28 February 2006

IEEE Spectrum Reports on Cyborg Psychiatry

The March online issue of IEEE Spectrum reports on the use of electromagnetic technology in Psychiatry. It is a 4-page report, with a better technological slant than the NYT article discussed in the previous Cyborg posting.

The technology McGuffee uses, vagus nerve stimulation, was the first to enter routine clinical use. A pacemakerlike device about the size of a pocket watch, implanted under the skin of the chest, pulses a nerve in the neck [see illustration, "Vagus Nerve Stimulation"]. In about 16 percent of patients like McGuffee, according to clinical studies, that electric pulsing completely quashes the symptoms of depression. It was approved as a depression therapy, for use in conjunction with drugs, by government regulators in the European Union and Canada in 2001. Last June, it became the first psychiatric device to be reviewed and approved in the United States, which has more stringent requirements for medical devices. Nevertheless, a number of psychiatrists remain unconvinced that the therapy works in enough people to outweigh the risk and cost of surgery.

Vagus nerve stimulation isn't the only technology being touted for treatment of the severely depressed. Another technique, repetitive transcranial magnetic stimulation, uses powerful magnets to generate current in well-defined portions of the brain [see illustration, "Repetitive Transcranial Magnetic Stimulation"]. Many research groups around the world have experimented with the technology. At last count the results of more than 60 depression trials performed in Australia, Israel, Taiwan, the United States, Europe, and elsewhere had been published. But clinical use is just beginning. The technology is winding its way toward a review by U.S. regulators, and the company behind it, Neuronetics Inc., in Malvern, Pa., says it could be approved within the year.

And these two are just the ones closest to the clinic. Researchers are exploring three other, more experimental technologies. One uses direct current to produce a change in the brain similar to that of magnetic stimulation. Another uses transcranial magnetic stimulators to spark seizures just as electroconvulsive therapy does but, it is hoped, without the amnesia that can accompany it. The third experimental technology borrows a device used to control the tremors of Parkinson's disease. Surgeons have begun implanting electrodes in patients' brains to switch off malfunctioning brain circuits involved in depression and obsessive-compulsive disorder.

Read the whole thing here. Here is more from IEEE:

After one year, one in six patients treated with the nerve stimulator was free of depression, and 56 percent got some meaningful benefit—as measured by a standardized questionnaire used to rate the severity of a patient's depression. Of those who did respond, about 70 percent continued to benefit after two years. But waiting a year to see if the treatment worked in a disease that comes at irregular intervals was highly unusual. The lack of a control group that had the device implanted but not turned on to counteract the placebo effect was stranger still. In August 2004, the U.S. Food and Drug Administration, which regulates the marketing of medical devices, decided not to allow Cyberonics to sell the vagus nerve stimulator as a depression treatment, overruling its own advisors in the process.

.... Deep-brain stimulation has been in use for years to treat the tremors of Parkinson's disease. In that case, 3- to 5-volt pulses at about 100 Hz are applied to a part of a brain circuit that malfunctions and causes the tremors. The stimulation suppresses the activity of neurons near the electrode, mimicking their surgical destruction, but with a key twist. "Basically, it's reversible and tunable brain surgery," says Schlaepfer. Turn the device on, and that section of the brain goes off-line. Turn it off, and the neurons spring back into action. It's a simplistic view, of course, and scientists still don't know if the electrode's current blocks brain traffic by holding the cells at too high a voltage to propagate a signal, exhausts their supply of chemical transmitters, overlays a meaningless jamming signal on them, or does something different entirely.

The device has also been used to treat severe obsessive-compulsive disorder; indeed, this was its first use in psychiatry. In that treatment, neurosurgeons had been destroying a few cubic millimeters of a particular structure in the brain. Now surgeons have begun inserting electrodes instead of destroying those tiny parts of the brain.

A group based at the University of Toronto and led by neurosurgeon Andres Lozano and neurologist Helen S. Mayberg reported the first trial of deep-brain stimulation for depression only a year ago. (Mayberg has since become a professor at Emory University, in Atlanta.) Imaging studies led them to Broadmann area 25, a pair of structures deep in the brain just above and behind the eyes that become active when people are sad. It has abnormally high blood flow in people with treatment-resistant depression; antidepressant drugs tend to reduce the amount of blood flow there. So the Toronto researchers implanted electrodes powered by a Medtronic stimulator in that spot in six patients. Five of the six responded well initially, and four continued to do so six months out. According to Lozano, those four are still doing well two years later. Lozano, who has been implanting deep-brain stimulators for more than a decade, says that not enough is known about why patients respond or don't respond to the procedure to say if there is a need to tweak the technology. "We don't know if it's the electrodes or the patients," he says.

Although the seminal work was done using stimulators made by Medtronic, another maker of implantable stimulators, Advanced Neuromodulation Systems Inc. (ANS), in Plano, Texas, holds the relevant intellectual property rights, according to Rohan Hoare, the company's vice president of corporate strategy and development. ANS is now replicating Mayberg and Lozano's results in a pilot study using its Libra deep brain stimulation system. The main difference between the Medtronic systems used in Toronto and Bonn and ANS's devices is that Medtronic's delivers a constant-voltage pulse, which allows the current to vary depending on the impedance of the brain, while its competitor delivers constant current, allowing the voltage to vary. ANS's vice president for scientific affairs, Tracy Cameron, notes that most animal research has been done using constant-current stimulators and hypothesizes that this approach may be more in tune with the brain's physiology.

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Brain Implants for Parkinson's, Epilepsy, Depression: We Are All Cyborgs Now

In a recent New York Times article, patients and doctors discuss the new neuro-implant technology called neuromodulation. Used as treatment for disorders from Parkinson's disease, depression, and epilepsy, to chronic pain disorders and tremors. But that is just the beginning. In this industry, the sky is the limit. Read on:

Don Falk stretched his right arm over his head, past the faint marks where a surgeon sank two wires deep in his brain, to show how uncontrollable tremors in his hand used to slap him awake in the morning.

It was just one of many difficulties he suffered as his Parkinson's disease advanced. Falk had trouble shaving and walking, and his medications caused his head to twitch awkwardly, making him self-conscious in church.

''It's the day-to-day living that is so hard with Parkinson's,'' he said.

In May, Falk, 52, started to get better with the help of an emerging class of implantable medical devices called neuromodulators -- tiny machines that stimulate the central nervous system to treat a host of disorders. Analysts say they could be the next big thing for some of the market's hottest medical technology companies.

....Neuromodulators are technological cousins of implantable heart defibrillators, a $5.5 billion market that's growing at nearly 20 percent a year.

The devices do have some hurdles. While they've been shown to be safe and effective at treating some disorders, they're generally recommended only after drugs and other less invasive treatments fail.

The surgical procedure can be complex, and the devices themselves are expensive, about $50,000 for the deep brain stimulator, less for other devices in the class. And that doesn't include the costs of surgery.

The results are impressive, but ''it's not a big moneymaker,'' said Dr. Richard Veyna, Falk's neurosurgeon at Methodist Hospital in this Minneapolis suburb. Not enough doctors know about the technology, and at current insurance reimbursement rates simpler procedures are more profitable, Veyna said.

Perhaps surprisingly, the risks of brain surgery rarely dissuade patients, maybe because they are tired of living with Parkinson's symptoms and have seen other treatments fail, he said.

Falk said he didn't hesitate about brain surgery. ''My tremor was so bad I just wanted it done,'' he said. His adult children didn't think twice either: ''They did not like me just sitting there, shaking and stuff.''

Falk touts his procedure to other Parkinson's patients, telling them that his medication has been cut by two-thirds and his insurance covered the procedure.

Competition, higher volume and technological advances drove down the costs of implantable cardiac devices, and could do the same for the neuromodulators. Only a small number of people who might benefit from the devices -- people who suffer from Parkinson's, tremors, epilepsy, chronic depression or chronic pain -- are now getting them, Wald said.

''Neurostimulation to me, in fact the whole neurological space, is what cardiology was 10 years ago,'' Wald said. ''The opportunity is just vast.''

....Dr. Todd Sitzman, an anesthesiologist in Hattiesburg, Miss., has used them in hundreds of patients with chronic pain over the last decade.

''Does it work from the patient's perspective? Without question,'' said Sitzman, who sits on the National Pain Foundation's board of directors. ''It is a therapy that gives them some relief and some semblance of a life.''

Companies are already pushing to develop new applications for the devices. They see potential uses in treating diseases including depression, obsessive-compulsive disorder, erectile dysfunction, traumatic brain injuries, obesity, angina, incontinence and ringing in the ears.

Read the entire article here.

Hat tips to Singularity News (Multipolarity News) and The Speculist.

Personally, it seems to me that these companies are thinking too small. If implants can help the blind to see, there is no reason they cannot do much more than the planned uses listed in the NYT article. I prefer correcting damage and defects biologically, but there will definitely be a period of time when the hardware will be able to accomplish things the wetware is not capable of. Think of it as the need to use crutches, temporarily. Eventually, you put them aside and walk on your own.

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Taming Cancer: Researchers Transform Melanoma back to Normal Tissue

The key to cancer, and the key to aging, is learning how to control the differentiation and de-differentiation of cells. A previous article here discusses the same general topic.

Scientists at Northwestern University and the Stowers Institute for Medical Research have reprogrammed malignant melanoma cells to become normal melanocytes, or pigment cells, a development that may hold promise in treating of one of the deadliest forms of cancer.

A report describing the group's research was published in the Feb. 27 online edition of the Proceedings of the National Academy of Sciences that will appear in the March 7 issue of the journal.

The experiments were conducted as a collaboration involving the laboratories of Mary J. C. Hendrix, president and scientific director of the Children's Memorial Research Center, Northwestern University Feinberg School of Medicine, and Paul M. Kulesa, director of Imaging at the Stowers Institute for Medical Research in Kansas City, Mo.

The study demonstrated the ability of malignant melanoma cells to respond to embryonic environmental cues in a chick model -- in a manner similar to neural crest cells, the cell type from which melanocytes originate -- inducing malignant cells express genes associated with a normal melanocyte.

The researchers also showed that the malignant melanoma cells lost their tumor-causing ability as they became reprogrammed by the embryonic microenvironment to assume a more normal melanocyte-like cell type.

"Using this innovative approach, further investigation of the cellular and molecular interactions within the tumor cell embryonic chick microenviroment should allow us to identify and test potential candidate molecules to control and reprogram metastatic melanoma cells," Hendrix said.

....Kulesa's laboratory transplanted adult human metastatic melanoma cells, isolated and characterized by the Hendrix laboratory group, into the neural tube of chick embryos.

The transplanted melanoma cells did not form tumors.

Rather, like neural crest cells, the melanoma cells invaded surrounding chick tissues in a programmed manner, distributing along the neural-crest-cell migratory pathways throughout the chick embryo.

The investigators found that a subpopulation of the invading melanoma cells produced markers indicative of skin cells and neurons that had not been present at the time of transplantation.

Taken together, results of this study suggest that human metastatic melanoma cells respond to and are influenced by the chick embryonic neural-crest-rich microenvironment, which may hold promise for the development of new therapeutic strategies, the researchers said.

"This idea was pioneered 30 years ago by scientists who thought that the complex signals within an embryonic field may reprogram an adult metastatic cancer cell introduced into such an environment and cause it to contribute in a positive way to an embryonic structure," Kulesa said.

....One of the hallmarks of aggressive cancer cells, including malignant melanoma, is their unspecified, plastic nature, which is similar to that of embryonic stem cells.

The Hendrix lab has shown that the unspecified or poorly differentiated cell type serves as an advantage to cancer cells by enhancing their ability to migrate, invade and metastasize virtually undetected by the immune system.

Read the entire report here.

Whether a cell becomes one tissue type, another tissue type, a stem cell, or a cancer cell--is determined by the gene expression of that cell. Scientists are closing in on the signals that control a cell's gene expression.


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New Cognitive Portals at Wikipedia

Wikipedia is a cooperative encyclopedia that also provides various topic portals for use as personal research launching points. Two of the newer portals made available are the Mind and Brain Portal, and the Psychology Portal.

The Mind and Brain portal is the more complete cognitive science portal, of the two. This portal provides an overview, featured articles, links to key people in the cognitive sciences, and links to the various disciplines of cognitive science--including computer science, linguistics, neuroscience, philosophy, psychology, cybernetics, and general cogsci.

Related portals at Wikipedia include Philosophy of mind, Neuroscience, Linguistics, and Computer science.

The quality of articles at Wikipedia can be uneven, but the links to outside websites are generally of high quality.

Thanks to Mindhacks.


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27 February 2006

Noncoding RNA--To Activate Genes, Influence Differentiation

Noncoding RNA has been used by researchers to silence specific genes for years. Now researchers from UC Riverside and Institut für Molekulare Immunologie in Munich, have learned more about the versatility of noncoding RNAs, and ways in which genes can be activated by them.

Frank Sauer in Riverside and Elisabeth Kremmer in Munich, have been studying the molecular mechanisms for cell differentiation in the fruit fly, Drosophila. They have been focusing on epigenetic factors, primarily protein gene activators. This research is reported in the Feb. 24 edition of the journal Science. This Eurekalert newsrelease gives more information:

The paper explains how proteins, known as epigenetic activators (such as Ash1 from the fruit fly Drosophila), bind to their target DNA and activate genes that determine what function a cell will have in the body.

"The fact that these epigenetic activators, such as Ash1, turn on the expression of specific target genes has been known for some time. However, the mechanisms by which epigenetic activators recognize and bind these target genes was not yet known" Sauer pointed out

"What we were able to show is that the epigenetic activator Ash1is recruited to a target gene through cell-type specific non-coding RNA" he said.

The paper examined how the activator Ash1 binds to target DNA elements, known as Trithorax-reponse elements (TREs), located in the gene Ultrabithorax (Ubx). Non-coding RNA is produced by and retained at the TREs of Ubx, and helps activate the expression of the Ubx gene by attracting Ash1 to the TREs. The transgenic transcription of non-coding TRE RNA can change the type and function of cells.

"As a result, we can now use non-coding RNAs as tools to actively determine cell fate," Sauer said. "Over the last few years, researchers have focused on how noncoding RNAs silence genes," said Anthony Carter, of the National Institute of General Medical Sciences, which partially funded the research. "Dr. Sauer's work has revealed that noncoding RNAs have a broader range of functions than was previously known, and suggests a model for how they can help activate, rather than silence, a key regulator of animal development."

Read the entire newsrelease here.

If scientists can learn to differentiate and de-differentiate various cell types at will, the keys to controlling cancer, and cell replacement for aging treatments (SENS etc), will be at hand. This type of research is an important step.


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Post-genomics: Understanding Proteomics and Protein Interaction Networks

A recent collaboration between Johns Hopkins University and the Institute of Bioinformatics in Bangalore, has produced some surprising results in protein-protein interactions. Proteins are the prime movers in the cell. Understanding how proteins interact with each other will fill in many of the gaps in our understanding of cell function--both normal and pathological.

The findings, reported in the March issue of Nature Genetics, were made using a database of more than 25,000 protein-protein interactions compiled by the Hopkins-IOB team. The result is believed to be the most detailed human "interactome" yet describing the interplay of proteins that occur in cells during health and disease.

"Genes are important because they are the blueprints for proteins, but proteins are where the action is in human life and health," says Akhilesh Pandey, M.D., Ph.D., an assistant professor at the Institute of Genetic Medicine and the departments of Biological Chemistry, Oncology and Pathology at The Johns Hopkins University School of Medicine. "This ability to find links between sets of proteins involved in different genetic disorders offers a novel approach for more rapidly identifying new candidate genes involved in human diseases," he says.

The analysis included interactions among 1,077 genes coding for proteins linked to 3,133 diseases, the researchers report. Significantly, it showed that proteins encoded by genes that are mutated in inherited disorders were likely to interact with proteins already known to cause similar disorders. In addition, the researchers disproved the long-held belief among scientists that the relative importance of a specific protein is always reflected by the number of other proteins it interacts with in the cell.

According to Pandey, the team's comparison of almost 25,000 human, 16,000 yeast, 5,500 worm, and 25,000 fly protein-protein interactions showed that, among these more than 70,000 links, only 16 were common to all four species.

Researchers say this low level of interactome overlap among species was surprising. It showed that current rapid-testing methods for identifying protein interactions are likely to miss true interactions.

....Using this kind of comprehensive comparison of information about human and other organisms allowed Pandey's group to identify 36 previously unknown protein-protein interactions, nine of which were tested in the laboratory to verify what the analysis suggested. "We proved they were valid," Pandey says. "By linking computerized sleuthing to laboratory experiments to confirm those findings, we expect to be able to eventually fill in many blanks in human protein-protein interactions."

From a 2004 report in Nature, this abstract explains the goal of postgenomics:

A key aim of postgenomic biomedical research is to systematically catalogue all molecules and their interactions within a living cell. There is a clear need to understand how these molecules and the interactions between them determine the function of this enormously complex machinery, both in isolation and when surrounded by other cells. Rapid advances in network biology indicate that cellular networks are governed by universal laws and offer a new conceptual framework that could potentially revolutionize our view of biology and disease pathologies in the twenty-first century.

Here is the source for the report. Hat tip to Snowcrash at Biosingularity Blog.

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Robotic Surgery Update: Da Vinci Heart Surgery

Using the Da Vinci robotic surgeon system, surgeons should soon be able to operate on the heart without stopping the beating. Conventional heart surgery is done with the patient placed on cardiovascular bypass, with a machine pump circulating the blood, while the heart sits idle for the convenience of the surgeon and the safety of the patient. Now George Mylonas of Imperial College London has developed motion compensation software that should allow the robotic surgeon to compensate for the motion of the beating heart, and operate on the organ without stopping it first.

This New Scientist news report discusses this new development:

In traditional bypass surgery the heart is stopped and an artificial pump is used to keep blood flowing around the body. This is highly traumatic as it involves open heart surgery, and means the blood flow is re-routed through a machine. Alternatively, some surgeons now prefer the less drastic approach of slowing the heart down by cooling it. However, even when the heart beats more slowly it is still a moving target, says Rajesh Aggarwal, a surgeon and specialist in minimally invasive procedures at ICL, whose department has been working with Mylonas. "It's a difficult procedure on a stationary piece of tissue, let alone when it is moving," he says. The new system would allow the procedure to be carried out with the chest closed.

The da Vinci robot uses a two-camera endoscope that feeds images to the surgeon's viewer. Images from the left and right cameras are fed to each of the surgeon's eyes separately, providing a 3D view of the tissue being operated on. Mylonas's system exploits this by fitting an infrared eye tracker to the viewer. This monitors each eye to detect precisely where the surgeon is looking, and then calculates the distance to the point their gaze is fixed upon using triangulation.

The software first constructs a 3D model of the heart by tracking the surgeon's eyes as they move over the organ. Then it creates a real-time moving image by recording the changes in the surgeon's focal point as the heart beats. The endoscope is calibrated to move forwards and backwards in time with this image, after which the heart appears stationary to the surgeon viewing it through the two cameras. The surgical instruments are also calibrated to move in synchrony with the beating heart, removing the need to constantly move them back and forwards, and allowing the surgeon to concentrate on performing the operation.

The increasing use of robotic surgery may very well lead to an increase in the number and proportion of women surgeons. In traditional surgery, a male surgeon's statistically superior 3-D spatial instincts might provide an advantage in maintaining orientation in a sometimes difficult to visualize surgical field. With robotic surgery, the surgical field is often cleaner and more limited in size and scope. In robotic surgery, the female's statistically superior fine motor skills might very well allow her rapid entry into the field. Robotic surgery is new and open territory. Anyone who can train to do the job well will be well compensated.

Here is the link to a previous article on robotic surgery, with more details.
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Rheumatoid Arthritis and Lymphoma: Cause and Effect?

Rheumatoid arthritis has been found to be associated with lymphoma. This Eurekalert newsrelease reports on a new study presented in the March issue of Arthritis and Rheumatism.

Drawing their sample from a national register of nearly 75,000 RA patients, the research team analyzed the medical records and case histories of 378 RA patients afflicted with malignant lymphoma between 1964 and 1995 and 378 individually matched, lymphoma-free controls. Using statistical analysis, the relative risks or odds ratios for lymphoma were assessed for three different levels of overall disease activity--low, medium, or high--based on disease duration and swollen and tender joint counts. Odds ratios for lymphoma were also compared to treatment in broad categories: any DMARD, any NSAID, aspirin, oral steroids, injected steroids, and cytotoxic drugs. No patient in the sample had received anti-TNF therapy. In addition, lymphoma specimens were reclassified and tested for Epstein-Barr virus (EBV).

Compared with low RA activity, medium RA activity was associated with an 8-fold increase in the risk for lymphoma. The odds ratio rose dramatically for high RA activity--to a 70-fold increase in lymphoma risk. The researchers also observed increased risks of lymphoma associated with pronounced, irreversible joint damage in the hands, feet, and knees documented in the last year before lymphoma diagnosis.

....Given the many uncertainties surrounding the link between lymphoma and chronic inflammatory diseases, this study has substantial clinical implications. As its lead author, Dr. Lars Klareskog of Karolinska University Hospital in Stockholm, observes, since lymphoma risk is strongly associated with exceptionally severe and longstanding RA activity, aggressive treatment may reduce the risk by reducing cumulative inflammation. "From a drug safety perspective," he notes, "our results provide background data that should be considered essential for the evaluation of lymphoma risk following therapy with TNF blockers, for example, as well as other new drugs."

Rheumatoid arthritis (RA) is related to reduced lifespan and increased mortality.
RA affects many critical systems of the body with a wide variety of manifestations and complications. Understanding HIV has led to remarkable new understandings of the immune system and cellular biology. Now it is time that medical science devoted the same type of research funding to the understanding of RA and related autoimmune disorders, that it devotes to HIV. The return in understanding from such a program would benefit everyone.
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26 February 2006

Gold vs. Rheumatoid Arthritis and Other Autoimmune Disease: Mystery Solved?

Gold has been used to treat Rheumatoid Arthritis (RA) since the 1930s. Now Harvard Medical School researchers have discovered why gold (and platinum) works against autoimmune disorders. Their research is reported in the 27 February issue of Nature Chemical Biology. From eurekalert pub releases:

"We were searching for a new drug to treat autoimmune diseases," says Brian DeDecker, PhD, HMS post-doctoral student in the Department of Cell Biology and a study co-author. At the time of this work, DeDecker was in the Harvard Medical School Institute of Chemistry and Cell Biology, which uses powerful chemical tools to illuminate complex biological processes and provide new leads for drug development. "But instead we discovered a biochemical mechanism that may help explain how an old drug works."

....During their search through thousands of compounds they found that the known cancer drug, Cisplatin, a drug containing the metal platinum, directly stripped foreign molecules from the MHC class II protein. From there, they found that platinum was just one member of a class of metals, including a special form of gold, that all render MHC class II proteins inactive.

In subsequent experiments in cell culture, gold compounds were shown to render the immune system antigen presenting cells inactive, further strengthening this connection. These findings now give researches a mechanism of gold drug action that can be tested and explored directly in diseased tissues.

Put differently, gold and platinum interfere with MHC class II proteins, "slowing down" the immune system a bit. By giving the immune system a rest, inflammation in the joints and other body tissues is allowed to subside. Scientists will now take this knowledge of how these precious metals modify immune function, and devise new and better drugs with fewer side effects.

Gold is being studied as a nano-therapy, to treat Alzheimer's and to introduce drugs into cells. The unique effect of gold and platinum on the immune system makes them potentially valuable materials for implants.

Read the entire release here.
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Alzheimer's and Parkinson's May be Linked to K Channel Gene Mutation

Potassium Channels are vital gateways in all body cells, and play a particular role in nerve cells for propagating action potentials, or nerve impulses. Now, researchers at the US NIH National Institute of Neurological Disorders and Stroke (NINDS), have linked mutations in potassium channel genes (KCNC3) to different types of spinocerebellar ataxias, cerebellar degeneration, and a form of mental retardation. The mutated KCNC3 genes are linked to nerve death in these disorders. In addition, abnormal potassium channels have been found in Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease--all severe progressively degenerative neuronal maladies.

"This type of gene has never before been linked to nerve cell death," says Stefan Pulst, M.D., of Cedars-Sinai Medical Center at the University of California, Los Angeles, who led the new study. The report will appear in the February 26, 2006, advance online publication of Nature Genetics.*

In the study, the researchers looked for the gene that caused a neurodegenerative movement disorder called spinocerebellar ataxia in a Filipino family. This disorder typically appears in adulthood and causes loss of neurons in the brain's cerebellum, resulting in progressive loss of coordination (ataxia). Dr. Pulst and his colleagues traced the disease in this family to mutations in a gene called KCNC3. The gene codes for one of the proteins that form potassium channels – pore-like openings in the cell membrane that control the flow of potassium ions into the cell. The researchers found a different KCNC3 mutation in a previously identified French family with a disease called spinocerebellar ataxia type 13, which causes childhood-onset ataxia, cerebellar degeneration, and mild mental retardation.

The KCNC3 gene codes for a type of potassium channel that normally opens and closes very quickly. This type of channel is particularly important in "fast-bursting neurons" that fire hundreds of times per second in the brain. "Fast-bursting neurons are like building blocks – they are used in the nervous system a lot," Dr. Pulst says. Among other places, these neurons are found in the brain's substantia nigra, where they aid in motor control, and in the hippocampus, where they play a role in learning. Previous studies have found abnormalities in the number of potassium channels in Parkinson's, Alzheimer's, and Huntington's diseases. Together with the new study, these findings suggest that potassium channel abnormalities may contribute to a wide variety of neurodegenerative diseases.

....Through cell culture experiments, the researchers learned that the KCNC3 mutations in the Filipino and French families affect the potassium channel very differently. The mutation found in the Filipino family completely prevented the potassium channel from functioning. The mutation from the French family caused potassium channels to open earlier than normal and close too late. This reduced the rate at which the neurons could fire.

Researchers have long known that potassium channels are important for neuronal function. Mutations in other potassium channel genes have been linked to problems such as epilepsy, cardiac arrhythmias, and periodic muscle paralysis. One type of potassium channel defect has also been found in a disorder called episodic ataxia type 1 that causes brief episodes of ataxia without neurodegeneration. However, potassium channel mutations have never before been linked to neurodegenerative disease or mental retardation. The findings were surprising because mice lacking the KCNC3 gene have only mild behavioral changes, Dr. Pulst says.

It is not yet clear exactly how the potassium channel mutations cause neurodegeneration. One theory is that the mutations might increase the amount of calcium that can enter cells, causing them to die because of excitotoxicity (overstimulation). The altered potassium channels might prevent neurons from coping well with oxidative stress – damage from reactive molecules called free radicals that are produced during metabolism. The mutations also might cause subtle developmental defects that reduce the long-term survival of neurons, the researchers say.

Potassium channels in many nerve types must be very fast, and their timing of opening and closing has to be precise. Very subtle changes in the gene sequence could throw off the timing of the channels. The more overt the changes, the earlier in life the defects would exhibit themselves as poor neuronal functioning.

This type of defect strikes me as a candidate for gene therapy, more than traditional pharmacotherapy. Until ultra-selective means of introducing genes into particular cell types are perfected, good and definitive therapies for such mutational changes may be delayed. Nevertheless, it is important to catalog these defects and their manifestations, so that scientists in all the various therapeutic approaches can evaluate potential therapies. This is the grunt work that absolutely must be done to pave the way for the magnificent treatments that will in time appear smooth and effortless.

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Flying Cars, Swimming Planes--I Want One that Does Them All

JW Bats of Our Technological Future Blog reports on the "Flying Car Project" at MIT. Here is the link to the newspaper article describing the project. Carl Dietrich is a 28 year old aerospace engineer with a record of innovation.

''People tend to smirk when you say you're trying to make a flying car: 'Oh, you're one of those guys.' " But, he insisted, ''This isn't just another flying car concept. We're very serious about producing a flying car and selling it."

Few who know Dietrich would bet against him. Even by MIT's standards, he is considered a standout -- so much so, in fact, that today he will be announced as the winner of the $30,000 Lemelson-MIT Student Prize. An outside panel of scientists and technologists chose Dietrich for his ''portfolio of novel inventions," including not just the flying car but also a desktop-size fusion reactor and a lower-cost rocket engine.

I wish Dietrich and his team the best of luck, since they plan to begin manufacturing the flying car in 2009. This other fellow has been trying to get his flying car ready for production and marketing for a long time.

CNN.com has an interesting story about a swimming plane that will be launched from a submarine 150 feet below the ocean's surface. The plane will swim to the surface and take off for its flight. At the end of its flight, the plane will land on the ocean and wait to be picked up by a robotic underwater vehicle..

The Cormorant, a stealthy, jet-powered, autonomous aircraft that could be outfitted with either short-range weapons or surveillance equipment, is designed to launch out of the Trident missile tubes in some of the U.S. Navy's gigantic Cold War--era Ohio-class submarines.

....The tubes are as long as a semi trailer but about seven feet wide -- not exactly airplane-shaped. The Cormorant has to be strong enough to withstand the pressure 150 feet underwater -- enough to cave in hatches on a normal aircraft -- but light enough to fly.

....The craft is made of titanium to resist corrosion, and any empty spaces are filled with plastic foam to resist crushing. The rest of the body is pressurized with inert gas. Inflatable seals keep the weapon-bay doors, engine inlet and exhaust covers watertight.

The Cormorant does not shoot out of its tube like a missile. Instead an arm-like docking "saddle" guides the craft out, sending it floating to the surface while the sub slips away. As the drone pops out of the water, the rocket boosters fire and the Cormorant takes off.

After completing its mission, the plane flies to the rendezvous coordinates it receives from the sub and lands in the sea. The sub then launches a robotic underwater vehicle to fetch the floating drone.

Here is the thing: I would like a car that can function as a camper, can swim on the water's surface, can dive like a submarine, and can fly like a plane. Engineers are beginning to think out of the box--just a little. But not nearly enough.

It is not a good sign that engineering enrollment in North America has declined. Although India and China can certainly produce top notch engineers, the jury is still out as to whether engineers trained in Asia are as innovative as European and North American trained engineers. We will all hope so, given the trends.

By the way, I have posted on the issue of declining engineering enrollments here, here, here, and here. It is one thing to wish nature had done things differently, it is quite another to base the future of your society on that wishful thinking, when you know it is not true.

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25 February 2006

Energy Storage: Global Climate Change or Just Cleaner Air?

Hat tip to the Energy Blog for this post on a new book dealing with advances in energy storage technologies. Energy analyst Richard Baxter's "Energy Storage: A Non-Technical Guide", details several newer technologies and their likely impact on the energy industry's shift to cleaner energy generation. Global Warming (Climate Change) and Peak Oil enthusiasts should be following this issue very closely, since in the long run energy storage will have a far greater impact on greenhouse gases and petroleum use than any political movements such as Kyoto or Peak Oil conservation.
From the Energy Blog:

The 302 page book is divided into six sections with a major emphasis on the technologies as indicated by the following outline:

* How energy storage can benefit the electric power industries
* How energy is stored in the fossil fuel markets
* Energy storage technologies
o pumped hydroelectric storage (PHS)
o compressed air energy storage (CAES)
o flow batteries-vanadium redux, zinc bromine, polysulfide bromide and cerium zinc
o sodium sulfide battery
o lead-acid battery
o nickle cadmium battery
o flywheels
o electrochemical capacitors
o superconducting magnetic energy storage
o thermal energy storage
+ design and operation of each technology
+ history of each technology
+ cost issues for each technology
+ examples of installations for each technology
+ prospects and challenges of each technologies
+ major developers of each technologies
* Applications of energy storage
* The role energy storage can play in renewable energy
* How energy storage could effect future energy development

Forty illustrations make reading and understanding the text much easier. Numerous references in each section and a 12-page bibliography are included for those interested in digging deeper into these technologies.

Energy Blog also points to this article by Baxter in EnergyPulse.

The benefits of using wind energy can be quite high. A number of studies by US Government Laboratories (NREL, LLNL, etc.) have shown that adding wind to a diesel-powered local grid can reduce fuel consumption by 40%-50% and total costs by 30% to 50% for areas with plentiful wind resources.(1) However, because of the small size of these power grids (lack of system inertia, etc.) simply adding wind turbines to small power grids cannot be done haphazardly—a systematic review of the load and potential additional wind turbines must be undertaken to ascertain potential benefits, and to determine what level of wind penetration is best. For many of these power grids, the opportunity exists to have wind resources well in excess of 50% of the peak load.

The same studies that showed that increasing the wind penetration can lower the diesel fuel costs on these systems also showed that adding a storage component can gain an additional 10%-20% in system cost reductions. Although wind turbines provide power with no fuel cost, they bring with them operational characteristics that cause the overall system to operate at sub-optimal conditions many times due to the variability of the wind energy, the non-dispatchability of the wind energy, and the additional system stabilization requirements (frequency and voltage) required. By alleviating some of the stress on the system by operating as a dynamic source and sink for power (a shock absorber), energy storage can be a beneficial additional to these island grids for three general reasons: reducing diesel starts/runtime, providing system stability, and improving the reliability of supply from increasing the level of wind penetration for the system.

The value of energy storage to the system increases as the wind penetration increases, as there will be an increasing amount of time that the available wind power exceeds the total system loads. According to one NREL study(2), at 50% wind penetration, storage can provide 20% greater fuel saving and 20% fewer diesel run-tine than non-storage wind/diesel systems alone.

Here is a website from the Engineering Department of SDSU in San Diego giving a general introduction to the topic of energy storage.
Here is an excellent introduction to large scale energy storage from Imperial College London.

Whether one believes in catastrophic anthropogenic global climate change, or merely wants cleaner air to breathe for the indefinite future, integrating storage technologies into the energy infrastructure is excellent news.

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24 February 2006

Nanotechnology Learns from Biology

Nanotechnologists too often approach the assembly of their nano-machines on a de novo basis, ignoring the legions of nano-machines that evolved over a billion years ago. Nano-engineers had better begin learning from the biologically evolved nanodynamic structures, or they will be made irrelevant by bio-nano engineers.

An Oxford University physicist sees the future of nanotechnology in the workings of one of Nature's tiniest motors, that which allows some bacteria to swim by rotating slender filaments known as flagella.

'The bacterial flagellar motor is an example of finished bio-nanotechnology, and understanding how it works and assembles is one of the first steps towards making man-made machines on the same tiny scale,' said Dr Richard Berry, a Tutorial Fellow in Physics at Oxford University. 'The smallest man-made rotary motors so far are thousands of times bigger.'

This motor has the same power-to-weight ratio as an internal combustion engine, spins at up to 100,000 rpm and achieves near-perfect efficiency. Yet at only 50 nanometres across, one hundred million would fit onto a full-stop. The only other natural rotary electric motor is in the enzyme ATP-synthase.

Dr Berry is a member of the Rotary Molecular Motors Group in the Oxford Department of Physics. He presented his research at the Biophysical Society's Annual Meeting in Salt Lake City, Utah, on Sunday 19 February.

The physicist and his Japanese colleagues changed the proteins normally found in the motor of E Coli to make it run on sodium instead of hydrogen ions. This allowed them to reduce its speed of rotation by lowering the level of sodium ions present. They also made the actions of the motor more easily detectable by attaching tiny beads to stubs of flagella. Ultimately 26 distinct steps could be observed in each of its revolutions.

'The motor runs on electric current, the flow of hydrogen or sodium ions across the cell membrane, and each step may be caused by one or two sodium ions passing through the motor,' explained Dr Berry.

The tools involved included optical tweezers, which employ light beams to hold and to measure transparent particles, and a high-speed fluorescence microscope which can capture 2500 images per second.

Here is the source for this report.

Dr. Berry presented his findings to a meeting of Biophysicists in Salt Lake City on February 19.

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Virochips, Prostate Cancer, XMRV Virus--A Sexually Transmitted Disease?

We know that several viruses are linked to cancer, including Human Papillomavirus (HPV), Ebstein Barr Virus (EBV), and others. We know that HPV is spread sexually, making cervical cancer a de facto STD. Now we learn that prostate cancer, at least in some cases, is linked to a virus that has never been found in humans before. This discovery was made possible by a Virochip, a diagnostic device that allows simultaneous testing for 1000 viruses.

This News-Medical-Net release discusses a new finding that a virus, XMRV, has been found in prostate specimens in 8 of 20 men with prostate cancer and two mutated copies of a gene, RNaseL. RNaseL gene serves as a protective mechanism against some viruses. If the gene is mutated, it can no longer protect as well against viral infection.

In a study of 150 men, the researchers identified the virus, called XMRV, and determined that it is 25 times more likely to be found in prostate cancer patients with a specific genetic mutation than men without the mutation.

"This is a virus that has never been seen in humans before," said co- author Eric Klein, M.D., Head of Urologic Oncology at the Glickman Urologic Institute of Cleveland Clinic. "This is consistent with previous epidemiologic and genetic research that has suggested that prostate cancer may result from chronic inflammation, perhaps as a response to infection."

Cleveland Clinic researcher, Robert H. Silverman, Ph.D., previously discovered a gene called RNaseL that fights viral infections. Men with mutations in this gene are at greater risk for prostate cancer. In their study, Cleveland Clinic and University of California researchers examined tissue samples of 86 prostate cancer patients whose prostates had been surgically removed.

....The ViroChip contains genetic sequences of more than 1,000 viruses. Using the chip and the patient samples from Cleveland Clinic, they found the XMRV virus in eight (40%) of the 20 men with two mutated copies of the RNaseL gene and only (1.5%) of the 66 men who had one copy or no copy of the mutated gene. Laboratory pathology at Cleveland Clinic confirmed the presence of the virus in prostate tissue.

While the genetics of prostate cancer are complex, one of the first genes implicated in the process was RNaseL, which serves as an important antiviral defense mechanism. Given the anti-viral role of this gene, some scientists have speculated that a virus could be involved in a subset of prostate cancer cases.

"While we can't state that this virus causes prostate cancer, these are remarkable findings because of the association of the virus with the mutation," said Dr. Robert Silverman, collaborating investigator in the study. "This project was possible only because of the willingness of physicians and scientists in different areas of expertise at the two institutions to work closely together towards a common goal, that of identifying a new infectious agent in prostate cancer."

Read the entire report here.

At this time there is no reason to consider prostate cancer a sexually transmitted disease. Most prostate cancers are probably caused by other factors than this virus. The possibility remains that at least in some men, this virus was sexually transmitted, and may have led to prostate cancer. There are enough reasons to practice safe sex, without adding another one. Nevertheless, there it is. Take care of yourselves.
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Access to Orbit--and Beyond

Peak Oil Debunked Blog posted an excellent discussion of the space elevator yesterday. The space elevator concept has been discussed for many decades. Arthur C. Clarke has been one of the foremost promoters of the idea. Despite many potential problems with the space elevator, the economics of boosting a payload to low earth orbit (LEO), and geostationary orbit beyond (GEO), suggest that we humans are not using our imaginations productively enough. As both Buckminster Fuller and Arther Clarke suggested, a geostationary ring of connected satellites, with connecting "spokes" of space elevators anchored to earth's equator, would provide an excellent launching pad from which to reach the moon and other planets in the solar system.

LEO on the Cheap is an interesting free online book that discusses the concept of approaching space economically, without the massive redundancy of NASA. Other approaches include a massive "gun launcher", as well as an electromagnetic rail launcher, and an asynchronous skyhook. (see dynamic systems) This is an interesting discussion of current launch concepts, and this is another plan. Here is another suggestion of getting from here to there.

What will we do when we get to orbit? Here are a few ideas. There are many more possibilities, but they all depend on getting to orbit first. Here are the basics of space flight, from the JPL. Spacefuture.com has many interesting articles, and a good links page. Also see the sidebar to the right, under Outer Space. And for those concerned about climate change, here is the ultimate guide to the control of earth's climate.

Unless humans wish to share the fate of the dinosaurs, they had better learn to use their large brains for something other than shallow entertainments, and dimwitted news shows.

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23 February 2006

Holy Grail of Enzymatics: Making Enzymes that Make Anything You Want

Berkeley Lab, a US DOE national laboratory located near Berkeley, CA, released this news of significant progress in the intelligent design of enzymes in the lab. Ever since scientists learned they could design new genes--and thus new proteins--in the lab, they have been hoping to gain enough specificity in the design of enzymes to allow the use of artificial enzymes to create new and useful molecules that have never existed in nature. Clearly, that is nano-assembly in an enzymatic form, with potential approaching anything Eric Drexler may have dreamed for his own nanoassemblers.

In nature, the divergent evolution of promiscuous enzymes is achieved through trial and error, similar to the way in which the human immune system works. Multiple combinations of many different amino acid substitutions are tested in promiscuous enzymes until an evolutionary path that achieves a desired result is found. The amino acid substitutions that significantly drive molecular evolution are called “plasticity residues.”

The Berkeley researchers identified the plasticity residues for the Grand fir sesquiterpene synthase, then systematically recombined mutations of these residues through site-directed mutagenesis, based on a mathematical model developed by Yoshikuni. Construction of the seven sesquiterpene synthases was accomplished with the screening of fewer than 2,500 mutants. An alterative approach, called directed evolution or molecular breeding, that is currently being tested at other laboratories, requires the screening of tens of thousands to a million or more mutants.

“The enzyme synthase was there ready to be evolved, and with our methodology, we were able to rapidly and efficiently evolve it down a pathway of our choice,” Keasling said. “We are recapitulating evolution into intelligent design. In the case of this particular Grand fir enzyme synthase, it naturally makes a soup of small amounts of 52 different products. We were able to focus it instead on making large amounts of one of seven of those products.”

While the researchers have not yet reached the point where they can design a promiscuous enzyme to make any kind of product they want, even one that does not occur in nature, this demonstration represents a significant step in that direction. The idea would be to one day be able to design an enzyme synthase that would evolve along a specific functional pathway to yield a desired molecular product, then introduce it into microbes for mass production. In addition to synthesizing therapeutic drugs, other possible applications would include flavors, fragrances and nutraceuticals.

“Our ultimate goal is to be able to put as much chemistry as we can into microbes,” said Keasling, a pioneer and leading authority in the burgeoning scientific field of synthetic biology. “We can use microbes to do a lot of complicated chemistry, and the way in which this will be done is through the use of enzymes. One can imagine where you could take a series of promiscuous enzymes that would make different parts of a molecular compound, and combine them to obtain a final product that could do whatever you needed it to do.”

Since plasticity residues also play other important biological roles, in addition to the evolution of promiscuous proteins, Keasling and Yoshikuni said their technology, with some modifications, could prove useful for designing novel functions into other types of enzymes and proteins, as well as protein ligands and receptors, transcription factors and antibodies.

This research was largely funded through grants by the Bill and Melinda Gates Foundation, the National Science Foundation, and the U.S. Department of Agriculture.

Go here to read the whole report.


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SAT Predicts Life Achievement, IQ

Hat tip to Kevin of Intelligence Testing blog for pointing to a study by Vanderbilt University psychology researchers David Lubinski and Camilla Benbow, along with Rose Mary Webb (Appalachian State University) and April Bleske-Rechek (University of Wisconsin-Eau Claire), high SAT scores at young ages can reveal who will be the high achievers of the future. Lubinski and Benbow have been working on this project for decades now, and have substantiated their findings repeatedly.

The findings are reported in the article "Tracking Exceptional Human Capital Over Two Decades" in the March issue of Psychological Science, a journal of the Association for Psychological Science (previously the American Psychological Society).

The study compared 380 young SAT takers and 586 graduate students. Students under age 13 who scored in the top .01 percentile of their age group on the SAT in the early 1980s were considered having exceptional cognitive abilities; 20 years later (2003-2004), these students were surveyed on their education, career, success, and life satisfaction. Graduate students who had been enrolled in a top-ranked engineering, mathematics, or physical science program in 1992 also took the survey in 2003-2004.

....The results of this longitudinal study on the ability of the SAT to predict long-term achievement and life satisfaction come as other research is demonstrating the potential flexibility of the SAT to be an accurate measure of IQ.

The material in italics is extracted from a Science Blog report. Follow the link at the beginning of the italics for the full report. A word of caution on the Science Blog: I have caught them deleting comments that disagreed with the opinions of the author of individual reports. This is not illegal, but in the blog world, it is not considered ethical unless there is an excellent reason.

Update 2 March 2006: Ben Sullivan of the Science Blog offers a comment here, to clarify the phenomenon of "disappearing comments."

As I state in the followup comment, I would appreciate if any readers would notify me of any censorship of comments on any of the blogs that I link. Removing spam is one thing--we all hate spam. Censorship of ideas is something else, and it happens all too often on political blogs. It should certainly not be happening on science blogs, although sometimes it does.


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22 February 2006

New Key to Learning and Memory?

Not only is Ghrelin a hot topic among Yale University memory researchers, but Harvard Medical School researchers have identified another possibly key hormone involved in control of memory--myocyte enhancer factor 2 (MEF2). The research appears in the latest issue of Science.

The uncovering of the MEF2 pathway and its genetic switch helps fill in a theoretical blank in neurobiology, but what excites the researchers are the potential implications for the clinic. "Changes in the morphology of synapses could turn out to be very important in a whole host of diseases including neurodegenerative as well as psychiatric disorders," said Azad Bonni, MD, PhD, HMS Associate Professor of Pathology who, with colleagues, authored one of the papers. Michael Greenberg, PhD, HMS Professor of Neurology at Children’s Hospital Boston, who led the other team, believes that the MEF2 pathway could play a role in autism and other neurodevelopmental diseases.

The protein works by either activating or actively repressing target genes. In working on a group of neurons in the developing rat cerebellum, HMS research fellow in pathology Aryaman Shalizi, and HST medical student Brice Gaudilliere along with Bonni and their colleagues, found the MEF2 repressor promoted synaptic differentiation. In a separate study, Steven Flavell, a graduate student in neurology, Greenberg, and their colleagues found the MEF2 activator inhibited the growth of dendritic spines in the rat hippocampus, an area of the brain associated with memory and learning. Flavell, and also the Bonni team, found the activated, or dendrite-whittling, form of MEF2 comes on in response to increased neuronal activity.

That MEF2 activation leads to the inhibition of synapse formation, makes sense in light of what is known about the nervous system. In memory and learning, as well as development, activity leads to a sculpting, or cutting away, of synapses. What may be more surprising is the way activity causes MEF2 to switch from repressor to activator.

What Bonni and his colleagues found is that molecules modify a particular spot on MEF2, and transform it into a repressor. By removing the modification, known as sumoylation, MEF2 becomes an activator.

MEF2 was first identified in neurons in the 1990s. In 1999, Zixu Mao, then an HMS research fellow, working with Bonni, Greenberg, and colleagues showed that MEF2 promotes neuronal survival but little else was known about the protein. Though they knew that MEF2 comes in activated and repressor forms, neither team knew how exactly the protein works. They suspected it might play a role in regulating activity-dependent synaptic remodeling and set out to find out if that was the case.

For those interested, you can read the rest of the release here.

It is likely that MEF2 is particularly active in early childhood, when the neuronal tree is being "pruned" most actively. But given that neuronal plasticity continues well into adulthood, this particular peptide may be another one to watch, in terms of spawning treatments for dementia.
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Ghrelin: Peptide Can Boost Learning and Fight Dementia

Ghrelin is a peptide hormone known to be produced in the stomach and the hypothalamus. When the stomach is empty, ghrelin is produced, stimulating hunger in the brain via the "orexin pathway." Now we are learning that ghrelin does more than simply stimulate the appetite. Ghrelin may hold one of the keys to improving learning and blocking dementia. In addition, new drugs for combatting the obesity epidemic and other conditions may likely be found from research into ghrelins and the orexin pathway.

Eurekalert presents this newsrelease that introduces research on ghrelin from Yale University.

Researchers at Yale School of Medicine have found evidence that a hormone produced in the stomach directly stimulates the higher brain functions of spatial learning and memory development, and further suggests that we may learn best on an empty stomach.

Published in the February 19 online issue of Nature Neuroscience by investigators at Yale and other institutes, the study showed that the hormone ghrelin, produced in the stomach and previously associated with growth hormone release and appetite, has a direct, rapid and powerful influence on the hippocampus, a higher brain region critical for learning and memory.

The team, led by Tamas L. Horvath, chair and associate professor of the Section of Comparative Medicine at Yale School of Medicine, and associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences, and Neurobiology, first observed that peripheral ghrelin can enter the hippocampus and bind to local neurons promoting alterations in connections between nerve cells in mice and rats. Further study of behavior in the animals showed that these changes in brain circuitry are linked to enhanced learning and memory performance.

Because ghrelin is highest in the circulation during the day and when the stomach is empty, these results also indicate that learning may be most effective before meal-time.

....Horvath said that high ghrelin levels or administration of ghrelin-like drugs could also protect against certain forms of dementia, because aging and obesity are associated with a decline in ghrelin levels and an increased incidence of conditions of memory loss like Alzheimer's disease.

Here is more about the Orexin pathway and its activities. Ghrelin also acts to stimulate growth hormone secretion. This is one peptide hormone that holds a lot of promise.
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Harvard Sticks with its Prejudices--Dispenses with Reform

The Washington Post newspaper published an editorial today dealing with the latest in the Lawrence Summers affair--Summers' resignation from Harvard. A lot will be written about the rise and fall of Lawrence Summers as Harvard President, but this editorial does a fair job of summarizing the issue.

Prejudice Wins

Wednesday, February 22, 2006; Page A14

UNIVERSITIES EXIST to pose tough questions, promote critical thinking, and generally challenge complacency and prejudice. When he became president of Harvard five years ago, Lawrence H. Summers determined that the university was not living up to this mission: It was infected by its own complacencies and prejudices, and he did not shrink from saying so. This outspokenness won Mr. Summers support across the university: A new online poll conducted by the Harvard Crimson found that 57 percent of undergraduates supported him -- only 19 percent thought he should resign -- and the deans of several faculties praised his leadership. But Mr. Summers alienated a vocal portion of the Arts and Sciences faculty, which pressed last year for a vote of no confidence in him and recently forced a second such vote on to the schedule for next week. Yesterday Mr. Summers preempted that second vote by announcing that he would step down in the summer. Because of the prestige of Harvard, his defeat may demoralize reformers at other universities.

Mr. Summers fought several well-publicized battles with Harvard's establishment. He refused to rubber-stamp appointees chosen by the faculties, blocking candidates who seemed insufficiently distinguished and pressing for diversity in political outlook. This prompted complaints that he was acting like a corporate chief executive -- as though there were something wrong with that. Next, Mr. Summers had the temerity to suggest that Cornel West, a professor of Afro-American studies, produce less performance art and more scholarship. This plea for academics to do academic work was construed as racist. After the terrorist attacks of Sept. 11, 2001, Mr. Summers criticized Harvard's hostility to the U.S. armed forces and called attention to the cultural gap between elite coastal campuses and mainstream American values. The fact that these commonsensical positions alienated people at Harvard speaks volumes about the cultural gap that troubled Mr. Summers.

Perhaps most explosively, Mr. Summers raised the possibility that the underrepresentation of women in science and engineering faculties might reflect innate gender differences in ability. His claim was not that women were less intelligent on average, but rather that fewer women than men might be outstandingly bad or outstandingly good at math, with the result that the pool of math geniuses from which universities recruit is disproportionately male. "I would far prefer to believe something else, because it would be easier to address what is surely a serious social problem if something else were true," he noted. But he was immediately branded a sexist.

Mr. Summers can be undiplomatic, as he acknowledged in his resignation letter. But university professors, of all people, should not require mollycoddling; they should be willing to embrace leaders who ask hard questions about how well they are doing their jobs. The tragedy is that the majority at Harvard seems to have known that. But, in university politics as elsewhere, loud and unreasonable minorities can trump good sense.

Alan Dershowitz published an editorial in boston.com today entitled "Coup against Summers Dubious Victory for the Politically Correct." The entire article is well written, but I will quote just the last paragraph. Dershowitz points out that the Faculty of Arts and Sciences at Harvard is merely one faculty out of several, and overloaded with the senile devotees of political correctness.

It was arrogant in the extreme for a plurality of a single faculty to purport to speak for the entire university, especially when that plurality is out of synch with the mainstream of Harvard. It was dangerous for the corporation to listen primarily to that faculty, without widely consulting other professors, students, and alumni who supported Summers. Now that this plurality of one faculty has succeeded in ousting the president, the most radical elements of Harvard will be emboldened to seek to mold all of Harvard in its image. If they succeed, Harvard will become a less diverse and less interesting institution of learning governed by political-correctness cops of the hard left. This is what happened in many European universities after the violent student protests of the late 1960s. It should not be allowed to happen at Harvard in the wake of the coup d'etat engineered by some in the Faculty of Arts and Sciences.

There is a new president at Harvard now--the same as the old president before Summers. His name is Political Correctness, and he is a cold and killing dogma. You may not be surprised to know that he is president of many universities across North America, perhaps your own school?

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Predicting Life Extension and Human Longevity

Over at the Speculist Blog, Stephen Gordon talks about the joys and perils of predicting trends in human longevity and life extension. Stephen once predicted--boldly, he felt--that 2014 would be the date for life extension to take off. Now Stephen is in the uncomfortable position of being upstaged by a biologist from Stanford, Shripad Tuljapurkar.

In this article, Dr. Tuljapurkar makes many interesting predictions concerning the effects on the world of increasing average lifespan past the 100 year mark. Overpopulation, increased inequality, a trend toward more serial monogamy, and the raising of the retirement age are some of his predictions. Dr. T. sets the date 2010 as the beginning of the rising lifespan.

The Speculist feels that a lot of unanticipated things will happen between now and 2010, and certainly between now and 2030. The Speculist represents a fairly optimistic blog-vision of the future. But read both the above article, and the reaction by the Speculist.

Personally, I feel that the acceleration has already begun. Not only are new drugs such as statins, ACEIs, ARBs, modafinil, donezepil, memantine, and many others changing many of the underlying processes of degeneration in the body and mind, but the process of new drug discovery is exploding rapidly. In addition, many people have gone on their own into personal life extension experimentation, taking pharmaceuticals and non-pharmaceuticals alike. Vitamin stores are happy to sell resveratrol, quercetin, carnosine, lipoic acid, Curcumin, DHEA, and other promising non-pharmaceuticals to an ever more sophisticated buying public.

Besides all that, a new generation of scientists has grown up with the idea that life extension is not wrong or unnatural, but is completely natural, ethical, and a worthy goal to pursue. These scientists are finding that the people who control the purse-strings are growing more agreeable as well. The tsunami has been spawned by the underlying groundswell, and will not be stopped. ETA: any time now.

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Exposing the Brain

Hat tip to both Develintel and Intelligence Testing blogs, for pointing me to this useful download for teaching the neuroanatomy of the brain. Brain Voyager Brain Tutor is a free download educational program with great visuals, that lets you look at the brain, and slices of the brain, from different angles and vantage points.

Here is the description from the website:

BrainVoyager Brain Tutor is an educational program that teaches knowledge about the human brain the easy way. The program lets you interactively explore high-quality 3D head and brain models, which can be rotated, moved and zoomed in real-time. The head and brain models have been computed with BrainVoyager QX using data from magnetic resonance imaging (MRI) scans. Besides having fun with the rotatable 3D models, the program contains information about the major lobes, gyri and sulci of the cerebral cortex, which are revealed in color simply by clicking on a part of the brain. The next release of BV Brain Tutor will also contain Brodman areas and brain regions revealed by functional MRI.

BrainVoyager Brain Tutor runs on all major computer platforms including Windows, Linux and Mac OS X. The Mac version of BV Brain Tutor recently won the runner-up prize for the Best Original Qt Application developed with the commercial Qt license in Trolltech's Qt/Mac Application Developer Contest. BV Brain Tutor can be freely downloaded here.

Both Develintel and Intelligence Testing have some good posts up recently. Go over and check them out.

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21 February 2006

Glycomics: The next level of Gene Expression after Genomics and Proteomics?

Move over genomics, and proteomics. Now there is glycomics, the study of the carbohydrates in the cell. This is but another level of gene expression, and many of the the same tools used in genomics and proteomics are being called into service in understanding this new level of complexity. Expect many new pharmaceuticals to come from an understanding of this very complex field.

Though they are not charged with storing genetic information like DNA or acting as enzymatic workhorses like proteins, carbohydrates nevertheless do carry information and are responsible for important biological functions, playing a central role in many types of intercellular communication events, protein folding, cell adhesion, and immune recognition.

One of the most important frontiers of basic research in biology today is to understand the human glycome--all of the types of carbohydrate structures in the human body and what they do. This is a profoundly difficult endeavor. The total number of carbohydrate structures in humans may be 10,000 to 20,000, although it is hard to fix a hard number to this, says Paulson. Nevertheless, he adds, "We think understanding the glycome is possible now. We didn't think that three years ago."

From another source:

As the human genome sequence is nearly deciphered, it is important to turn the attention to the physiological functions of the genes. Thus, the study of the gene products, the proteins, is the next big challenge. The proteins, however, are not the final gene products in many cases. It has been shown that carbohydrates participate in post-translational modifications and in many other functional regulations, hence the study of the glycome, the entire collection of carbohydrates is essential in order to determine the functions of all genes, and will greatly enhance the field of chemical genetics.

By analogy with the term ‘proteome’, the term ‘glycome’ has been coined for the glycan repertoire of an organism. Also, in the wake of ‘genomics’ and ‘proteomics’, the word ‘glycomics’ has become the trendy term for the characterisation by structure and function of the glycans in the system under study. In this section of Current Opinion in Structural Biology, four reviews take us to the frontiers of knowledge on the biosyntheses and roles of glycosaminoglycans (GAGs), and two of the exotic decorations of glycoproteins, O-mannosyl and O-GlcNAc glycans. Two reviews focus on new approaches to the study of carbohydrate–protein interactions: carbohydrate microarrays to examine proteins for carbohydrate-binding activity and NMR spectroscopy for analyses of the structural details of carbohydrate–protein interactions in solution.

* Complex glycans are important modulators of numerous biological processes, ranging from organ development to wound healing to the modification of diseases such as cancer. Although there are some exceptions, glycans do not generally control biological processes in a digital 'on or off' manner; rather, they 'fine-tune' biological functions.

* Complex glycans are either linear or branched structures that can exist alone or attached to other biomolecules. Owing to variation in branching patterns and in the individual monosaccharides that comprise the chain, glycans are information-dense biomolecules.

* Recent advances in several areas of research — including the development of analytical techniques, numerous genetic studies, new synthetic strategies and the advent of bioinformatics platforms — have raised the exciting possibility that glycan-based drugs could be developed for many diseases.

* Structure–function studies in this area have already led to important advances, both scientifically and in terms of drug development. Two examples of the latter are the development of second-generation antithrombotics with increased efficacy and increased clinical usefulness, and the development of improved forms of glycoprotein drugs.

* The US National Institutes of Health has recently sponsored the development of a consortium that brings together leaders in the field of glycan chemistry and biology to systematically catalogue and study glycan structure and function. This endeavour promises to provide a wealth of important information for the development of novel therapeutics and diagnostics, in a similar way to other federally sponsored initiatives in genomics and proteomics.

...It has become increasingly clear over the past decade that GAGs at the cell surface influence the interactions of cells with their immediate environment in ways that are sensitive to the fine structure of GAGs with respect to monosaccharide sequence and sulfation pattern. At the molecular level, the degree of specificity with which heparan sulfate (HS) sequences interact with, for instance, fibroblast growth factors and their receptors is a continuing source of interest and controversy. Studies at the whole-organism level have revealed the consequences of the absence of several of the enzymes of GAG biosynthesis, including some specific sulfotransferases. These knockout experiments have demonstrated that sulfate substitutions at particular positions on the GAG structure are necessary for specific aspects of embryonic development. Kusche-Gullberg and Kjellén present a concise but comprehensive summary of recent work on the identification and characterisation of the sulfotransferases that form the intricate GAG sulfation patterns.

Specific interactions between extracellular proteins and the GAGs heparin and HS are recognized to be dependent on variations in the details of sequence and substitution. In contrast, the galactosaminoglycans, known as chondroitin sulfates (CSs), have, in the past, been assumed to play a relatively inert, structural role, particularly in the extracellular matrix. Sugahara and co-authors review recent literature showing that CS, as well as HS, may be involved in development and morphogenesis, wound repair and infection, and that this involvement is dependent on patterns of sulfate substitution. CS in the central nervous system may act as a barrier to neuronal cell growth; the use of chondroitin-degrading enzymes to permit the regrowth of nervous tissue after, for example, spinal cord damage may be of considerable medical significance. On the other hand, some over-sulfated CS sequences present in the brain bind to growth factors and may play a part in neuritogenesis. Work on the model organism C. elegans has shown that GAGs are essential for correct development; the absence of chondroitin synthase (induced by RNAi of the sqv-5 gene, orthologous to human ChSy) can lead to serious anomalies, such as gonadal malformation and a profound disregulation of cell division in the early stages of embryogenesis, by mechanisms not yet fully understood. A current topic of research concerns the involvement of CS with specific sulfation patterns in infection, with particular reference to malaria in pregnancy.

In comparison with genomics and proteomics, the advancement of glycomics has faced unique challenges in the pursuit of developing analytical and biochemical tools and biological readouts to investigate glycan structure-function relationships. Glycans are more diverse in terms of chemical structure and information density than are DNA and proteins. This diversity arises from glycans' complex nontemplate-based biosynthesis, which involves several enzymes and isoforms of these enzymes. Consequently, glycans are expressed as an 'ensemble' of structures that mediate function. Moreover, unlike protein-protein interactions, which can be generally viewed as 'digital' in regulating function, glycan-protein interactions impinge on biological functions in a more 'analog' fashion that can in turn 'fine-tune' a biological response. This fine-tuning by glycans is achieved through the graded affinity, avidity and multivalency of their interactions. Given the importance of glycomics, this review focuses on areas of technologies and the importance of developing a bioinformatics platform to integrate the diverse datasets generated using the different technologies to allow a systems approach to glycan structure-function relationships.


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