Sam Weller's microscope

This is an old one that I dredged up from 2006: it never got used then, and I am trying to establish a backlog for while I go travelling, and i imagine it is now somewhat dated, but i may get one reader to run and find out. Please take that into account.

Sam Weller in Pickwick Papers spoke of the problems of seeing. "If they was a pair o' patent double million magnifyin' gas microscopes of hextra power, p'raps I might be able to see through a flight o' stairs and a deal door, but bein' only eyes, you see, my wision's limited", he declared.

As an undergraduate, I often wished we had one of Sam's microscopes, so we could look at genes, and see what the chromosomes did. This was at a time when the genetic code was just beginning to be decoded, long before anybody would think of sequencing a genome for a Ph D — something that can be done in 24 hours, these days.

The advances have been magnificent, but until now, there has been no sign that the equivalent of Sam's dreamt-of unlimited wision has escaped us. Nobody has been too surprised, because a bit of simple physics will tell you that the idea is ridiculous. Impossible, say the older and more experienced scientists.

Somebody, I think it was probably Asimov, once said something along the lines of, "If an old, respected scientist tells you something is possible, he's almost certainly right. But if an old, respected scientist tells you something is impossible, he's very likely wrong." These days, of course, we would have to eschew the gender-specific language that marks this as an old adage — but could this old adage be right?

Quite probably, where Sam's microscope is concerned. In the August 31 (2006!) issue of Nature, there was a story about using multiphoton fluorescence microscopy to watch chromosomes change their form in order to activate their genes to synthesize key proteins in fruit fly cells.

Jie Yao used MPM to make images living salivary gland tissue of Drosophila (fruit flies). Now that takes me back 40 years to crisp autumn and winter mornings in an east-facing lab, where one ripped the heads off fruit fly grubs to drag out the salivary glands, which contain massively multistranded chromosomes. These were then placed on a slide, squashed and marinated in acetic orcein — to this day, the smell of vinegar takes me back to that time.

Proust had his petites madeleines, I have maggot innards in vinegar to switch on my recollections. That is probably the least elegant contrast of the two cultures that I have ever penned before breakfast, but that's how it is, or was.

Unlike other methods, which lack penetrating power and can damage the specimen, MPM delivers crisp, clear images, even in thicker tissue samples like Drosophila salivary glands, and from here, I will rely more heavily in the account I have had from Cornell.

Whenever a cell is stressed it produces proteins that help the cell resist stress. The process is triggered by a molecule called heat shock factor (HSF), which interacts with genes to cue the synthesis of new proteins, but this well-known process had never been seen in living cells.

The polytene cells in the salivary glands, with their giant, multistranded chromosomes, have hundreds of sets of the genome instead of the usual two sets in conventional cells. This enlarges the usual nuclear dimensions by about 10 times, making them large enough to image the detail — which is why we used to squash and stain them four decades back. They are still worth looking at.

The results were stunning. "Within two weeks we had spectacular pictures," says Professor John Lis, Jie Yao's supervisor. The images included pictures of the genes (hsp70 genes) that protect flies from the effects of extreme heat. By cranking up the heat, the researchers could activate these genes, and by using fruit flies specifically bred to carry fluorescent proteins on HSF, they could watch the transcription factors in action.

"This is the first time ever that anyone has been able to see in detail, at native genes in vivo, how a transcription factor is turned on, and how it then is activated," says Watt Webb.