There are few things in life that can be more terrifying and potentially disastrous than getting a diagnosis of having Parkinson's disease. Facing the prospect of having your body literally giving out on you and you not being able to exert any sort of control over it can be a difficult thing to contend with.
While medical science has come a long way in the treatment of Parkinson's, present day medical treatments are still lacking in having a huge effect on this particular condition. However, there are a few ways to effectively deal with the onset of Parkinson's and there are a few people leading the way on this front. The treatment is yoga therapy and one of the people leading the charge is Colleen Carroll.
As a yoga teacher for over 15 years, Colleen began to consider that yoga was not only helpful for the rank and file, but that yoga could actually be beneficial for people suffering from disorders such as Alzheimer's, MS, epilepsy and Parkinson's. This led her to Loyola Marymount University where she studied in the yoga therapy RX program, which is a course on using yoga in a clinical setting. After completing the 2 year program Colleen began to focus her yoga techniques to deal primarily with those suffering from Parkinson's.
While there are many deeply complicated issues surrounding why and how Parkinson's effects the human body, the main issue with this condition is that it effects gait, muscle coordination and balance. With yoga therapy, these are combated through simple techniques of breathing, proper posture and simple but specific movements. While Parkinson's results in tremors and muscle rigidity, therapeutic yoga is aimed at promoting fluidity and control.
While this is certainly no miracle cure, these simple techniques have shown great promise in combating the symptoms of Parkinson's disease, prevention of the worsening of the disease and has also proven to improve the physiological effect this disease has on a person such as anxiety, depression and sleep disorders.
Parkinson's disease can be a scary and troubling diagnosis to get, but it doesn't have to be the end of the world. Medications can certainly help, but medicines are not the only line of defense when battling Parkinson's disease. With yoga therapy, you can have a way to not only fight and battle back Parkinson's disease, but you can improve your quality of life in the process.
April 16, 2011
potentials of nanotechnology
Back in September 2004, the US National Cancer Institute (NCI) launched the Alliance for Nanotechnology in Cancer to stimulate and coordinate research in biology, engineering and materials science to push cancer nanotechnology forward. Just over 2 years on, such research is attracting increasing attention: in a round-up of last year's breakthroughs in the burgeoning field of nanotechnology from Forbes magazine, anticancer nanoparticles featured in the top five.
Nanotechnology is being applied to cancer in two broad areas: the development of nanovectors, such as nanoparticles, which can be loaded with drugs or imaging agents and then targeted to tumours, and high-throughput nanosensor devices for detecting the biological signatures of cancer. Combined, such technologies could lead to earlier diagnosis and better treatment for patients with cancer.
Spearheading efforts to expedite the clinical application of these technologies, the NCI currently funds eight Centers of Cancer Nanotechnology Excellence (CCNE) in the United States, in addition to 12 other smaller programmes. "We've pulled most of the key players in medical nanotechnology into this programme, and we're spending about US$35–40 million a year on these approaches," says Piotr Grodzinski, Director of the NCI Alliance. The NCI Alliance is actively pursuing both the therapeutic and diagnostics aspects of cancer nanotechnology with follow-up programmes in sight. Grodzinski hopes that by then nanotechnology will have matured into a clinically useful approach.
Robert Langer's team have shown the potential of targeted nanoparticles to deliver anticancer drugs.
Early signs are promising. The research highlighted in the Forbes list was conducted by a team led by Robert Langer, a chemical engineer who is Institute Professor at the Massachusetts Institute of Technology (MIT), USA, and also one of the two principal investigators for the MIT–Harvard CCNE. Langer, with Omid Farokhzad, Assistant Professor of Anaesthesia at Brigham and Women's Hospital, Boston, USA, and colleagues, uses polymeric nanoparticles coated with aptamers — RNA-based targeting moieties — to guide them towards the tumour, where they bind, enter the cells and then dissolve to spill out their contents — the anticancer drug docetaxel. The nanoparticles are also coated with polyethylene glycol (PEG) to aid their safe passage through the bloodstream and into the tumour cells. A single injection of such nanoparticles coated with aptamers that bind to prostate-membrane-specific antigen eradicated tumours in a mouse model of prostate cancer (PNAS 103, 6315–6320; 2006). "Extensive animal models show that this approach is both safe and efficacious," says Langer.
One of the key challenges in creating effective nanoparticles is targeting them to appropriate tissues and cells. Although biological targeting using aptamers or antibodies on the surface of nanoparticles is one popular option, other researchers are beginning to exploit the physical characteristics of the particles to guide them to desired locations. "The size, shape, physical properties, density and charge all affect how particles travel through the body, and whether or not they will cross biological membranes," says Mauro Ferrari, a professor of nanotechnology at the University of Texas Health Science Center, the M.D. Anderson Cancer Center, and Rice University in Houston, USA. His work shows that biological barriers such as the vascular wall dominate the distribution of injected nanoparticles in the body, even for particles that are decorated with exquisite biological recognition moieties. A judicious choice of size and shape of a nanovector particle can enhance by orders of magnitude the amount of drug delivered to the target lesion site. "I believe that the era of 'rational design' of nanoparticles has arrived, and that optimal design will occur based on principles of engineering and physics," Ferrari says.
Joseph DeSimone, professor of chemistry and chemical engineering at the University of North Carolina at Chapel Hill, USA, is putting these principles into practice. DeSimone has adapted fabrication technologies from the electronics industry to produce shape-specific organic nanoparticles. "We basically make moulds out of a really low-surface-energy fluoropolymer that allows us to synthesize truly engineered particles with desired characteristics," says DeSimone. DeSimone's engineered process allows the precise control over particle size (20 nm to >100 m), particle shape (spheres, cylinders, discs, toroidal), particle composition (organic or inorganic, solid or porous), particle cargo (hydrophilic or hydrophobic therapeutics, biologicals, imaging agents), particle compliance (stiff, deformable) and particle surface properties (Avidin–biotin complexes, targeting peptides, antibodies, aptamers, PEG chains).
Nanoparticles are not the only way to encapsulate a drug or imaging agent into a small carrier, but DeSimone suggests that the nanotechnology approach offers crucial advantages. "With liposomes [which have previously been used to deliver drugs] you kinetically trap what cargo molecule you can, but you can't modify the amount that gets trapped," says DeSimone. "Our moulds enable us to make organic particles loaded with therapeutic cargoes at any amount — 5%, 20% or whatever we want."
DeSimone is also taking a cue from naturally occurring particles, such as red blood cells, to produce compliant nanoparticles that can deform to pass across biological barriers such as sinusoids in the spleen or the blood–brain barrier. "The ability to get through these barriers and the flow characteristics of particles — whether they flow through the centre of a capillary or along cell walls — are dictated by size, shape, surface chemistry and compliance," says DeSimone.
Liquidia Technologies Inc., based in Morrisville, North Carolina, USA, was spun-off from DeSimone's laboratory a few years ago to develop this technology platform. Right now, the company is working on feasibility studies, as well as research collaborations with some large pharmaceutical and medical device companies. "These feasibility studies will run through the rest of 2007, with the goal of focused out-licensing and joint product development deals within the next 18 months," says Luke Roush, Vice President of Business Development at Liquidia. "These studies will also provide data that will validate application of our technology platform, and help us advance knowledge about how to apply it in areas of clinical need," adds Roush.
The synergy between the therapeutic and diagnostic/monitoring applications of nanotechnology could be particularly potent. Linda Molnar, a programme officer at the NCI Alliance, sees a future in which new imaging agents, new diagnostic chips and new targeted therapies come together to facilitate a form of personalized medicine in which early and more accurate detection leads to rapid initiation of treatment, followed by diagnostic tests to see whether the patient is responding. If they do, good; if not, another therapy can be tried and the process repeated — what Molnar refers to as real-time therapeutic monitoring. "The sooner you can detect the cancer and start treatment, and know that you're treating that patient with a therapy that they respond to, the better," says Molnar. "That's why people are excited, and why people at the NCI have made such a large investment in nanotechnology for cancer."
As novel nanomedicine products move from the laboratory to the clinic, the issue of regulatory approval of these new technologies will come to the fore. In many cases these products will combine established drugs with materials already used in FDA-approved therapies, and no special provisions are in place to deal with nanomedicine at present. An FDA spokesperson said, "All nanotechnology applications will at this point fall within the existing framework for review of all products submitted to CDER [Center for Drug Evaluation and Research]; [however], CDER is discussing how nanotech products may be treated differently, if necessary."
Nanotechnology is being applied to cancer in two broad areas: the development of nanovectors, such as nanoparticles, which can be loaded with drugs or imaging agents and then targeted to tumours, and high-throughput nanosensor devices for detecting the biological signatures of cancer. Combined, such technologies could lead to earlier diagnosis and better treatment for patients with cancer.
Spearheading efforts to expedite the clinical application of these technologies, the NCI currently funds eight Centers of Cancer Nanotechnology Excellence (CCNE) in the United States, in addition to 12 other smaller programmes. "We've pulled most of the key players in medical nanotechnology into this programme, and we're spending about US$35–40 million a year on these approaches," says Piotr Grodzinski, Director of the NCI Alliance. The NCI Alliance is actively pursuing both the therapeutic and diagnostics aspects of cancer nanotechnology with follow-up programmes in sight. Grodzinski hopes that by then nanotechnology will have matured into a clinically useful approach.
Robert Langer's team have shown the potential of targeted nanoparticles to deliver anticancer drugs.
Early signs are promising. The research highlighted in the Forbes list was conducted by a team led by Robert Langer, a chemical engineer who is Institute Professor at the Massachusetts Institute of Technology (MIT), USA, and also one of the two principal investigators for the MIT–Harvard CCNE. Langer, with Omid Farokhzad, Assistant Professor of Anaesthesia at Brigham and Women's Hospital, Boston, USA, and colleagues, uses polymeric nanoparticles coated with aptamers — RNA-based targeting moieties — to guide them towards the tumour, where they bind, enter the cells and then dissolve to spill out their contents — the anticancer drug docetaxel. The nanoparticles are also coated with polyethylene glycol (PEG) to aid their safe passage through the bloodstream and into the tumour cells. A single injection of such nanoparticles coated with aptamers that bind to prostate-membrane-specific antigen eradicated tumours in a mouse model of prostate cancer (PNAS 103, 6315–6320; 2006). "Extensive animal models show that this approach is both safe and efficacious," says Langer.
One of the key challenges in creating effective nanoparticles is targeting them to appropriate tissues and cells. Although biological targeting using aptamers or antibodies on the surface of nanoparticles is one popular option, other researchers are beginning to exploit the physical characteristics of the particles to guide them to desired locations. "The size, shape, physical properties, density and charge all affect how particles travel through the body, and whether or not they will cross biological membranes," says Mauro Ferrari, a professor of nanotechnology at the University of Texas Health Science Center, the M.D. Anderson Cancer Center, and Rice University in Houston, USA. His work shows that biological barriers such as the vascular wall dominate the distribution of injected nanoparticles in the body, even for particles that are decorated with exquisite biological recognition moieties. A judicious choice of size and shape of a nanovector particle can enhance by orders of magnitude the amount of drug delivered to the target lesion site. "I believe that the era of 'rational design' of nanoparticles has arrived, and that optimal design will occur based on principles of engineering and physics," Ferrari says.
Joseph DeSimone, professor of chemistry and chemical engineering at the University of North Carolina at Chapel Hill, USA, is putting these principles into practice. DeSimone has adapted fabrication technologies from the electronics industry to produce shape-specific organic nanoparticles. "We basically make moulds out of a really low-surface-energy fluoropolymer that allows us to synthesize truly engineered particles with desired characteristics," says DeSimone. DeSimone's engineered process allows the precise control over particle size (20 nm to >100 m), particle shape (spheres, cylinders, discs, toroidal), particle composition (organic or inorganic, solid or porous), particle cargo (hydrophilic or hydrophobic therapeutics, biologicals, imaging agents), particle compliance (stiff, deformable) and particle surface properties (Avidin–biotin complexes, targeting peptides, antibodies, aptamers, PEG chains).
Nanoparticles are not the only way to encapsulate a drug or imaging agent into a small carrier, but DeSimone suggests that the nanotechnology approach offers crucial advantages. "With liposomes [which have previously been used to deliver drugs] you kinetically trap what cargo molecule you can, but you can't modify the amount that gets trapped," says DeSimone. "Our moulds enable us to make organic particles loaded with therapeutic cargoes at any amount — 5%, 20% or whatever we want."
DeSimone is also taking a cue from naturally occurring particles, such as red blood cells, to produce compliant nanoparticles that can deform to pass across biological barriers such as sinusoids in the spleen or the blood–brain barrier. "The ability to get through these barriers and the flow characteristics of particles — whether they flow through the centre of a capillary or along cell walls — are dictated by size, shape, surface chemistry and compliance," says DeSimone.
Liquidia Technologies Inc., based in Morrisville, North Carolina, USA, was spun-off from DeSimone's laboratory a few years ago to develop this technology platform. Right now, the company is working on feasibility studies, as well as research collaborations with some large pharmaceutical and medical device companies. "These feasibility studies will run through the rest of 2007, with the goal of focused out-licensing and joint product development deals within the next 18 months," says Luke Roush, Vice President of Business Development at Liquidia. "These studies will also provide data that will validate application of our technology platform, and help us advance knowledge about how to apply it in areas of clinical need," adds Roush.
The synergy between the therapeutic and diagnostic/monitoring applications of nanotechnology could be particularly potent. Linda Molnar, a programme officer at the NCI Alliance, sees a future in which new imaging agents, new diagnostic chips and new targeted therapies come together to facilitate a form of personalized medicine in which early and more accurate detection leads to rapid initiation of treatment, followed by diagnostic tests to see whether the patient is responding. If they do, good; if not, another therapy can be tried and the process repeated — what Molnar refers to as real-time therapeutic monitoring. "The sooner you can detect the cancer and start treatment, and know that you're treating that patient with a therapy that they respond to, the better," says Molnar. "That's why people are excited, and why people at the NCI have made such a large investment in nanotechnology for cancer."
As novel nanomedicine products move from the laboratory to the clinic, the issue of regulatory approval of these new technologies will come to the fore. In many cases these products will combine established drugs with materials already used in FDA-approved therapies, and no special provisions are in place to deal with nanomedicine at present. An FDA spokesperson said, "All nanotechnology applications will at this point fall within the existing framework for review of all products submitted to CDER [Center for Drug Evaluation and Research]; [however], CDER is discussing how nanotech products may be treated differently, if necessary."
role of nanotechnology in biology
Nanotechnology refers to the interactions of cellular and molecular components and engineered materials—typically clusters of atoms, molecules, and molecular fragments—at the most elemental level of biology. Such nanoscale objects— typically, though not exclusively, with dimensions smaller than 100 nanometers—can be useful by themselves or as part of larger devices containing multiple nanoscale objects. At the nanoscale, the physical, chemical, and biological properties of materials differ fundamentally and often noninvasive access to the interior of a living cell affords the opportunity for unprecedented gains on both clinical and basic research frontiers.
unexpectedly from those of the corresponding bulk material because the quantum mechanical properties of atomic interactions are influenced by material variations on the nanometer scale. In fact, by creating nanometer-scale structures, it is possible to control fundamental characteristics of a material, including its melting point, magnetic properties, and even color, without changing the material’s chemical composition.
Nanoscale devices and nanoscale components of larger devices are of the same size as biological entities. They are smaller than human cells (10,000 to 20,000 nanometers in diameter) and organelles and similar in size to large biological macromolecules such as enzymes and receptors— hemoglobin, for example, is approximately 5 nm in diameter, while the lipid bilayer surrounding cells is on the order of 6 nm thick. Nanoscale devices smaller than 50 nanometers can easily enter most cells, while those smaller than 20 nanometers can transit out of blood vessels. As a result, nanoscale devices can readily interact with biomolecules on both the cell surface and within the cell, often in ways that do not alter the behavior and biochemical properties
of those molecules. From a scientific viewpoint, the actual construction and characterization of nanoscale devices may contribute to understanding carcinogenesis.
Noninvasive access to the interior of a living cell affords the opportunity for unprecedented gains on both clinical and basic research frontiers. The ability to simultaneously interact with multiple critical proteins and nucleic acids at the molecular scale should provide better understanding of the complex regulatory and signaling networks that govern the behavior of cells in their normal state and as they undergo malignant transformation.
Nanotechnology provides a platform for integrating efforts in proteomics with other scientific investigations into the molecular nature of cancer by giving researchers the opportunity to simultaneously measure gene and protein expression, recognize specific protein structures and structural domains, and follow protein transport among different cellular compartments. Similarly, nanoscale devices are already proving that they can deliver therapeutic agents that can act where they are likely to be most effective, that is, within the cell or even within specific organelles. Yet despite their small size, nanoscale devices can also hold tens of thousands of small molecules, such as a contrast agent or a multicomponent diagnostic system capable of assaying a cell’s metabolic state, creating the opportunity for unmatched sensitivity in detecting cancer in its earliest stages. For example, current approaches may link a monoclonal antibody to a single molecule of an MRI contrast agent, requiring that many hundreds or thousands of this construct reach and bind to a targeted cancer cell in order to create a strong enough signal to be detected via MRI. Now imagine the same cancer-homing monoclonal antibody attached to a nanoparticle that contains tens of thousands of the same contrast agent—if even one such construct reaches and binds to a cancer cell, it would be detectable.
unexpectedly from those of the corresponding bulk material because the quantum mechanical properties of atomic interactions are influenced by material variations on the nanometer scale. In fact, by creating nanometer-scale structures, it is possible to control fundamental characteristics of a material, including its melting point, magnetic properties, and even color, without changing the material’s chemical composition.
Nanoscale devices and nanoscale components of larger devices are of the same size as biological entities. They are smaller than human cells (10,000 to 20,000 nanometers in diameter) and organelles and similar in size to large biological macromolecules such as enzymes and receptors— hemoglobin, for example, is approximately 5 nm in diameter, while the lipid bilayer surrounding cells is on the order of 6 nm thick. Nanoscale devices smaller than 50 nanometers can easily enter most cells, while those smaller than 20 nanometers can transit out of blood vessels. As a result, nanoscale devices can readily interact with biomolecules on both the cell surface and within the cell, often in ways that do not alter the behavior and biochemical properties
of those molecules. From a scientific viewpoint, the actual construction and characterization of nanoscale devices may contribute to understanding carcinogenesis.
Noninvasive access to the interior of a living cell affords the opportunity for unprecedented gains on both clinical and basic research frontiers. The ability to simultaneously interact with multiple critical proteins and nucleic acids at the molecular scale should provide better understanding of the complex regulatory and signaling networks that govern the behavior of cells in their normal state and as they undergo malignant transformation.
Nanotechnology provides a platform for integrating efforts in proteomics with other scientific investigations into the molecular nature of cancer by giving researchers the opportunity to simultaneously measure gene and protein expression, recognize specific protein structures and structural domains, and follow protein transport among different cellular compartments. Similarly, nanoscale devices are already proving that they can deliver therapeutic agents that can act where they are likely to be most effective, that is, within the cell or even within specific organelles. Yet despite their small size, nanoscale devices can also hold tens of thousands of small molecules, such as a contrast agent or a multicomponent diagnostic system capable of assaying a cell’s metabolic state, creating the opportunity for unmatched sensitivity in detecting cancer in its earliest stages. For example, current approaches may link a monoclonal antibody to a single molecule of an MRI contrast agent, requiring that many hundreds or thousands of this construct reach and bind to a targeted cancer cell in order to create a strong enough signal to be detected via MRI. Now imagine the same cancer-homing monoclonal antibody attached to a nanoparticle that contains tens of thousands of the same contrast agent—if even one such construct reaches and binds to a cancer cell, it would be detectable.
FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR
Human lung adenocarcinomas with activating mutations in EGFR (epidermal growth factor receptor) often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs), but the magnitude of tumour regression is variable and transient1, 2. This heterogeneity in treatment response could result from genetic modifiers that regulate the degree to which tumour cells are dependent on mutant EGFR. Through a pooled RNA interference screen, we show that knockdown of FAS and several components of the NF-κB pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF-κB through overexpression of c-FLIP or IKK (also known as CFLAR and IKBKB, respectively), or silencing of IκB (also known as NFKBIA), rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic or pharmacologic inhibition of NF-κB enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF-κB inhibitor IκB predicted for improved response and survival in EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF-κB as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers and provide insight into the mechanisms by which tumour cells escape from oncogene dependence.
Peptidomimetics
There are many instances where the native information within a natural peptide ligand can be conferred/duplicated or mimetized into a non-peptide molecule, preferably of low molecular weight, hence the basis for the field of peptidomimetics(PM's). The desire to convey the three dimensional information present in a peptide into small nonpeptide molecules is what encompasses the field of peptidomimetics.
Many research groups, both in academia and in pharmaceutical companies search constantly for non-peptide compounds that have better bioavailability and stability, perhaps even with greater receptor selectivity. The known structure-activity interactions and conformational foldings of peptide structures aid a great deal in the design of novel peptidomimetics. There are a number of factors that help in the rational design of PM's such us: binding site optimal fit, conformational stabilization, (given by rigid elements and the positioning of specific functional groups), polar or hydrophobic regions (inside strategic reactive pockets) that favor the basic atomic interactions provided by hydrogen , electrostatic and hydrophobic bonding.
The goal in PM's is to obtain molecules that mimic the specific molecular interactions of natural proteins and their ligands. The protein to protein interaction of biologivally active peptides at the receptor level can be obtained by small molecules, in an agonistic fashion or can be blocked, in an antagonistic fashion.
To obtain PM's generally the biological researcher will have to screen compound libraries(either natural products or synthetic products). Combinatorial chemistry, amethod that was heavily used in the mid to late 90's can be a tool to generate vast numbers of peptidic and non-peptidic molecules As an example of a PM's , an inhibitor of angiotensin-converting enzyme (ACE), was developed, this PM's is called Captopril. Also, morphine , an opiod alkaloid, represents a classic example of a nonpeptidic compound found that mimics an endogenous peptide. Morphine replicates the biological effect of beta endorphin, on the respective receptor. A number of important aspects regarding conformational resctriction, peptide bond replacement, addition of turn mimetics and combinatorial library screening ,are investigated in order to search and find novel ligands, within the field of peptidomimetics.
Many research groups, both in academia and in pharmaceutical companies search constantly for non-peptide compounds that have better bioavailability and stability, perhaps even with greater receptor selectivity. The known structure-activity interactions and conformational foldings of peptide structures aid a great deal in the design of novel peptidomimetics. There are a number of factors that help in the rational design of PM's such us: binding site optimal fit, conformational stabilization, (given by rigid elements and the positioning of specific functional groups), polar or hydrophobic regions (inside strategic reactive pockets) that favor the basic atomic interactions provided by hydrogen , electrostatic and hydrophobic bonding.
The goal in PM's is to obtain molecules that mimic the specific molecular interactions of natural proteins and their ligands. The protein to protein interaction of biologivally active peptides at the receptor level can be obtained by small molecules, in an agonistic fashion or can be blocked, in an antagonistic fashion.
To obtain PM's generally the biological researcher will have to screen compound libraries(either natural products or synthetic products). Combinatorial chemistry, amethod that was heavily used in the mid to late 90's can be a tool to generate vast numbers of peptidic and non-peptidic molecules As an example of a PM's , an inhibitor of angiotensin-converting enzyme (ACE), was developed, this PM's is called Captopril. Also, morphine , an opiod alkaloid, represents a classic example of a nonpeptidic compound found that mimics an endogenous peptide. Morphine replicates the biological effect of beta endorphin, on the respective receptor. A number of important aspects regarding conformational resctriction, peptide bond replacement, addition of turn mimetics and combinatorial library screening ,are investigated in order to search and find novel ligands, within the field of peptidomimetics.
April 14, 2011
Schizophrenia 'in a dish'
Researchers are making inroads in the daunting challenge of modelling mental illness, thanks to patients' cells.
Before committing suicide at the age of 22, an anonymous man with schizophrenia donated a biopsy of his skin cells to research. Reborn as neurons, these cells may help neuroscientists to unpick the disease he struggled with from early childhood.
Experiments on these cells, as well as those of several other patients, are reported today in Nature1. They represent the first of what are sure to be many mental illnesses 'in a dish', made by reprogramming patients' skin cells to an embryonic-like state from which they can form any tissue type.
Recreating neuropsychiatric conditions such as schizophrenia and bipolar disorder using such cells represents a daunting challenge: scientists do not know the underlying biological basis of mental illnesses; symptoms vary between patients; and although psychiatric illnesses are strongly influenced by genes, it has proved devilishly hard to identify many that explain more than a fraction of a person's risk.
"All of us had been contacted by patients asking 'when can I get my stem cells to solve my schizophrenia'. It's not as simple as that," says Russell Margolis, a psychiatrist and neurogeneticist at Johns Hopkins University in Baltimore, Maryland, who was not involved in the study. "It's an additional piece to the puzzle as opposed to the answer."
Cocktail recipe
Since researchers reported that cocktails of particular genes can be used to reprogram human cells to an embryonic-like state2,3, scientists have learned to coax these 'induced pluripotent stem cells' (iPSCs) into various cell types and used them to try to work out what goes awry in disease. So far, iPSC-derived models have been published for about a dozen diseases, from rare heart conditions4,5 to hereditary blood diseases6.
Fred Gage, a neuroscientist at the Salk Institute for Biological Studies in San Diego, California, and his team created iPSC models from the cells of the 22-year-old man mentioned above, as well as those of two brother–sister pairs, all of whom had either schizophrenia or related conditions such as schizoaffective disorder.
When the authors transformed the iPSCs into neurons, they noticed that the patient-derived cells made fewer connections, or synapses, with other neurons in the same dish than did neurons from people without psychiatric disorders. However, tests showed that the patients' neurons conducted electrical pulses just as well as normal neurons did.
Interestingly, the antipsychotic medication loxapine, used to treat schizophrenia, boosted the number of synapses formed by the patient-derived neurons to normal levels.
Four other antipsychotic drugs had no consistent effect, although Gage notes that all of the drugs benefited cells from at least one patient. His team also reported differences in gene expression between the neurons of patients with schizophrenia and those of healthy people, including changes in genes related to synapse function and others previously implicated in genetic studies of the disease.
Michael Owen, a psychiatric geneticist at Cardiff University, UK, agrees that synapses are a reasonable place to look for differences between neurons from people with schizophrenia and those of healthy individuals. However, he says it is a logical leap to conclude that such differences underlie schizophrenia.
Moreover, differences between cells derived from patients with mental illnesses and those of healthy people could reflect changes brought about by the process of creating iPSCs and not the disease itself, warns Kwang-Soo Kim, a stem-cell scientist at McLean Hospital in Belmont, Massachusetts. This could be problematic in mental illness, in which the differences between healthy and disease cells may be slight, Kim says.
So far, many of the iPSC models published are for diseases resulting from mutations in a single gene. Mental illnesses couldn't be more different. A recent study of more than 3,000 people with schizophrenia suggested that thousands of genetic variations contribute to the disease7. Equally problematic is the fact that one patient's form of schizophrenia may have different genetic and environmental causes from another's, says Owen. "These disorders are not really disorders. There's no such thing as schizophrenia. It's a syndrome. It's a collection of things psychiatrists have grouped together."
Model targets
Stephen Haggarty, a chemical neurobiologist at Massachusetts General Hospital in Boston, is tackling the genetic complexity of mental illness head-on. His team is creating neurons from patients with specific mutations implicated in schizophrenia, bipolar disorder and other conditions. Scientists do not know what most mutations linked to schizophrenia do to a cell, and iPSC models offer a way to find out, says Haggarty.
Despite these challenges, iPSC models of mental illness may be the best hope for identifying the fundamental defects that underlie these diseases – and ways to reverse them. Most antipsychotic drugs target the same dopamine receptor, and iPSC models could be "a way to find new treatments that are not more of the same", says Margolis.
Evan Snyder, a stem-cell biologist studying mental illness at the Sanford–Burnham Medical Research Institute in San Diego, says it will be a long slog before scientists identify differences in the neurons of psychiatric patients that are relevant to their disease. "We'd like to think that one can model a complex disease like schizophrenia in a dish, but we have to realize this is the ultimate in reductionism."
Nonetheless, he and other scientists are optimistic that, with enough scientists creating iPSCs from enough patients, real insight into the confounding diseases will follow. "We've got to start somewhere," says Snyder.
Before committing suicide at the age of 22, an anonymous man with schizophrenia donated a biopsy of his skin cells to research. Reborn as neurons, these cells may help neuroscientists to unpick the disease he struggled with from early childhood.
Experiments on these cells, as well as those of several other patients, are reported today in Nature1. They represent the first of what are sure to be many mental illnesses 'in a dish', made by reprogramming patients' skin cells to an embryonic-like state from which they can form any tissue type.
Recreating neuropsychiatric conditions such as schizophrenia and bipolar disorder using such cells represents a daunting challenge: scientists do not know the underlying biological basis of mental illnesses; symptoms vary between patients; and although psychiatric illnesses are strongly influenced by genes, it has proved devilishly hard to identify many that explain more than a fraction of a person's risk.
"All of us had been contacted by patients asking 'when can I get my stem cells to solve my schizophrenia'. It's not as simple as that," says Russell Margolis, a psychiatrist and neurogeneticist at Johns Hopkins University in Baltimore, Maryland, who was not involved in the study. "It's an additional piece to the puzzle as opposed to the answer."
Cocktail recipe
Since researchers reported that cocktails of particular genes can be used to reprogram human cells to an embryonic-like state2,3, scientists have learned to coax these 'induced pluripotent stem cells' (iPSCs) into various cell types and used them to try to work out what goes awry in disease. So far, iPSC-derived models have been published for about a dozen diseases, from rare heart conditions4,5 to hereditary blood diseases6.
Fred Gage, a neuroscientist at the Salk Institute for Biological Studies in San Diego, California, and his team created iPSC models from the cells of the 22-year-old man mentioned above, as well as those of two brother–sister pairs, all of whom had either schizophrenia or related conditions such as schizoaffective disorder.
When the authors transformed the iPSCs into neurons, they noticed that the patient-derived cells made fewer connections, or synapses, with other neurons in the same dish than did neurons from people without psychiatric disorders. However, tests showed that the patients' neurons conducted electrical pulses just as well as normal neurons did.
Interestingly, the antipsychotic medication loxapine, used to treat schizophrenia, boosted the number of synapses formed by the patient-derived neurons to normal levels.
Four other antipsychotic drugs had no consistent effect, although Gage notes that all of the drugs benefited cells from at least one patient. His team also reported differences in gene expression between the neurons of patients with schizophrenia and those of healthy people, including changes in genes related to synapse function and others previously implicated in genetic studies of the disease.
Michael Owen, a psychiatric geneticist at Cardiff University, UK, agrees that synapses are a reasonable place to look for differences between neurons from people with schizophrenia and those of healthy individuals. However, he says it is a logical leap to conclude that such differences underlie schizophrenia.
Moreover, differences between cells derived from patients with mental illnesses and those of healthy people could reflect changes brought about by the process of creating iPSCs and not the disease itself, warns Kwang-Soo Kim, a stem-cell scientist at McLean Hospital in Belmont, Massachusetts. This could be problematic in mental illness, in which the differences between healthy and disease cells may be slight, Kim says.
So far, many of the iPSC models published are for diseases resulting from mutations in a single gene. Mental illnesses couldn't be more different. A recent study of more than 3,000 people with schizophrenia suggested that thousands of genetic variations contribute to the disease7. Equally problematic is the fact that one patient's form of schizophrenia may have different genetic and environmental causes from another's, says Owen. "These disorders are not really disorders. There's no such thing as schizophrenia. It's a syndrome. It's a collection of things psychiatrists have grouped together."
Model targets
Stephen Haggarty, a chemical neurobiologist at Massachusetts General Hospital in Boston, is tackling the genetic complexity of mental illness head-on. His team is creating neurons from patients with specific mutations implicated in schizophrenia, bipolar disorder and other conditions. Scientists do not know what most mutations linked to schizophrenia do to a cell, and iPSC models offer a way to find out, says Haggarty.
Despite these challenges, iPSC models of mental illness may be the best hope for identifying the fundamental defects that underlie these diseases – and ways to reverse them. Most antipsychotic drugs target the same dopamine receptor, and iPSC models could be "a way to find new treatments that are not more of the same", says Margolis.
Evan Snyder, a stem-cell biologist studying mental illness at the Sanford–Burnham Medical Research Institute in San Diego, says it will be a long slog before scientists identify differences in the neurons of psychiatric patients that are relevant to their disease. "We'd like to think that one can model a complex disease like schizophrenia in a dish, but we have to realize this is the ultimate in reductionism."
Nonetheless, he and other scientists are optimistic that, with enough scientists creating iPSCs from enough patients, real insight into the confounding diseases will follow. "We've got to start somewhere," says Snyder.
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