Fuel

There is an experiment I have never been able to shake, and I want to start with it because everything else in this season is downstream of it.

You take two mice. You anaesthetise them, open a flap of skin along the flank of each, and stitch them together so the wounds heal as one. Within a couple of weeks their capillaries have grown across the join. They now share a circulatory system. Whatever is dissolved in one mouse's blood arrives, diluted, in the other. They walk around joined at the hip for the rest of their lives.

The technique is called parabiosis and it is much older than the story I am telling: the French physiologist Paul Bert made the first pairs in 1864, a century before anyone had heard of a fat hormone. It is a blunt instrument, and it answers exactly one question, but it answers it beautifully. The question is: is there something in the blood?

At the Jackson Laboratory in Bar Harbor, Maine, a researcher named Douglas Coleman used it on two strains of famously fat mice, in a pair of experiments published in 1969 and 1973.

The first strain was called obese, shortened to ob. These mice ate enormously and became enormously fat. The second was called diabetic, db. Same thing to look at: huge, hungry, unwell. Two strains, two different broken genes, one apparently identical result. Nobody knew what either gene did.

Coleman joined them.

An ob mouse stitched to a normal mouse stopped overeating and lost weight.

Think about what that means. Something in ordinary mouse blood, crossing into the ob mouse, told it to stop eating. The ob mouse was not broken in its appetite or its willpower or its character. It was missing a signal that normal blood contained, and the moment it received that signal from someone else's circulation, it behaved normally. Whatever it was, it was a substance, and it was in the blood, and the ob mouse could not make it.

Then he joined a db mouse to a normal mouse.

The normal mouse stopped eating and starved to death.

I want to give that a second, because it is one of the strangest results in the history of this field and it is the reason the whole story eventually goes where it goes. The db mouse was not missing the signal. The db mouse was flooding its partner with it, in quantities so large that a healthy animal receiving the overflow stopped eating altogether. The db mouse was producing the signal in enormous excess, and was itself completely unable to hear it.

So Coleman could describe, in the 1970s, a thing nobody had seen, isolated, named or measured. There was a hormone. Fat tissue made it. It told the brain how much fat the body was carrying, and the brain used that number to set appetite. The ob mouse could not make the hormone. The db mouse could not receive it. And both, from the outside, just looked fat.

That is a complete and correct theory of a molecule that would not be found for another twenty years.

I find this genuinely moving, and not only for the obvious reason. Coleman was working on mice at a research institute in Maine, on a question most people at the time did not think was a question. The prevailing view of obesity, then and for a long time afterwards, was that it was a behaviour. A failure of restraint. Something you did. Coleman's mice were saying something else entirely: that appetite is regulated by a chemical signal reporting the size of the fat stores, and that if the signal breaks, the animal will eat, and there is nothing the animal can do about it.

He could not prove it. He had no molecule. He had two dead mice and an inference.

It took until 1994 for somebody to find the thing he had described. When they did, it was one of the great moments in modern biology, and it produced almost exactly the opposite of what everyone expected.

Next episode: eight years, a laboratory in New York, and the search for a gene nobody could see.