In March, eight 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 balloons. Doctors gave them steroids to counteract the drugs, 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 taken a closer look at 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 lupus, or serious inflammation of the liver after hepatitis infections, 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 decided 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 receptor found on many other immune cells. These receptors are known as Siglecs.
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. 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.
Now we can return to the unlucky drug volunteers. The drug they took 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 leukemia and arthritis are caused by out-of-control immune systems, TGN1412 looked like a promising drug. But when doctors gave it to humans, it sent the immune system into a rage, producing massive amounts of inflammation and other sorts of damaging responses.
