think logarithmically

The natural way of thinking about numbers, according to a report out in today's issue of Science magazine, is to think logarithmically, i.e. to plot them onto a line leaving equal distances between 1, 10, 100 ... The researchers came to this conclusion after studying the maths skills of indigenous people in the Amazonas area.

Now this suggests to me that schools go against nature by teaching children to think of numbers linearly (where 1,2,3 get equal spacing), an effort which has to be reversed as soon as the same children grow up to be scientists, because they have to re-learn the logarithmic way of thinking, where orders of magnitude are more important than individual numbers, as in the progression from metre, to millimetre, micrometre, nanometre, picometre, etc.

What a waste. They should start teaching logs in the first year at school ...

life on the basalt edge

Just a week after Science magazine revealed life one mile below the sea floor, today's issue of Nature carries a paper demonstrating surprisingly rich biodiversity on the sea floor even in the absence of hot springs.

Katrina Edwards and colleagues at the University of Southern California have analysed samples from the basalt seam along the mid-Pacific spreading zone. They found microbial biodiversity by several orders of magnitude higher than in the water column above the sites, and comparable even to soil.

The researchers calculated how much biomass could theoretically be supported by chemical reactions with the basalt. They then compared this figure to the actual biomass measured. “It was completely consistent,” Edwards said.

Expect the usual press coverage about how life could have originated down there, and so on. But what I find most intriguing is that 30 years after the discovery of black smokers, the frontiers of life on Earth are still sufficiently blurred to come up with two major surprises in the space of of a week. So in all honesty, we should admit that we still don't know where the limits of life on Earth really are. And this makes it difficult to predict where life may or may not be possible in the rest of the Universe.

titan book

I'm quite sure it was only a few months ago that the Huygens probe landed on Saturn's moon Titan, but obviously I must be wrong, as the first book about Titan based on the Cassini/Huygens exploration has already hit the shops:

Titan unveiled

Fast moving times indeed. Don't bother reading the research papers, the book will come round soon ...

at last: the female genome

Almost a decade after the "human" genome, which was a blend of several male specimens of our species, and months after the individual genomes of some horrid old blokes, genomics has finally overcome the final hurdle and decoded the genome of a woman.

This step was achieved in the Netherlands, and the pioneering sequencee is a geneticist called Marjolein Kriek, I am told.

I'm sure there will be people defending the practice of sequencing lots of males first, as females don't have a Y chromosome, but then again, males don't have X-inactivation, so if you look at epigenetics as well, you only get the complete picture when looking at both sexes.

I have a nagging suspicion that this is a surviving trace of the age-old sexist assumption that the male is the "normal" specimen of our species, while women are deviations of the norm. To be admired in countless textbooks where the male anatomy is depicted and explained first, and the female is then described in terms of how it deviates from the male.

Source: SpektrumDirekt

phoenix has landed

Pleased to hear that the Phoenix craft has safely landed on Mars and sent back first pictures. Researchers hope to find Martian ice within the reach of its robotic arms, and maybe the Martian equivalent to Oetzi ... Check out the phoenix mission website, which has pictures, science background, and Martian weather reports ...

did the Neanderthals have autism ?

The short story on the back page of this weeks Nature (vol.453, p.562) has an interesting premise: that the Neanderthals developed the "nerdy" genes which in moderate doses make you good at maths and physics, while more extreme cases end up with autism. Easy to imagine that it's the lack of social cohesion that sealed their demise when they were competing against the more politically minded (and probably aggressive) Cro Magnon. The story suggests that the presence of autism genes in our population, which largely descends from Cro Magnon humans, is due to the (debated) interbreeding with Neanderthals.

The author, New Scientist correspondent Jeff Hecht, got one detail wrong -- the autism-related genes aren't dying out, as he suggests at the end of the story (which is set in a not-too distant future). On the contrary, the technological revolutions of the last two centuries, with the huge growth in demand for maths/phys/engineering type people, has ensured that the genes have spread and autism is much more common than it used to be when it was first described.

life under the sea floor

In today's issue of Science magazine, a team led by John Parkes of the University of Cardiff reports archaea thriving in rocks more than 1km below the sea floor.

The researchers found these microorganisms in 111 million year old sediment
located 1626 meters below the sea floor, and
living in temperatures of 60 - 100 degrees
Celsius (140 - 212 degrees Fahrenheit). Their
environment is characterized by thermal
energy sources and high concentrations of
methane and hydrocarbons, and these archaea appear to be
metabolically active and dividing in it.

Reference:

Extending the Sub-Sea-Floor Biosphere
Erwan G. Roussel,1 Marie-Anne Cambon Bonavita,1 Joël Querellou,1 Barry A. Cragg,2 Gordon Webster,2 Daniel Prieur,1 R. John Parkes2*

Science 23 May 2008:
Vol. 320. no. 5879, p. 1046
DOI: 10.1126/science.1154545

abstract

astrobiology reviewed

A nice review of my previous book, Astrobiology, has just been brought to my attention. It's on the website of the Astrobiology Society of Britain -- didn't even know that society existed. Read the review here.

alanis is back

... at the point where she started, according to this interview.

Good to hear her new album is about quantum mechanics. At least it's called Flavors of Entanglement. It may be about breakups though. looking forward to it, anyway.

science TV

It's great fun to watch when a stuffy old funding agency like the DFG (Deutsche Forschungsgemeinschaft) starts running after the YouTube generation, with the worthy aim to get young people interested in science. The resulting "DFG Science TV" isn't bad, actually. I would even argue it's too good.

They announced a weekly video blog from ten research projects. Which I would have expected to be amateurish, as we scientists don't tend to be good at making videos or at appearing in them. What I've seen of the clips, however, was highly professionally edited and reminded me more of a BBC nature documentary cut into 3 min. pieces than of anything you'd expect to see on youtube or myspace videos.

I've done a short news feature on this for Current Biology. Alternatively, check out DFG Science TV for yourself. (Despite the English name, it's in German, still.)

la galana i la mar

I've been playing Mor Karbasi's album "The beauty and the sea" on closed loop since it arrived last Thursday and love it to bits.

Intriguingly, there are 6 old songs (mostly traditional Ladino) and 7 new ones which she co-wrote with her mother and a multi-talented guy called Joe Taylor (also producer, guitars, bass, oud, backing vocals!) . But the whole package fits so perfectly that you never realise there's a gap of 500 years between one half and the other.

Apart from the voice, I also love the haunting recorders. And there is something about the melodies of these songs from the tradition of the Sephardim that is distinct from all other music I know. For instance the recorder motif in La galana, which I've figured out how to play on the flute -- you wouldn't find that kind of melody anywhere else.



photo from Mor's MySpace profile

blogless scientists?

Earlier this month, I held my annual half-day writing course for scientists at Cambridge. Like I did the last few times, I asked people at the end of the proceedings whether they were using blogs or other web2.0 features for their scientific communications, and each time I had an overwhelming silence as a response.

Is that because scientists are stuck on web1.7, or are they afraid to admit that they waste time on facebook, I wonder? I haven't spent all that much thought on the possibilities, but it strikes me that a lot of the communications that have in the past been channelled through boring meetings could be made a lot more efficient (and searchable!!!) through the use of blogging.

Thus, instead of the journal clubs we used to have back in the 90s, each lab could have a journal blog highlighting papers relevant to their field of inquiry. Instead of workshop meetings, there could be online exchanges of some kind.

Maybe these things are going on somewhere and I've just missed them, but my impression is that research scientists, who were very quick to pick up email and websites in the 90s, have somehow managed to miss out on the opportunities of the web2.0 revolution. Any opinions ?

front page platypuses

I've edited my front page in order to accommodate a direct link to my new book, which is out now.

In the UK, it can be ordered from (ranked by best availability)

Wiley (publisher)

Blackwell's

amazon.co.uk

Foyle's

Waterstone's

WHSmith

happy birthday atomium

One of the perks of being a chemist, of course, is that you're allowed to play with toys like the ball-and-sticks models used to recreate molecular structures. Now one architect took this occupation to a larger scale and the result was the Atomium which was created for the Brussels Expo in 1958 and thus turns 50 this year.

It represents a unit cell (cubic space-centred) of the crystal structure of alpha iron. Rather than letting the cube rest on one of its faces, as you would find it illustrated in textbooks, the architect emphasized the 3-fold symmetry axis (i.e. the space diagonal) by arranging it vertically. (Now if we could get the thing to rotate around this axis, that would be truly spectacular.)

The Atomium has been recently refurbished -- now it's so shiny that I even spotted it from the train, though I didn't know when or where to look! Celebrations of its 50th birthday will be running all summer.

platypuses out today ?

At least in the UK, and in theory, my new book The birds, the bees and the platypuses should be available to buy from today. It is listed as available at Amazon.co.uk and at Waterstone's.

Only trouble is I haven't received any copies yet, so I can't tell you whether it really exists or whether it's any good :)

Publication in the US by John Wiley & Sons is two months later, scheduled for July 14.

party animal

Have just finished my piece on the platypus genome, which should hopefully be published in July.

Among the many things I learned here is the new finding that the platypus has hundreds of genes for pheromone receptors, 50% more than the mouse. If these serve the same function as in rodents, we must conclude that platypus is the wildest party animal that ever roamed our planet. But there is of course the more boring possibility that it uses the receptors for a different purpose altogether, e.g. for finding food under water.

cool spiders

... and finally the third part of the book is about cool stuff, such as nanotech and new materials. Sometimes we aren't quite as clever as Nature, so one of the coolest materials ever, spider silk, is still beyond our grasp:

Spinning lessons

They may have eight hairy legs, a very small brain and a big image problem, but there is at least one thing that spiders can do much better than we can, namely producing extremely strong fibers.

Nature is in many ways a better engineer than mankind. Whether you look at the ways that diatoms, mussels or snails make their shells, butterflies seem to change their colors, or trees withstand strong winds, there is always a lesson for human engineers to be learnt. And sometimes, nature’s engineering is so clever we still have trouble figuring out how it works. But when we do, the rewards to be gained from the lesson can be enormous.

One of the most spectacular examples of how nature beats our best efforts is spider silk. Like our hair, sheep wool and silk clothes, it consists mostly of protein. But the polypeptide chains are aligned and interwoven in mysterious ways that make the product much stronger than these materials. Optimized by evolution to be able to stop an insect in full flight, this is in fact the strongest material we know in strength per weight terms. If you compare a spider’s thread with a steel wire of the same diameter, they will be able to support roughly the same weight. But the silk is six times lighter, so it is really six times stronger than steel, and the spider wins every time.

So why are suspension bridges still dangling on steel ropes rather than silken ones? The trouble is we can’t make spider silk as nicely as the spider can. Sure, we can express the proteins of which it is made in other organisms, including goats that will have spidroin in their milk (to which I will come back later), and we will soon be able to spin those into some kind of fiber, but given our limited understanding of the processes going on in the spider’s silk gland, the result may not live up to the natural product.

A small scattering of biologists in various labs around the world are trying to get behind the spiders’ secret. First they need the right genes. Until recently, only very few DNA sequences of silk protein genes were known. In 2001, John Gatesy and Cheryl Hayashi with their coworkers at the University of Wyoming in Laramie presented a comprehensive overview of gene sequences from a wide variety of eight-legged silk producers including tarantulas and other animals that separated from the “true spiders” more than 200 million years ago. They showed that the amino acid sequences are extremely diverse between species. About the only thing they all have in common is the occurrence of unusual repetitive sequences following four simple patterns: poly-alanine (An), alternation of glycine and alanine (GA), then combinations of glycine with a small subset of amino acids (X) with or without proline: GGX and GPGXn.

Given that these motifs have been retained (or evolved convergently) over a time span of more than 200 million years, it appears likely that their properties hold important clues to how the silk proteins interact to form silk. So far the only structural information we have is about the finished silk, where it is known that the alanine-rich repeats occur in quasi crystalline domains, while the glycine-rich repeats adopt more disorderly states which are poorly understood.

From these genes, the spider makes the corresponding proteins, called fibroins. Nothing special there - proteins can make hair and wool and the brittle type of silk that insects make their cocoons of. But these materials aren’t tough enough for spiders. To make the special, stronger-than-steel brand of protein filament, spiders have a special silk gland, a complex structure where the magical transformation of protein solution into silk thread takes place. Although this transformation is only poorly understood so far, it is known that it involves a substantial increase in the proportion of the protein chain that is arranged as a beta-pleated sheet.

In a 2001 review in Nature, Oxford zoologists Fritz Vollrath and David Knight, who have been studying the silk production in the orb spider Nephila clavipes for many years, summed up the current knowledge. First, it should be noted that these spiders not only have one kind of silk gland, but seven pairs producing seven different types of silk for different uses, and even the protein composition in these glands is significantly different. The one that has been best characterized is the dragline silk which is produced by the major ampullate gland.

This gland consists of three major regions: a central bag (B zone) flanked by a tail (A zone) and the duct (D) leading towards the exit (Figure XXX ???). The lining of the A and B zones contains the cells which secrete the protein material, the major component of which is a 275 kDa protein containing the polypeptides spidroin I and spidroin II. The A zone specializes on the spidroin protein which forms the strong core of the thread, while the B zone is believed to secrete the as yet poorly understood glycoprotein material that ends up coating it. To be secreted from a cell, proteins must be wrapped up in membrane bubbles called secretory vesicles. In the A zone cells, these vesicles contain protein filaments, the precise structural organization of which is still under investigation. In the B zone vesicles one finds liquid crystals of the coat glycoprotein. Knight and Vollrath think that the liquid crystalline state has an important role to play in the production of the silk thread, to which we shall return later.

Let us follow the route of a spidroin molecule from the secretion through to the finished thread. On leaving the cells of the A zone (as the secretory vesicles merge with the cell membrane and empty their contents to the outside), our protein finds itself in a small spherical droplet with lots of other spidroin molecules. The protein concentration in the whole gland is around 50% - higher than in most protein crystals. Most proteins would aggregate into insoluble lumps at much lower concentrations. This highly viscous protein mass flows down the A-tail into the bag (B-zone), where it gets coated by the secretion of the B zone cells. At the exit of the bag the liquid is funneled into the much narrower duct (D). During this transition, the droplets are slowly distorted into long thin shapes aligned with the direction of the flow. It is assumed that a similar transformation happens to the molecules. Initially they must have been in a rather compact conformation to avoid aggregation, but as they move into the duct, they are stretched out and aligned in a way which will eventually allow them to form those intermolecular links that hold the thread together.

The spinning solution or dope is now in a liquid crystalline state, with proteins aligned in an orderly fashion, but still able to slide past each other. This is thought to be an important part of the spider’s secret weapon. As the material is slowly and gently narrowed down in the first two legs of the tripartite duct, molecules have time to orient themselves in a favorable way so they can eventually form intermolecular beta sheet interactions and possibly disulphide bonds when it comes to making the actual thread. This step happens at a point ca. four millimeters before the exit, and it happens quite suddenly. Although the molecular details are far from clear, it is thought that as the dope is drawn out to a thin thread that retracts from the walls of the duct, the molecules align even further and form hydrogen bonds defining the complex beta sheet patterns found in the finished product. In the process, the protein becomes more hydrophobic and practically ejects some of the water content it has been carrying until this point. Finally, most of the water is stripped off the surface when the thread leaves the exit spigot, helping the spider to avoid water loss and making its thread even tougher.

This broad picture drawn by Vollrath and Knight combines anatomical with some structural data. However, the exact details of the crucial structural transitions are far from understood. The trouble is that the most powerful tools for the determination of protein structures, X-ray crystallography and NMR, require a protein crystal or a homogeneous solution, respectively. As yet, there is no method that could give you the atomic detail structure of a protein molecule flowing down the duct of a spider’s silk gland.

And yet, even in the absence of a full understanding in molecular terms, maybe one could copy the spider’s technique on a microscopic scale, by supplying a dope with the right protein composition and passing it through a spinning device modeled on the spider’s gland? The only comparable man-made material, aramid (KEVLARTM, the fiber used in bullet-proof vests), is spun from hot sulfuric acid. Thus, an ambient temperature process leading to something similar would be very attractive, even if the resulting fiber turned out only as good as Kevlar, and not quite as good as authentic spider silk.

But first, you need to produce the proteins in reasonable quantities. Unlike silk moths, spiders have an aggressive territorial behavior, which means they won’t be cooperating with any ideas of high-throughput farming. Expressing the silk proteins in bacteria or yeasts doesn’t work either. The curious repetitive nature of their sequences invites the microbes to take shortcuts and produce abridged versions of the protein chains.

Thus, if you want to use the silk to catch fighter jets rather than flies, you’d better get an animal that can produce more than a few milligrams of the precious material. The company Nexia Biotechnologies Inc. at Montreal, Canada, first succeeded in breeding goats that are genetically modified in a way that they secrete spidroin protein in their milk. It turned out that the secretory cells of mammary glands aren’t that different from those of silk glands, only there are a lot more of them in a goat, which makes milking goats a lot more economical than milking spiders.

Since the summer of 2000, Nexia boasts the possession of two African dwarf goats, Peter and Webster, who have been shown to carry the appropriate spider gene. A couple of breeding generations later, there will be a flock of females producing spidroin in their milk by the gram. Nexia keep mum about which way exactly they want to spin that milk-silk protein into strong fibers on an industrial scale. As soon as they can do that, however, applications ranging from surgical threads through to missile protection and aviation security will be conquered rapidly by the new material.

Although some of the applications envisaged are substantially scaled up in comparison to a spider’s web, there is also a case of scaling down from there. In an attempt to turn a visible thread into an invisibly thin nanowire, the group of Michael Stuke at the Max-Planck-Institute for Biophysical Chemistry in Göttingen stripped spider silk down to the core, using ultraviolet laser technology. They obtain very strong nanowires, currently with as little as 100 nm diameter. Plans for the future include coating this thread in metal to make it conductive.

But even when we can copy the spider’s thread and use it on various length scales, the hairy little arthropods can still do one better. As Stefan Schulz and his coworkers at the Technical University of Braunschweig, Germany, reported in 2000, the female tropical spider Cupiennius salei leaves a thread marked with sex pheromones, which induce any male of her species to vibrate excitedly. The vibrations are transmitted through the thread, which rapidly switches from a role of odor dispenser to that of a phone line. The female vibrates back, and you can figure out the rest for yourself. I wonder whether anybody wants to set up a company banking on that technology ...

(2001)

Further reading

J.Gatesy et al. Science, 2001, 291, 2603.
F.Vollrath, D.P.Knight, Nature, 2001, 410, 541.
M. Papke et al., Angew. Chem. Int. Ed. 2000, ...


What happened next

I recently did a feature on spider silk for Oxford Today.

artweeks

I really like the Oxford Artweeks which is when hundreds of artists (professional and amateur alike) display there work either in their own homes or in public buildings like schools and churches. The events are already running in the county this week, and will hit the city next Saturday 17th, so I can have a nice walkabout and see some art I wouldn't otherwise be able to see.

What troubles me a little bit, though, is that the artists seem to have vanished from our neighbourhood. Back in 2000/01 there were 2 or 3 exhibitions in our street, and a few more in nearby streets, and now there is nothing. I have to go to the city centre or to North Oxford to get my art fix. Not sure what happened there ...

the times they are a'changing

looking back on the 15 years from which I've sampled the texts for my platypus book, I have also become aware of how much science coverage in newspapers and magazines has changed during this time.

One of my first pieces, back in 1993, was 150 lines on the structure of the enzyme nitrogenase. No way I could get something as seriously technical published in a national newspaper today.

What happened in the interim is that everything switched to daily deadlines. Newspapers now slot "science" stories in with the current news, but the result is of course that only those get reported that are newsy enough to be able to compete with the shock and horror stories from around the world.

Monthly magazines, of course, still appear monthly, but they too have started doing daily reporting online. Again, the necessary speed and competition with other news media hasn't exactly improved the depth and quality of the reporting.

I have been uneasy about these changes for a while now, but never seen them discussed anywhere. Now there has been a feature in MediaGuardian which highlights some of the problems that I am also worried about.

I guess the take-home lesson is, treasure your monthly magazines as long as they exist -- one day all reporting may get switched to become the intellectual equivalent of fast food.

platypus genome

I'm very pleased to report that, just days before publication of my book "The birds, the bees and the platypuses", the genome sequence of Ornithorhynchus anatinus, also known as the duck-billed platypus, is being published in Nature (issue of 8.5.).

As was to be expected from the unusual phenotype, the genetic features are a colourful mixture of things shared with other mammals, reptiles, and indeed birds. Apart from explaining how the platypus and the small group it belongs to, the monotremes, is so different from everything else, the genome is also useful as an external reference point for genomic studies drawing comparisons between mammals.

I'm also preparing a longer feature article about the genome, which will appear in due course (in German, though).

biofuels from waste materials

As the hype around farmed biofuels (such as corn ethanol) turns to autocombustion, it is important to remember that there is another way, namely to make biofuels from agricultural waste materials. As these materials will be of different nature in different climate zones, many different approaches are needed around the globe.

In Cuba, for instance, the major agricultural waste is bagasse from sugar cane. Researchers are developing ways of "cracking" cellulose in the bagasse in order to produce bioethanol. A recent paper from the university of Matanzas has looked at the best way of doing this pretreatment:

Martín, C., Marcet, M., and Thomsen, A. B. (2008). "Comparison between wet oxidation and steam explosion as pretreatment methods for enyzmatic hydrolysis of sugarcane bagasse," BioRes. 3(3), 670-683.

The full text of the paper should soon appear in BioResources.

sexy platypuses

Following on the crazy camels, here's a chapter from the "sexy" section of the book. It's the chapter which gave the book its weird and wonderful title:

The birds, the bees and the platypuses

I suggest a title with every piece I write, but editors tend to have a mind of their own, so less than half of my suggested titles survive in the published versions. This one got through, and it must be my favorite title ever. But the story is sexy, too.

What is the molecular difference that makes us male or female? At first glance it’s simple: the male has a (fairly degenerate, see page XXX) Y chromosome instead of the second X chromosome. More precisely, the presence of a single gene in the Y chromosome, known as SRY, makes you develop male characteristics. In its absence, the development reverts to the default option which is female. Things get more complicated when biologists start talking about the birds and the bees. In birds, you know, it’s the other way round: females have a pair of different sex chromosomes, while males have a matched pair -- and don’t even think about the bees. But the record holder for the most confusing sex determination system must be the duck-billed platypus. After decades of uncertainty, Australian researchers have established that this animal has no less than five pairs of sex chromosomes, including one that resembles ours, and one that is more reminiscent of birds.

The ever-popular platypus is one of only three surviving species from the deepest branch of mammalian evolution, the monotremes. Thus, its sex determination is of interest not just as a curiosity but also for any light it might throw on the early evolution of our mammalian ancestors. Using fluorescence in situ hybridization (FISH), the group of Frank Grützner at the Australian National University in Canberra has sorted out the platypus’s ten sex chromosomes, which have the confusing habit to merge into one large chain during cell division. They found that there are five male-specific (Y) chromosomes, which can pair up with five different X chromosomes. In the chain, they are always found in the same order. At one end of the chain there is a pair that resembles our own XY pair (although it confusingly lacks the SRY gene), but the pair at the other end shows some similarity with the ZW chromosomes of birds. The authors even suspect that the latter pair was the first to develop a sex-specific difference, while the others were recruited later, and the one that resembles ours came in last.

This surprisingly bird-like feature in the mammal that lays eggs and sports a duck-like bill might overthrow the old dogma that sex chromosomes evolved independently in birds and mammals. Maybe we originally inherited the same system still found in birds and morphed it into ours. Platypus may have preserved the transition state of this important evolutionary change.

(2004)


Further reading

F. Grützner et al., Nature, 2004, 432, 913.


What happened next

I’m ashamed to admit that I haven’t followed platypus’s sex life as closely as I should have, so I don’t really know. I’ll make a New Year’s resolution to catch up with this.

-------------------------------------------

watch this space, there is more platypus news coming up very soon !!!

The beauty and the sea

I recently raved about the music of Mor Karbasi, and then I managed to miss the release of her debut album, a few weeks ago. This very enthusiastic review of The Beauty and the sea woke me up. I've ordered the CD, which should turn up soon. Watch this space

Lucy in the Sky with Diamonds

Albert Hofmann, the chemist who first made LSD and experimented with its effects on the mind, died aged 102 -- goes to show that at least this drug doesn't kill you. I still wouldn't try it though, being a control freak with respect to my mind.

Here is an obituary and a news story.

PS a few years ago, I very nearly translated a book of his, which would have been published on the occasion of his 100th birthday. I don't know what happened exactly, but I guess the publishers got cold feet because it was positive about drug induced experiences.

crazy camels

just two weeks to go until the release (in Europe) of "The birds, the bees, and the platypuses". As I mentioned before, the book has three parts, a crazy, a sexy, and a cool one. (although some of the stories may tick more than one of these boxes, and I don't like boxes anyway, so don't take the categories too seriously!)

Here's a chapter from the crazy section:

Magic bullets from the desert

This story began quite inconspicuously with a conversation I had in my office, back in the days when I was still doing research at the University of Oxford. A former colleague had come back to do some experiments in the course of a collaborative project that I didn’t know anything about. When I asked him what his experiments were about, he said he was studying the interaction between lysozyme and camel antibodies. “Lysozyme” was the boring part of that sentence, as everybody in this lab had some connection to this classic workhorse of protein and enzyme studies. But the other half was news to me, so I pricked up my ears and asked: “Camel? What’s special about camels?” So he told me, and I must have retold this story more than a dozen times in various formats. It’s still one of my favourites.


It all started with a mutiny in a university teaching lab, some time in the late 1980s. A bunch of biology students were told to do the immunology experiments that countless others had done before them, fishing antibodies from human blood serum, and separating them into different groups. They were not too keen, as the serum might contain HIV, and also because the results of the experiment were well known and already documented in their textbooks. Their tutors offered to sacrifice a few mice instead -- not a very popular choice either. Eventually, a few liters of serum leftovers were discovered in the freezers of the research labs -- they were from dromedaries. This exotic sample inspired the students sufficiently to give up the strike action and start working on the separation of the antibodies. They found the usual distribution of immunoglobulins that one expects to see, but they also discovered a group of smaller antibodies that did not correspond to anything known to science.

This episode happened at the Free University of Brussels, and it might have ended in obscurity, had not two researchers at this university, Raymond Hamers and Cecile Casterman investigated more deeply. They believed that that the smaller antibodies were not just degraded copies of the real ones, but that they were of a special kind. They repeated the students’ experiments with fresh samples from camels and llamas, and confirmed that all the animals in this group (the camelidae) produce some amounts of antibodies which are very different from the standard ones in that they are lacking the pair of protein molecules known as the light chains. They consist only of the heavy chains, which is why they are now referred to as heavy chain or HC antibodies. (In normal antibodies, a pair of heavy chains is arranged in a symmetrical Y shape, with one light chain attached to each of the branches.)

Ordinary antibodies are horrible things to deal with, as they are complicated molecular assemblies, very difficult to produce in bacteria, too bulky for many medical applications, and may trigger an unwanted immune response in a patient (yes, there are antibodies against antibodies!). Therefore, many labs have tried to find something simpler, to construct miniature antibodies combining the binding specificity of a real antibody with some extra user friendliness. Serge Muyldermans and Lode Wyns, also working at the Free University of Brussels, were pursuing research in this direction. They took up the trail of the camels, but it was quite a trek. In the beginning, it was far from clear that these molecules were functional antibodies with the high variability and specificity of the real thing. What they needed to do was to find a camel, immunize it with a specific antigen, wait a year, and see whether the camel had produced specific HC antibodies against that substance. A party of researchers travelled to Morocco, bought a camel, immunized it ... and had it stolen before they could get at the precious serum!

These practical problems were eventually overcome with a little royal help. His Highness, General Sheikh Maktoum Bin Rashid Al Maktoum, then the ruler of Dubai in the United Arab Emirates, supported the research by providing camel serum from his renowned veterinary research centre. What the researchers found out about the camel antibodies was even more promising for medical and biotechnological applications than they could have hoped for.

It turned out that the HC antibodies, like normal ones, recognize a wide range of antigens, but they interact with them in different places. Thus, HC antibodies raised against small enzymes such as lysozyme or ribonuclease can penetrate the active site and provide a potent inhibitor for the enzyme, while conventional antibodies would bind somewhere more accessible.

This all boils down to the fact that in a conventional antibody, the antigen recognition is provided by two sites (at the upper ends of the “Y”), each composed of two different molecules, a heavy chain and a light chain, resulting in a rather bulky arrangement. In HC antibodies, each binding site is contained in a narrowly defined region of one molecule, the variable domain of the heavy chain. This is why it reaches the parts that other antibodies can’t. This also means that it is a lot easier to further miniaturize this antibody. If you want to miniaturize a human antibody by cutting off all the parts that are not involved in binding, you get enormous difficulties trying to keep the binding domains of the heavy and of the light chain together. With the camel version, you can just genetically isolate the DNA for the binding domain, get bacteria to make it, and you’ve got your miniature antibody, known to scientists as a single domain antibody.

Single domain antibodies are the ideal tool for a range of applications from scientific research tools through to diagnostic kits to be used at home. One very promising field is imaging of living tissue, and especially cancer diagnosis. When trying to localize a tumour, you want a label that, apart from recognizing the particular molecules found on tumour cells, penetrates easily into the tumour. Once it has done that and bound to the target, you want to be able to wash out any unbound leftover material as easily, so that it won’t show up in the picture. Common antibodies fail on these accounts, but preliminary tests suggest that single domain binders derived from camel HC antibodies could be used. It also appears that they will not normally provoke an immune response as full-size (non-human) antibodies would. Furthermore, the small size of these molecules allows scientists to use them as building blocks for constructs which might contain two different binding sites, or even a binding site combined with an enzymatic or other activity. They could even be harnessed inside the cell, as so-called intrabodies.

A typical example of an antibody-based consumer product is the home pregnancy test kit which you dip into a urine sample, and then wait for a blue stripe to turn up. One version of this, designed to indicate the presence of a characteristic pregnancy hormone, consists of two different kinds of antibodies against this hormone. One set is glued to the solid support in the window area where you want the blue stripe to appear. When hormone molecules float by, they will get bound by these antibodies. A second set of antibodies, recognizing a different part of the hormone molecule, is charged with blue-colored particles. When this second set comes across the hormone molecules firmly bound to the first set, it will bind to them and thus make the blue color accumulate in the window. As this kind of test requires two kinds of antibodies which bind the target in different ways such that they not interfere with each others binding, a combination of conventional antibodies on the solid surface and camel-type antibodies in the liquid would be ideally suited.

(2000)


Further reading

Muyldermans Serge, et al., Trends Biochem. Sci., 2001, 26, 230- 235,



What happened next

Since 2002, a spin-out company called Ablynx has begun to develop a number of products based on the advantages offered by camelidae antibodies. As of 2007, Ablynx has over 90 staff and contracts with several pharma giants. The first drug based on camel antibodies has just entered a phase I clinical trial. Watch this space.
T. N. Baral et al., Nature Med. 2006, 12, 580.