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Corante Blogs examine, through the eyes of leading observers, analysts, thinkers, and doers, critical themes and memes in technology, business, law, science, and culture.

The Press Will Be Outsourced Before Stopped

Vin Crosbie, on the challenges, financial and otherwise, that newspaper publishers are facing: "The real problem, Mr. Newspaperman, isn't that your content isn't online or isn't online with multimedia. It's your content. Specifically, it's what you report, which stories you publish, and how you publish them to people, who, by the way, have very different individual interests. The problem is the content you're giving them, stupid; not the platform its on."
by Vin Crosbie in Rebuilding Media

Travels In Numerica Deserta

There's a problem in the drug industry that people have recognized for some years, but we're not that much closer to dealing with it than we were then. We keep coming up with these technologies and techniques which seem as if they might be able to help us with some of our nastiest problems - I'm talking about genomics in all its guises, and metabolic profiling, and naturally the various high-throughput screening platforms, and others. But whether these are helping or not (and opinions sure do vary), one thing that they all have in common is that they generate enormous heaps of data.
by Derek Lowe in In the Pipeline

Disrobing the Emperor: The online “user experience” isn't much of one

Now that the Web labor market is saturated and Web design a static profession, it's not surprising that 'user experience' designers and researchers who've spent their careers online are looking for new worlds to conquer. Some are returning to the “old media” as directors and producers. More are now doing offline consulting (service experience design, social policy design, exhibition design, and so on) under the 'user experience' aegis. They argue that the lessons they've learned on the Web can be applied to phenomena in the physical and social worlds. But there are enormous differences...
by Bob Jacobson in Total Experience

Second Life: What are the real numbers?

Clay Shirky, in deconstructing Second Life hype: "Second Life is heading towards two million users. Except it isn’t, really... I suspect Second Life is largely a 'Try Me' virus, where reports of a strange and wonderful new thing draw the masses to log in and try it, but whose ability to retain anything but a fraction of those users is limited. The pattern of a Try Me virus is a rapid spread of first time users, most of whom drop out quickly, with most of the dropouts becoming immune to later use."
by Clay Shirky in Many-to-Many

The democratisation of everything

Over the last few years we've seen old barriers to creativity coming down, one after the other. New technologies and services makes it trivial to publish text, whether by blog or by print-on-demand. Digital photography has democratised a previously expensive hobby. And we're seeing the barriers to movie-making crumble, with affordable high-quality cameras and video hosting provided by YouTube or Google Video and their ilk... Music making has long been easy for anyone to engage in, but technology has made high-quality recording possible without specialised equipment, and the internet has revolutionised distribution, drastically disintermediating the music industry... What's left? Software maybe? Or maybe not."
by Suw Charman in Strange Attractor

RNA Interference: Film at Eleven

Derek Lowe on the news that the Nobel Prize for medicine has gone to Craig Mello and Andrew Fire for their breakthrough work: "RNA interference is probably going to have a long climb before it starts curing many diseases, because many of those problems are even tougher than usual in its case. That doesn't take away from the discovery, though, any more than the complications of off-target effects take away from it when you talk about RNAi's research uses in cell culture. The fact that RNA interference is trickier than it first looked, in vivo or in vitro, is only to be expected. What breakthrough isn't?"
by Derek Lowe in In the Pipeline

PVP and the Honorable Enemy

Andrew Phelps: "Recently my WoW guild has been having a bit of a debate on the merits of Player-vs.-Player (PvP) within Azeroth. My personal opinion on this is that PvP has its merits, and can be incredible fun, but the system within WoW is horridly, horribly broken. It takes into account the concept of the battle, but battle without consequence, without emotive context, and most importantly, without honor..."

From later in the piece: "When I talk about this with people (thus far anyway) I typically get one of two responses, either 'yeah, right on!' or 'hey, it’s war, and war isn’t honorable – grow the hell up'. There is a lot to be said for that argument – but the problem is that war in the real historical world has very different constraints that are utterly absent from fantasized worlds..."
by Andrew Phelps in Got Game

Rats Rule, Right?

Derek Lowe: "So, you're developing a drug candidate. You've settled on what looks like a good compound - it has the activity you want in your mouse model of the disease, it's not too hard to make, and it's not toxic. Everything looks fine. Except. . .one slight problem. Although the compound has good blood levels in the mouse and in the dog, in rats it's terrible. For some reason, it just doesn't get up there. Probably some foul metabolic pathway peculiar to rats (whose innards are adapted, after all, for dealing with every kind of garbage that comes along). So, is this a problem?.."
by Derek Lowe in In the Pipeline

Really BAD customer experience at Albertsons Market

Bob Jacobson, on shopping at his local Albertsons supermarket where he had "one of the worst customer experiences" of his life: "Say what you will about the Safeway chain or the Birkenstock billionaires who charge through the roof for Whole Foods' organic fare, they know how to create shopping environments that create a more pleasurable experience, at its best (as at Whole Foods) quite enjoyable. Even the warehouses like Costco and its smaller counterpart, Smart & Final, do just fine: they have no pretentions, but neither do they dump virtual garbage on the consumer merely to create another trivial revenue stream, all for the sake of promotions in the marketing department..."
by Strange Attractor in Total Experience

The Guardian's "Comment is Free"

Kevin Anderson: "First off, I want to say that I really admire the ambition of the Guardian Unlimited’s Comment is Free. It is one of the boldest statements made by any media company that participation needs to be central to a radical revamp of traditional content strategies... It is, therfore, not hugely surprising to find that Comment is Free is having a few teething troubles..."
by Kevin Anderson in strange
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

The Loom

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December 31, 2004

The Whale and the Antibody

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Posted by Carl Zimmer

Ambulocetus.jpgEvolutionary biologists face a challenge that's a lot like a challenge of studying ancient human history: to retrieve vanished connections. The people who live in remote Polynesia presumably didn't sprout from the island soil like trees--they must have come from somewhere. Tracing their connection to ancestors elsewhere hasn't been easy, in part because the islands are surrounded by hundreds of miles of open ocean. It hasn't been impossible though: studies on their culture, language, and DNA all suggest that the Polynesians originally embarked from southeast Asia. We may never be able to retrieve the full flow of history that carried people thousands of miles to the middle of the Pacific, but we can know some things about it, and we can rest assured that some things are definitely not true (such as the sprouting-from-the-ground theory).

Whales are a lot like Polynesians. All living species of whales look a lot like each other, and not very much like any other animals. They all have horizontal tail flukes, blowholes, and smooth skin free of scales or fur. Darwin argued that whales were not simply created in the oceans in their current form, but instead descended from land mammals which had adapted to life in the ocean. He pointed out that whales share a number of traits with land mammals, such as milk and a placenta. Their blowhole connects to a set of lungs very much like those of land mammals and nothing like the gills of fish.

protolymph.gifDarwin wigged out more than a few people with this argument. Whales just seemed too different, too distinct to have evolved by small steps from a four-legged ancestor. And creationists loved to point out how unlikely this transition seemed--on par with turning a cow into a shark. They also liked to point out that no intermediate fossils had ever been found. But as I wrote in my book At the Water's Edge, paleontologists began to find those fossils in the 1980s. Today, the transition whales made from land to sea is wonderfully well documented. Paleontologists have found complete skeletons of creatures such as the 45 million year old Ambulocetus (reconstructed here by the gifted artist Carl Buell). The transformation was not some sudden macromutation, but a gradual series of changes over millions of years, featuring shrinking legs, lengthening tails, loosening hips, and migrating noses.

In the coming century, I suspect fossils will help scientists reconstruct other major transitions. But they'll also start reconstructing others that have left no record in rocks A fascinating case in point has been published on line at the Proceedings of the National Academy of Sciences. Jan Klein and Nikolas Nikolaidis of Penn State have drawn a rough map that charts the evolution of the immune system.

Our immune system is as awesome as a whale's body--in terms of the complexity of its parts and the way those parts work together so well. It keeps viruses, bacteria, tapeworms, and even cancer cells at bay, while generally sparing our own tissues from its withering attack. All animals share a rudimentary immune system, but Klein and Nikolaidis focused on a second system that is found only in vertebrates. Only we vertebrates have immune systems that can learn.

This learning system is a network of cells, signals, and poisons. Among its most important cells are T cells and B cells. They originate in the bone marrow, although the T cells have to finish their development in the thymus, an organ near the heart. These cells are unusual in many ways, most important of which are some of the receptors they make on their surface. The cells have a special set of tools that cut up the receptor genes and paste them into new arrangements, so that the genes produce receptors with new shapes. Depending on its shape, a receptor can grab onto certain molecules. Those molecules may come from a bacteria toxin, or they coat nerves or muscle cells. Our bodies can usually eliminate the immune cells that have an affinity for our own tissue. If they don't, we end up with autoimmune diseases such as muscular dystrophy.

The surviving B cells and T cells are introduced to molecules from invading pathogens (antigens) by other immune cells called macrophages. The macrophages devour bacteria or virus-infected cells and then put some of the molecules of their victims on their surface. They travel to the lymph nodes to show off their conquests. If T cells or B cells bump into one of these macrophages, their receptor may fit reasonably well onto an antigen. That fit sends a signal to their DNA, triggering them to multiply. Some of the cells they produce receptors cut and pasted into newer shapes, some of which do an even better job of fitting on the antigen. These winners get to reproduce more. In other words, our immune systems use a version of natural selection to fine tune their recognition of pathogens.

These B cells and T cells can then fight off a disease. The T cells may destroy cells infected with the pathogen, because most cells in the human body have receptors they can use to display antigens. In other cases, they can whip up macrophages into a furious frenzy of killing. Or they may spur B cells to produce antibodies. The B cells spray out the antibodies into our bodies, and when they come into contact with their particular pathogen, they may drill into it, stop it from invading cells, or tag the pathogen to make it an easier target for macrophage attack. Some B cells and T cells that can recognize a pathogen sit out the battle. If we should be exposed to the same disease years later, these memory cells can leap into action so quickly that the new infection may not even make us sick.

You can find this same remarkable system in humans, albatrosses, rattlesnakes, bullfrogs, and all other land vertebrates. You can also find it in most fish, from salmon to hammerhead sharks to sea horses. There are some variations from species to species, but they've all got B cells, T cells, antibodies, thymuses, and the other essential components. But you won't find it in beetles, earthworms, dragonflies, or any other invertebrate on land. Nor will you find it in starfish, squid, lobsters, or lampreys in the water. All these other animals rely instead on rudimentary immune systems that cannot learn.

For those who reject evolution, this sort of pattern tells them nothing. Like everything else in nature, they can only wave their hands and declare it the inscrutable work of a designer (lower case d or upper case D as they are so inclined on a given day). But immunologists and other scientists who actually want to learn something about the immune system find this view useless. Instead, they look at how animals with an antibody-based immune system are related to one another. And what they find is both straightforward and astonishing. All of the living animals with an antibody-based immune system descend from a common ancestor, and none of the descendants of that common ancestor lack it. That means that the antibody-based immune system evolved once, about 470 million years ago.

I need to back up in the history of life a few hundred million years to explain how scientists know this. Studies on fossils and genes agree that everything we call an animal (including sponges and jellyfish) shares a common ancestor not shared by plants, fungi, or other major groups of organisms. Exactly when that ancestor lived is a subject of fierce debate, but one of the latest estimates puts the date at about 650 million years ago. This ancestor probably had a simple immune system, because all animals, from sponges on, have at least some sort of defense against pathogens. Over the next 100 million years or so, the major groups of animals branched off from one another, and while some branches evolved some new defenses of their own, the antibody-based immune system only appears in our own branch, the vertebrates.

Animals with some--but not all--of the key traits of vertebrates, such as heads and brains, lived at least 530 million years ago. The only living relics of these early branches are hagfish. Later, our ancestors also evolved a vertebral column, becoming true vertebrates. Lampreys represent the deepest branch of vertebrate evolution, splitting off perhaps 500 million years ago from their common ancestor with us. They lack many traits that other vertebrates have--most obviously a jaw. A number of other weird jawless vertebrates filled the oceans between about 500 and 360 million years ago, but except for lampreys, they're all long gone. One of these branches gave rise over 470 million years ago to fish with jaws--known as gnathostomes. Gnathostomes later gave rise to sharks and other "cartilaginous" fishes, as well as ray-finned fishes, and land vertebrates.

You may have already guessed the kicker of all this history. Lampreys and invertebrates don't have an antibody-based immune system. Sharks, ray-finned fish, and land vertebrates do. Sharks, ray-finned fishes, and land vertebrates all share a common ancestor that is not shared by lampreys or other invertebrates. The simplest way to explain this coincidence is to conclude that the antibody-based immune system evolved after lampreys branched off from our own lineage, but before sharks and other living gnathostomes began to branch apart. We can't dig up fossil antibodies, but we can know when they evolved.

Scientists have sometimes treated the transition from rudimentary immune system to antibody-based immune system as a great leap. Lampreys don't have antibodies, B cells, T cells, thymuses, or the rest, and all gnathostomes do. Some creationists have even tried to turn this into an argument against evolution, claiming that something as complex as the adaptive immune system could not have emerged gradually. But it's important to bear in mind that tens of millions of years of evolution separate our common ancestor with lampreys and the earliest gnathostomes. And in their new paper, Klein and Nikolaidis argue that the evolution of the antibody-based immune system was a lot like the evolution of whales: a gradual, step-wise process.

Most of the components of the antibody-based immune system were actually already in place long before gnathostomes evolved. Lampreys, for example, don't have a thymus, but they do have the structures and cell types that form the thymus. In gnathostomes, the thymus develops as cells switch on special genes in a particular order. Lampreys have these genes, as so many other animals. Instead of building thymuses, they build other structures, such as eyes and gill arches. It would have only required altering the switches that determine when and where these genes become active to produce a new organ.

B cells and T cells are known as lymphocytes. Lampreys don't have lymphocytes, but Klein and Nikolaidis point out that they do have "lymphocyte-like cells." (The picture above shows what these cells look like.) Lymphocyte-like cells develop like lymphocytes, under the control of many of the same genes that control the development of lymphocytes. Once they are mature, these cells have almost the same structure and chemistry as lymphocytes--but they don't produce the antibodies and receptors of B cells and T cells. Exactly what they do in lampreys isn't clear.

What about those receptors and antibodies? Klein and Nikolaidis point out that they aren't quite as novel as they may look at first. They are made up of building-blocks of simple proteins arranged in different ways. And guess what--many of these simpler proteins are found in lampreys and invertebrates, where they serve other functions. The same goes for many of the proteins that B cells and T cells use to communicate with one another. Other proteins are made by genes that are unique to gnathostomes, but show a kinship to entire families of genes found in other animals. The most likely explanation is that an ancestral gene duplicated by accident, and later one of the copies was recruited to the evolving immune system.

Klein and Nikolaidis point out that some truly new things appeared as the antibody-based immune system emerged. But just because something is new doesn't mean that it couldn't have evolved. The best-understood example of a new feature is the cut-and-paste machinery that allows B cells and T cells to mix up their receptors into new shapes. Scientists have been working out its evolution for years now, but just last week some scientists from Johns Hopkins published a paper in Naturethat brought the picture into remarkable focus. Our genomes are rife with virus-like sequences known as transposable elements that produce enzymes whose sole function is to make copies of the transposable DNA and insert those copies somewhere else in our genomes. In a few cases, these transposable elements have evolved from pests to helpers, carrying out important functions in our cells. The genes that are responsible for cutting and pasting immune cell receptors bear a clear resemblance to transposable elements in other animals. So the evolution of a new cut-and-paste mechanism was actually just the domestication of an in-house virus.

I suppose that creationists might claim that these components could not possibly have come together into an antibody-based immune system. But there's no proof behind this sort of categorical dismissal, just a personal feeling of disbelief. These folks would still be left with the fact that the evolutionary tree of life and the biochemistry of vertebrates and other animals are all consistent with a gradual evolution of this system. It would all have to be a spectacular coincidence, or perhaps an intentional deception on the part of the designer. Who knows. Who cares, really? (Aside from certain Pennsylvania senators.) What's exciting here is the future research that could shed more light on this transition. Klein and Nikolaidis propose introducing lamprey genes into vertebrates and vice versa to see just how close the ancestors of lampreys had gotten to an antibody-based immune system before they branched off on their own. Obviously, some half a billion years of independent evolution will muddy up the results, but it should be possible to see whether gnathostome immune genes can organize the lamprey immune system to act more like our own. What I'd be even more excited by would be a deep-sea discovery of a living fossil--a jawless fish that is more closely related to us than lampreys. They filled the seas 400 million years ago, and perhaps a few are lurking in some deep sea trench. Such a fish might have a crude antibody-based immune system, with only a few genes recruited and others yet to be pulled in. Perhaps it could do a mediocre job of learning to recognize diseases--but a mediocre job is better than no job at all.

It may sound like a crazy dream, but then again, so did walking whales.

Update 1/2/05: Panda's Thumb has more on the evolution of the immune system.

Comments (7) + TrackBacks (0) | Category: Evolution


COMMENTS

1. Joseph Poliakon on December 31, 2004 01:54 PM writes...

Carl, The "Whale and the Antibody" article is a great evolutionary data dump, but this is the Eve of 2005. No rearview mirror "evo-stuff" on 2005’s Eve…Whatzup for the next few air-breathing decades I/We have on the planet? Happy New Year Y2K + 5?!?

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2. david h on January 1, 2005 09:20 PM writes...

What a great way to end the year. Go, man!

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3. Jason Malloy on January 2, 2005 03:20 AM writes...

This research is fantastic! Great year-ender.

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4. DaveScot on January 3, 2005 12:23 AM writes...

Let me get this straight.

Science doesn't really know for sure whether dinosaurs were warm or cold blooded but it claims to know what kind of immune systems they had?

Gimme a break.

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5. Ivan on January 4, 2005 05:40 AM writes...

Well, phylogenetic bracketing, showing that ALL gnathostomes, from sharks and rays, to teleost fish, to coelacanths and lungfish, amphibians, reptiles, birds and mammals, all display the same sort of immune system, would hint that dinosaurs and other extinct vertebrates also had the same immune system. It is more parsimonious to reason that this immune system arose once in the common ancestor of all vertebrates, rather than arising convergently in every lineage.

And as for the cold-blooded/ warm-blooded issue, it is complicated, since the closest relatives of dinosaurs are crocodiles (cold-blooded) and birds (warm-blooded), so we don't have a cut-and-dried answer.

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6. coturnix on January 10, 2005 01:49 AM writes...

Great post for The Tangled Bank, or is "Size Matters" better? Dunno, but send one or the other or both:
http://sciencepolitics.blogspot.com/2005/01/next-tangled-bank.html

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7. Jeff Lipton on January 12, 2005 10:08 AM writes...

Wonderful article. However, muscular dystrophy is an inherited disorder of the dystrophin protein, not an autoimmune disease.

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