My research is published with Open Access!

June 8, 2009

My latest paper has just been accepted for publication in the Journal of Experimental and Clinical Cancer Research. This is an open-access, online-only scientific journal. When the paper comes out I will cover it in another post. Meanwhile, let me exhort my fervent commitment to open access scientific publishing.

The cycle of scientific endeavour typically goes like this (substitute your favourite researcher if you want):

  1. Somebody gives me money
  2. I do research
  3. I write up the tattered remnants of my grand designs into a decent manuscript and send it to a journal
  4. The journal sends the paper off to other scientists who review it for free, while I review papers from other scientists in other journals in my spare time because of loyalty to the Scientific Endeavour or something
  5. The journal decides, hopefully, to print it and then charges me at least 1000 USD for the luxury. It also charges subscribers and university libraries fo the right to read the article in print or online, making it impossible for anyone outside the system to access the knowledge I have painstakingly assembled.
  6. The Cancer Fund or the NIH (substitute your favourite funding body) counts my journal articles and then, hopefully, gives me more money.

While both I and the funding bodies (which are often backed by public tax-money) want the results to be as accessible as possible, the lock-in behind paywalls becomes an unfortunate consequence of the fact that journal article are nearly the only metric of achievement by which I can be measured.

Furthermore, I need access to all the journals in my field. It’s not the case that one could simply be substituted for another. This means that my university is almost completely price-insensitive, a situation upon which the scientific publishers have been quick to capitalise. Elsevier, one of the “Big 3” together with Springer and Wiley, has had an operating profit margin above 35% in recent years in the science and medicine section of its business.

A recent industry report (not online) from Deutsche Bank on scientific publishing states that “We believe the publisher adds relatively little value to the publishing process.” This is true. The value added lies, besides the typesetting, mainly in that the credibility of the research can be boosted by the strong brand of a prestigious journal. And I don’t have to add that that sort of bias in the scientific community is a problem even though some may benefit from it.

A bunch of corporate behemoths are making obscene amounts of money by keeping (mainly) tax-funded research results out of the public domain. Outrage is warranted.

The solution? Open access publishing, of course!

There are a few different models for open access, including self-archiving of manuscripts and data on public servers. But the simplest and best-functioning solution, in my humble opinion, is the open access journal. It’s just like an ordinary journal but with free online access for everyone. The costs of publication are covered by a fee (again, around 1000 USD) payed by the scientists themselves (us).

The health worker whose hands are in the foreground will be able to read my latest article online without a subscription, should he/she want to.

The health worker whose hands are in the foreground will be able to read my latest article online without a subscription, should he/she want to.

The cost is not greater than for many traditional journals, and is offset by the greater availability of the article. Some studies suggest that open-access articles are cited at least twice as often, at least in certain fields. But most of all, there is an imperative stemming from our purpose as scientists to generate knowledge and actively share it around the world. We have no reason to keep supporting the self-serving oligopolies of knowledge that still publish most scholarly articles, when we can instead make them freely available to the entire world.


Anatomy of the cell’s brain

May 22, 2009

For some time, I have been wanting to write a post on the ”hardware” of information processing in the cell. AK’s Rambling Thoughts has however beat me to it, in a series of four blog posts describing certain core principles. If I try to sum up the most important points, here they are:

  • Enzymatic reactions can function, in principle, as analog computer circuits.
  • The sheer number of interlinked reactions, both enzymatic and involving the regulation of protein transcription, allow us to view the cell as a computer with a huge processing power.
  • Many of the analog circuits are wired with positive and negative feed-back mechanisms that enable them to give a digital, all-or-none response. This entails a loss of processing power, which is in AK’s opinion offset by advantages of speed.
  • The computing is “modularised” in the cell, meaning that some reactions occur only in specialised compartments (a synaptic bouton, for example), and communication within the cell can take the form of chemical gradients occurring as a consequence of reactions taking place only in one location.

AK gives many specific and detailed examples of the mechanisms that are involved in each of these processes. But to me, the real power of the discussion lies in the presuppositions that are not very explicitly stated, but very strongly supported by AK’s examples.

The cell deals in processing information
It is easy enough to see that cells process matter. They take up glucose and other nutrients and transform them into energy and structural components. It is not intuitive for many to think of these processes as manipulation of information, but here’s how I see it:

If the cell is going to be successful at all, it needs very fine-tuned regulation of its diverse activities. Any regulation that takes place in response to external factors can be thought of as an internal representation in the cell of its exterior. A map, if you wish, in many dimensions – oxygen tension, concentrations of nutrients, activities of hormones, and so on. This map will then be the input into the cell’s “decision machinery”, which will output some sort of behaviour.

Historically, the decision system has often been conceptualised as a set of enzymes acting linearly and without a lot of interconnections. With more sophisticated models derived from computer theory, it is far more likely that we will be able to capture some of the complex goings-on and generate accurate predictions of how these systems will behave.

Important principles emerge even from only a very general knowledge of the signalling networks
We do not have to know exactly which enzymes do what in order to make some pretty powerful inferences about the signalling network. Based only on a few known classes of interaction, like positive and negative feedback, it’s possible to envision properties of the whole system. Prime among these is the strong nonlinearity that must be expected when there are so many parameters.

In a way I envy physicists. If I poke my teacup, they will be able to predict exactly where it will move to, and when, and in what position it will stop. But if I poke a member of one of my cell cultures (gently), or Zelda, my mother’s Chinese Crested, there is no telling what will happen.

Zelda. Yes, she is cute.

Zelda. Yes, she is cute.

Suddenly the system might go into one of these digital, all-or-none responses. I do not believe they are motivated by speed, by the way, because I do not see why an analog response could not be as fast. Sometimes they are probably motivated simply by the necessity to decide some things one way or another. In particular, this concerns “cell fate decisions”, when the cell decides whether to replicate, or to commit apoptosis. There can be no half-measures with some things.

The cell is not a unit
Some things appear to us at first to be one and indivisible. For example, it came as a small shock to me when I learned that my brain sleeps in regions – it’s not at all necessary for the whole brain to sleep at once. I have also discovered an interesting subdivision when I am daydreaming. Rather often, I start constructing arguments or writing a speech in my head. No visual imagery attached. That’s left hemisphere activity. And then I find myself having hummed a tune with no lyrics, almost without noticing, perhaps for several minutes. That’s the right hemisphere entertaining itself when I am not watching.

The “I” of the cell can be similarly elusive. Some cells are several decimetres long, making it impossible for diffusion of small molecules to carry information from one part of the cell to another. Besides the specialised long-distance information transfer systems (such as axonal transport mediated by the cytoskeleton), such a cell is a set of functionally semi-independent decision-making centres. It’s a bit like an 18th-century colonial empire with faraway patches of land, only intermittently connected by slow sailing vessels.

There are times when I feel a pang of jealousy over discoveries already made, that other people have lived to experience. But then I remember that the pace of discovery has only increased and keeps increasing, and then I feel the same sense of wonder as one might before the sky on a starry night, when I think of what we will know about these systems in one or two decades.

Behavioural conditioning of immune response: antiinflammatory effects can be conditioned to an unrelated stimulus

May 3, 2009

ResearchBlogging.orgIt is now well established that there are links between the brain and the immune system. A whole field, called psychoneuroimmunology, devotes itself to the study of how these systems are interconnected. The term psychoneuroimmunology was coined by Robert Ader and Nicholas Cohen, two scientists who were able in 1975 to show that it was possible in rats to couple a sugary drink (unconditioned stimulus) to an immune-suppressing drug (conditioned stimulus), and then use the sugary drink to induce immune suppression.

Immune modulation by behavioural conditioning
A paper published last year in the journal Psychotherapy and Psychosomatics shows that the antiallergic effects of antihistamines can be behaviourally conditioned in humans. Marion Goebel and co-workers recruited patients with allergic rhinitis and divided them into three groups. All three groups got an antihistamine coupled with a novel-tasting drink daily for five days. Then, after allowing some time so no antihistamine would remain in the body, the experiment started.

One group got the novel-tasting drink with a placebo pill, one group got a glass of water with a placebo pill, and the third group got a glass of water with the real antihistamine. The authors then measured subjective symptoms, skin prick reaction and the activation of white blood cells known as basophils.

Basophils (the two centremost heavily-staining cells) in a smear of peripheral blood. These cells are very important in the triggering of an allergic response.

Basophils (the two centremost heavily-staining cells) in a smear of peripheral blood. These cells are very important in the triggering of an allergic response.

The group that got just water and a placebo pill did show a reduction of symptoms and skin prick test reaction, but not of basophil activation. The group that got the real antihistamine had a reduction in all three measures. Interestingly, the group with the novel-tasting drink an placebo pill also showed improvement on all three counts, to levels comparable to the drug group!

Work with the brain – that’s where the memory is
In humans, it has been known for some time that allergic responses can be fairly easily conditioned. Perhaps that is one reason why some people have strange allergic symptoms to things like electric fields, which cannot possibly induce allergies. (In fact, is has been shown that it’s not the electric field itself that does it, but rather the sensation of being in an electric field. The condition of electromagnetic hypersensitivity can be very disabling – the symptoms are real even though the biological foundation isn’t there.)

The present study suggests that antiallergic effects can also be conditioned. For a humble young physician like myself, it’s a useful reminder that the drugs we prescribe often don’t work the way we think they do.

Full reference:
Goebel, M., Meykadeh, N., Kou, W., Schedlowski, M., & Hengge, U. (2008). Behavioral Conditioning of Antihistamine Effects in Patients with Allergic Rhinitis Psychotherapy and Psychosomatics, 77 (4), 227-234 DOI: 10.1159/000126074

The heart regenerates. I stand corrected, with pleasure!

April 28, 2009

So, today I have lectured for five hours on the diseases of the cardiovascular system. It’s the fifth consecutive year that I have the honour of lecturing on this topic for some of the undergraduates in our department.

Dissection of the thorax and abdomen, shown in situ. Joseph Maclise, 1856.

Dissection of the thorax and abdomen, shown in situ. Joseph Maclise, 1856.

One aspect that I have always brought up is that heart muscle cells essentially don’t reproduce in adulthood. This is why a myocardial infarction leaves a permanent fibrous scar, that will remain for life. The heart cannot heal back to its normal functionality. And the low proliferative capacity of the heart muscle cells is probably closely linked to the strange phenomenon that they never give rise to cancer.

Alas, this has changed. A paper appeared just a few days ago from the Frisén laboratory showing that heart muscle cells do proliferate, but slowly. About half of them are replaced at some point during adulthood. The technique used to demonstrate this is based on the detection of carbon-14, levels of which increased dramatically in the entire atmosphere of the earth in the 1950’s and 60’s due to test detonations of nuclear bombs. The DNA in heart muscle cells from people who were already adults at that time was found to contain far more carbon-14 than expected, indicating that new cells had been formed.

Science has a podcast with Jonas Frisén where he explains what it’s all about.

When I was in high school, I used to wonder what it felt like to be a teacher, when old knowledge was proven false. Suddenly, I thought, a lot of past work would seem counterproductive.

But this is not how I feel at all! It’s a delightful sensation, a feeling of moving forward.

This reevaluation is a reminder that all our knowledge is provisory, and can be overturned at any time by new evidence. I shudder to think of a world where we didn’t question our old beliefs.

Reversible apoptosis: cancers can postpone the point of no return

April 21, 2009

ResearchBlogging.orgApoptosis – programmed cell death – is one of those processes that are only supposed to go one way. Once begun, there is no turning back. The cell begins to degrade itself through the activation of caspases, proteolytic enzymes that cleave the structural elements of the cell, leading to a series of morphological and biochemical changes. The cell digests itself from the inside, turning itself to a soup of dead organic molecules inside the cell membrane. In the end, it fragments neatly into membrane-enclosed bags that are small enough for nearby cells to phagocytose, i.e. eat up.

Evidence for reversible apoptosis
In a recent paper in the British Journal of Cancer, Tang et al. show that apoptosis may be reversible. They have taken a panel of several cancer cell lines and treated them with an inducer of apoptosis for a few hours, and then washed it off. When they monitored the cells over the next hours, they found that many cells transiently exhibit morphological signs of apoptosis: they shrunk, the nuclei condensed, and mitochondria were degraded, but a few hours later the cells returned to their normal shape. The limiting event from which the cells had no chance of return was when degradation of the nucleus had begun. Caspases were activated at the same modest level from 3 up to 48 h after induction, even though the cells were back to their normal shape before 24 h.

Human fibroblast undergoing nuclear fragmentation in a late stage of apoptosis. The nucleus is stained in blue and the cytoplasm in green. Photomicrograph by Joerg Schroeer.

Human fibroblast undergoing nuclear fragmentation in a late stage of apoptosis. The nucleus is stained in blue and the cytoplasm in green. Photomicrograph by Joerg Schroeer.

Loss of bistability in the apoptosis signalling network
In terms of the signalling network, apoptosis should be a bistable process. The cell should very firmly be either apoptotic or non-apoptotic. Cells that start to digest themselves and then stop should have a strong fitness penalty. We would expect the evolutionary process to select strongly against a reversibility trait both in an organism and in a group of cells. Contrary to this expectation, the reversibility trait predominates in all the cell lines investigated in this study. Something has been lost, or gained, in their signalling network. But how can they survive a partial self-degradation?

Mitochondria – redundant in cancer cells?
The hallmarks of apoptosis that are investigated in the present study reflect degradation in three steps: First, the cytoskeleton, leading to cell shrinkage. Then, the mitochondria, shutting off the cell’s aerobic metabolism. And finally, the nucleus, with the entire gene regulatory system. But the cytoskeleton is made to be remodelled, so it’s not that surprising that the cells can cope. With the mitochondria, it’s a different story. Cancer cells almost universally switch to anaerobic metabolism during progression. This is known as the Warburg effect. It is a very curious phenomenon that still awaits explanation. Many of the mitochondria in tumour cells therefore lack any useful function. In a sense they are little more than decoration, present mainly for historical reasons.

The hen and the egg
Is it the case that tumour cells first acquire apoptosis resistance through mutations that repeal the bistability of their signalling network, and then are forced to rely less on their mitochondria because they are sometimes degraded? Or is it the other way around? Or are these two processes driven by unrelated factors, leading to reversibility of apoptosis by chance, as it were?

It is too early to draw any conclusions. Further studies should investigate reversibility in relation to biochemical and not just morphological parameters. I will write more on the properties of bistable signalling networks and their robustness during the coming week.

Full reference:
Tang, H., Yuen, K., Tang, H., & Fung, M. (2008). Reversibility of apoptosis in cancer cells British Journal of Cancer, 100 (1), 118-122 DOI: 10.1038/sj.bjc.6604802

New thoughts, new blog

February 16, 2009

Welcome to my blog!

Chances are that if you are reading this, you are an old friend of mine. Thanks for looking in! I will rely on you and everybody else who reads this blog to force me to sort my thoughts into some sort of order. At the moment, I am trying to figure out lots of things in science at the same time, and will use this blog to try to pin down a few ideas and make sense of them.