Wanted: Hominids for Clinical Drug Trials

By Carl Zimmer | May 2, 2006 4:10 pm

In March, six men entered a London hospital to receive an experimental drug. The men were volunteers, and the drug–a potential treatment for arthritis and leukemia–appeared from animal tests to be safe. But within minutes of the first round of doses, there was trouble. The men complained of headaches, of intolerable heat and cold. The drug made one man’s limbs turned blue, while another’s head swelled like a balloon. Doctors gave them steroids to counteract the side-effect, and managed to save their lives. But several ended up on life support for a time, and they all may suffer lifelong disruptions to their immune systems.

How could such a devastating disaster come from a trial that followed all the rules, including tests on both mice and monkeys? According to a paper published today, the drug developers might have thought twice if they had known more about our evolutionary history.

Humans suffer from a number of immune disorders that don’t bother other primates. HIV evolved from a virus that infects chimpanzees, but when chimpanzees get infected, their immune system doesn’t collapse the way ours does. Chimpanzees don’t get serious inflammation of the liver after hepatitis infecitons, and don’t seem to suffer from lupus or bronchial asthma. All of these disorders are associated with an overreaction by a group of white blood cells known as T cells. This puzzling pattern led scientists at the University of California at San Diego Medical School to see if T cells behave different in humans than in chimpanzees, and if so, why.

They started with one intriguing clue: human T cells don’t make a group of receptors found on many other immune cells. These receptors are known as Siglecs (a nice snappy abbreviation of “sialic acid-recognizing Ig-superfamily lectins.” And breathe.)

No one is quite sure what the function of Siglecs is. It is clear that they bind sialic acids, which are sugary molecules that coat our cells, including immune cells. Scientists have speculated that by recognizing sugars on our own cells and sending a dampening signal, Siglecs might help our immune systems avoid attacking our own tissues.

The scientists decided to compare human T cells directly to those of apes. It turns out that unlike humans apes produce a lot of Siglecs on their T cells. And those Siglecs make their T cells behave differently than ours. The scientists used antibodies to bind to several T cell receptors that are known to play important roles in how the immune system responds to threats. In humans, tickling those receptors caused the T cells to multiply madly. In chimpanzees, by contrast, the response was muted.

Could it be that Siglecs were muffling the response of ape T cells? To test the possibility, the scientists cleared Siglecs off of chimpanzee T cells. The altered chimpanzee T cells responded much more strongly when their receptors were tickled. The scientists also manipulated human T cells, adding Siglecs to their surfaces. Now the human cells were much more muted in their responses.

The scientists detail their results in the Proceedings of the National Academy of Sciences (link to come here). They propose that our ancestors lost their Siglecs some time after our lineage branched off from that of chimpanzees about six million years ago. The scientist also suggest that when the Siglecs disappeared, our lineage became prone to damaging overreactions from T cells that other apes did not suffer.

Why would natural selection favor Siglec-free T cells in the face of these diseases? It’s possible that our ancestors faced some awful pathogen that required a powerful T cell response. Perhaps this reaction even helped our ancestors spread to new environments where they faced new disease.

It’s also possible that natural selection had nothing to do with it. The diseases associated with the overactive human T cell take a long time to develop, and so they may not have interfered with child bearing–and thus with passing on genes from generation to generation.

There’s one particularly intriguing coincidence to consider here: sialic acids have clearly undergone a dramatic evolutionary change of their own. Mammals generally make two kinds of sialic acids. An estimated 3.2 million years ago, our ancestors lost the ability to make one of them. A mutation disabled the gene in some ancestral hominid, and after time that broken gene spread throughout the entire species.

Previous studies have shown that the disappearance of those sugars caused many changes in human Siglecs. New Siglecs evolved, some of which shifted from binding to the old sugars to binding to the new ones. There may have been a shake-up in the whole Siglec-sialic acid system, and the loss of Siglecs from T cells may have been just one side effect.

Now we can return to the unlucky drug volunteers. The drug they got is called TGN1412. It works by binding to a T cell receptor called CD28. Previous research had suggested that binding to CD28 could cause a cascade of events that would ultimately tame an out-of-control immune system. That’s certainly what seemed to happen to mice and monkeys. Since arthritis is caused by out-of-control immune systems, TGN1412 looked like a promising drug. The doctors took care to give the human subjects 1/500 the dose given to the monkeys. Neverthless, it apparently sent their immune systems into a rage, producing massive amounts of inflammation and other sorts of damaging responses.

Guess what one of the receptors was that scientists examined in the new Siglec paper. That’s right–CD28. It’s possible, then, that the drug failed in humans because we have lost the mechanism that keeps a response to CD28 under control.

At this point, this hypothesis is just one possible explanation that needs to be tested. Ajit Varki, one of the authors of the new study, told me that his team has asked for a sample of the drug from its manufacturer to test it on human and ape T cells. So far, the company, Tegenero Inc., has refused.

If it does hold up, it may offer a cautionary lesson about drug tests. Testing a drug on a mouse or a monkey may tell you something about how the drug will work in humans–but only if it acts on biology that we share with those animals. And in some cases, where a drug is affecting proteins that evolved after our split with chimpanzees, no living animal may offer a reliable clue. The more we learn about our evolutionary history, the more we’ll understand about how drugs work.

(Postscript: Last year I wrote about another way in which how this ancient evolutionary event makes a big difference to modern medicine–in this case, stem cell research. If human stem cells are reared with animal tissues, they can pick up the lost sugar and wind up being rejected by our immune systems.)

Update, 5/2/06 3 pm: Fixed up a few late-night errors.

Update 5/2/06 4 pm: In the comments, Nick Matzke reminds me that I’ve already written about how malaria might have had a hand in this immune system disruption here. Memories fade, but blogs are forever.

CATEGORIZED UNDER: Uncategorized
MORE ABOUT: Evolution

Comments (8)

  1. I couldn’t find the PNAS paper, but did activation of CD28 alone in human T-cells lead to proliferation?

    Normally, T-cell activiation depends on two molecular signals. One through the T-cell receptor, which recognizes a specific antigen processesed and displayed by an antigen presenting cell, and another through a molecule delivered by the same cell that recognizes CD28. There are some ways of getting around this in the lab, so I wonder what they did to get T-cells to proliferate just through CD28.

    Part of TGN1412′s problem, I had thought, was that it can activate T-cells via CD28 alone, independent of T cell receptor recognition, cutting antigen presenting cells out of the loop. This seemed to work in mice and primates because TGN1412 appeared to favor T regulatory cells, which keep autoreactive T-cells in check. In humans, TGN1412 likely recongized other T-cells, resulting in out of control inflammation.

    I wonder if the promiscuous activity of TGN1412 in humans was due to a lack of Siglics?

  2. Ewen–I have no clue why PNAS doesn’t put their papers on-line immediately upon lifting the press embargo. But as soon as they do–which should be in the next day or two–I’ll set up the link.

  3. typo: “Neverthless, it apparently their immune systems…”

  4. Surely this is a piece of the story, from a previous post of yours:

    The authors of the new study set out to find the difference between these parasitic cousins. They focused on how each species of Plasmodium gets into red blood cells. Every Plasmodium species uses special molecular hooks on its surface to latch onto receptors on the cell, and then noses its way through the membrane to get inside. The parasite has a number of hooks, each of which is adapted to latch onto particular kinds of receptors. One of the most important groups of receptors that Plasmodium needs to latch onto are sugars known as sialic acids, which are found on all mammal cells.

    These sugars play a crucial but mysterious role in human evolution. As I’ve written here (and here), almost all mammals carry a form of the sugar called Neu5Ac on their cells, as well as a modified version of it, known as Neu5Gc. In most mammals, this modified form, Neu5Gc is very common. In humans, it’s nowhere to be found. That’s because the enzyme that converts the precursor Neu5Ac into Neu5Gc doesn’t work. We still carry the gene for the enzyme, but it became mutated about three million years ago and stopped working.

    Since chimpanzees make Neu5Gc and we don’t, the researchers hypothesized that the two Plasmodium species must use different strategies to latch onto red blood cells. To test their hypothesis, they genetically engineered cells to produce the molecular hooks used by human Plasmodium falciparum, and other cells to produce the chimp parasite hooks. The researchers then mixed the engineered cells with red blood cells from humans and chimpanzees to see how well they attached. In another set of experiments, they made human blood cells more chimpanzee-like by adding Neu5Gc sugars to them, to see if the change helped the chimpanzee parasites attack them, or if it impaired the attacks of human parasites.

    Their results show that humans are uniquely vulnerable to Plasmodium falciparum because our ancestors lost the Neu5Gc sugar. Plasmodium falciparum prefers to bind to Neu5Ac, the sugar we still carry. At the same time, the sugar we lost somehow blocks Plasmodium falciparum’s hooks from latching onto Neu5Ac. That’s why chimpanzees don’t get sick with Plasmodium falciparum, despite carrying both kinds of sugars. On the other hand, we don’t get sick with chimpanzee malaria, because Plasmodium reichenowi prefers attaching to Neu5Gc, the sugar we lost.

    The scientists argue that some seven million years ago the common ancestor of chimpanzees and humans carried both kinds of sugars on their cells. This ancient ape would sometimes get sick with malaria, caused by the common ancestor of today’s P. rechnowi and P. falciparum. This ancient parasite preferred to latch onto Neu5Gc to get into its host’s blood cells.

    Looks to me like maybe hominids have been running from malaria over the last few million years and this has thrown some other things out of whack. Immunologically speaking, of course.

  5. Death for the honest anti-Darwinists….

  6. luca

    Very interesting piece.

    I’ve diffused it through my colleagues at work (Mol. Inform. dep. of a big pharma) – was expecting to stir much more noise, though…

  7. Did Bush win re-election because of the false propaganda his government fed to the corporate media?

  8. So, help me understand-I get lost in all the medical terminology. If the researchers are aware of this dramatic difference in the way several large diseases impact humans versus humans, doesn’t it seem strange that it would be deemed safe to test something on humans that was safe in monkies? I don’t see how that shows anything really!

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The Loom

A blog about life, past and future. Written by DISCOVER contributing editor and columnist Carl Zimmer.

About Carl Zimmer

Carl Zimmer writes about science regularly for The New York Times and magazines such as DISCOVER, which also hosts his blog, The LoomHe is the author of 12 books, the most recent of which is Science Ink: Tattoos of the Science Obsessed.

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