Glial cells, including astrocytes and oligodendrocytes, are a focus of research in regenerative medicine because they help neurons stay healthy. If neurons are dying, restoring glial cells could be the key to survival.

ScienceDaily.com, January 28, 2010 — Researchers at the Ludwig Institute for Cancer Research (LICR) at the University of California, San Diego School of Medicine and Moores UCSD Cancer Center have shown one way in which gliomas, a deadly type of brain tumor, can evade drugs aimed at blocking a key cell signaling protein, epidermal growth factor receptor (EGFR),that is crucial for tumor growth. In a related finding, they also proved that a particular EGFR mutation is important not only to initiate the tumor, but for its continued growth or “maintenance” as well.

The findings, which appear during the week of January 18 in an online early edition of the Proceedings of the National Academy of Sciences, provide both new insights into the behavior of gliomas as well as potential new drug targets and treatment strategies.

“The results suggest that the expression of EGFR is required for tumors to keep growing, and we’ve shown for the first time that there are mechanisms that the tumor is using to circumvent the need for the receptor,” said Frank Furnari, PhD, associate professor of medicine at the UCSD School of Medicine and associate investigator at the San Diego branch of the LICR, adding that other cancers may use similar tactics. “We need to find out more about the signaling pathways that brain tumors use to get around targeted therapeutics, such as those directed at EGFR.”

In aggressive gliomas, extra copies of the EGFR gene are produced, and half of such tumors also carry an EGFR mutation, which ramps up tumor growth and portends a poor prognosis. Clinical trials of anti-EGFR agents have been disappointing; brain tumors may respond initially, but later become resistant to the drugs. To better understand why, Furnari, Webster Cavenee, PhD, professor of medicine and director of San Diego’s LICR branch, and their group wanted to find out if the mutant EGFR was needed by tumors for their continued growth.

The team — including postdoctoral fellows Akitake Mukasa, MD, PhD, and Jill Wykosky, PhD — created a genetic system in mice in which they could control the expression of mutated EGFR, turning it off and on with the drug tetracycline. They found that the tumors’ growth would stop for a period of time when tetracycline blocked EGFR, much like what is seen in patients who respond to EGFR inhibitors. But the tumors would start to grow again, even without EGFR, meaning something else was driving tumor growth.

The researchers examined individual tumors that had sidestepped or “escaped” the need for mutant EGFR to sustain their growth. In some cases, tumors that would normally have killed mice in 20 days were stable for months with the blocked expression of mutant EGFR. The scientists used microarray technology to test for genes that had not been previously expressed in the tumors but were now overexpressed in tumors that no longer required EGFR. They finally found one, KLHDC8 which, when inhibited, halted tumor growth.

“That finding makes us think that this gene would be a reasonable target,” Cavenee said. “About half of the individual tumors that didn’t need mutant EGFR to grow expressed that gene and, if we silenced the gene, those tumors did not grow.”

Cavenee thinks this could be a model for the behavior of other tumors. “If the tumors use the same strategy to get around receptor inhibitors, then targeting that alternate pathway plus the receptor up front should give a longer response because it’s hitting the primary event plus the escape route,” he said.

Now the research team is searching for other genes expressed in tumors that can escape EGFR dependence, and looking for biological pathways that might be involved.

Other contributors include: Keith L. Ligon, MD, PhD, Dana-Farber Cancer Institute, and Lynda Chin, MD, Dana-Farber and Brigham and Women’s Hospital.

Funding support came from the SUMITOMO Life Social Welfare Services Foundation, The Paul Taylor American Brain Tumor Association, the National Institutes of Health, the National Foundation for Cancer Research and the Goldhirsh Foundation.

Glioma
Classification and external resources

Brain: Glioma: Gross; fixed tissue, horizontal section brain stem and cerebellum with obvious gelatinous appearing neoplasm a pontine glioma. Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

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Neurons and their communication

Most cells in the nervous system are of two fundamentally different types: neurons and glial cells. This post is mostly about the communication of information between neurons and each other as well as muscles and organs.

It was only after our discovery and understanding of electricity that we discovered that muscle movement is mediated by the flow of electricity along nerve fibers.

Neurons and glial cells

Membrane potential

Membrane potential is the difference in electrical charge between the inside and outside of a cell. This was first demonstrated in the intercellular recordings of axons by Alan Hodgkin and Andrew Huxley in 1939 experiment with squid giant axon. Unusually large axons are useful for eneration of escape reflexes as they conduct more quickly.

They demonstrated that axons at rest are electically polarized, with a Resting Membrane Potential of approximately -60mV/-70 mV (i.e. compared to the outside). it is fundamental to setting off spikes by opening certain ion channels.

  • You can check/record the MP you can use the tip of an electrode inside the neuron and compare it with the extracellular fluid outside the neuron
  • The voltage is always charged negatively inside an alive cell i.e. -70mV or -90mV
  • There are selective, semi-permuable channels in the membranes

In a biological membrane, the Reversal potential (also known as the Nernst potential) of an ion is the membrane potential at which there is no net (overall) flow of ions from one side of the membrane to the other. In the case of post-synaptic neurons, the reversal potential is the membrane potential at which a given neurotransmitter causes no net current flow of ions

Concentration ratio (amount) of ions is unimportant. The voltage potential decides when ions leak out of channel. If more voltage outside -> membrane potential takes place. Different ion channels have particular target voltages.

The Nernst Equation

The equilibrium potential is determined by 4 things:

  1. The concentration of ion inside and outside of the cell
  2. The temperature of the solution
  3. The valence of the ion
  4. The amount of work required to separate a given quantity of change

The equation that describes the equilibrium potential was formed by a physical chemist called Walter Nernst (1888):

E (ion) is the membrane potential at which the ionic species is at the equilibrium. R is gas constant, T temperature, F is Faraday’s constant, Z the valence of the ion, while ion/ion are the concentration of the ion outside and inside the cell.

Neurotransmitters

Neurotransmitters are endogenous chemicals which relay, amplify, and modulate signals between a neuron and another cell. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to receptors in the membrane on the postsynaptic side of the synapse. Release of neurotransmitters usually follows arrival of an action potential at the synapse, but may follow graded electrical potentials.

Excitatory and inhibitory Neurotransmitters

The only direct effect of a neurotransmitter is to activate one or more types of receptors. The effect on the postsynaptic cell depends, therefore, entirely on the properties of those receptors.

Some neurotransmitters (for example, Glutamate), the most important receptors all have excitatory effects: that is, they increase the probability that the target cell will fire an action potential.

Other neurotransmitters (such as GABA), the most important receptors all have inhibitory effects.

There are, however, other neurotransmitters, such as acetylcholine, for which both excitatory and inhibitory receptors exist; and there are some types of receptors that activate complex metabolic pathways in the postsynaptic cell to produce effects that cannot appropriately be called either excitatory or inhibitory. Thus, it is an oversimplification to call a neurotransmitter excitatory or inhibitory—nevertheless it is so convenient to call glutamate excitatory and GABA inhibitory that this usage is seen very frequently.

Action Potential

An AP is generated by the rapid influx of Na+ ions followed by a slightly slower efflux of K+ ions. Although the generation of an AP does not disrupt the concentration gradients of these ions across their membrane, the movement of charge is sufficient to generate a large and brief deviation in the membrane potential.

Propagation of the AP along the axon allows communication of the output of the cell to its synapses. Neurons posses many different types of ionic channels in their membranes, allowing complex patterns of action potential to be generated and complex synaptic computations to occur within single neurons.

The Action Potential of Neurons

Action potentials play multiple roles in several types of excitable cells such as neurons, myocytes, and electrocytes. The best known action potentials are pulse-like waves of voltage that travel along axons of neurons.

A.P are used in long distance communication i.e. 1 long neuron in giraffe’s neck. Spikes are calculated in all or nothing sense (they either occur or not). Bigger axons carry out A.P faster i.e. so small preys can escape faster.

  • When Cell is stimulated, permeability of cell membrane changes, and this alters distribution of charge in the cell body
  • Voltage gated channels on the membrane open / close depending on the voltage changes in the membrane (closed when no stimulant)
  • A stimulus polarizes the membrane and this opens up Na+ / sodium channels to open, Na+ ions rush in to the cell
  • Cell becomes + inside and – outside 5. Na+ channel close while K+ / potassium channel opens and K+ rushes out
  • Cell returns to being + outside and – inside 7. K+ channel close 8. Membrane polarity changes along the membrane
  • This repeats and AP spreads, and AP travels down the neuron like a wave

Snapshot of AP would include:

  1. Membrane capacitance discharging
  2. Na+ channels opening
  3. K+ channels opening Na+ (Sodium) and K+ (potassium) ion channels.

Myline capacitance and Saltatory conduction

One important electrical property of neurons is their capacitance in their cell membranes, which is the electrical insulator and non-conductor capacity of neurons.

A neurons capacitance is proportional to its membrane surface area, so large neurons, have larger capacitances. Capacitance also decreases with the distance between the two conducting surfaces.

Saltatory conduction is the process by which the myelin propagate rapid conduction of action potentials down the axon, their capacitance not only increases the membrane resistance of the axon in myelinated areas of the node of ranvier, but also increases the distance between the conducting surfaces, decreasing the membrane capacitance.

Cable Theory

Cable theory can be used to explain the current flow in axons. Although it was developed in 1855 to model the transatlantic telegraph cable, it was only used to describe action potentials in 1946 by Hodgkin and Rushton.

The current is the product of a conductance and a voltage difference. The conductance is that of the ion channels which are opened by the presynaptic neuron and they are therefore time-dependent (or, more precisely, dependent on the state of the presynaptic neuron). The voltage difference is the difference between the present voltage and the reversal potential of the ion species which can pass through the channel. For an excitatory synapse, the reversal potential will be higher than the resting potential, for an inhibitory synapses, it will be lower.

The neuron is treated as an electrically passive, perfectly cylindrical transmission cable, which can be described by a partial differential equation.

In here V(x, t) is the voltage across the membrane at a time t and a position x along the length of the neuron, and where λ and τ are the characteristic length and time scales on which those voltages decay in response to a stimulus. These scales can be determined from the resistances and capacitances per unit length.

Cable theory’s simplified view of a neuronal fiber. The connected RC circuits correspond to adjacent segments of a passive neurite. The extracellular resistances re (the counterparts of the intracellular resistances ri) are not shown, since they are usually negligibly small; the extracellular medium may be assumed to have the same voltage everywhere.

Post-Synaptic Potential

Communication between Neurons – Neurotransmitters transition at the synaptic cleft.

PPs are changes in the membrane potential of the postsynaptic terminal of a chemical synapse. Postsynaptic potentials are graded potentials, and should not be confused with action potentials although their function is to initiate or inhibit action potentials. They are caused by the presynaptic neuron releasing neurotransmitters from the terminal button at the end of an axon into the synaptic cleft. The neurotransmitters bind to receptors on the postsynaptic terminal, which may be a neuron or a muscle cell in the case of a neuromuscular junction. These are collectively referred to as postsynaptic receptors, since they are on the membrane of the postsynaptic cell. Neurotransmitters bind to their receptors by having a particular shape or structure, somewhat like the way a key fits into certain locks.

  1. Neurotransmitters are stored in (pre-)synaptic vesicles at end of axon (of the pre-synaptic cell/neuron)
  2. As AP reaches terminal end of an axon, Ca+ influx through Ca+ channels, causes these vesicles to diffuse with pre-synaptic membrane
  3. Neuro transmitters go across the synaptic cleft, and diffuse bind to specific receptors, and act for a temporary time
  4. NT action is terminated by reuptake pumps that force them back in to the axon terminals or by enzymes and terminates their effect at the post-synaptic membrane

Read more…………….

How Memories Are Made, And Recalled

Artist’s rendering of neuron activity. Researchers have recorded the activity of hundreds of individual neurons making memories. (Credit: iStockphoto/Sebastian Kaulitzki)

UCLA — What makes a memory? Single cells in the brain, for one thing.

For the first time, scientists at UCLA and the Weizmann Institute of Science in Israel have recorded individual brain cells in the act of calling up a memory, thus revealing where in the brain a specific memory is stored and how the brain is able to recreate it.

Reporting in the current online edition of the journal Science, Dr. Itzhak Fried, senior study author and a UCLA professor of neurosurgery, and colleagues recorded the activity of hundreds of individual neurons making memories in the brains of 13 epilepsy patients being treated surgically at UCLA Medical Center.

Surgeons had placed electrodes in the patients’ brains to locate the origin of their seizures before surgical treatment — standard procedure in such cases. Fried made use of the same electrodes to record neuron activity as memories were being formed.

The patients watched several video clips of short duration, including such things as landmarks and people, along with other clips of Jerry Seinfeld, Tom Cruise, “Simpsons” character Homer Simpson and others. As the patients watched, the researchers recorded the activity of many neurons in the hippocampus and a nearby region known the entorhinal cortex that responded strongly to individual clips.

A few minutes later, after performing an intervening task, the patients were asked to recall whatever clips came to mind.

“They were not prompted to recall any specific clips,” Fried said, “but to use ‘free recall’ — that is, whatever popped into their heads.”

The researchers found that the same neurons that had responded earlier to a specific clip fired strongly a second or two before the subject reported recalling that clip. These neurons did not fire, however, when other clips were recalled. Ultimately, it was possible for the researchers to know which clip a patient was recalling before the patient announced it.

Fried noted that the single neurons that were recorded as they fired were not acting alone but were part of a much larger memory circuit of hundreds of thousands of cells caught in the act of responding to the clips.

The study is significant, he said, because it confirms for the first time that spontaneous memories arise through the activity of the very same neurons that fired when the memory was first being made. This link between reactivation of neurons in the hippocampus and conscious recall of past experience has been suspected and theorized for sometime, but the study now provides direct evidence for such a link.

“In a way, then,” Fried said, “reliving past experience in our memory is the resurrection of neuronal activity from the past”

Other authors of the study included first author Hagar Gelbard-Sagiv, Michal Harel and Rafael Malach of the Weizmann Institute and UCLA postdoctoral scholar Roy Mukamel.

The research was funded by the U.S. National Institute of Neurological Disorders and Stroke, as well as the Israel Science Foundation and the U.S.–Israel Binational Science Foundation.

And……………

Beauty Through The Eye Of The Microscope

Starlike astrocytes and other so-called glial cells serve as scaffolding for the
billions of neurons that make possible memory and the human mind. The brain of a newborn human has 100 billion nerve cells. A baby’s billions of neurons are supported by about a trillion glial cells, which account for 90% of the cells in the human brain.

Glial cells are vital in the efficient transmission of messages between nerve cells. Science shows us hidden images that can be exquisitely beautiful and often resemble abstract painting, such as the microscopic picture of the human nerve cell shown at left. Thus, that which enables us to perceive and appreciate beauty is, by itself, a work of art.

Deciphering the Chatter of Monkeys and Chimps

 

 

The New York Times, by Nicholas Wade  —  Walking through the Tai forest of Ivory Coast, Klaus Zuberbühler could hear the calls of the Diana monkeys, but the babble held no meaning for him.

That was in 1990. Today, after nearly 20 years of studying animal communication, he can translate the forest’s sounds. This call means a Diana monkey has seen a leopard. That one means it has sighted another predator, the crowned eagle. “In our experience time and again, it’s a humbling experience to realize there is so much more information being passed in ways which hadn’t been noticed before,” said Dr. Zuberbühler, a psychologist at the University of St. Andrews in Scotland.

Do apes and monkeys have a secret language that has not yet been decrypted? And if so, will it resolve the mystery of how the human faculty for language evolved? Biologists have approached the issue in two ways, by trying to teach human language to chimpanzees and other species, and by listening to animals in the wild.

The first approach has been propelled by people’s intense desire — perhaps reinforced by childhood exposure to the loquacious animals in cartoons — to communicate with other species. Scientists have invested enormous effort in teaching chimpanzees language, whether in the form of speech or signs. A New York Times reporter who understands sign language, Boyce Rensberger, was able in 1974 to conduct what may be the first newspaper interview with another species when he conversed with Lucy, a signing chimp. She invited him up her tree, a proposal he declined, said Mr. Rensberger, who is now at M.I.T.

But with a few exceptions, teaching animals human language has proved to be a dead end. They should speak, perhaps, but they do not. They can communicate very expressively — think how definitely dogs can make their desires known — but they do not link symbolic sounds together in sentences or have anything close to language.

Better insights have come from listening to the sounds made by animals in the wild. Vervet monkeys were found in 1980 to have specific alarm calls for their most serious predators. If the calls were recorded and played back to them, the monkeys would respond appropriately. They jumped into bushes on hearing the leopard call, scanned the ground at the snake call, and looked up when played the eagle call.

It is tempting to think of the vervet calls as words for “leopard,” “snake” or “eagle,” but that is not really so. The vervets do not combine the calls with other sounds to make new meanings. They do not modulate them, so far as is known, to convey that a leopard is 10, or 100, feet away. Their alarm calls seem less like words and more like a person saying “Ouch!” — a vocal representation of an inner mental state rather than an attempt to convey exact information.

But the calls do have specific meaning, which is a start. And the biologists who analyzed the vervet calls, Robert Seyfarth and Dorothy Cheney of the University of Pennsylvania, detected another significant element in primates’ communication when they moved on to study baboons. Baboons are very sensitive to who stands where in their society’s hierarchy. If played a recording of a superior baboon threatening an inferior, and the latter screaming in terror, baboons will pay no attention — this is business as usual in baboon affairs. But when researchers concoct a recording in which an inferior’s threat grunt precedes a superior’s scream, baboons will look in amazement toward the loudspeaker broadcasting this apparent revolution in their social order.

Baboons evidently recognize the order in which two sounds are heard, and attach different meanings to each sequence. They and other species thus seem much closer to people in their understanding of sound sequences than in their production of them. “The ability to think in sentences does not lead them to speak in sentences,” Drs. Seyfarth and Cheney wrote in their book “Baboon Metaphysics.”

Some species may be able to produce sounds in ways that are a step or two closer to human language. Dr. Zuberbühler reported last month that Campbell’s monkeys, which live in the forests of the Ivory Coast, can vary individual calls by adding suffixes, just as a speaker of English changes a verb’s present tense to past by adding an “-ed.”

The Campbell’s monkeys give a “krak” alarm call when they see a leopard. But adding an “-oo” changes it to a generic warning of predators. One context for the krak-oo sound is when they hear the leopard alarm calls of another species, the Diana monkey. The Campbell’s monkeys would evidently make good reporters since they distinguish between leopards they have observed directly (krak) and those they have heard others observe (krak-oo).

Even more remarkably, the Campbell’s monkeys can combine two calls to generate a third with a different meaning. The males have a “Boom boom” call, which means “I’m here, come to me.” When booms are followed by a series of krak-oos, the meaning is quite different, Dr. Zuberbühler says. The sequence means “Timber! Falling tree!”

Dr. Zuberbühler has observed a similar achievement among putty-nosed monkeys that combine their “pyow” call (warning of a leopard) with their “hack” call (warning of a crowned eagle) into a sequence that means “Let’s get out of here in a real hurry.”

Apes have larger brains than monkeys and might be expected to produce more calls. But if there is an elaborate code of chimpanzee communication, their human cousins have not yet cracked it. Chimps make a food call that seems to have a lot of variation, perhaps depending on the perceived quality of the food. How many different meanings can the call assume? “You would need the animals themselves to decide how many meaningful calls they can discriminate,” Dr. Zuberbühler said. Such a project, he estimates, could take a lifetime of research.

Monkeys and apes possess many of the faculties that underlie language. They hear and interpret sequences of sounds much like people do. They have good control over their vocal tract and could produce much the same range of sounds as humans. But they cannot bring it all together.

This is particularly surprising because language is so useful to a social species. Once the infrastructure of language is in place, as is almost the case with monkeys and apes, the faculty might be expected to develop very quickly by evolutionary standards. Yet monkeys have been around for 30 million years without saying a single sentence. Chimps, too, have nothing resembling language, though they shared a common ancestor with humans just five million years ago. What is it that has kept all other primates locked in the prison of their own thoughts?

Drs. Seyfarth and Cheney believe that one reason may be that they lack a “theory of mind”; the recognition that others have thoughts. Since a baboon does not know or worry about what another baboon knows, it has no urge to share its knowledge. Dr. Zuberbühler stresses an intention to communicate as the missing factor. Children from the youngest ages have a great desire to share information with others, even though they gain no immediate benefit in doing so. Not so with other primates.

“In principle, a chimp could produce all the sounds a human produces, but they don’t do so because there has been no evolutionary pressure in this direction,” Dr. Zuberbühler said. “There is nothing to talk about for a chimp because he has no interest in talking about it.” At some point in human evolution, on the other hand, people developed the desire to share thoughts, Dr. Zuberbühler notes. Luckily for them, all the underlying systems of perceiving and producing sounds were already in place as part of the primate heritage, and natural selection had only to find a way of connecting these systems with thought.

Yet it is this step that seems the most mysterious of all. Marc D. Hauser, an expert on animal communication at Harvard, sees the uninhibited interaction between different neural systems as critical to the development of language. “For whatever reason, maybe accident, our brains are promiscuous in a way that animal brains are not, and once this emerges it’s explosive,” he said.

In animal brains, by contrast, each neural system seems to be locked in place and cannot interact freely with others. “Chimps have tons to say but can’t say it,” Dr. Hauser said. Chimpanzees can read each other’s goals and intentions, and do lots of political strategizing, for which language would be very useful. But the neural systems that compute these complex social interactions have not been married to language.

Dr. Hauser is trying to find out whether animals can appreciate some of the critical aspects of language, even if they cannot produce it. He and Ansgar Endress reported last year that cotton-top tamarins can distinguish a word added in front of another word from the same word added at the end. This may seem like the syntactical ability to recognize a suffix or prefix, but Dr. Hauser thinks it is just the ability to recognize when one thing comes before another and has little to do with real syntax.

“I’m becoming pessimistic,” he said of the efforts to explore whether animals have a form of language. “I conclude that the methods we have are just impoverished and won’t get us to where we want to be as far as demonstrating anything like semantics or syntax.”

Yet, as is evident from Dr. Zuberbühler’s research, there are many seemingly meaningless sounds in the forest that convey information in ways perhaps akin to language. 

as explained by John Cleese

The-Scientist.com, January 27, 2010, by Bob Grant  —  When he addresses the nation tonight (27th January), US President Obama is expected to call for a three-year freeze on federal spending for any programs not dealing with the military or homeland defense. But with the budget boosts for federal science agencies provided by 2009’s American Recovery and Reinvestment Act drying up in 2011, science advocates are concerned that Obama’s funding freeze may spell the steep budgetary drop-off in the next fiscal year that many dread.
“Certainly it does concern us,” Kerry Peluso, associate vice president for research administration at Emory University in Atlanta, told The Scientist. “We want to see our researchers continue to be able to do their research.”

Though the announcement is not yet official, the White House has released some details of the proposed freeze in the run up to Obama’s State of the Union address tonight and the release of his FY2011 budget proposal, which is slated for Monday (1st February). “The three-year freeze over the course of 10 years will save on the order of $250 billion,” said press secretary Robert Gibbs at a White House press briefing yesterday.

In an entry posted yesterday on The White House Blog, Vice President Joe Biden’s chief economist and economic policy adviser Jared Bernstein said that Obama’s freeze would be more like surgery and less like a hatchet job. “…the entire theory of the President’s proposed freeze is to dial up the stuff that will support job growth and innovation while dialing down the stuff that doesn’t,” Bernstein wrote. “Under our plan, some discretionary spending will go up; some will go down. That’s a big difference from a hatchet.”

But some aren’t entirely convinced that science funding will be spared the axe. “We are extremely concerned about the proposed freeze on non-security discretionary spending, particularly in light of the compelling evidence that an innovation-driven economy is the future,” said Mary Woolley, president and CEO of science advocacy group Research!America. “We’re looking to the President for national priority-setting that’s consistent with that goal.”

The Federation of American Societies for Experimental Biology (FASEB), another science advocacy organization, is holding out hope that Obama’s past statements on the importance of science and research in rebuilding the economy portend a reprieve for federal research funding agencies, such as the National Institutes of Health and the National Science Foundation. “We’re hopeful that science is enough of a priority in the president’s agenda that the scientific agencies we care about will not be included [in the freeze],” FASEB spokesperson Carrie Wolinetz told The Scientist. “It’s something that we’re waiting to hear more details about.”

Alzheimer’s Disease: Another example of the atrophy and enlarged ventricles seen in Alzheimer’s disease.
Alzheimer’s can be seen in a presenile form, that is, before the age of 65.
Note the dark substantia nigra suggesting that this does not have accompanying Parkinson’s disease.  Description By:Margaret Grunnet,M.D., (Image Contrib. by: UCHC )

Alzheimer’s Disease – Closeup of a senile plaque (arrows), showing stick like abnormal neurites collected in a ball.
Because it has no amyloid center, this type of plaque is known as a diffuse plaque.

Description By:Margaret Grunnet,M.D., Image Contrib. by:Margaret Grunnet,M.D. UCHC

Emory University, January 26, 2010  —  Alzheimer’s disease (AD) researchers are testing the effectiveness of gene therapy for the first time to treat patients with this common brain disease. Emory University is one of 12 institutions participating in a nationwide study to test the experimental medication, CERE-110.

The Phase 2 clinical trial seeks to enroll a total of 50 study participants with mild to moderate AD.

Previously studied in animals and in a small study to assess safety in humans, CERE-110 appears to induce long-term production of Nerve Growth Factor (NGF) by brain cells. NGF is a naturally occurring protein that helps nerve cells, or neurons, survive in the brain. These neurons produce a chemical, acetylcholine, which plays a vital role in memory and cognitive function.

“Since NGF supports the survival and function of the neurons that deteriorate in people with Alzheimer’s disease, we hope to slow the worsening of their symptoms with this new therapy,” says James Lah, MD, associate professor of neurology, Emory University School of Medicine and lead investigator of the study at Emory.

During the Phase 2 clinical trial, a neurosurgeon will inject CERE-110 directly into the nucleus basalis of Meynert (NBM) of the brain, an area where neuron death occurs in AD. CERE-110 packages the gene for NGF within a shell from the adeno-associated virus. Putting an extra copy of the NGF gene into cells drives them to make more NGF. The original virus is not known to cause disease — and as an extra precaution, most of the insides of the virus are removed.

“Adeno-associated viral vectors like the one used in this study have proven safe in extensive animal testing, as well as several other human trials for neurodegenerative diseases,” says Nicholas Boulis, MD, assistant professor, department of neurosurgery, Emory University School of Medicine. Boulis has previously conducted neurosurgical adeno-associated gene therapy and is performing the surgery in the Emory study.

A Phase 1 study was conducted where the treatment was found to be generally safe and well tolerated. The 10 subjects underwent cognitive testing, measures of activities of daily living, and MRI and PET (positron emission tomography) scans. Researchers observed increases in brain metabolism in several cortical regions of the brain at six months and 12 months in some of the participants, as compared to other severity-matched individuals with AD, suggesting a potential reversal of patterns typically observed in AD. With follow up ranging from six months to more than four years post-treatment, there have been no side effects thought to be caused by CERE-110.

In previous studies, CERE-110 reversed brain degeneration in aged animals and in animal models intended to create cholinergic degeneration, a feature that characterizes changes in early AD. The overall study is conducted by the Alzheimer’s Disease Cooperative Study (ADCS), a nationwide consortium of research centers and clinics supported by the National Institute on Aging (NIA), National Institutes of Health, and coordinated by the University of California San Diego. Ceregene, Inc., the study sponsor, is a San Diego-based biotechnology company providing CERE-110 for the study.

Weill Cornell Medical College Study Lays Groundwork for New Treatments for Cardiovascular Disease and Other Conditions

Rendering of blood flowing in a blood vessel. In a significant step toward restoring healthy blood circulation to treat a variety of diseases, a team of scientists at Weill Cornell Medical College has developed a new technique and described a novel mechanism for turning human embryonic and pluripotent stem cells into plentiful, functional endothelial cells, which are critical to the formation of blood vessels. (Credit: iStockphoto/Osman Safi)

 

Cornell Scientists Create Usable Blood Vessels from Human Stem Cells

 

 

Weill-Cornell Medical College, NEW YORK (Jan. 26, 2010) — In a significant step toward restoring healthy blood circulation to treat a variety of diseases, a team of scientists at Weill Cornell Medical College has developed a new technique and described a novel mechanism for turning human embryonic and pluripotent stem cells into plentiful, functional endothelial cells, which are critical to the formation of blood vessels. Endothelial cells form the interior “lining” of all blood vessels and are the main component of capillaries, the smallest and most abundant vessels. In the near future, the researchers believe, it will be possible to inject these cells into humans to heal damaged organs and tissues.

The new approach allows scientists to generate virtually unlimited quantities of durable endothelial cells — more than 40-fold the quantity possible with previous approaches. Based on insights into the genetic mechanisms that regulate how embryonic stem cells form vascular endothelial cells, the approach may also yield new ways to study genetically inherited vascular diseases. The study appears in the advance online issue of Nature Biotechnology.

“This technique is the first of its kind with serious potential as a treatment for a diverse array of diseases, especially cardiovascular disease, stroke and vascular complications of diabetes,” says Dr. Shahin Rafii, the study’s senior author. Dr. Rafii is the Arthur B. Belfer Professor in Genetic Medicine and co-director of the Ansary Stem Cell Institute at Weill Cornell Medical College, and an investigator of the Howard Hughes Medical Institute.

In recent years, enormous hopes have been pinned on stem cells as the source of future cures and treatments. Indeed, human embryonic stem cells have the potential to become any one of the more than 200 types of adult cells. However, the factors and pathways that govern their differentiation to abundant derivatives that could be used to repair organs have remained poorly understood.

A major challenge for Dr. Rafii’s lab has been to improve their understanding, and hence control, of the differentiation process (how stem cells convert to various cell types), and then to generate enough vascular endothelial cells — many millions — so they can be used therapeutically.

To meet this challenge, the scientists first screened for molecular factors that come into play when stem cells turn into endothelial cells. Their findings led them to a strategy that significantly boosts the efficiency of producing these cells.

Then, the researchers tracked the differentiation process in real-time using a green fluorescent protein marker developed by Dr. Daylon James, the study’s first author and assistant research professor in the Department of Reproductive of Medicine at Weill Cornell Medical College. They found that when they exposed stem cells to a compound that blocks TGF-beta (a growth factor involved in cell specialization) at just the right time during cell culturing, the propagation of endothelial cells dramatically increased.

Even more striking, they found that the cells worked properly when injected into mice. The cells were quickly assimilated into the animals’ circulatory systems, and functioned alongside normal vasculature.

To achieve long-lasting clinical benefits, there remain additional hurdles to exploiting endothelial cells generated in vitro. Indeed, a fundamental prerequisite to using vascular cells in regenerative medicine has been the proper assembly in vivo of new blood vessels from stem-cell-derived cells, according to Dr. Sina Rabbany, who is an adjunct professor at Weill Cornell Medical College and professor of bioengineering at Hofstra University. Dr. Rabbany emphasizes that, in addition to manipulating biological factors implicated in endothelial cell differentiation, the impact of blood flow on endothelial cells is critical to engineering durable, vascularized organs. With the plentiful supply of endothelial cells that the new methods provide, Dr. Rabbany’s team is working to build biological scaffolds that model the microenvironment of the vasculature, so that the vessels they generate will be functional and long-lasting in patients.

Another major obstacle to clinical use of cultured endothelial cells is the potential of immune rejection when the cells are injected into a patient. To address this risk, one approach would be to create a large, genetically diverse bank of human embryonic stem cells that, on demand, could be converted into endothelial cells that are compatible with specific patients.

“Given the success rate our group has shown in generating human embryonic stem cells from donated normal and diseased embryos, this new approach has broad implications not only for regenerative medicine, but also for the study of genetic diseases of the vasculature,” states Dr. Zev Rosenwaks, who is director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine as well as the director of the Tri-Institutional Stem Cell Initiative Derivation Unit at Weill Cornell Medical College.

The new endothelial cell culture is currently being validated in ongoing research at Weill Cornell using a number of stem cell “lines,” or “families” of stem cells. “Employing a highly sophisticated derivation technology, we have been able to generate 11 normal and diseased human embryonic cell lines from discarded embryos at the Tri-Institute Derivation Unit at Weill Cornell,” states Dr. Nikica Zaninovic, an assistant professor at the Department of Reproductive of Medicine who is spearheading the human embryonic stem cell derivation effort. Using the new differentiation methods, several of these new embryonic stem cell lines have been turned into vascular cells.

Testing in humans is the next major step in verifying the ability of this breakthrough cell-based approach to restore blood supply to injured organs. Armed with this new technology and under the umbrella of support from the Ansary Stem Cell Institute and Tri-Institutional Stem Cell Initiative (Tri-SCI), this team of scientists is hoping to transfer their methods to the clinic within the next five years.

The current study sheds light on the generation of human embryonic vasculature in ways that have not previously been feasible due to obstacles associated with the use of human embryonic tissue. As Dr. James explains, “The unbiased screening technique we used is a major technological advance that opens up possibilities for discovery of how human embryonic stem cells morph into the specific mature cells that compose the brain, liver, pancreas, and so on. Our general approach can be applied to additional human tissues and help other stem cell research groups develop and maintain specialized cell types in the larger effort to understand human development — and to heal many different kinds of human diseases and injuries.”

The Tri-Institutional Stem Cell Initiative, supported by a generous gift from The Starr Foundation, is a collaborative venture of Memorial Sloan-Kettering Cancer Center, The Rockefeller University, and Weill Cornell Medical College.

Ansary Stem Cell Institute

The Ansary Stem Cell Institute, established at Weill Cornell Medical College in 2004 through the generous donation of Shahla and Hushang Ansary, brings together a premier team of scientists to focus on stem cells — the primitive, unspecialized cells with an unrivaled capacity to form all types of cells, tissues and organs in the body. The vision of the Ansary Institute is to help lead the way in 21st-century medicine by employing this new field of research with tremendous potential to relieve human suffering. The Institute permits the multidisciplinary collaboration and creativity of Weill Cornell’s researchers, as well as helps to attract the best and brightest young researchers in the field. Scientists at the Institute hope to discover the wellspring of adult stem cells in the body and ways to manipulate them to treat human illness. In particular, they hope to understand the regulation of cells that give rise to such essential components as blood vessels, insulin-producing cells in the pancreas (which are damaged in diabetics), and neurons of the brain and nervous system.

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University’s medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson’s disease, and most recently, the world’s first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston, making Weill Cornell one of only two medical colleges in the country affiliated with two U.S.News & World Report Honor Roll hospitals. For more information, visit www.med.cornell.edu.  Contact Info: Andrew Klein ank2017@med.cornell.edu

Read more………………..

 

New Way to Generate Abundant Functional Blood Vessel Cells from Human Stem Cells Discovered

 

ScienceDaily.com — In a significant step toward restoring healthy blood circulation to treat a variety of diseases, a team of scientists at Weill Cornell Medical College has developed a new technique and described a novel mechanism for turning human embryonic and pluripotent stem cells into plentiful, functional endothelial cells, which are critical to the formation of blood vessels.

Endothelial cells form the interior “lining” of all blood vessels and are the main component of capillaries, the smallest and most abundant vessels. In the near future, the researchers believe, it will be possible to inject these cells into humans to heal damaged organs and tissues.

The new approach allows scientists to generate virtually unlimited quantities of durable endothelial cells — more than 40-fold the quantity possible with previous approaches. Based on insights into the genetic mechanisms that regulate how embryonic stem cells form vascular endothelial cells, the approach may also yield new ways to study genetically inherited vascular diseases. The study appears in the advance online issue of Nature Biotechnology.

“This technique is the first of its kind with serious potential as a treatment for a diverse array of diseases, especially cardiovascular disease, stroke and vascular complications of diabetes,” says Dr. Shahin Rafii, the study’s senior author. Dr. Rafii is the Arthur B. Belfer Professor in Genetic Medicine and co-director of the Ansary Stem Cell Institute at Weill Cornell Medical College, and an investigator of the Howard Hughes Medical Institute.

In recent years, enormous hopes have been pinned on stem cells as the source of future cures and treatments. Indeed, human embryonic stem cells have the potential to become any one of the more than 200 types of adult cells. However, the factors and pathways that govern their differentiation to abundant derivatives that could be used to repair organs have remained poorly understood.

A major challenge for Dr. Rafii’s lab has been to improve their understanding, and hence control, of the differentiation process (how stem cells convert to various cell types), and then to generate enough vascular endothelial cells — many millions — so they can be used therapeutically.

To meet this challenge, the scientists first screened for molecular factors that come into play when stem cells turn into endothelial cells. Their findings led them to a strategy that significantly boosts the efficiency of producing these cells.

Then, the researchers tracked the differentiation process in real-time using a green fluorescent protein marker developed by Dr. Daylon James, the study’s first author and assistant research professor in the Department of Reproductive of Medicine at Weill Cornell Medical College. They found that when they exposed stem cells to a compound that blocks TGF-beta (a growth factor involved in cell specialization) at just the right time during cell culturing, the propagation of endothelial cells dramatically increased.

Even more striking, they found that the cells worked properly when injected into mice. The cells were quickly assimilated into the animals’ circulatory systems, and functioned alongside normal vasculature.

To achieve long-lasting clinical benefits, there remain additional hurdles to exploiting endothelial cells generated in vitro. Indeed, a fundamental prerequisite to using vascular cells in regenerative medicine has been the proper assembly in vivo of new blood vessels from stem-cell-derived cells, according to Dr. Sina Rabbany, who is an adjunct professor at Weill Cornell Medical College and professor of bioengineering at Hofstra University. Dr. Rabbany emphasizes that, in addition to manipulating biological factors implicated in endothelial cell differentiation, the impact of blood flow on endothelial cells is critical to engineering durable, vascularized organs. With the plentiful supply of endothelial cells that the new methods provide, Dr. Rabbany’s team is working to build biological scaffolds that model the microenvironment of the vasculature, so that the vessels they generate will be functional and long-lasting in patients.

Another major obstacle to clinical use of cultured endothelial cells is the potential of immune rejection when the cells are injected into a patient. To address this risk, one approach would be to create a large, genetically diverse bank of human embryonic stem cells that, on demand, could be converted into endothelial cells that are compatible with specific patients.

“Given the success rate our group has shown in generating human embryonic stem cells from donated normal and diseased embryos, this new approach has broad implications not only for regenerative medicine, but also for the study of genetic diseases of the vasculature,” states Dr. Zev Rosenwaks, who is director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine as well as the director of the Tri-Institutional Stem Cell Initiative Derivation Unit at Weill Cornell Medical College.

The new endothelial cell culture is currently being validated in ongoing research at Weill Cornell using a number of stem cell “lines,” or “families” of stem cells. “Employing a highly sophisticated derivation technology, we have been able to generate 11 normal and diseased human embryonic cell lines from discarded embryos at the Tri-Institute Derivation Unit at Weill Cornell,” states Dr. Nikica Zaninovic, an assistant professor at the Department of Reproductive of Medicine who is spearheading the human embryonic stem cell derivation effort. Using the new differentiation methods, several of these new embryonic stem cell lines have been turned into vascular cells.

Testing in humans is the next major step in verifying the ability of this breakthrough cell-based approach to restore blood supply to injured organs. Armed with this new technology and under the umbrella of support from the Ansary Stem Cell Institute and Tri-Institutional Stem Cell Initiative (Tri-SCI), this team of scientists is hoping to transfer their methods to the clinic within the next five years.

The current study sheds light on the generation of human embryonic vasculature in ways that have not previously been feasible due to obstacles associated with the use of human embryonic tissue. As Dr. James explains, “The unbiased screening technique we used is a major technological advance that opens up possibilities for discovery of how human embryonic stem cells morph into the specific mature cells that compose the brain, liver, pancreas, and so on. Our general approach can be applied to additional human tissues and help other stem cell research groups develop and maintain specialized cell types in the larger effort to understand human development — and to heal many different kinds of human diseases and injuries.”

The Tri-Institutional Stem Cell Initiative, supported by a generous gift from The Starr Foundation, is a collaborative venture of Memorial Sloan-Kettering Cancer Center, The Rockefeller University, and Weill Cornell Medical College.  Source: Adapted from materials provided by New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College.


CVS, Medco at vanguard of effort to match patients, drugs by genetic tests
 

 
Boston.com, January 26, 2010, by Carolyn Y. Johnson  —  For years, hype has built around personalized medicine – a tantalizing future in which insights gleaned from genetic tests will result in individualized treatment, guiding the drugs people take and at what doses.

Now, moves by two large companies that focus on controlling drug costs are leading the way for the field to become a routine part of medicine.

CVS Caremark, the Woonsocket, R.I., company that is the largest provider of prescriptions in the United States, said late last year it expects to begin offering genetic testing services to clients of its pharmacy benefit management program this year. It also invested in Generation Health, a company with offices in Waltham that is focused on helping companies manage costs and improve health by using genetic information.

A CVS competitor, Medco Health Solutions, offers genetic tests to guide the use of two drugs and plans to add four more tests this year. Medco has 270 clients, representing 7 million people, participating in its personalized medicine program.

The companies work with insurance plans or large employers and use their buying power to keep drug costs low. They want to use genetic tests to sift out patients who are unlikely to benefit from a drug they have been prescribed or who could experience dangerous or costly side effects.

When a doctor submits a prescription, for example, the company that manages a patient’s drug benefits may call the doctor and offer a genetic test. Ultimately, results might discourage the doctor from prescribing a drug that won’t work, help determined what dosage to use, or suggest an equally effective generic option. CVS said that testing would be integrated into the prescription-filling process.

“The hope is that as we learn more and more about the genome . . . we’ll be in the situation where a lot of different kinds of medications will have the choice of the medication or the dosing of the medication indicated by a genetic test,’’ said Dr. Troyen Brennan, chief medical officer of CVS.

The companies’ interest in using genetic information stems from a longstanding problem: Drugs may be more effective in some patients than others, and doctors often have no way of knowing before they prescribe them. Insight from genetics is beginning to explain some of those differences.

Patients with a particular genetic makeup do not effectively break down Plavix, an anticlotting drug. Variations in two genes affect how people re spond to the common blood thinner warfarin. Genetic testing provides a new way to understand which drugs will work for which patients, meaning people and insurers might have a new tool to avoid paying for drugs that may not work.

“We’re in a good place, theoretically, because we’re being hired to help people manage their prescriptions,’’ said Dr. Robert Epstein, chief medical officer of Medco.

Still, using genetic testing to better target drugs is controversial. Even as evidence has emerged that variations in a particular gene may change a person’s response to a drug, the evidence may not exist that changing the dose or drug leads to a better outcome or is more cost effective, given the cost of the test. The Food and Drug Administration has changed the labels of various drugs, sometimes mentioning a gene that may affect response to the drug but not always recommending or requiring a test.

“The FDA can label drugs to say that this medication is only indicated if you have this [genetic] finding,’’ as it does for the cancer drug, Herceptin, said Dr. Marc S. Williams, vice president of the American College of Medical Genetics. But in other cases it has not gone so far.

“Predicting the dose better does not translate automatically into better safety for patients,’’ Williams said.

The interest of pharmacy benefit management companies in personalized dosages is intriguing, he said, because they reach so many patients and can begin to collect data to better understand how drugs and genes interact. Medco has entered a partnership with the FDA to begin to answer some of those questions by collecting data and studying factors such as safety, physician participation, and the tests’ usefulness.

To advocates for personal medicine, the companies’ interest is a powerful vote of confidence.

“This is the most exciting thing in personalized medicine today, because Medco and CVS are big players with enormous impact in the field,’’ said Edward Abrahams, executive director of the Personalized Medicine Coalition, an education and advocacy organization, which is funded by diagnostic, pharmaceutical, and health insurance companies, and hospitals, among others. “The point of personalized medicine is to develop better efficacy, better outcomes, fewer adverse events, and lower systemic costs. The pharmacy benefits manager is interested in all of those things.’’

In Medco’s personalized medicine program, genetic testing is offered to patients prescribed the breast cancer drug tamoxifen or warfarin. Responses to both have been found to be affected by particular genes, although how and whether to test has been a subject of considerable debate within the medical community.

Warfarin, which can cause bleeding in high doses, is a common cause of emergency room visits for adverse drug reactions, according to the FDA. Variations in two genes have been shown to affect how people respond to the drug, indicating they may need a lower dose.

Having a variation of a gene involved in the metabolism of tamoxifen has been shown to increase the risk of a recurrent cancer, and knowing this could allow a physician to prescribe a different treatment.

In both cases, Medco does not require the physician to order a test in order to prescribe the drug, but it tells them a gene test is available.

An example of the potential benefit from the use of such information could come from one of the most-prescribed drugs, Plavix.

A 2008 study found that a variation in a gene that occurs in about a third of the population causes them to not respond as well to the drug because they do not metabolize it properly. The FDA changed the label to include the genetic risk last year. Last fall, Medco said it would compare Plavix with another drug, Effient, to see how a person’s genetic makeup affected his or her response to the drug. Because Plavix will lose its patent status in 2011, if it is found to be as effective as Effient for people with a particular genetic makeup, it could give patients who get a test a cheaper option.

“How can we help clients maintain the affordability of insurance and drugs and make the best outcome,’’ Epstein asked. “The problem is not with the science, it’s with the adoption.’’

Carolyn Y. Johnson can be reached at cjohnson@globe.com.  

The Wall Street Journal, January 26, 2010  —  The emergence of a new field of diagnostics is changing the way both patients and doctors view pre-treatment initiatives, according to Northland Securities Senior Analyst Stephen D. Simpson. This move to so-called “personalized medicine” may result in increasing opportunities for life sciences companies who research treatments for specialized diseases, and for those larger companies who will wish to acquire them.

“Personalized medicine is the idea that you can use genetic information about a patient to better diagnose and treat them. For example, there is a range in how people will respond to blood thinning drug like Coumadin, and you can predict that through genetic testing,” said Simpson, explaining that such genotype studies could lead to more appropriate prescriptions and dosing recommendations based on a patient’s susceptibility to certain medicines.

“The more we know about patients’ individual conditions, individual diseases, the better you can diagnose them and the better you can fine tune that therapy to get maximum effect and minimum side effects,” he said.

As smaller, more innovative companies in the life sciences space move toward genetic diagnostics and personalized medicine, Simpson predicts the bigger industry names, such as Abbott (ABT), Life Technologies (LIFE) and Millipore (MIL) will be on the prowl for attractive acquisition targets.

“If you have a test, a very good test that has good clinical use but for a relatively small application in terms of patient population, more likely than not you’re going to be acquired,” said Simpson, citing Genzyme (GENZ) and Alexion (ALXN) as two possible acquisition targets going forward.

“I just don’t see those companies staying independent for a particularly long period of time because Wall Street constantly demands growth, constantly demands the new things,” he said. “So many times it’s a path of least resistance to take a lucrative bio bid from a pharmaceutical company or a larger health care company that looks at acquisitions as a way of substituting their own slowing organic growth.”

Medco and other pharmacy benefit managers say future profits depend on matching drugs to patients based on their genes

BusinessWeek.com, January 25, 2010, by John Carey  —  The dirty little secret about drugs is that they only work in about half of the people who take them. So says an educational nonprofit called the Personalized Medicine Coalition, and many drug executives concede as much. Of the $292 billion spent in the U.S. on prescription drugs in 2008, as much as $145 billion went to medications that didn’t help individual patients, said Jerel Davis, project manager at McKinsey, at a recent conference. And billions more are being spent to treat adverse drug reactions and other complications. “When you look at the data, it’s shocking,” says Dr. Robert S. Epstein, chief medical officer at Medco Health Solutions (MHS), a $51 billion company that manages drug prescriptions for 60 million Americans.

Researchers know how to solve this problem. First, figure out the differences between those patients who respond to a drug and those who don’t, then treat only to those who will benefit. But this personalized medicine approach “has been slower to develop than we thought 10 years ago,” says Richard K. Schatzberg, CEO of Generation Health, a startup that offers targeted medicine services. Lack of enthusiasm in the drug industry is a big reason; companies would lose billions of dollars if only those who actually benefit were to use such blockbuster drugs as antidepressants, arthritis medicines, and cholesterol pills.

Now, however, the promise of personalized drug treatments appears more realistic, thanks to new players on the sceneand a new business model. The recent entrants are pharmacy benefit managers (PBMs) such as Medco and CVS Caremark (CVS). Medco is testing patients for genetic variations that explain why they respond differently to drugs like warfarin, a widely used blood thinner, and tamoxifen for breast cancer. CVS Caremark has taken a majority stake in Generation Health and expects to launch a similar testing program in May. The move by the PBMs “is transformative,” says Edward Abrahams, executive director of the Personalized Medicine Coalition, whose members include scientists, health-care providers, payers, and patients’ groups. “We are talking about better care for millions of people and keeping costs down for employers, whose insurance costs are exploding. It could be the tipping point.”

PBMs plan to make money by selling personalized medicine services to employers, which are willing to pay them higher fees for improved health outcomes and lower prescription costs. Medco and other PBMs also hope to win market share from their slower-moving competitors. “It is a differentiator for us,” says Dr. Jane Barlow, vice-president for Medco’s personalized medicine business. Plus, they expect genetic testing will increase the percentage of patients using certain cheaper generic drugs, thus increasing profits. Medco has signed up 200 employers to its program, representing 7 million people. “This has been the fastest adoption of a new program in Medco history,” says Epstein. One early—and eager—adopter: IBM (IBM), which expects better health outcomes and cost savings, says Dr. Martin Sepulveda, an IBM vice-president for health matters.

SECOND OPINION

The idea took a long time to bear fruit at Medco, even though it was an obsession for Epstein, an epidemiologist by training. “Back in 2000, Rob Epstein explained to me this would change the face of medicine—and make all the pharmaceutical companies nervous,” recalls Schatzberg. “It took longer than he thought.” The company’s first foray into personalized treatments in 2002 foundered. Epstein wanted to do genetic testing on asthma patients to predict better which ones might end up in the hospital, “but I couldn’t see the return on investment,” he says.

The business case improved as scientists identified more genes linked to drug responses. For many medicines, enzymes produced in the liver are crucial. Some enzymes change drugs so that they are excreted from the body. Others convert drugs that have no effect when first administered into a medically active form. Because of variations in genes, these enzymes may work quickly or slowly or not at all. One example is tamoxifen, used to prevent breast cancer recurrence. In 20% of people, the enzyme that usually activates this drug is partially or completely ineffective, and the drug provides little or no benefit.

A turning point for Medco came in 2005, when a Food & Drug Administration advisory committee recommended that genetic information be considered in making treatment decisions with warfarin. The blood thinner is widely prescribed to prevent clots, but it’s notoriously difficult to get the dose right. “We know that we kill people with warfarin all the time,” says Dr. Issam Zineh, associate director for genomics at the FDA’s Center for Drug Evaluation Research. Too much warfarin raises chances of bleeding and strokes caused by bleeding; too little allows deadly clots to form. The cost of using the wrong doses is estimated to be in the billions of dollars per year. With a genetic test, doctors can determine if people will need more or less warfarin than the standard 5-milligram dose.

When Epstein looked at Medco’s medical records of its million patients on the drug, he discovered something alarming: As many as 25% of them ended up in the hospital within six months of starting on warfarin. “Avoiding one hospitalization could underwrite the cost of the test for 100 patients,” Epstein reasoned. Medco worked with the Mayo Clinic to measure the clinical benefits and cost savings from genetic tests for warfarin. The final data won’t be released for several months, but Medco found that employers were eager to sign on for the testing service anyway. Now, when Medco sees a prescription coming in for warfarin, it recommends genetic testing to the doctor and patient. In Medco’s experience, 67% of doctors and 82% of patients agree to testing.

“THE INCENTIVES ALIGN”

The next drug Medco personalized was tamoxifen. Identifying women who can’t metabolize the drug into its active form and putting them on a different drug reduces the cancer’s chances of recurrence—and the costs of future treatment. Coming soon is a test for another blood thinner, the blockbuster Plavix. Pinpointing those who benefit will enable Medco to keep more patients on the drug when it goes generic, instead of switching to a more expensive alternative that doesn’t require a test. A bonus is that the results from any given genetic test are usually applicable to many drugs. The same variation that determines the response to Plavix, for instance, can help determine how Valium, heartburn drugs like Nexium, and the antidepressant Celexa should be used.

The PBMs’ foray into individualized treatments “is where the business rubber meets the road,” says Michael Stocum, managing director of consultant Personalized Medicine Partners. “The incentives align. Patients want to get the right drug, and payers are willing to pay if they get a benefit.”

Targeting drugs to those who benefit will obviously cut revenues for some drugmakers. But the pharmaceutical industry itself has started to back away from trying to sell the same medicines to everyone, says former Pfizer drug researcher Dr. Bruce H. Littman, now president of consultant Translational Medicine Associates. “The blockbuster mentality is still in place, but drugmakers are coming around,” he says.

If they don’t, the FDA may not be pleased. In the future, the agency may balk at approving drugs that can’t be directed to the right patients—and payers may decline to reimburse. Amgen, for one, strongly backs the use of a test for a gene called KRAS for its $8,400-per-month colon cancer drug, Vectibix. About 40% of people have a variation of KRAS that prevents the drug from working. Drugmakers “see a future business model where they just want all of the smaller market of appropriate patients,” says Generation Health’s Schatzberg.

Given these trends, the once overhyped idea of personalized medicine “is really starting to get legs,” says Dr. Eric Topol, chief academic officer at Scripps Health. “The old way of giving therapeutics will be obsolete.”

1)  A Breakfast Staple That Blocks Heart Failure

January 25, 2010, by Mehmet C. Oz, MD, and Michael F. Roizen, MD |

Fruit, veggies, exercise — they all make the heart-healthy list. And now, according to a new study, so does this breakfast staple: cereal.

But we’re not talking about Cocoa Puffs. We’re talking about whole-grain cereals — like steel-cut oats, shredded wheat, or muesli. Men in a study who noshed at least once a week on whole-grain cereals were significantly less likely to experience heart failure.

Longer Life in Every Bowl?
Several studies suggest that it’s the fiber in whole-grain cereals that may quell risk factors for heart failure, including high blood pressure, high blood sugar, and obesity. The other heart-protective habits addressed in the study: maintaining a healthy body weight, exercising regularly, eating lots of fruits and vegetables, drinking alcohol only in moderation, and not smoking.

A Combo Protects Best
Men who practiced at least four of the six lifestyle habits on the study’s heart-healthy list cut their risk for heart failure in half. So start stacking the odds in your heart’s favor with these heart-helping strategies:

  • Sneak more fruits and veggies into your day.
  • Even a minimal amount of exercise may help protect your heart.
  • Alcohol – one drink of wine, beer, or liquor per day for most women, and two drinks per day for most men. This also is the general recommendation given by the U.S. Department of Agriculture and the U.S. Department of Health and Human Services.

.

Benefit

Keeping your blood pressure at 115/76 mm Hg can make your Real-Age as much as 12 years younger.

References 

Relation between modifiable lifestyle factors and lifetime risk of heart failure. Djousse L. et al., JAMA 2009 Jul 22;302(4):394-400.

2)  Burn More Fat with This Wonder Breakfast
January 25, 2010, by Mehmet C. Oz, MD, and Michael F. Roizen, MD |

Your workouts might melt even more body fat if you eat this at breakfast: whole-grain cereal.

Why? A small study suggests that eating healthy carbs in the morning may turbocharge your fat-burning furnaces when you exercise later on in the day.

Good Carbs, Bad Carbs
The key here is the whole grain — because the study showed that low-glycemic-index carbs (the high-fiber kind) were what moved the dial on fat burning. When sedentary women ate these kinds of carbs as part of a healthy breakfast, they burned far more body fat during an hour walk later in the day, compared with women who ate a wimpy-carb breakfast. The winning breakfast? Muesli, fresh fruit, skim milk, and low-fat yogurt..

More to the Fat-Burning Story
Seems when you eat high-fiber carbs, you store fewer carbs as a fuel source, forcing your body to use fat for energy instead. Thus, the extra fat-burning boost during exercise. Two additional benefits experienced by the healthy carbs group: extra fat-burning during a post-breakfast rest period and greater feelings of fullness. Burn extra fat and not feel hungry? Sold! Now, make your workouts feel easy with this important balance of energy-boosting nutrients.

.

Benefit
Maintaining a constant desirable weight can make your RealAge 6 years younger.

References
Fat oxidation during exercise and satiety during recovery are increased following a low-glycemic index breakfast in sedentary women. Stevenson, E. J. et al., Journal of Nutrition 2009 May;139(5):890-897.

3)  The Strange Side Effect of Healthy Food

January 25, 2010, by Mehmet C. Oz, MD, and Michael F. Roizen, MD |

We’re big fans of nuts. Meaning, the ones from trees, not necessarily the ones that make the nightly news kicker because of counterfeiting a $1 bill (not making this up) or trying to rob a bank with a note on the back of a subpoena issued to the robber. Tree nuts (and peanuts, which are legumes) add healthy fats to your diet and reduce your risk of heart disease and diabetes.

But one type of nut in particular does a funny thing sometimes: It leaves a bitter taste in your mouth for weeks. We got a note from a woman whose son experienced this after eating an entree liberally sprinkled with pine nuts. The bitter taste got worse whenever he ate anything, especially sweets (a stay-away-from-sweets strategy we don’t recommend). Other pine nut eaters have experienced the same thing, and a journal report linked the lingering bitter taste to nuts that were imported from China in 2008.

Scientists aren’t sure what could cause your taste buds to get tripped up like this, but suggest that if pine nuts aren’t stored in a cool, dry place, oxidation could occur and quickly turn them rancid and bitter. Why the bitterness sticks around, nobody knows. But it does usually get better in 1 to 3 weeks. If this hassle has visited your mouth, try flavonoid-rich foods (vegetables and fruits) as well as Altoids (recommended by past victims). And if the pine nuts you’re about to put on your salad are from 2008 and China, don’t try them; buy fresher ones.

4)  How Are Your Arteries? Take This Free Test

January 25, 2010, by Mehmet C. Oz, MD, and Michael F. Roizen, MD |

Would you know if your arteries were stiffer than a double martini? New research suggests there’s a way to know that doesn’t involve doctors, insurance, or machinery.

An easy sit-and-reach test that indicates how flexible your body is may also tell you how flexible your arteries are. In study participants over age 40, a stiffer body corresponded to stiffer arteries (and higher heart disease risk).

The test: Warm up for 10 minutes (easy walking is fine). Then, sit on the floor with your legs straight out in front of you, feet about 12 inches apart. Place a yardstick between your feet, with the 0 mark pointing toward your body, and the 15-inch mark even with your heels. Tape it in place. Place one hand on top of the other, lightly touching the yardstick. Now, reach forward slowly by dropping your head toward or between your arms, maintaining contact with the yardstick. Have someone check where your fingertips land. Average flexibility for someone age 40 to 45 means hitting the 15-inch mark if you’re male, 17 if you’re female. The range shortens by about 2 inches per decade for men beyond age 45 (until age 66+, in which case average guys still hit the 10 or 11); it shortens by about 1 inch per decade for women beyond 45.

True, people and their arteries are more flexible when they do more cardiovascular exercise. But this study looked at flexibility independent of that and still found a link. So, will stretching, yoga, and Pilates soften up your arteries? There’s no answer yet, but don’t wait to dive in — they’re smart components of any exercise and stress-reduction routine.

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