There’s a new report in Molecular Cell (29, 541-551) from Gokhan Hotamisligil’s group suggesting that cellular stress might actually be helpful in certain contexts.

The Hotamisligil lab has published numerous reports on the importance of endoplasmic reticulum (ER) stress in metabolic dysfunction. Their previous data have suggested that insulin resistance (pre-diabetes, if you will) leads to a greater demand for insulin from the pancreatic beta cells. But this increased demand means more protein production, which can stress the ER and result in apoptosis. If this occurs in the islets overt diabetes can result.

In addition to his basic science experience, Gokhan also has a clinical background and he mentioned to me once that he used to see tuberous sclerosis complex (TSC) patients and was struck by the numerous benign tumors that form throughout their bodies. Now his interests are coming full circle as his group is reporting on ER stress in TSC and a potential therapy angle that could result from this insight.

The normal versions of the disease genes of TSC, TSC1 and TSC2, encode for proteins that form a complex that inhibits mTOR, the mammalian target of rapamycin. mTOR is a critical protein that integrates the nutritional state of the cell and cell growth by activating nuclear factors that control protein translation in response to increased amino acid levels. So TSC deficiency results in hyperactivation of mTOR, which leads to increased cell growth and is probably an explanation for the high number of benign tumors in these patients. While rapamycin, an inhibitor of mTOR, is a possible therapeutic treatment for TSC sufferers, it also has many nasty side-effects, especially over the long-term, so its potential in this regard is rather limited.

Given the increased protein production that results when mTOR is hyperactivated, it is possible that ER stress could occur in TSC-deficient cells. In this new report, Umut Ozcan et al. now show that lack of TSC does result in ER stress, including in the tumors that form in the Tsc2 KO mouse, as well as in a resected human TSC-derived tumor. They also show that this ER stress results in insulin resistance, tying in these results with the lab’s previous studies.

Clearly the level of ER stress caused by the defect in TSC, however, is not sufficient to cause apoptosis given the high number of benign tumors that form in this disease. But the team reasoned that if TSC1- or TSC2-deficient cells were treated with thapsigargin, a chemical inducer of ER stress, then perhaps they could tip the balance towards cell death. They were able to show this and, importantly, at the dosage of thapsigargin used normal cells were not killed. This result indicates the absence of TSC makes cells more vulnerable to ER-stress-induced apoptosis, which the group then used to their advantage in vivo. They injected Tsc2+/- mice, which develop kidney adenomas after 1 year, with thapsigargin once a day for a week and that resulted in apoptosis in the tumor cells but not in nearby healthy tissue. It wasn't reported, however, if this treatment was sufficient to shrink the tumor or return normal kidney function.

These findings are summarized in this schematic from the paper:

These results suggest a possible way to treat TSC. Unfortunately thapsigargin is too toxic and too blunt a tool to be used in the clinic. For example, pancreatic beta cells, even healthy ones, are quite vulnerable to ER stress-induced apoptosis. But nonetheless this study does point in a new direction for the development of a future therapeutic option in treating cancers that involve hyperactivation of mTOR.

Posted by Randy Levinson at 04:42 PM | Permalink | Comments (1)

There’s a new report in Molecular Cell (29, 541-551) from Gokhan Hotamisligil’s group suggesting that cellular stress might actually be helpful in certain contexts.

The Hotamisligil lab has published numerous reports on the importance of endoplasmic reticulum (ER) stress in metabolic dysfunction. Their previous data have suggested that insulin resistance (pre-diabetes, if you will) leads to a greater demand for insulin from the pancreatic beta cells. But this increased demand means more protein production, which can stress the ER and result in apoptosis. If this occurs in the islets overt diabetes can result.

In addition to his basic science experience, Gokhan also has a clinical background and he mentioned to me once that he used to see tuberous sclerosis complex (TSC) patients and was struck by the numerous benign tumors that form throughout their bodies. Now his interests are coming full circle as his group is reporting on ER stress in TSC and a potential therapy angle that could result from this insight.

The normal versions of the disease genes of TSC, TSC1 and TSC2, encode for proteins that form a complex that inhibits mTOR, the mammalian target of rapamycin. mTOR is a critical protein that integrates the nutritional state of the cell and cell growth by activating nuclear factors that control protein translation in response to increased amino acid levels. So TSC deficiency results in hyperactivation of mTOR, which leads to increased cell growth and is probably an explanation for the high number of benign tumors in these patients. While rapamycin, an inhibitor of mTOR, is a possible therapeutic treatment for TSC sufferers, it also has many nasty side-effects, especially over the long-term, so its potential in this regard is rather limited.

Given the increased protein production that results when mTOR is hyperactivated, it is possible that ER stress could occur in TSC-deficient cells. In this new report, Umut Ozcan et al. now show that lack of TSC does result in ER stress, including in the tumors that form in the Tsc2 KO mouse, as well as in a resected human TSC-derived tumor. They also show that this ER stress results in insulin resistance, tying in these results with the lab’s previous studies.

Clearly the level of ER stress caused by the defect in TSC, however, is not sufficient to cause apoptosis given the high number of benign tumors that form in this disease. But the team reasoned that if TSC1- or TSC2-deficient cells were treated with thapsigargin, a chemical inducer of ER stress, then perhaps they could tip the balance towards cell death. They were able to show this and, importantly, at the dosage of thapsigargin used normal cells were not killed. This result indicates the absence of TSC makes cells more vulnerable to ER-stress-induced apoptosis, which the group then used to their advantage in vivo. They injected Tsc2+/- mice, which develop kidney adenomas after 1 year, with thapsigargin once a day for a week and that resulted in apoptosis in the tumor cells but not in nearby healthy tissue. It wasn't reported, however, if this treatment was sufficient to shrink the tumor or return normal kidney function.

These findings are summarized in this schematic from the paper:

These results suggest a possible way to treat TSC. Unfortunately thapsigargin is too toxic and too blunt a tool to be used in the clinic. For example, pancreatic beta cells, even healthy ones, are quite vulnerable to ER stress-induced apoptosis. But nonetheless this study does point in a new direction for the development of a future therapeutic option in treating cancers that involve hyperactivation of mTOR.

Posted by Randy Levinson at 04:42 PM | Permalink | Comments (1)

I found the past two online installments of Nature to be particularly strong.

Sunday's issue had two papers showing that activation of the aryl hydrocarbon receptor (AHR) -- a ligand-dependent transcription factor that mediates the action of environmental toxins such as dioxin -- plays a role in the pathophysiology of EAE, the commonly used animal model of multiple sclerosis.

Marc Veldhoen et al. and Francisco Quintana et al. found that AHR exacerbated EAE by promoting the differentiation of Th17 cells and the production of IL-22. Remarkably, Quintana and his colleagues went on to show that the effect of AHR depended on the agonist they used; whereas one agonist promoted EAE, a different agonist suppressed the pathology by inducing regulatory T cells. The authors don't go too far downstream to nail down the transcriptional pathways that are responsible and account for the dual effect of AHR (which is in and of itself not unprecedented), but the possibility that environmental toxins might use this receptor to modify the course of multiple sclerosis in people is very interesting.

Then, on today's edition of the journal, there are two RNA-related papers that are also very interesting. The first one is a proof-of-principle study by Joacim Elmén et al., showing that it is possible to silence microRNAs in non-human primates. Although therapeutic effects of blocking microRNAs in rodents have been published, there has been scepticism about translating the approach to the clinic. Elmén and his colleagues now show that it is possible to silence a liver microRNA in the green monkey by delivering a locked-nucleic-acid-modified "antimiR". Moreover, this silencing approach had a functional readout -- decreased plasma cholesterol -- and no obvious toxicity. This is a reassuring finding for those interested in targeting microRNAs in humans with therapeutic purposes.

The second RNA-related paper reports a somewhat unexpected finding. There are reports that you can use siRNA to target proangiogenic molecules like VEGF or its receptor, and block pathological angiogenesis in patients with neovascularization linked to age-related macular degeneration. Now, Mark Kleinman and his colleagues show that it doesn't quite matter what molecule you target because a large number of siRNAs (even if some that target non-genomic sequences or antiangiogenic genes) have the same antiangiogenic effect. As long as the siRNA is 21-nucleotides or longer, it will exert an anti-angiogenic effect mediated by the TLR3 signaling cascade. This "class effect" implies that generic siRNAs might be therapeutic agents, and that siRNAs might have unanticipated actions on the vascular and immune systems.

Posted by Juan Carlos Lopez at 01:25 PM | Permalink | Comments (0)

A lot has been said about the link between calorie restriction and aging -- eat less, live longer. But if that wasn't enough, there seems to be a new reason to do away with snacking: calorie restriction has an anti-depressant effect in mice, which depends on orexin-mediated signaling.

Michael Lutter and his colleagues tested mice in two animal models of depression -- forced swim (a "depressed" animal will stop trying to escape from the water and will therefore cease to swim) and social defeat (a mouse that has been bullied will express its "depression" by reduced social interactions with other mice). The authors found that, if the mice were on calorie restriction, both their latency to stop swimming and their likelihood to engage in social interactions increased. In other words, the restricted mice did not show signs of depression.

But if the mice lacked orexin, calorie restriction had no effect. Orexin's claim to fame is its relationship to narcolepsy -- people (and some dog breeds) without orexin fall asleep without warning. But orexin has also been linked to the regulation of food and drug reward, pointing to a role for orexin in emotional processes. Lutter et al. further strengthen the link of orexin with depression by showing that mice in the social-defeat model have epigenetic modifications in the orexin promoter, which lead to decreased expression of the orexin gene in the "depressed" mice.

Clearly, the mechanistic link between depression, orexin and calorie restriction could do with some additional tightening. Similarly, the existing animal models of depression and their relevance to human depression are consistently criticized by the community. One also wonders about the behavioral (or "psychological", if you will) effects of calorie restriction per se on an animal that is undergoing a stressful situation like the one the mice experience in the forced-swim and social-defeat tests. In other words, is the increased latency to show depression a true anti-depressant effect, or is it that the mouse's hunger causes it to be more anxious in the context of the behavioural testing it is exposed to?

All of that said, other effects of calorie restriction that were originally met with scepticism now enjoy widespread acceptance. Maybe the same will turn out to occur in this fascinating case.

Posted by Juan Carlos Lopez at 04:36 PM | Permalink | Comments (1)

There's a remarkable number of drugs that people use for which the mechanism of action is unknown, and two papers in the Journal of Neuroscience illustrate this point from two different perspectives.

Methylprednisolone is an anti-inflammatory drug that is often used -- with modest success -- in multiple sclerosis and (off label) after spinal cord injury. People think that its effect depends on its ability to dampen inflammation but, as Jin-Moo Lee and colleagues show, the drug seems to act in vitro and in vivo (at least in rats) by preventing oligodendrocyte apoptosis through the indirect activation of glucocorticoid receptors. By contrast, the drug has no such protective effect on neurons, which may start to account for its limited therapeutic effect.

The second paper has to do with a drug that people use with recreational, as opposed to therapeutic, purposes -- ecstasy. Carla Busceti and her colleagues report that giving ecstasy to mice results in a transient increase in the phosphorylation of tau -- the same molecule that is phosphorylated in Alzheimer disease and in a series of conditions known as tauopathies. They further show that the increased phosphorylation, which is primarily seen in the hippocampus, depends on both GSK3β and cdk5, a pair of kinases known to phosphorylate tau. So, ecstasy induces the expression of Dickkopf-1, which inhibits Wnt signalling, thereby increasing GSK3β activity, and it also induces the expression of p25, a known activator of cdk5. It's very hard to know if there is any relationship between these biochemical changes and neurological diseases, but it would be very interesting to see if there is an increased incidence of any tauopathy in frequent users of ecstasy. I guess we'll have to wait for epidemiological studies to know the answer.

Posted by Juan Carlos Lopez at 04:00 PM | Permalink | Comments (0)

This week's issue of JAMA struck me as pretty interesting. They normally publish stuff that's too clinical or epidemiological for my taste and in comparison to what we publish, but this time they had a themed issue on genomics with four articles reporting associations between gene variants and diseases of different systems.

Two of the articles are relevant to the cardiovascular system. First, Tamali Bhattacharyya and colleagues established a link between polymorphisms that affect the function of paraoxonase 1 (an HDL-bound enzyme with cardioprotective properties), oxidative stress and cardiovascular disease. As might be expected, forms of the enzyme with higher activity were associated with less oxidative stress and a reduced risk of cardiac events.

The second paper, by Irene Bezemer and her colleagues, disclosed gene polymorphisms linked to deep vein thrombosis. These variants affected several genes (CYP4V2, SERPINC1, GP6, KLKB1 and F11), and some of these were also linked to higher levels of coagulation factor XI, hinting at a possible molecular mechanism.

Next, a study by Joyce van Meurs and colleagues reports polymorphisms in the low-density lipoprotein receptor-related protein LRP5 that are associated with osteoporosis. As mutations in LRP5 had already been linked to bone disorders, it is not entirely surprising that variants of this gene would lead to reduced bone density and increased fracture risk.

Last, but not least, there's a very intriguing contribution by Elisabeth Binder and her colleagues, who found that variants in the FKBP5 gene (which encodes a protein that interacts with the glucocorticoid receptor to modulate its cortisol-binding affinity and has therefore been linked to physiological responses to stress) interact with the occurrence of abuse during childhood, predicting the severity of posttraumatic stress disorder (PTSD) in adulthood. The gene variants themselves were not good predictors of PTSD. So, this is a fine example of gene-environment interactions in the context of mental disease.

Very interesting associations indeed. Hopefully they'll lead to some hardcore molecular work that results in some mechanistic insight into the biological meaning of this gene polymorphisms that goes above and beyond the correlations found in these studies.

Posted by Juan Carlos Lopez at 05:00 PM | Permalink | Comments (0)

Two papers in Nature these past few days reported on some very intriguing biology of cancer cells.

Some tumor cells have the peculiar property of acting like anaerobic cells, producing lactate even in the presence of oxygen -- a property known as aerobic glycolysis or the Warburg phenomenon. The molecular mechanisms behind this phenotype are not clear, but the first of these two papers provides a very solid clue to account for it. Heather Christofk and her colleagues show that a switch between isoforms of the glycolytic enzyme pyruvate kinase is crucial for aerobic glycolysis and tumorigenesis. Tumor cells express the embryonic M2 isoform of pyruvate kinase, but by knocking it down and replacing it with the M1 (adult) isoform, the authors reversed aerobic glycolysis and reduced tumor growth in mice.

The second paper takes a look at the hardcore signaling that takes place inside tumor cells. We know very well that the Ras-PI3K-AKT pathway is crucial for tumor maintenance. The new study, by Kian-Huat Lim and colleagues, shows that blocking the AKT-mediated phosphorylation of endothelial nitric oxide synthase (eNOS) also inhibits tumor maintenance. As eNOS enhances the nitrosylation and activity of Ras proteins, which are required for tumorigenesis, the authors come full circle by proposing a (mutated) Ras-PI3K-AKT-eNOS-(wild-type) Ras pathway for tumor growth.

Posted by Juan Carlos Lopez at 02:04 PM | Permalink | Comments (1)

A recent paper in Cell Stem Cell provides some interesting new information about the origin of hematopoietic stem cells (HSCs), arguably the best characterized population of stem cells in the organism, and the one population that has been successfully used in regenerative medicine for some time.

We already knew that, in the mouse, the placenta acts as a very early reservoir for HSCs. But do they come from the circulation or are they born there? In the new study, Katrin Rhodes and her colleagues looked in mouse embryos that lack a functional heart and have therefore no circulation, and found that bona fide, multipotential HSCs develop in the placental vasculature in the absence of blood flow.

The authors admit that there were fewer HSCs in the placentas of mutant mice than in the placentas of wild-type controls, indicating that blood circulation may after all make a contribution to the total number of HSCs, but these observations do provide good evidence that the placenta is more than a mere reservoir of stem cells, simply waiting for the liver to become the first true hematopoietic organ.

Posted by Juan Carlos Lopez at 03:23 PM | Permalink | Comments (1)

Modeling Parkinson disease in animals has been very hard. The chemical models (6-OHDA and MPTP) are good to study cell replacement therapies, but not so great for pathogenesis. And the genetic models have failed to give the mouse something like true Parkinson disease -- there may be alpha-synuclein aggregates or structures akin to Lewy bodies, but no cell death, or vice versa. To add to the debate, Silke Nuber and her colleagues just published in J. Neurosci. a conditional model of Parkinson in which alpha-synuclein expression can be switched off by feeding the animals doxycyclin. This is an image from the paper, showing the expression of the transgene in the two divisions of the substantia nigra of the mice.

Their key finding was that turning alpha-synuclein expression off in mice that started to show neurodegeneration and behavioral symptoms halted disease progression but did not reverse it. This is quite different to what Jose Lucas and his colleagues showed years ago in Huntington disease. In that case, turning the expression of huntingtin off did reverse the motor symptoms in mice.

Albeit interesting, one wonders about the relevance of the findings of Nuber and colleagues to true Parkinson disease. Similar to previous attempts to reproduce the disease in mice, their model was not perfect -- there was neurodegeneration, but no Lewy bodies.

Posted by Juan Carlos Lopez at 03:10 PM | Permalink | Comments (0)

Gout is an inflammatory disease that results from the deposition of uric acid crystals in the joints. It tends to be somewhat common in people with high levels of uric acid in the blood, which is, in turn, often the result of reduced renal excretion of the acid. How does this chain of events come about? Two papers in Nature Genetics give us a clue: Veronique Vitart and her colleagues and Angela Doring and her colleagues independently identified variants in the gene SLC2A9 that are linked to variability in uric acid concentrations.

SLC2A9 encodes a fructose transporter, but Vitart and colleagues found that the protein can also transport uric acid when expressed in Xenopus oocytes. Moreover, the transporter was already known to be expressed in the kidney. So, this molecule could very well turn out to be a therapeutic target for gout. The image below, from Ed Euthman, shows uric acid crystals in a human joint.

Posted by Juan Carlos Lopez at 04:39 PM | Permalink | Comments (3)

Speaking of mammals (see the end of my previous entry), not even rats and mice always cut it when it comes to providing good models of human disease. Take, for example, cystic fibrosis. There are a couple of mouse models of the disease (we have published at least one of them), but the community does not seem to be satisfied with them. It is therefore great to see a pair of papers in the JCI reporting on two new attempts at generating the ideal model of cystic fibrosis.

The two of studies are very similar. In the first one, Xingshen Sun and colleagues report the first description of genetically engineered ferrets. They started by targetting the CFTR gene (the gene affected in the disease) in fibroblasts using an adeno-associated viral (AAV) construct, and then used a nuclear transfer protocol to obtain cloned ferrets heterozygous for the CFTR mutation. In the second one, Christopher Rogers and colleagues employed a similar strategy in pigs to obtain heterozygous piglets carrying the CFTR mutation.

The next steps will be to establish how much these models truly recapitulate human disease, and then use them to learn new biology about the disease and/or for preclinical drug-discovery work.

The figures, taken from the papers, show the cloned CFTR ferrets and a non-cloned albino at different ages, and the first CFTR heterozygous pig at one day of age.

Posted by Juan Carlos Lopez at 03:40 PM | Permalink | Comments (5)

People with acne will find this JCI paper of interest. 13-cis retinoic acid can be used to treat acne, as it can kill human sebaceous-gland cells by apoptosis. The molecule is teratogenic, though, making it necessary to look for alternatives. As the mechanism of action of 13-cis retinoic acid is unknown, Amanda Nelson and her colleagues tried to elucidate it, hoping to identify new targets for the treatment of the bothersome skin condition. Using transcriptional profiling of skin cells from people with acne and cultured sebaceous glands, they found that lipocalin-2 was distinctively upregulated by treatment with 13-cis retinoic acid. They also found that the apoptotic effect of 13-cis retinoic acid indeed depended on the expression of neutrophil gelatinase–associated lipocalin (NGAL), the protein encoded by lipocalin-2; by using siRNA to lipocalin-2, they blocked the apoptotic effect, and by adding recombinant NGAL, they promoted it. It is therefore conceivable that manipulating NGAL expression could lead to a new way to fight acne.

A more serious pathology with a connection to retinoids is Matthew-Wood syndrome, a fatal disease characterized by multisystem developmental malformations that has been linked to mutations in STRA6. STRA6 interacts with retinol-binding protein 4 (RBP4), which is, in turn, a carrier of retinoids (vitamin A and its derivatives). A paper published in Cell Metabolism establishes that the biochemical interaction between STRA6 and RBP4 is indeed functionally relevant. Studying zebrafish embryos, Andrea Isken and colleagues found that Stra6 deficiency allows more Rbp4 to remain free and to carry an excess amount of retinoids to several embryonic tissues, including bone, heart and eye. In fact, reducing the levels of Rbp4 prevented these effects. The findings provide a nice molecular account of Matthew-Wood syndrome, although I cannot help but wish that the authors had done the in vivo experiments in a mammal. I must confess that, when we evaluate papers at Nature Medicine, we're seldom enthused by data from zebrafish, Drosophila or C. elegans, as the relevance of these models to human physiology tends to be harder to ascertain. Nothing personal against the fish or the invertebrates, though.

Posted by Juan Carlos Lopez at 01:27 PM | Permalink | Comments (0)

Three papers published this past Sunday touch upon different aspects of the aging problem. The first one appeared in Nature and is authored by Rui Yi and colleagues, who found that microRNA-203 promotes the differentiation of skin stem cells by repressing "stemness". In stratified epithelia, stem cells located basally are crucial for self renewal. As these cells leave the basal zone, they differentiate and cease to behave like stem cells. What the authors found is that microRNA-203 is crucial for this differentiation process, leading the stem cells to exit the cell cycle. Mechanistically, this effect depends on repression of p63 expression, a molecule that had previously been shown to regulate stem-cell maintenance in epithelia.

The second one is on one of my favorite topics -- progeria. Writing in Nature Cell Biology, Paola Scaffidi and Tom Misteli report that expression of mutant lamin-A, the molecule that causes Hutchinson-Gilford Progeria Syndrome (HGPS), interferes with the function of human mesenchymal stem cells (hMSCs) by promoting the activation of downstream
effectors of Notch, affecting the differentiation potential of hMSCs. The in vivo relevance of these results to HGPS and to normal aging remains to be established, but the possibility is indeed tantalizing.

The third one is a Brief Communication in Nature Genetics. In it, Marc Vermulst and his colleagues establish a link between mitochondrial DNA (mtDNA) deletions and aging in the so-called Polga mice, which harbor a proofreading-deficient copy of polymerase gamma and are characterized by premature aging. They found that the rate at which different tissues accumulate mtDNA mutations before they reach phenotypic expression differs profoundly -- brain, heart and gut are among the most affected parts of the body. The question remains, though, if these mtDNA mutations are also relevant during normal aging in wild-type mice and, of course, in humans.

Posted by Juan Carlos Lopez at 04:01 PM | Permalink | Comments (1)

Even though my background is in neuroscience, I rarely write about this topic. But wo papers on amyotrophic lateral sclerosis (ALS) from the latest issue of the Journal of Neuroscience struck me as interesting to talk about.

In the first one, Fiona Laird and her colleagues generated transgenic mice that express wild-type and mutant forms of the human protein dynactin p150-Glued. As mutant forms of this molecule had been linked to ALS, they decided to explore the mechanism whereby dynactin p150-Glued contributes to the pathology. They found that expression of dynactin p150-Glued carrying a mutation that had been linked to the disease in patients led to motor neuron disease in transgenic mice, something that was not seen in mice overexpressing the wild-type form of the human protein.

The paper is very nice in that it provides a very detailed account of the neuropathology the authors see in the mouse, including some intriguing evidence of autophagic cell death. The picture below, which comes from the paper, is a silver-stained section of the spinal cord from a mutant mouse, showing dark, presumably dying, motor neurons (arrowheads) that are not seen in control mice. Unfortunately, the authors didn't get to explore the hardcore molecular mechanisms that account for the motor neuron death. But they now have a useful system to ask more mechanistic questions to understand the role of dynactin p150-Glued in cell death and investigate its actual relationship to human ALS.

The second study deals with a question that has occupied the field for some time. We know that mutations in superoxide dismutase (SOD) are linked to familial forms of ALS, but where does SOD need to be expressed to cause disease: in neurons, in glia, in muscle? Dick Jaarsma and his colleagues tried to get at this question by generating transgenic mice that expressed mutant SOD only in neurons. The figure below, from the original paper, shows spinal cord sections from mice that expressed the mutant protein only in neurons (top left and bottom right) or ubiquitously (top middle).

This is not the first time that neuron-specific expression of SOD has been tried, but it is perhaps the first time in which it is found to effectively kill the motor neurons. In other words, these findings fly in the face of other studies reporting no motor neuron death in mice with neuron-specific expression of mutant SOD and of papers specifically identifying a contribution of extraneuronal SOD to ALS. Not unexpectedly, there is at present no definitive way to reconcile these disparate observations, other than invoking technical differences in the studies or stating that the cell-autonomous effect reported by Jaarsma et al. does not negate an additional contribution from glial SOD. What we can say for sure is that we don't yet understand the neuron/glia/muscle interplay in ALS, and that it will be quite hard to establish if the contributions of mutant SOD from each of these sources in transgenic mice are indeed relevant to the human condition.

Posted by Juan Carlos Lopez at 02:51 PM | Permalink | Comments (0)

As I approach the age at which the word 'prostate' starts sounding like a funereal drum, I become more interested in studies such as those published this week in the NEJM and about three weeks ago in Nature Genetics.

The NEJM paper, by Lilly Zheng and colleagues, shows that single-nucleotide polymorphisms (SNPs) in five chromosomal regions, each of which had previously and independently been associated with prostate cancer, have a cumulative association with the disease when considered in combination. The authors estimate that the five SNPs and a family history of prostate cancer account for as many as 46% of the cases in the Swedish population they studied.

The three Nature Genetics papers, by Julius Gudmundsson et al., Gilles Thomas et al. and Rosalind Eeles et al., all of which are nicely summarized in the journal's March editorial, disclose multiple new susceptibility loci associated with prostate cancer that, together with other loci identified in 2006 and 2007, give us plenty of new avenues to explore in order to understand the disease.

The most immediate implication of findings of this sort is often diagnostic -- if you identify gene variants that are linked to a disease, you can ask questions about how good these variants are at predicting onset and/or progression of the pathology. Validating the diagnostic value of these genomic data often requires blinded samples analyzed in a prospective (preferably longitudinal) fashion.

The findings could also help us understand the biology of the disease, although this almost always takes more time and is not always pursued, as it is very challenging: you need to identify with precision the protein whose gene harbors the relevant SNP, then establish how the SNP affects protein function, and finally look at how this altered function modifies the physiology of the cell as it becomes tumorigenic in an in vivo setting.

This is what we at Nature Medicine look for when we evaluate submissions that report new associations of SNPs or mutations with disease, which is why we don't tend to publish too many of these kind of studies. That said, these ruminations do not take anything from the value of these four studies, which shine some more light on the black box that prostate cancer has turned out to be.

Posted by Juan Carlos Lopez at 04:58 PM | Permalink | Comments (0)

In addition to the Insight on Cardiovascular Disease, edited by Nature Medicine's own Michael Basson, a couple of papers caught my attention from this past Thursday's issue of Nature.

First, the analysis of multiple sclerosis (MS) lesions by laser-capture microdissection and proteomics, which led May Han and colleagues to identify two potential therapeutic targets for the disease -- tissue factor and protein C inhibitor -- both of which participate during coagulation. Indeed, the authors went on to show that blocking the action of thrombin (which signals downstream of tissue factor) or administering activated protein C (to counter the increased levels of its inhibitor) ameliorated pathology in an animal model of MS. The image below, from the Nature paper, shows astrogliosis in a chronic MS plaque, revealed by and anti-GFAP antibody.

Second, the discovery by Xiaoyong Yang and colleagues of a link between O-GlcNac transferase and insulin resistance. We already knew that glucose flux through the hexosamine biosynthetic pathway leads O-GlcNac transferase to attach the sugar O-linked beta-N-acetylglucosamine (O-GlcNac) to proteins, thereby acting as a nutrient sensor. The new study shows that O-GlcNac transferase has a binding site for phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3), a key mediator of insulin signaling. Upon binding, PI(3,4,5)P3 recruits O-GlcNac transferase to the plasma membrane, where it sticks O-GlcNac to proteins of the insulin signaling pathway, reducing their responsiveness to insulin (see the figure below, which I borrowed from the paper; O-GlcNac transferase is labeled as OGT). In vivo, liver overexpression of O-GlcNac transferase causes insulin resistance, pointing to the likely functional relevance of this mechanism.

Posted by Juan Carlos Lopez at 03:25 PM | Permalink | Comments (0)

Two sets of papers caught my attention over the past couple of days. Apologies if they are old hat for those of you who work in these fields. It's hard to keep up with all the ToC alerts I get.

The first is a doublet from Nature on the mechanism whereby certain tumors acquire resistence to chemotherapy. The studies, by Wataru Sakai and colleagues and by Stacey Edwards and colleagues focused on tumors that carry mutations in BRCA2 and are therefore sensitive to platinum compounds like cisplatin. In some cases, these tumors develop resistance to cisplatin, and what both studies show is that the development of resistance depends on the appearance of new mutations in BRCA2, which restore the open reading frame of the protein. Although this is perhaps not incredibly surprising, particularly because similar secondary mutations had been observed in cases of resistance to imatinib in leukemia, this finding has obvious clinical implications for people who become unresponsive to cisplatin.

The other paper, by Marielle Gold and her colleagues in PLoS Pathogens, reports on the existence of a novel population of human T cells that innately recognize Mycobacterium tuberculosis (Mtb). These cells, which the authors isolated from newborns who were very unlikely to have ever been exposed to the bacterium, exist at relatively high frequencies and respond to Mtb-infected cells by producing IFN-γ. The authors assert that this is the first demonstration of a human innate pathogen-specific T cell and refer to preliminary experiments showing that other thymocytes can also respond to other pathogens including Staphylococcus aureus and Escherichia coli. How this innate recognition comes about in the fisst place strikes me as a pretty interesting question for follow-up studies.

Posted by Juan Carlos Lopez at 03:43 PM | Permalink | Comments (0)

A couple of days ago I was saying that the problem with blogging (at least for me) is lack of discipline. So I figured that one way to become a bit more disciplined, and hopefully post stuff that people will find of interest, would be to write a brief entry every time I come across a paper that I think is particularly interesting. I'm calling this category of entries "Journal club" for lack of a better name, as I don't think I want to (nor could) write an extensive critique of the paper in question. Instead, the purpose of doing this is to flag a paper as something that is of interest to an editor of Nature Medicine, and let those of you who work in the relevant field do the detailed evaluation of the contribution.

To get things rolling, here's three papers:

1) A study by Stephen Hauser and his colleagues in the NEJM reports that rituximab, a drug used for the treatment of non-Hodgkin lymphoma and rheumatoid arthritis, could also be useful to treat multiple sclerosis. Their clinical trial involved 104 people, 69 of whom received two one-gram doses of the drug (which acts by depleting CD20+ B cells). The trial lasted 48 weeks and showed a reduction in the number of inflammatory brain lesions and clinical relapses in the treated patients versus the controls over this time period. Although the trial wasn't designed to establish long-term safety or efficacy, it is indeed promising for people with MS.

2) In Immunity, Jackson Egen and his colleagues report on their use of high-resolution multiplex static imaging and intravital multiphoton microscopy to give us an unprecedented look at granulomas -- masses of inflammatory cells that arise owing to the persistence of an infectious agent in host tissue and that are critical for host protection.

Granulomas, which are often seen in people with tuberculosis, contain different cell types including lymphocytes, macrophages and fibroblasts. In their study, the authors found that, after infection with Mycobacterium bovis, Kupffer cells in the liver capture circulating bacteria and subsequently form the nucleus of a new granuloma by recruiting uninfected liver-resident macrophages and blood-derived monocytes. Within the granuloma, these cells set up an immobile matrix that attracts a dynamic population of T cells in a TNF-alpha-dependent manner. You ought to check out their movies.

3) To continue with the microbiology theme and the topic of the interaction of bacteria with host tissue, Science just published a study on the mechanism whereby tissue abscesses can inhibit bacterial growth. Brian Corbin and his colleagues found that calprotectin -- a neutrophil-derived protein -- can stall the growth of Staphylococcus aureus inside an abscess. Mechanistically, the effect of calprotectin depended on its ability to chelate Zn2+ and Mn2+, thereby interfering with the transcriptional machinery of the bacterium. In vivo, mice lacking calprotectin had abscesses with higher levels of metals that seemed to favor staphylococcal proliferation. Whether metal chelation can work as a general strategy to inhibit bacterial growth inside an abscess remains to be seen, but the possibility is certainly tantalizing.

Posted by Juan Carlos Lopez at 02:02 PM | Permalink | Comments (0)