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Behind the picture: Sir John Sulston’s worm cell drawings

Sir John Sulston is best known for the leading role he played in the Human Genome Project. But earlier in his career, he studied the development of the nematode worm. Sarah Harrop tells the story behind a lab notebook entry which contributed to a Nobel Prize-winning breakthrough.

Sketches showing coloured representations of how nematode worm cells divide

A page from John Sulston’s 1980 lab notebook showing his cell-tracking method (Image: Wellcome Images under CC BY 4.0)

 

These intricate biro scribblings are from the 1980 lab notebook of Sir John Sulston, completed when he was a young postdoc at the MRC Laboratory of Molecular Biology (LMB) in Cambridge. They’re the result of hours spent staring at the embryos of nematode worms under the microscope, hand-drawing their tiny cells as they divided.

Early 1980s technology wasn’t up to photographing the cells at a high enough resolution to see them dividing. So John took on the ambitious task of watching and recording each and every cell division of the developing embryo to trace the origin of each cell.

“It was sort of grunt work,” recalls John, somewhat modestly. “I sat there and did two sessions a day for about a year and a half, just picking up cells at a certain point and following each one.”

Such painstaking work required monumental powers of concentration. So John holed himself up alone in a small room at the LMB “not much bigger than a large cupboard” to block out all distractions. With the door closed and the lights low, he would sit at his microscope for four-hour stretches without a break.

As well as dividing, the cells moved relative to one another, so John needed to develop a colour system to keep track. Red denotes cells nearest to the viewer, green the next layer down, then black, blue and violet – a simple but tidy scheme that allowed John to visualise the cells in three dimensions.

The numbers show the time of day at which the sketch was made, and the encircled figures show the age of the worm embryo in minutes. The long strings of letters start with the name of one of the immature cells that can give rise to other cell types – in this case MST cells (today known as MS). Every cell divides into two daughter cells, known as the anterior daughter (‘a’) and the posterior daughter (‘p’). So the strings of letter a’s and p’s after this show the exact ‘family tree’ of every cell.

Completing a task like this was clearly a labour of love. How did John possibly manage to focus for so long?

“Well, it’s not something I would particularly hanker after doing for my whole life,” he muses. “But for that length of time, where I was discovering something new each day –for example where a particular muscle cell or neuron comes from – it was intensely satisfying.”

So why study worm embryos? John’s group leader at the time, Sydney Brenner, had chosen the nematode worm, C. elegans, as a model organism because despite its simplicity, containing fewer than 1,000 cells, it shares common features with humans.

Once John and colleagues had established the normal cell lineage of the whole worm and its embryo, the cells were mapped onto the detailed anatomy being worked out by another group of scientists led by John White. Then scientists were able to study the how genes control development at the cellular level by studying ‘mutant’ worms that didn’t behave in the normal way.

One aspect of development that was studied was the controlled death of unwanted cells. In 2002, John, Sydney Brenner and Bob Horvitz were rewarded with the Nobel Prize for Physiology or Medicine for ‘their discoveries concerning genetic regulation of organ development and programmed cell death’.

Programmed cell death is a critical part of the functioning of our bodies and goes wrong in a huge array of diseases. For example, cells die inappropriately in neurodegenerative conditions such as dementia, and divide out of control without programmed cell death kicking in in cancer. Entire biotechnology companies now exist based on the science behind the process.

So it could be said that these humble biro drawings made on a scruffy A4 piece of paper played a significant part in our modern understanding of disease.

Sarah Harrop

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