Another long blogging hiatus, as I was away for about a week. Hopefully we can recover some consistency, particularly now that I found several things to blog about. A couple of them have to do with that infamous talk I gave in Madrid and the related post on this blog. Some friends have pointed me in the direction of a series of comments that some people have made about both talk and post, which might be worth talking about.

Before that, though, I got a couple of requests to post the mock cover of Nature that I presented at the talk, and I thought I would oblige. The original photograph is by Vedia, and the mock-up is by my friend and fellow NPG employee Simon Fenwick.

Readers in the USA may find the cover meaningless, as the Eurovision Song Contest is a non-event on this side of the Atlantic. But in Europe, Eurovision is more of a big deal, and this year it's got a lot more publicity than ever, due in part to contestants like the one representing Spain this year, who graced this imaginary cover. And for those interested, you should check out the Ireland representative, which is perhaps even wackier than this one.

Posted by Juan Carlos Lopez at 03:34 PM | Permalink | Comments (0)

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)

A neuroscientist friend of mine who is an enthusiast of tango will be very interested in this article that I read in the news today. It reports that dancing tango could benefit patients with Parkinson's and Alzheimer's diseases.

Image: PeterForret

Unfortunately, the news report doesn't have a reference for this claim, although a cursory look in PubMed discloses this paper, which showed preliminary evidence for some benefit of tango on Parkinson's patients. The news report did say, though, that the First International Congress of Tangotherapy will take place next July in Argentina. Their current speaker list looks somewhat slim for a three-day meeting, but you never know how many more people will ultimately participate, even though I didn't see any dancing-only sessions in the program.

Image: Luke Robinson

By the way, pending future evidence that tango is also good for people with Alzheimer's disease, I must be skeptical; it didn't seem to help the memory of my tango-dancing friend, who forgot about me a long time ago.

Posted by Juan Carlos Lopez at 11:16 AM | Permalink | Comments (0)

The article and accompanying editorial published in JAMA earlier this week regarding the issue of ghostwriting made, yet again, a strong point about the influence of pharmaceutical companies on the communication of science.

In a nutshell, a series of primary and review articles authored by Merck regarding their drug rofecoxib were allegedly written by communication firms that provide writing services for companies and individuals. In addition, some articles were signed by academics who allegedly did not have much to do with the study, but were invited by the company to lend their name (and their prestige) to the papers.

There seems to be something seriously wrong with this picture, but let's go step by step. Is there anything wrong with companies that write papers for hire? The JAMA editorial seems to think so:

"...there was no disclosure that the manuscript had been written by Scientific Therapeutics Information Inc, a company specializing in [...] writing papers for a price. Perhaps some [...] would see little or no harm in this failed disclosure because all other disclosures were made. However, if there was nothing to hide, why were the names (and affiliations) of the individuals who actually wrote at least the first draft of the manuscript omitted? Experienced authors know that the initial draft (in this case paid for by Merck) sets the tone for the manuscript. Moreover, it is unfair to the authors of the first draft not to provide them with credit for their work. Another problem with failing to disclose "ghost writers" is that there is a reasonable assumption that the principal investigator was involved with writing the manuscript from the beginning."

Why were the names omitted and credit was not given to the ghost writters? I would probably ask the opposite: Why should they be included? Scientific Therapeutics Information entered into an agreement with Merck according to which STI would write the paper and Merck would pay -- that's their compensation. Why should they be also authors? It's like saying that papers should always include the names of all the technicians, as they did experiments that are reported in the manuscript. I'm sure many researchers would find this idea amusing.

Now, does the first draft really set the tone of the manuscript? What does that mean, anyway? In my experience, if the first draft of an article is bad, it will be discarded and people will start over. There's no such thing as an article's tone, at least not as something that the paper is born with from the time you first sit down in front of your computer and start typing.

And is there really an assumption that the principal investigator was involved with writing the manuscript from the beginning? I'd actually say the opposite -- my assumption tends to be that the PI more often than not sees a draft written by the postdoc. In fact, many senior PIs would not dream of writing a first draft, but would impose it on junior researchers to get the paper into very good shape before they get involved.

This point is relevant to the second crime of which the Merck people stand accused -- getting senior PIs to be authors in papers for which they didn't do much work. These researchers are a little like those PIs who get involved in reading the paper once the draft is essentially final. And yet, we don't often hear people asking for those PIs not to sign those papers.

Of course, this example is dumb -- those PIs did contribute with the money to support the lab, and they may even have provided some intellectual input to the work (although, again, there are some senior PIs that let the lab in the hands of their postdocs, who pretty much decide by themselves what project they want to pursue). But even if the example is dumb, it does raise the point of what threshold must you cross to become the author of a paper.

Is it enough to be the owner of the lab for you to sign everything that comes out of it? Some would probably agree, even though no-one would dream of splitting the credit for painting the Sistine Chapel between Michelangelo and the Pope just because the latter "owned" the chapel. What if you "just" gave the mouse used for the experiments? Would you want to be author or not? Opinions will vary, but it's not necessarily outrageous to appear in a paper for giving people such a crucial reagent. And what if you only gave intellectual input? Again, opinions will vary, but some people will value this kind of contribution more than giving the mouse or being the owner of the lab space.

So, why are we horrified about the idea that someone approached by a company to author a paper agrees to do it? After all, this kind of guest authors are often told that they are welcome to change anything they don't like in the paper they are given. So, depending on how serious you are about this task, you may end up being really comfortable to give your name to a manuscript if you really worked hard on it. In fact, who hasn't heard of cases in which someone ends up in someone else's paper because of extensive discussions throughout the preparation of the manuscript?

I think that a crucial point in this discussion is included in the JAMA editorial: "...it is clear that at least some of the authors played little direct roles in the study or review, yet still allowed themselves to be named as authors". Sure, but how little is "little"? In fact, some of the people who have been identified as guest authors have disputed the allegation precisely by stating that they did have a lot to do with the preparation of the manuscript. The same question goes for them: how much is "a lot"?

So, to my mind, the problem here are not so much the pharmaceutical companies for approaching people to author their papers, but how much people think they need to work to feel comfortable as authors of manuscripts of which they were not the leaders. Unfortunately, as I illustrated above, there's no simple answer to this question, because there are many pathways that you can follow to end up being guest author in a paper -- sheer seniority and ownership of the lab, sharing a key reagent or giving vaulable discussion.

The one thing that is different in this case is that money is exchanging hands -- the pharma company allegedly offered money in exchange for the scientist's name. So, if you just took the cash and signed the manuscript without even looking at the paper, sure, that's clearly unethical. But if you did work on it, is it still inappropriate to charge a fee for your input? It may be against the rules of your institution, but I wonder if it's inappropriate from a strictly ethical standpoint.

So, in the Merck case, if I were the Dean of any of the people who have been named as ghost authors, I would take the problem very seriously and launch an investigation to ascertain how much they really worked on the study. If they did, in fact, contributed enough (acknowledging that the definition of "enough" will vary depending on who you ask) and they didn't break any rules of their institution, the institution needs to make this very clear to the community. And if it turns out that the authors really just took the money and ran, then disciplinary action must surely follow.

I share the view expressed in the JAMA editorial that integrity in medical research is paramount. However, I disagree with overarching, one-size-fits-all decisions about how to handle situations as complex as the issue of authorship. To my mind, these decisions can trivialize the problem by offering solutions that are a bit too simplistic and may end up being regarded as empty rhetoric.

Posted by Juan Carlos Lopez at 03:04 PM | Permalink | Comments (5)

You may or may not have noticed that I haven't been blogging for over a week; I was in Madrid giving a talk in which I tried to make the point that we don't discriminate against authors on the basis of nationality, language or any other non-scientific aspect. In a previous entry, I had already shared some data to back this statement up, and I used the same and additional data during the talk to drive the point home. It was quite amusing to see that some people still didn't believe me: "sure, I can see that your graphs show that you don't discriminate, but I still don't believe you". What is there left to say?

In any case, I must confess that the talk got a little boring when people started asking me questions about open-access publishing. It was fascinating to see how difficult it was for some people to understand that scientfic publishing costs money, and that there are different models to recover your costs -- the author-pays model, the subscription model, and everything in between. The talk got boring (at least to me) because I have very little patience with this discussion when people stop putting forward compelling arguments in support of their ideas or, as in this case, when people just don't seem to want to get the simple point I was trying to make: as there are different models, publishing groups ought to choose the model that works best for each of them. In our case, the subscription-based model is the only one that seems viable for the time being. How difficult is it to get this point?

Anyway, a funny thing was that there was a lot of press covering the talk, which was part of a larger event organized by our Madrid office to present a new "How to publish in the Nature journals" guide in Spanish (I'll write an entry about the guide some other day). As a result, a couple of newspapers ran stories and interviews with yours truly, and there's even this video I found. Enjoy!

Posted by Juan Carlos Lopez at 09:44 AM | Permalink | Comments (2)

...would seem to be the message from three papers published over the past few days in different venues.

First, the NEJM published this past weekend a report showing that using a cholesterol-absorption inhibitor (ezetimibe) in combination with statins reduces LDL below what each drug achieves on its own but, alas, there is no similar additive effect on the progression of atherosclerosis.

Then, JAMA published today that rimonabant, the cannabinoid receptor inhibitor that promotes weight loss, has no effect on the progression of atherosclerosis either, although the authors do warn that more studies are needed before we know for sure if this is the case.

Last, a study in PLoS Medicine published yesterday claims that people with Alzheimer's disease are better off without neuroleptics for the treatment of their psychiatric symptoms. These drugs seem not to have significant beneficial effects to outweigh their side effects.

It would seem that every time we look at a drug using higher-magnification lenses we uncover something to discorage us from its use. At this rate, I don't look forward to a future in which the only thing you can buy safely from a drugstore will be aspirin.

P.S. Who comes up with the names of these clinical trials? ENHANCE and STRADIVARIUS? You must be joking! If only their outcomes were as uplifting as their names...

Posted by Juan Carlos Lopez at 07:27 PM | Permalink | Comments (1)

One of my colleagues was telling me the other day that we at the journal have a bias in favor of the USA. She was specifically making this comment with regard to our reviewer pool, which is indeed dominated by US-based scientists. But then again, there are many more scientists here than in any other country in the world.

In terms of authors, though, there doesn't seem to be such bias in favor of the US or against any country in particular. Have a look at this graph, which shows the ratio of published to submitted papers as a function of country.

Each color represents a year -- from 2007 to 2004, top to bottom. Note that this plot includes papers submitted not only to Nat Med, but it's pooled data from NMed, NNeuro, NGenet, NSMB, NCellBio, NImmunol and NBT. I didn't plot the actual number of submitted papers because, of course, we get our largest number of submissions from the US. But this graph clearly shows that we don't favor the US over, say, Italy or Spain. The graph also shows that countries that have invested heavily in science over the past few years, like Australia, show a steady increase in their ratio of successes over failures. Sure, countries like China and India still have some catching up to do, but they'll get there, trust me.

LatAm stands for Latin America. South Pacific includes Singapore, Hong Kong and Taiwan. Scandinavia includes Sweden, Norway, Denmark and Finland.

Posted by Juan Carlos Lopez at 04:50 PM | Permalink | Comments (5)