Counting lumps in the lawn: a look back at the 1975 Nobel Prize

It’s Nobel time again. This morning, the world learned the news that William C. Campbell and Satochi Omura as well as Youyou Tu had won this years’ Prize for Physiology and Medicine for their discoveries in novel therapies against infections caused by roundworm parasites and for her discoveries of new therapy for malaria, respectively.

So here at Cancer Research UK, we thought we’d look back at our own Nobel history, and at the very first of our amazing tally of six Nobel Laureates: Renato Dulbecco, who was deputy director of our London Research Institute between 1971 and 1977.

It was during this time that Dulbecco – together with Howard Temin and David Baltimore – won the Nobel Prize for Physiology and Medicine for discoveries “concerning the interaction between tumour viruses and the genetic material of the cell”.

So let’s take a trip back to where Dulbecco made his discoveries: 1950s Southern California, and to the dawn of modern cancer science, and see what exactly all the fuss was about…

A problem of measurement

The ultimate goal of modern medical research is to first figure out the molecular nuts and bolts needed to build and maintain an animal, and then use this knowledge to fix the molecular failures that lead to defects and disease.

But in the mid-20^th century, biologists had barely started work on the first part of this problem. They were stumped by two huge barriers: the difficulty of growing animal cells in the lab, and the lack of a tool with which to probe how they work.

In 1950, a lucky collision between extreme wealth and extreme discomfort jumpstarted the field by fixing both these issues. The richest cotton baron in California, Colonel James G. Boswell, had been hospitalised with a serious case of shingles and, finding out from his doctor that almost nothing was known about the virus that caused the painful disease – Varicella Zoster – decided to throw some money at the problem.

He offered the California Institute of Technology (Caltech), $225,000 (more than $2.25m, or about £1.5m, in today’s terms) to spend on research into animal viruses. Boswell’s hoped-for cure did not arrive in time to fix his shingles (in the end, his doctor prescribed a daily dose of bourbon, which the formerly teetotal Boswell took to with gusto), but his money was well-spent: working at Caltech at that time was a visionary researcher called Max Delbrück – and he was more than happy to take on Boswell’s challenge.

As Boswell had discovered, the study of viruses – known as virology – was very much in the Dark Ages. Nobody had even managed to develop a way of measuring levels of virus particles in infected organisms, let alone finding out anything useful about them.

And like with so many things, you simply can’t do proper biology without being able to measure.

Delbrück quickly summoned two of his lab members, Renato Dulbecco and Seymour Benzer, and asked whether either of them would be interested in taking on the project.

Benzer was quite happy with what he was doing, and said no. Dulbecco, however, was interested, as he’d originally trained in his native Turin as a medic, and he agreed to look into it.

After a three-month road-trip scoping out the nascent virology scene around the US, he returned to Caltech… where he was promptly banished to a small lab in the second basement for his decision to work on a very nasty virus causing Western Equine Encephalitis, which scared the pants off the rest of the department.

Dulbecco in the desert near LA (left) Image courtesy of Kathy Weston

Dulbecco realised that, to do any meaningful work with animal viruses, he first had to sort out how to grow them in the laboratory rather than in infected animals; only then could he move on to figuring out how to measure how infectious they were.

So, in his dingy sub-basement at Caltech, after much trial and error, Dulbecco managed to hit upon a way of growing flat ‘lawns’ of chicken cells that he could infect with virus. Where the virus particles infected the cells and multiplied, holes called ‘plaques’ appeared in the cellular lawn as the cells died – and by counting the holes, Dulbecco could also count how many viruses he’d added.

His publication of this work, in 1952, marked the date of a huge step forward in research on both viruses and how they cause disease in animals – including humans. Being able to measure how well a virus can infect its host is the very first step in developing ways to stop it.

But what about cancer?

So far, so good… but how could counting viruses help cancer researchers? The answer became clear when Dulbecco met a new colleague, Harry Rubin, who wanted to extend Dulbecco’s method to a class of virus that didn’t kill the host cells, but instead caused them to develop into tumours.

Using Dulbecco’s tissue culture techniques, Rubin, subsequently joined by Howard Temin, discovered that instead of plaques, tumour viruses caused the normal tissue culture cells to form little clumps of odd-looking rounded cells, all heaped up on each other, growing out of the otherwise flat cell monolayers. Such ‘transformed’ cells, as they were known, could grow for far longer than normal cells, and cause tumours in laboratory animals.

Temin and Rubin’s method, published in 1958, was a gift to the cancer research community. While tumour viruses only contained sufficient DNA to specify the make up of just a handful of proteins, they were so powerful that they could bend an entire animal cell to their will.

To do this, the tumour viruses had to be hijacking the cells’ central command systems, (which were still, in 1950, a mystery). And if an intrepid scientific detective followed in their tracks, they would be led to the same destination.

In other words, unpicking how viruses worked would lead to the cellular mechanisms they were subverting – the same mechanisms known to go haywire in cancer.

It was a way in to previously unknown territory which cancer researchers were willing and able to map out. With the tools and equipment now to hand, the molecular study of cancer began in earnest, and the field exploded into action.

The enemy within

But how exactly did these rare tumour viruses turn a cell to the dark side? When a cell is infected with a tumour virus, it has two fates: it either blows up, releasing more infectious virus, or, as Temin and Rubin had observed, it becomes cancerous. Mysteriously, in the latter case, the genetic material of the virus seemed to disappear.

For his next achievement, Dulbecco, together with his long-term collaborator Marguerite Vogt, showed that the viral DNA was incorporating itself into the DNA of the host cell, meaning that forever after, whenever the host cell divided, the viral DNA came along for the ride.

This was the first evidence that cancer could be caused by a hereditary change in a cell’s DNA, and was the crucial observation that won Dulbecco a share of a Nobel Prize.

And so to London…

Renato Dulbecco’s association with Cancer Research UK came about thanks to his friendship with Sir Michael Stoker, then Director of our predecessor organisation, the Imperial Cancer Research Fund (ICRF). By the 1970s, Dulbecco, who had fought with the Italian Resistance during World War II, was extremely dubious about the political climate in the US; the Vietnam War was still raging, Richard Nixon was President, and for left-leaning Europeans it was all getting a bit much.

Dulbecco had watched with interest as Stoker transformed the ICRF laboratories in Lincoln’s Inn Fields into a haven for the world’s best tumour biologists – the perfect refuge for him.

Like many other American biologists of that era, he realised he could work with an amazing stable of scientific thoroughbreds, and there was the added benefit of being a lot closer to his native Italy. Dulbecco moved with his wife and daughter to Chislehurst in 1971, and stayed at the ICRF for six years as Deputy Director, during which time his team made further important discoveries in tumour biology – and of course, he won the Nobel Prize. He was also highly regarded by those he worked with, both as a mentor, and as a gentle, polite, yet scientifically rigorous colleague.

Dulbecco was eventually lured back to the US to be Director of the world-renowned Salk Institute in San Diego in 1977, continuing to be a major figure in both the practising and politics of science. He was a passionate anti-smoking campaigner, and was also one of the first to suggest the human genome should be sequenced, and only retired from the lab in 2006, at the age of 92.

He died in 2012, two days short of his 98^th birthday.

But like the cells Dulbecco transformed in the lab, his legacy lives on. From the 50s onwards, our understanding of cancer has grown beyond the wildest dreams of Dulbecco and his contemporaries. Just as they’d predicted, the use of viruses as a research tool to manipulate and control animal cells led us to many of the key genes involved in cancer, such as the p53 tumour suppressor gene and the cancer-causing oncogenes … discoveries in which Cancer Research UK scientists played a crucial role.

And since the 50s, as these discoveries led to newer and better ways to help people affected by the disease, cancer survival rates too have transformed, and more people now survive than ever before.

– Kathy

For a overview of Dulbecco’s life and times by his fellow Nobelist David Baltimore see http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/dulbecco-renato.pdf

In part adapted from “Blue Skies and Bench Space: Adventures in Cancer Research” by Kathy Weston