Category: cool research

In spite of a solid grounding in experimental practice and animal models, gene therapy has had a difficult road in the clinic. According to the Journal for Gene Therapy, over 1800 gene therapy-oriented clinical trials have been conducted worldwide since 1989, including 67 Phase III trials – typically the last stage in a drug’s journey to the market. However, only one gene therapy product has been approved for use in patients: Glybera, from Dutch company UniQure, which uses a virus to deliver a replacement for a damaged gene normally responsible for fatty acid metabolism. Importantly, Glybera is only available in the EU, although the company seems confident that they’ll win approval from the FDA in short order.

In other words, pharma and biotech companies are still feeling their way in this new land – but that’s not to say that there aren’t a lot of really cool and promising studies out there. A lot of neat stuff has been bubbling up around muscular dystrophy (MD), which encompasses a family of disorders arising from mutations of the gene encoding the dystrophin protein. Dystrophin is critical to the proper arrangement and stabilization of muscle fibers and, without it, muscle tissue wastes away until patients ultimately perish from failure of the muscles of the heart and/or respiratory system.

Now, something you should know about dystrophin. It’s big – I mean epically big. Burj Khalifa big. Blue whale big. Let me put this in perspective: the median length of a human protein is 375 amino acids, but dystrophin contains a whopping 3,677. The DNA encompassed by the gene spans 0.07% of the total human genome, and the process of transcribing the gene into a protein-coding messenger RNA molecule takes SIXTEEN HOURS. This is a damn long gene – the kind that would make Marcel Proust or David Foster Wallace proud.

It’s just slightly smaller than this picture, in other words.

But here’s the cool part – you don’t need the whole thing.

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Short answer: because they can be.

An interesting new article in PLoS ONE, by an interesting guy whose work I’ve just now become acquainted with… Aaron Clauset, formerly of the Santa Fe Institute and now at the University of Colorado at Boulder, who uses computer modeling and data analysis to investigate the principles underlying complex systems ranging from the dynamics of social networks and terrorist cells (probably not as dissimilar as one might expect) to evolutionary biology.

Clauset goes solo on this article, a theoretical piece simply titled ‘How Large Should Whales Be?‘ It’s essentially a follow-up to a study he published in Science in 2008, looking at the distribution of body sizes among terrestrial animals.

In that earlier work, he and co-author Douglas Erwin plotted more than 4,000 land-dwelling bird and mammal species (both living and extinct) from the past 2 million years  based on their body mass, and arrived at a curve that was heavily skewed toward the left (low body mass) with a long tail tapering off toward larger and larger body masses:

  Fig. 1.

(image from Science)

This reveals a clear peak that appears to represent an optimal minimum size (approximately 40 grams) from an evolutionary perspective, below which remarkably few species seem to tip the scales. The great majority of species analyzed are  considerably larger than this ‘peak minimum’, although true heavyweights are relatively rare. Clauset and Erwin arrive at a model that describes this long tail of bigger body sizes as the result of two competing forces. On the one hand, bigger animals are less likely to be eaten by predators and may be better capable of dealing with short-term changes in resource availability than their small-bodied colleaguesThis tendency is described by an evolutionary principle known as Cope’s rule, which states that organisms in a given generation of a particular lineage will generally tend to be larger than their ancestors. On the other hand, excessively large animals become less energetically efficient, reproduce more slowly and are generally more prone to extinction events. So, to bust out the cliches, size DOES matter… but bigger isn’t always better.

And yet – as Captain Ahab learned the hard way – the rules change at sea. A 7,000 kg elephant may be king of the hill on terra firma, but that’s only twice as massive as the smallest whale species – such as the adorably puny pygmy right whale, which typically weighs in at a mere 3-3,500 kg.

File:Caperea marginata 3.jpg

Try not to step on it.

And as Clauset shows, many of the mammals that spend their entire lives at sea are notably larger than even the mightiest mammoths of yesteryear.

Figure 1 Terrestrial and fully aquatic mammal species mass distributions.

So what gives? The reason turns out to be a single factor – body temperature regulation.

For land mammals and birds, Clauset describes a relatively firm 2 g minimum, below which animals lose body heat into the air too rapidly to maintain their proper internal temperature. However, body heat is generally transferred into water much more rapidly than in air, pushing the minimum mammalian body size up to a whopping 7 kilograms. Using this as a starting point, he applied computational modeling to predict the likely size distributions for cetacean species based on the same parameters he previously applied with land-based species, and the results were astonishingly close to the real distributions for the world’s 77 living cetacean species.

Figure 3 Comparison of data and model predictions.

Accordingly, this single factor seems to be sufficient to entirely explain the striking difference in range of sizes between land and sea mammals. These thermoregulatory limits would also have shaped the timing with which marine mammal species began to appear on the evolutionary timeline, with the earliest mammals far too small to survive a full-time seafaring life. This is in keeping with current estimates that suggest that the earliest whale ancestors took their first big dip around 50 million years ago, well over 150 million years after the first mammals came on the scene.

This study provides strong additional support for a surprisingly simple and elegant general model for how the distribution of animal body sizes has shifted over time. Or, as the author modestly notes, “Rarely in biological systems are the predictions of mathematical models so unambiguous and rarely are they upheld so clearly when compared to empirical data.” What remains now, he concludes, is to determine whether our cold-blooded contemporaries the fish, reptiles and amphibians, have played by the same evolutionary rules.