Friday levity: 'Nature' discusses ghosts.

One of the pleasures of thumbing through old issues of science journals is the opportunity to accidentally discover articles or letters that make you do double takes, often followed by face palms. 

As I was about to read a letter in Nature bemoaning the closure of the Hoffmann-La Roche Institute of Molecular Biology in Nutley, NJ (Nature, 1995, 373, 184; deja vu, anyone?) I came across a letter on the same page that pristinely tosses out the following for readers' benefit (click for clarity...or the lack thereof).

I love the fact that the letter writer dismisses one hypothesis about ghosts only to come up with another. And this isn't 1885, it's 1995. Oh how I miss the old Nature.

Chemical compounds from mouthwash may target cancer cells

Apoptosis or programmed cell death is one of the great truths of cellular life, an essential process that’s not only required to make way for new cells but to prevent old cells from going haywire. When cells circumvent this great truth they start dividing uncontrollably and contribute to cancer. Our knowledge of cancer over the last three decades has confirmed the central role that a breakdown in the usual mechanisms of apoptosis plays in pushing a cell across the tipping point into a cancerous state. Of the many strategies to fight cancer, one consists of trying to find drugs that force cells to regain their normal balance of apoptosis. Now this effort may have found an unlikely ally.

Chlorhexidine is an antibacterial and plaque-fighting compound that is a common component of mouthwash, usually present as a 0.1% or 0.2% solution. In a paperpublished in the journal Angewandte Chemie, scientists in Germany report an unexpected effect of chlorhexidine and its related cousin alexidine: they inhibit cancer cells in the mouth by blocking an important protein-protein interaction. This research opens up new directions in investigating this class of compounds as anticancer agents and also sheds light on the value of finding novel potential uses for everyday chemical compounds. One of the great advantages in this endeavor is that the “repurposed” compounds have already run the gauntlet of safety tests required by the FDA, potentially shortening the period of approval for their new uses.

Protein-protein interactions (PPIs) are often considered the next frontier in drug discovery. They are involved in almost every important molecular-level event in health and disease. Traditional drugs work by blocking the action of single proteins (typically fitting into them like a key fits into a lock) but since there are many more protein-protein interactions than single proteins, there is enormous potential in developing drugs that disrupt these interactions, many of which are upregulated in diseases like cancer. Unfortunately targeting PPIs is difficult because of a variety of reasons; they have large, spread-out interfaces which makes it difficult for small organic molecules to span their surface area, and typically the ones which do are too big to satisfy the many qualities of an ideal drug, such as an ability to get inside cells in the first place.

One of the most well studied PPIs is the interaction between a family of pro-apoptotic and anti-apoptotic proteins called the Bcl-2 family. These proteins are present in all our cells. As their name indicates, one group of proteins speeds up apoptosis while the other group inhibits it. In a normal cell there is a usually a precise balance between these two activities engineered by the two sets of proteins binding to each other and regulating each other’s function. It’s a delicate dance which ensures that the cells are active only when needed and any cells gone haywire are eliminated. In cancer this precise balance is disrupted and the anti-apoptotic proteins are over-expressed and become dominant. One anti-apoptotic protein named Bcl-Xl in particular keeps its usually equipotent pro-apoptotic protein partner named Bak bound up and prevents the cell from committing suicide; this molecular-level feud leads to uncontrolled cell division. Over the years researchers have tried to find many druglike molecules and peptides which could block Bcl-Xl and free up the Bak protein. But none of the attempts have resulted in a clinically marketed drug.

What the researchers in Germany did was to screen about 4000 everyday chemical compounds to look for ones that might block the Bcl-Xl protein. They found two which, surprisingly, had very different uses. Chlorhexidine and alexidine are common components of mouthwash. Both compounds were found to inhibit the Bcl-Xl – Bak interaction at a concentration that’s much lower than that found in mouthwash. Surface-exposed oral cells in the mouth are thus bathed in a rather potent concentration of small molecules that prevent at least one important mechanism involved in cancer from manifesting itself. The researchers also did further experiments, including computer modeling, that localized the site of binding of the two compounds on the Bcl-Xl protein. This site was the same as that occupied by the Bak protein, further supporting the blocking interaction of the mouthwash components with the anti-apoptotic protein.

Finally the researchers tested these two compounds against cancerous cells from the tongue and the pharynx. Both compounds were found to significantly reduce the degree of apoptosis suppression in these cells, connecting the molecular level interaction of the molecules to actual anticancer effects.

This study is interesting for several reasons. It directly leads to a new class of compounds that may have promising anticancer activities; very likely the compounds’ structures would have to be modified by chemists to improve their properties, but this is what chemists have always done best. The therapeutic concentration that’s required for inhibiting the proteins is already exceeded in your garden variety mouthwash; this may also indicate a healthy margin of safety. A more intriguing question to ask is whether the use of mouthwash correlates with lower incidence of oral cancer. The literature on the relationship between mouthwash and oral cancer has been confusing and there don’t seem to be large-scale studies investigating a possible connection. By suggesting a possible mechanism of cancer prevention, this study provides a strong motivation to gather epidemiological data about possible anticancer effects of mouthwash and its components. It’s too early to start dousing your mouth with mouthwash though since these compounds only target one kind of interaction and we don’t have enough data on higher concentrations and long-term effects. But it’s definitely a promising start that points the way to interesting experiments, and that’s what science is best at doing.

Most tantalizingly though, the study asks what other kinds of therapeutic effects may be hidden in everyday chemical products, in our bathroom and kitchen closets. Nature is much more interesting than we think and molecules often lead double lives. Contemplate this the next time you brush your teeth or wash your dishes.

First published on the Scientific American Blog Network.

Solomon Snyder on academic publishing: ask for adequate, not exhaustive, documentation

Image: Corpus Callosum

Renowned neuropharmacologist Solomon Snyder has a thought-provoking take on what seems to be one of the two evils that has plagued modern academia: publication (the other one is the job market). I have previously blogged about the increasing conservatism of academic publishing myself, and in this case “conservatism” also translates to “excessive rigor”.

Snyder starts by lamenting the startling fact that the average duration for a modern American biomedical scientist to start his or her academic career is about the same as that for a neuro or cardiovascular surgeon, people whose specialty is usually considered to be in the top tier of their profession; the difference of course is that a cardiovascular surgeon starts making $500K right off the bat while a new assistant professor starts making $80K and almost never goes beyond $200k or so. The long trudge begins with graduate education, the average duration of which has stretched out over the last three decades (these days, a 5 year Ph.D. is considered relatively quick). Every part of the academic process, from getting a postdoctoral position to your first job to your first grant, has turned into a war of attrition. The “winners” who emerge at the end of it are often demoralized academics in their early 40s whose best years may be behind them. And the situation seems to only be getting worse.

But the article’s really about publishing papers. Snyder hits the nail when he says that academic publishing has become so rigorous in asking for exhaustive experimentation and documentation that it dissuades many authors from publishing their best ideas, ideas which are interesting and valid but which may not have been completely fleshed out. He points to reviewers’ insistence that authors perform a comprehensive set of experiments – often ranging over several months – that would qualify their manuscript for publication. Anyone who has tried to publish biomedical papers must be well aware of how tedious and demoralizing the experience can be. This long-drawn process significantly impacts the progress of science:

“Why does it take so much longer to move from test tube to the printed page? One element is a journal review process that is substantially lengthier, especially in terms of experiments required to address the concerns of referees. To anticipate such referee responses, scientists preemptively carry forward experimentation more exhaustively than is necessary to document their assertions. Yet, we can clone genes in a couple of days. Shouldn’t we be able to complete experiments to satisfy reviewers in a few weeks rather than the 7–12 months typically consumed in revision, not to mention the many years devoted to developing the original manuscript? If one spends 5 years accumulating the data for a manuscript and another year revising it to satisfy referees, benefits to the public are delayed for years.”

In contrast Snyder points to his postdoctoral advisor, another legendary scientist named Julius Axelrod at the NIH who churned out discovery after discovery in short order and won a Nobel Prize (the Axelrod dynasty is nicely charted out in Robert Kanigel’s book “Apprentice to Genius”). The point that Snyder is making is that in those days the reviewing process was much quicker but the quality of science doesn’t seem to have suffered in spite of this speedier turnaround. What has gone wrong since then?

Snyder partially places the blame at the feet of Cell founder Benjamin Lewin who wanted Cell to showcase papers that were essentially complete stories; from hypotheses to final products. But Lewin also made the process highly streamlined. Reviewers were warned to stay away from insults, stick to succinct criticism and suggest adequate but not unrealistic experiments and further studies. The objective was to get the best science out in a form that was interesting enough to spark further inquiry but which was not necessarily the last word.

Lewin understood the piecemeal nature of science where researchers build on each other’s discoveries. This understanding of the scientific process has since been subverted by academic reviewers, partially to cull a flood of proposals and ideas and partially to satisfy their own whims. Sometimes old boys’ networks can conspire to put sound science in a straitjacket. Expecting every research project to tell complete, final stories not only imposes unrealistic and demotivating standards on scientists but also ignores the always incomplete and provisional nature of science. Snyder asks that expectations for accepting papers be changed and points to recent developments like the journal eLIFE which incorporates some of his thinking. Blogger SciCurious suggests her own system of peer-review where a paper is simultaneously sent to a group of journals with different standards; after hearing back from reviewers, the authors can decide whether to push ahead with further experiments to satisfy the top-tier journals or whether to publish the paper in a lower-tier journal right away. But Snyder’s perspective points out that all journals – whether top tier or otherwise – should have a reviewing system that allows for rapid dissemination of results.

Reviews and authors need to seriously contemplate Snyder’s recommendations. Academic research has already turned into a long slog with its uncertain job market and draconian grant approval and does not to face need additional difficulties in the form of glacial and unrealistic reviewing standards. Let’s remember that the purpose of science is to generate ideas, not products. And it shouldn’t take very long for ideas to see the light of day.

First published on Scientific American Blogs.

First they came for the bloggers and I didn't speak up because...

Here's a breath of fresh air. I keep on thinking about Planck's quote about scientific revolutions not occurring until old generations die and new ones take their place and here's something of that sort happening, even if in a minor way. 

Prof. Phil Baran has started his own blog. It's easy to see this as a response to the commendable IBX oxidation experiment carried out by Blog Syn. That, by the way, was a great illustration of how science should work; research is published, it is then scrutinized, a few discrepancies are found, the original author responds and confirms the original results, and the new authors discover something new that had not been realized before.

But it's clear that the Blog Syn incident was only a seed for a realization that undoubtedly must have been crystallized in Phil's mind for a while. We have all seen how the old guard has often dismissed and scorned bloggers and their pesky, amateur blogs. Now here's someone from the new guard who clearly recognizes which way the winds are blowing:

Over the years I have vaguely followed some of them, mostly through my students or through being occasionally contacted by someone that runs a blog. Practically all of my colleagues roll their eyes the minute the word "blog" is uttered for a variety of largely justified reasons.  

But times are clearly changing...Last year I was at a dinner symposium where EJ Corey gave a brilliant impromptu talk before a toast. It was a captivating speech all about how things have rapidly changed over the span of his 80+ years. The take home message was that change is natural and you can either embrace it and adapt or be left behind. I'm no fortune teller but it is clear to me that blogging is here to stay and is gathering momentum.

There is something ironic about the fact that the words of the great E. J. Corey - an exemplar of the old guard who almost certainly is not going to start blogging anytime soon - should serve as an invitation to blog for the man who is widely regarded as one of the most creative synthetic organic chemists of his generation. 

Thank you Prof. Baran. Now, the next time they come for us, we know you will speak up because you are are a blogger.

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