Lungs – what are they really good for? More on lungless amphibians

March 27, 2009 This is a follow-up on yesterday’s post, which discussed a lungless frog species recently discovered on Borneo. Victor H. Hutchison has written a comment in the journal Current Biology that highlights a few interesting concepts.

Sometimes I give an introductory lecture on the histology of the human lung to undergraduates in our department. I invariably start off by asking the students what the organ is good for, and I always get the same two answers: Gas exchange and barrier function. I never realised that there is a third function in many animals, although it’s obvious when you think of it: flotation. As a submarine can regulate its buoyancy by filling tanks with either water or air, so can many amphibians regulate theirs with their lungs.

Hutchison explains that amphibians may be particularly susceptible to losing their lungs because they have rather inefficient breathing dynamics. Apparently, they cannot breathe by changing the volume of the thorax with muscles, like we do. Instead, thay have to force air into the lungs by a swallowing motion. Then, because of the higher pressure built up in the lungs, expiration takes place when they open their mouths again. Further factors that contribute to the redundacy of lungs are a higher body surface area to volume ratio, a permeable skin with capillaries growing into the epidermis (unlike ours, which stop in the underlying dermis), and low metabolic rates due to cold temperatures.

A unifying trait for the previously known lungless salamanders and the recently discovered lungless frog is that they live in cold streams. Hutchison therefore proposes that the loss of lungs helps keep these animals on the bottom, preventing them from being swept away by the water. He does not mention that gas exchange will be much more efficient in moving water than in a still-standing pond, but this seems an obvious observation to me.

Some amphibians have reduced lungs while still retaining the capacity to use them. One example is the Titicaca frog (Telmatobius culeus). This animal lives in high-altitude waters in the Andean mountains. Normally, these frogs stay underwater and use their many skin folds for gas echange. These folds have very superficial blood vessels and are ventilated by a “bobbing” motion. In addition, the frog’s blood is very rich in hemoglobin.

Titicaca frog. Image from Hutchison's paper.

Titicaca frog. Image from Hutchison's paper.

Hutchison remarks that there are probably more lungless frog species with specimens sitting around in museums of natural history, that have never been dissected. Perhaps these museums would be helped by a small CT scanner? (More likely perhaps, they would be helped by people with an interest in going through their vast collections and cataloguing them.)

Full reference:
HUTCHISON, V. (2008). Amphibians: Lungs’ Lift Lost Current Biology, 18 (9) DOI: 10.1016/j.cub.2008.03.006

Breathing in the bitter cold: lungless frogs and a fish without erythrocytes

March 26, 2009

ResearchBlogging.orgToday I stumbled upon two blog posts that really capture some of the beauty of the diverse adaptations in nature.

Random Biology writes about creatures living in cold waters. Water can carry oxygen at a far greater density at lower temperatures. This simple phenomenon, combined with the slower metabolism of cold tissues, has made it possible for certain salamanders to get along fine without lungs. All their breathing occurs through the skin.

In a recent paper in Current Biology, David Bickford and two colleagues describe the same phenomenon in a frog! It’s called Barbourula kalimantanensis, and lives in Borneo. Interestingly, it has apparently retained the lining of the lungs and thoracic cavity, called the mesothelium.

Barbourula kalimantanensis. Image from the paper by Bickford et al.

Barbourula kalimantanensis. Image from the paper by Bickford et al.

In a still more fascinating post, Biochemical Soul describes a fish with a new way of dealing with freezing temperatures. Or several, actually. It is the Channichthyidae family of icefishes, which live in Antarctic waters that are often below freezing point (but still liquid, of course, because of their salinity). These fishes have no hemoglogin, and consequently no red blood cells. They also lack myoglobin, the related molecule that stores oxygen in muscle cells. They rely instead on the greater oxygen-carrying capacity of their cold blood. With no erythrocytes, the viscosity of the blood decreases, which helps circulation. And to compensate for the lack of oxygen carriers in the blood, they have a 4-5 times increased stroke volume of the heart. This was originally described in 2006 by Thomas J. Near and coworkers in an open-access paper in Molecular Biology and Evolution.

Icefish. Image from the paper by Near et al.

Icefish. Image from the paper by Near et al, referenced below.

Cool stuff! (Don’t excuse the pun.)

Full references:
BICKFORD, D., ISKANDAR, D., & BARLIAN, A. (2008). A lungless frog discovered on Borneo Current Biology, 18 (9) DOI: 10.1016/j.cub.2008.03.010
Near, T. (2006). A Genomic Fossil Reveals Key Steps in Hemoglobin Loss by the Antarctic Icefishes Molecular Biology and Evolution, 23 (11), 2008-2016 DOI: 10.1093/molbev/msl071

Is the Central Limit Theorem an engine for biological stability?

March 25, 2009

Biological information systems, like any others, struggle constantly with randomness. Our bodies are precision instruments to measure very many things at the same time – light, vibrations, gas pressures, concentrations of salts and hormones, to mention a few. Any of these measurements can be thought of as a sample. Now, randomness can cause the sample to lie quite far off from the actual measure. A possible solution is to resample the sample! This is not intuitive, and I will explain it below. Perhaps this is the reason why many signalling pathways in biology have so many links in the chain from receiver to effector!

The Central Limit Theorem states that if you draw a sample from a population and calculate the mean of the sample, and then repeat it several times, the means will form a normal distribution around the true mean of the original population. This means that even if the original population has a wild distribution, repeated samples of the population come closer and closer to the true mean.

Take a look at this example to see what it means:

Image from Wikipedia

Image from Wikipedia

Here, the original distribution is on the top left – highly irregular. But if we take samples of two numbers at a time from this distribution and plot their means, we end up with the distribution on the top right – already a great step towards normality! With three and four in the sample, we get the bottom left and bottom right, respectively.

Nearly all cell surface receptors signal through a pathway of messenger molecules. Not just one, but a whole cascade. The traditional explanation for this phenomenon is that the signal can be easily amplified in this way. But perhaps the real driver is the stability of the readout that can be gained. There are similar organisational features in other places too, for example in the transmission of visual information from the retina. The signals pass through a few serially arranged neurons on their way to the visual cortex. Perhaps this is what prevents our field of view from flickering? (The rods are exquititely sensitive and can detect a single photon.)

Perhaps I should write this up and submit it to the journal of Medical Hypotheses? (This is one of the few scientific journals that require no proof whatsoever, and as a result the journal contains everything from well-supported testable hypotheses to completely far-out ideas, such as the benefits of masturbation against nasal congestion.)

What do you think? 🙂

Surely you’re joking, mr Ernberg!

March 20, 2009

Have we really solved the riddle of cancer? Yes, says Ingemar Ernberg, the venerable professor who has written the foreword to ”Prostatacancer”, hot off the presses of the Karolinska University Press.

I was somewhat surprised by his argument, which runs something like this: If there ever were a riddle of cancer, we have solved it by showing how the cell’s actions are controlled by gene regulatory networks. With ceaseless environmental perturbations of these networks, coupled with the powerful organizing principle of evolution, nothing mysterious remains.

Certainly, the advances in tumor biology have been tremendous over the past decades. And it is no coincidence that much of what we have learned about genetics and cell signaling has been discovered in the context of cancer. But can we really say that we understand these processes because we have identified the constituent parts and some of their connections?

If this were true, the riddle of consciousness was really solved in the 1800:s, when Golgi invented the silver staining that for the first time enabled us to see how neurons connect with axons and dendrites.

What professor Ernberg does not consider is the complexity that arises through the dynamic information transfer of the network. On this higher-order level, in cells just as in the nervous system, behavior emerges that cannot meaningfully be accounted for by cataloging the interactions of the component parts.

If this is not immediately obvious, consider the following. Certain genes, when upregulated, cause cells to proliferate a lot. An example is the c-myc gene. This gene can be accidentally moved to the place for the immunoglobulin gene in certain lymphocytes when they are infected with the Epstein-Barr virus. As a result, the lymphocytes proliferate enormously, and we have leukemia. Other genes, which sometimes cause cells to proliferate a lot, can also sometimes cause them to die a lot. An example is th JNK gene. There has been much controversy over whether JNK is pro- or antiproliferative. Now, it is generally accepted that it is both.

In total, we humans have around 20 000 genes. Even if each gene only interacts with 10% of the other genes, and the interaction is always linear, a model to explain the cell’s behaviour would be totally intractable even with enormous computing power. When many of the interactions are non-linear, it becomes clear that a successful description of this system, with the power to predict what it will do, must consider a higher level of organisation. Analogies abound; reading the Pickwick papers by Charles Dickens letter by letter vs. by the meaning of phrases and their conjunctions (D. Hofstadter, in Gödel, Escher, Bach), or understanding a city by copying the telephone directory vs. actually finding out where people are going every day and why (Sidney Brenner).

The riddle of cancer remains. The most important discovery we have made so far is that the riddle of cancer is identical the to riddle of Life itself; namely how the genes and proteins that are the basic units of biological information, as well as the basic operators on this information, together determine the fate of the cells which are the smallest units of life as we know it.

(I am indebted to professor Ernberg for having created much of the intellectual arena where I have encountered several of the more groundbreaking recent advances of thought in tumor biology, and I argue against him safe in the knowledge that he will only be pleased that his ideas are debated.)

Will your cell phone give you CANCER?

March 17, 2009

The world is full of hidden dangers, in some people’s view. Some things that were thought harmless at some point in history have turned out to be genuine killers – lead, tobacco smoke, and asbestos, to mention only a few examples.

Our historical success in identifying unobvious dangers has lead some people to develop mental models where there is always a widespread behaviour or exposure that is next in line to be uncovered as a cause for illness and mortality. Others believe (as I do) that with time, the remaining environmental hazards to be discovered will be less and less important, because the size of the adverse effect correlates strongly to how easy it is to detect, and therefore most of the really dangerous stuff is probably already known.

Whichever attitude people take, most agree that it is best to base specific recommendations on a dispassionate reading of the scientific data. However, opinions differ greatly about how strong the evidence has to be in order to restrict something that might be dangerous. “The principle of caution” states that it’s better to regulate when we are uncertain. But how uncertain?

A useful guide for determining the strength of evidence has been proposed by Austin Bradford Hill (1965). Its criteria have been summarised as follows: Causality becomes knowable when scientific experiments demonstrate, in a strong, consistent (repeatable), specific, dose-dependent, coherent, temporal and predictive manner that a change in a stimulus determines an asymmetric, directional change in the effect.

In this post, which I fear will be rather lengthy, I will try to review the evidence for and against dangers of mobile telephones. The positive health effects are significant (easier access to medical advice and emergency services, in particular), but we will only look at the possible risks here.


There is a debate over the health risks of electromagnetic radiation in general. When we use a mobile telephone, we expose ourselves to an electromagnetic field which penetrates about 4 cm into the head. Some national authorities have defined exposure limits. For example, the Swedish Radiation Safety Authority requires that all phones cause less energy absorption than 2 W/kg in human tissues, a limit that has been more or less arbitrarily chosen on the base of acute radiation effects. Absorption of radiation causes tissues to become warmer, and 2 W/kg is far below any measurable thermic effect. (This is the general principle of the microwave oven, and the only completely indisputable biological effect of electromagnetic fields.)

Other dangers have been seriously investigated, particularly the risk of cancer and of neurological disorders such as headaches, dizziness, and dementia.

Loud activist groups are lobbying for more restrictions. The most authoritative critics are probably the BioInitiative Group. They released a report in 2007 urging the prohibition of strong electromagnetic fields. I purports to “document serious scientific concerns about current limits regulating how much EMF is allowable”. But although scientists are among the authors, the document is not a piece of scientific criticism. It is a jumble of cherry-picked research reports and unfounded claims. The authors are quite consistent in only mentioning research that supports their own point of view. Furthermore, they accept controversial data regardless of prior probability.

Let’s say that I were to investigate whether my zodiac sign is a strong risk factor for Parkinson’s disease. If I were to choose a confidence level of 95%, I would end up being wrong 5% of the time, which is the usual cutoff in science. Now, let’s say I get a positive result. Does that mean that sagittarians are at increased risk for Parkinson’s? No, because I have to take into consideration the prior probability that my result is correct. And our current understanding of disease physiology and the differences between people born at different times in the year makes such a result utterly implausible, at best. This is, incidentally, why it is impossible to prove that homeopathy works without first changing our understanding of the laws of chemistry.

The BioInitiative report, fearless of ridicule, is thus forced to conclude that since adverse effects of very low intensity electromagnetic radiation have been seen in cells in certain experiments, it must be the information conveyed by the radiation rather than the heat in the tissue that causes damage. It seems to be envisioning “death rays” that can be specifically tailored to destroy tissues, and that coincidentally are similar to the electromagnetic fields that surround us every day.

No, the BioInitiative report is not serious. What, then, do the big public agencies have to say?

The WHO has concluded that there is no increased risk for cancer or any other diseases, but that cell phones may lead to traffic accidents and may interfere with pacemakers. The EU:s expert group has concluded that there is no increased risk for cancer except possibly for a benign tumour called acoustic neuroma, and only for these who have used the cell phone for more than ten years, with almost a doubling of the incidence rate.

Here is where risk communication comes into the picture. About 80-100 cases of acoustic neuroma are diagnosed every year in Sweden, with a population around 9 million people. The risk is consequently about 1/100 000 for a person in a year. An increase in the relative risk by 100% corresponds, then, to an increase in the absolute risk from 0.001% to 0.002%.

MRI image showing an acoustic neuroma

MRI image showing an acoustic neuroma

And this is the most tangible risk. With regards to other types of cancer and neurological diseases, risks completely fail to pass the Hill criteria. The effects, if any, are weak, inconsistent, unspecific, weakly dose-dependent if at all, incoherent and unpredictive. Sadly, space does not permit me to go through the entire literature in this post, but good summaries are available from the WHO and the EU.

In spite of the lack of evidence, the campaigners are making headway. In September 2008, MEPs voted 522 to 16 to urge ministers across Europe to bring in stricter radiation limits and said: “The limits on exposure to electromagnetic fields (EMFs) which have been set for the general public are obsolete. The European Parliament is greatly concerned at the Bio-Initiative international report which points in its conclusions to the health risks posed by emissions from devices such as mobile telephones, UMTS, WiFi, WiMax and Bluetooth, and also DECT landline telephones. The plenary therefore calls on the Council to […] set stricter exposure limits.”

The politicians have to listen to the people, after all, even when the people are wrong. The whole conundrum is hilariously exposed in this episode of “Yes Minister”. (Go to YouTube for the remaining parts of the episode.)

In my opinion, the moral of the story is not that our elected leaders must stand up for science (although that is also true), but that we must all aid and assist our decisionmakers to behave rationally. If they think people want homeopathy and prohibition of GMO-crops, then that is what we will end up with.

When we have superior knowledge, the democratic right to share it is also a duty.

Self-medication in a caterpillar

March 11, 2009

ResearchBlogging.orgSelf-medication among animals is sufficiently well studied to have a term of its own: zoopharmacognosy. Until now, such behaviour has mainly been observed among higher primates. Chimpanzees with intestinal parasites may seek out and eat shoots that are not part of their normal diet – indeed, that are toxic and make them look like they had just bitten deep in a slice of lemon. Sometimes, the same plants are used by local humans in traditional medicine.

Cool, right? But hardly rigorous. What we would really like to see in order to have good proof for the concept is an example of an animal eating a foodstuff whose medical properties can be proven, and furthermore only eating it in times of illness, and preferably suffering negative effects if they eat it when they are healthy.

A woolly bear caterpillar. Image from Wikipedia. NB: probably not the exact same species as in the study in question

A woolly bear caterpillar. Image from Wikipedia. NB: probably not the exact same species as in the study in question

Such a study has been published for the first time today, with a very surprising animal species as the protagonist: the woolly bear caterpillar. This is the larval stage of a moth of the Arctiidae family, which is apparently well known for its habits of communicating by ultrasonic sound waves, generated from a specialised organ.

Michael Singer and his co-authors have infected woolly bear caterpillars with an intestinal parasite and supplemented their diet with plants that contain substances called pyrrolizidine alkaloids (PA:s), but that are very nutrient-poor.

They found that infected larvae fared better if they ate the PA-containing plant-stuff, whereas uninfected larvae fared worse. Fewer parasites survived to reach maturity if they had access to PA. As a group, the caterpillars did not eat significantly more of the PA-food when they were infected, but there was a suggestive trend where the larvae with a greater infection load ate more PA.

In this case, the behaviour is clearly not socially learned, as it may be in the apes, but somehow coded into the neurological hardware of the caterpillar. Or rather, a subset of the caterpillars. If the parasites ceased to exist, the subpopulation most likely to eat PA-containing plants would be at a disadvantage since PA is toxic. Here is another instance of evolutionary dynamics creating a phenotype that is only advantageous in the face of an external threat – just like sickle-cell anemia in humans, which confers a measure of protection against malaria, and many other genetic diseases.

A 2005 Nature paper by the same authors showed that the peripheral taste nerve cells actually change their signalling in infected caterpillars and fire off more signals in response to PA. They speculate that the immunological response to infection is the direct cause of this change, which doesn’t even need to involve the neural cluster that resembles the caterpillar’s brain. From the perspective of information processing, this paper is a small triumph for those who try to find complex behaviours in relatively simple biological organisms.

Singer, M., Mace, K., & Bernays, E. (2009). Self-Medication as Adaptive Plasticity: Increased Ingestion of Plant Toxins by Parasitized Caterpillars PLoS ONE, 4 (3) DOI: 10.1371/journal.pone.0004796

BOth Carl Zimmer at The Loom and Ed Yong at Not Exactly Rocket Science have written excellent posts on the same research.

The Meaning of Systems Biology

March 9, 2009

Today, I had the pleasure of meeting prof. Marc Kirschner. He is the chairman of the department for Systems Biology at the Harvard Medical School. It’s a visionary place with about 200 scientists, small by American standards but far larger than my current department.

Marc Kirschner

Marc Kirschner

Kirschner is one of the world’s foremost cell biologists, and one of the first to thoroughly explore the information-processing capabilities of the cell. In his 1997 book Cells, Embryos and Evolution (written together with J.C. Gerhart), he discusses, for example, the capability of the cell to be used as a computing machine, in principle.

I read up a bit before meeting him, and came across an article he wrote for Cell in 2005 titled “The Meaning of Systems Biology”. Here he endeavours to explain what this new field is about, really. And he is the right person to do it, since he is more or less one of the founding fathers of the field.

Rarely have I seen such an established scientist move with such caution in his own field. He describes systems biology as a scientific branch in the making, and argues that only in retrospect will we know exactly what has come of this fruitful entanglement of genetics, molecular biology, cell biology, physiology, and evolutionary theory, all coupled with new high-throughput techniques.

Systems biology is not all about an increased data-generating capacity. It is, in Kirschner’s opinion, also about “a smaller scale view, totally compatible with and partially dependent on the global analysis of high-throughput biology. This view spans in vitro biochemistry to what is now called synthetic biology and it has as its goal the reconstruction and description of partial but complex systems.”

In the end, Kirschner only very reluctantly offers a rather long definition, which he says must remain tentative. At its core, I think it means that systems biology is the study of biological complexity through modelling of the underlying mechanisms, quantitative measurement, and theory.

So how did our meeting go? Well, I pitched a project idea that I’d given a lot of thought, and that is in my own opinion extremely elegant, well-conceived and likely to change the way we see the world. One’s ideas become like babies sometimes if you allow them to.

He thought there might be something in it, and suggested I should talk to the person in his department who has got the methods I would require – incidentally, the only person in the world who does. I certainly will. And then we’ll see where this ends!