potentially has effects on the functional activity of other interconnected brain systems. While it can provide therapeutic relief from symptoms of neurological diseases, it does not treat the underlying pathology.

But it provides both effective and rapid intervention from the effects of debilitating illnesses, restoring activity in deteriorating brain regions and aids understanding of the brain circuits involved in these disorders.