The tobacco industry produces a product that, used as intended, kills millions of people each year. So it seems a lot to ask the industry to assume ethical standards in another of its favorite endeavors—funding scientific research.

The tobacco industry is up to some of its usual antics, as reported by
The New York Times. It seems tobacco money helped fund one of the most controversial studies to recently emerge from The New England Journal of Medicine.

The study concluded that the widespread use of CT scans could prevent 80 percent of lung cancer deaths.

The primary author of the study, Claudia Henschke of Weill Cornell Medical College declared funding through a little-known group, the Foundation for Lung Cancer: Early Detection, Prevention and Treatment. It took an investigative
reporter checking tax records to discover that foundation is actually funded by the parent company of the Liggett group, which manufactures several cigarette brands. Henschke did not reveal the source of the foundation’s money to the journal—what’s more, she helped create the foundation and is its president; the dean of Weill Cornell is a director.

The study’s findings obviously are favorable to the tobacco industry. But they have been controversial in part because early screening can lead to unnecessary procedures for spots on a CT scan that are not an imminent threat to health. A $200 million follow-up trial is now under way at the NCI.

What the tobacco linkage will mean for the validity of the study in the minds of experts remains to be seen—although this quote, from Catherine D. DeAngelis, the editor of The Journal of the American Medical Association, is telling:

I would never publish a paper dealing with lung cancer from a person who had taken money from a tobacco company.

Why so much fuss?

As DeAngelis is undoubtedly aware, the industry’s influence in this study fits into an overall pattern.

Tobacco companies fund research that has the potential to minimize the severe effects of smoking, and they also underwrite unrelated, legitimate, research, to bolster their reputation. It’s also not unusual for tobacco companies to keep their fingerprints away from the research they fund.

Tobacco companies also have a well-documented history of trying to stir up ‘debate’ about the dangers of smoking and second-hand smoke. Their support of research to bolster their arguments helped, for many years,
create public uncertainty about the dangers of tobacco and staved off anti-tobacco legislation. Sowing doubt about generally-accepted science is a tactic that foes of global warming legislation successfully borrowed; indeed, the tobacco industry spawned some of the ‘think tanks’ that now fight against global-warming legislation by supporting industry-friendly scientists.

Manipulating science has been a core tactic of the tobacco industry for years. So it’s not surprising that some schools, such as Harvard’s School of Public Health, have banned tobacco money. The University of California system refused to follow suit, but they have implemented a system of extra scrutiny over research funded by the tobacco industry. Opponents of a ban in California argued that it would constrain ‘academic freedom.’

What do you think? Does the source of funding for the NEJM study throw its findings into doubt? Or is this all a bunch of fuss about nothing?

Finally, is it fair for the editor of the Journal of the American Medical Association to refuse lung cancer papers funded by the tobacco industry?

Posted by Charlotte Schubert at 02:59 PM | Permalink | Comments (5)

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)

Today is the 10th anniversary of the FDA's approval of sildenafil nitrate for the treatment of erectile dysfunction. A decade and over 30 million users later, there's very little left to say about Viagra that hasn't been said before. Maybe that's why the media coverage of the anniversary has been somewhat modest. I nevertheless found this pretty neat graphic in the Spanish newspaper El Mundo. It's, of course, in Spanish, but I hope you get the gist of it.

After this anniversary, Pfizer probably won't be looking forward to future ones; their patent on the drug is set to "go limp" between 2011 and 2013.

Image by n3wjack's world in pixels

Posted by Juan Carlos Lopez at 09:59 AM | Permalink | Comments (1)

Today's announcement that the British Prime Minister is ready to compromise and have a free vote on parts of his government's embryo research proposal is disappointing.

Britain has traditionally taken a much broader view of stem-cell research than, say, the US. So, for Gordon Brown to yield under the pressure from Catholic MPs, who had threatened to step down if a vote was not held, is nothing short of a step backwards.

One of the most controversial aspects of the Bill has to do with the generation of "cybrids" or "admix" embryos generated by injecting a human nucleus into an animal egg. Critics of the Bill cite ethical concerns. For example, Cardinal Keith O'Brien (Roman Catholic Archbishop of St Andrews and Edinburgh) stated that "It is difficult to imagine a single piece of legislation which more comprehensively attacks the sanctity and dignity of human life than this particular bill", and that the Bill could lead to experiments of "Frankenstein proportions".

Needeless to say, supporters of the Bill have urged the Catholic church to become more familiar with the facts before making such strong statements. In fact, if you look at what a cybrid really is and realize that it's something that may or may not even be successful, the alarms set off by opponents of the Bill seem rather out of proportion. (See this correspondence from MIT's Richard Hynes that we published some time ago, in which he clarifies the terminology and dismisses some of the most erroneous concerns about the generation of chimeras, hybrids and cybrids.)

Clearly, the Prime Minister's decision to compromise is political, and he sounds confident that the Bill will pass as intended despite the objections from the rebel MPs. Hopefully his gamble is correct, and we don't have to live through another case of science taking a backseat to religion.

Posted by Juan Carlos Lopez at 11:01 AM | Permalink | Comments (0)

I'm in the middle of preparing a talk that I'm scheduled to give in Madrid in a few days. The talk is called "Myths and realities of publishing in the Nature journals", and its goal, at least in part, is to dispel the myth that our journals discriminate against, say, Spanish-speaking countries or developing nations, and that we favor countries like the USA and Britain.

Thinking about the comments I've heard from people, this myth can be divided into at least four parts:

1. The fame myth -- "to publish in the Nature journals, you have to be a big name."

2. The friends myth -- "to publish in the Nature journals, you have to be a friend of the journal, and you have to be on first-name terms with everyone in the field so that you always draw positive reviewers."

3. The language myth -- "to publish in the Nature journals, you have to have the Queen's English, or the editors won't even read your paper."

4. The surname myth -- "to publish in the Nature journals, it's better if you are Dr. White and not Dr. Blanco. In fact, if I were to change the names of the authors in my paper to anglosaxon names, I'm sure you would have sent it out for external review at least."

Each of these myths can be rebutted, and part of my talk will consist of data proving that this is not the way we operate. For example, you don't need to be famous to publish in Nature Medicine. Just flicking through the last four issues of the journal (including April 2008), I found that 75% of the articles we published were authored by people I didn't know about before their submission.

That being said, I'm most interested in any evidence you may have in support of the myths. I want to make sure that my perception of the fairness of our processes is a legitimate one. So, if you know of any specific instance of discrimination, please send it over. I may even include it in the talk.

Posted by Juan Carlos Lopez at 10:25 AM | Permalink | Comments (2)

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)

Sighs of relief from the whole editorial community were heard this weekend, following a ruling denying Pfizer accces to confidential peer-review documents from the NEJM.

Pfizer is facing a lawsuit over injuries believed to have come from use of their drug Celebrex. So, this January the drug company filed a motion asking for peer-review documents -- including reviewers' names and confidential comments -- that might be relevant to the lawsuit and useful for its defense. (If you want to read all the details about the legal showdown between Pfizer and the NEJM, I would recommend that you read this excellent blog entry in "In the Pipeline".)

This past Friday, the U.S. District Court for the Northern District of Illinois ruled that "it is not unreasonable to believe that compelling production of peer review documents would compromise the process". And as Pfizer didn't explained in sufficient detail what they expected to find in the confidential documents, the court decided that "whatever probative value the subpoenaed documents and information may have is outweighed by the burden and harm that would result" to the journals.

I was also delighted by the news, but I'm somewhat uncomfortable by the fact that the decision in favor the journals was shaped in no small measure by Pfizer's inability to produce convincing-enough arguments. I wonder what would happen if a future motion makes a good case for what a company or any other party expects to find in our confidential information. Would the court then rule in favor of the company, setting a devastating precedent?

I must admit that my understanding of all the legal aspects that surround matters of this sort is very limited. But if journalists are protected from identifying their sources in court (what is often referred to as "privilege"), is that the same kind of protection that our "sources" -- our referees -- get when they share confidential information with us and when we promise to protect their anonymity? If this is not the case, why not? And is there something that we, the editors of scientific journals, could do to make sure that we have "privilege"?

The ruling favored us this time, setting some sort of precedent for the protection of confidential information at scientific journals, but the matter is far from closed, and heaven knows what will happen next time.

Posted by Juan Carlos Lopez at 05:44 PM | Permalink | Comments (4)

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)

Ahead of a meeting with a representative from the recently-formed UK Research Integrity Office, I sorted through my file of papers on research misconduct. Amongst them I found a ‘News in Brief’ page from Nature Medicine, 2005 . On it, I found the headline that had caused me to photocopy the page – “Many scientists admit to misconduct”, drawing attention to a paper in its sister publication Nature published a month earlier. The paper described a survey in which it was revealed that one in three scientists has committed some type of scientific misconduct.

The irony was that at the bottom of the same page was a short piece (from the same correspondent, Emily Singer) announcing “South Korean chalks up another stem cell victory”. The article highlighted the work of Woo-Suk Hwang in which he claimed to have cloned human embryonic stem cells in a paper published two months earlier in Science. The disgraced Professor, formerly of Seoul National University, is now used as a case-study for fraud in research (for example, Fraud Advisory Panel Occasional paper 01/07 Fraud in Research: Is it new or just not true?).

Was this incredible prescience on the part of the author, or just a strange coincidence of publishing?

Posted on behalf of Dr. Dave Wilson, Cardiff School of Biosciences, Cardiff University, Wales, UK

Posted by Juan Carlos Lopez at 10:06 AM | 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)

About 1,400 years ago, Pope Gregory the Great (image below) enumerated the Seven Deadly Sins -- sins that cut the sinner off from God. Now, Archbishop Gianfranco Girotti has drawn up a new list of Seven Deadly Sins for modern times.

"To sin is to violate the relationship of man with God", stated Archbishop Girotti. So, his new list has paid special attention to what one could call "social sins" that are linked to "the phenomenon of globalization”. This is how the BBC listed the new deadly sins:

Environmental pollution
Genetic manipulation
Accumulating excessive wealth
Inflicting poverty
Drug trafficking and consumption
Morally debatable experiments
Violation of fundamental rights of human nature

Wait a minute, though. Genetic manipulation? Surely not! So, does this mean that, if someone successfully cures a congenital disease using gene therapy, this person will go to Hell? I hope not. Otherwise, the Italian authors of a paper we published over a year ago may be a bit too close to the Vatican for comfort.

And morally debatable experiments? Aren't all experiments morally debatable? I admit that I don't know all the details of what the 'Osservatore Romano', the official newspaper of the Vatican, published, but hopefully there is some clarification for the benefit of those of us Catholics who had to learn to live by the law of the original deadly sins. Do morally debatable experiments refer only to experiments in embryonic stem cells, or are there other experiments one needs to be worried about?

Sure, one can see where the Catholic church is coming from with their proclamations of the new sins. But to place a good number of fine scientists twice in such an eclectic list and in the company of drug traffickers strikes me as somewhat disturbing. Good thing I'm no longer a practicing scientist. Otherwise, I would need to do a lot of explaining next time I visit my mom.

Posted by Juan Carlos Lopez at 10:04 AM | Permalink | Comments (4)

I always thought the ‘therapy’ in ‘aromatherapy’ was something nobody took seriously, sort of like ‘low-fat’ in ‘low-fat potato chip’ or ‘recycle’ in the Microsoft desktop’s ‘recycle bin’ (only in my nicey-nice hometown of Seattle would anyone get away with coining such a platitude).

But apparently the ‘therapy’ part of aromatherapy is real enough for the US National Center for Complementary and Alternative Medicine at the National Institutes of Health. The institute, which we have covered before, has sponsored a trial of aromatherapy—and the results are out!

Big news: aromatherapy doesn’t work. The best thing lemon did was lift the mood and lavender didn’t even do that. Surely there are other, more interesting and potentially effective alternative therapies to study. I’m not sure what. But at least they are not studying that substance of apparently limited effectiveness, prozac.

Posted by Charlotte Schubert at 08:23 AM | Permalink | Comments (1)

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)

There's a saying in Spanish that roughly translated says "Calamities never arrive alone". Following John McCain's statement on the "strong" evidence for a link between vaccines and autism, which Charlotte Schubert blogged about, the ruling in the case of Hannah Poling is a second calamity that is bound to add more fuel to a debate that hasn't been particularly productive.

The US government's decision to settle and agree to pay Hannah, who has autistic symptoms, for her care has been immediately heralded as a victory for supporters of the vaccine-autism link, even though officials have been careful to clarify that they didn't concede that vaccines cause autism.

The government can continue to clarify their position until they go blue in the face but, unfortunately, this ruling is bad news for the science that has debunked the autism-vaccines link, for the cost of health care in the US (which is bound to feel the effect of more settlements of this sort, if this case is accepted as precedent), and for herd immunity (the effectiveness of which may decrease if too many kids in a given pupulation stop being vaccinated).

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

I was listening yesterday to an interview with Madeleine Albright, former secretary of state, on KGNU, an online radio station based in Colorado.

While plugging her new book, she said that the job of secretary of state is more complex than when she had it. The reason? The position now requires more science savvy: the next secretary of state, she said is going to have to know about climate change, energy and public health.

So it’s not just a bunch of geeks thinking all this science stuff is getting more important. So-and yes I keep bringing this up-Madame Secretary, are you prepared to add your name to a call for a Science Debate?

Posted by Charlotte Schubert at 11:52 AM | Permalink | Comments (2)

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)

Pretty interesting report in Nature a week ago about the NIH's proposal to revamp its peer-review process. We plan to discuss the proposal in more detail at a later date, but I cannot help but refer to the graph that accompanied the story:

What I wanna know is who the one investigator with 11 NIH grants is. Truly remarkable! I'm willing to bet that this person has no strong criticisms of the quality of peer review at the NIH.

Anyway, this graph also reminded me of those plots you see of wealth distribution in New York or London, in which a few people have a lot of money, making those cities a lot less affordable for the rest of us.

Posted by Juan Carlos Lopez at 02:09 PM | Permalink | Comments (0)

Clearly, John McCain does not read this blog.

He blundered into Nature Medicine territory this week, saying that there was “strong evidence” for a link between autism and vaccines (there is not, a point we have driven home before).

Reminds me of a stumble McCain had last year with a reporter on another of our pet issues, HIV and condoms:

Q: “So no contraception, no counseling on contraception. Just abstinence. Do you think contraceptives help stop the spread of HIV?”
A: Mr. McCain: (Long pause) “You’ve stumped me.”

One blogger offers a charitable—and probably accurate—explanation for the autism statement:

The vast expansion of the state means that we expect our representatives to have opinions on everything from missile defense to flame-retardant pajamas. No one could possibly learn about every subject we expect them to know, even if he were not spending sixteen hours a day doing the grip-and-grin with voters, lobbyists, donors, and other politicians.

It would be interesting to hear more about the views of McCain and the other candidates on HIV prevention, contraception and even vaccination (another reason for a science debate). But at least he’s got the scientific consensus right when it comes to global warming.

Posted by Charlotte Schubert at 01:00 AM | Permalink | Comments (2)

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)

I saw this amusing paper in the latest issue of EMBO reports.

The article's title is "Six senses in the literature. The bleak sensory landscape of biomedical texts", and its authors -- Raul Rodriguez-Esteban and Andrey Rzhetsky -- argue that "scientific texts have a reputation for being factual, rational and 'dry" in contrast to other prose that is designed to evoke emotional responses". They therefore set out to obtain evidence that "the sensory-deprived writing style that dominates the biomedical literature impedes text comprehension and numbs the reader's senses and mind".

To that end, they measured the frequency of use of "sensory" words (terms related to the perception of color, smell, taste, touch, sound and time) in 250,000 articles from 78 biomedical journals and compared it to their frequency in news reports from Reuters, in articles in Wikipedia, and in the complete collected works of Poe, Shakespeare and Whitman. They found (surprise, surprise!) that articles and news reports were a lot "bleaker" in comparison to the works of literature. The figure below is some sort of homunculus that gives you an idea of the "sensory" characteristics of the different works they looked at. It shows the balance of "sensory" terms in the different bodies of work they compared, together with the average -- the face in the center.

The authors speculate that reading texts with the characteristic of a biomedical article "is similar to the effect of a long journey through a colourless flat terrain devoid of prominent features: a numbing of the senses", and suggest that "cognitively bleak biomedical texts can and should be transformed into perceptually richer prose".

All of this is well and good, but I must confess that, when I read scientific papers, I have very little patience for metaphors and analogies, which some authors, alas, love to use. Some of them are so gratuitous that it makes you wonder if their use of imagery and metaphor is itself, in fact, an attempt to "numb the reader's senses and mind".

Back when I was the Editor of Nature Reviews Neuroscience, I remember that a couple of my colleagues and I created something we dubbed "Analogy-watch" to record the most ridiculous analogies that we could find in scientific texts. (I regret to say that many of them were penned by some of our own in-house Editors.) Maybe as a result of that experience I've always tried to be careful and separate literature from science. I hope that prospective Nature Medicine authors don't rush to follow the authors' advice and instead use "sensory words" in moderation. Trust me, you don't wanna end up being part of our Analogy-watch file.

To close, I cannot help but pointing out that Calvin (of Calvin & Hobbes fame) had already observed an effect somewhat related to the one reported by Rodriguez-Esteban and Rzhetsky. I didn't see Calvin cited in the reference list, which is why I thought I would include the relevant "report" down here. (Note, you may have to save the image on your desktop, as it appears truncated in the blog page.)

Posted by Juan Carlos Lopez at 04:10 PM | Permalink | Comments (2)