Wanted: Hominids for Clinical Drug Trials

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.