Mustard gas – from the Great War to frontline chemotherapy

One hundred years ago a great conflict began that would change the world forever. World War I, also known as the Great War, would leave 17 million people dead or missing in action. Stuck in the squalid conditions of the trenches, it was a living hell for those on the front line.

But it was made even worse by the work of industrial chemists.

In July 1917, troops based in Ypres, Belgium, reported a shimmering cloud around their feet and a strange peppery smell in the air. Within 24 hours they started to itch uncontrollably and developed horrific blisters and sores. Some started coughing up blood.

A poppy field

They’d been poisoned by mustard gas – one of the most deadly chemical weapons deployed in battle.

And because mustard gas can be absorbed through the skin, gas masks were useless. Even fully clothed soldiers weren’t fully protected. It could take up to six weeks to die from mustard gas, and it was a terrible way to die.

Towards the end of the Great War, this gas had not only killed and crippled but instilled terror across the battlefield. The first use in Ypres alone left up to 10,000 people dead, with many more injured.

Mustard gas was one of a number of weaponised poison gases developed by Fritz Haber, a Professor at the prestigious University of Karlsruhe. Haber was a brilliant chemist, who invented a process for the industrial scale production of ammonia-based fertiliser. This brilliant discovery, known as the Haber process, played a huge role in avoiding worldwide famines and now feeds about a third of the world’s population. It won him the Nobel Prize in Chemistry in 1918.

But Haber’s role in chemical weapons’ development means his legacy will always have its dark side.

Even after the war, Haber enthusiastically promoted the use of poison gas. And his colleagues would go on to make other deadly gases – World War I is known to some as the chemists’ war.

But the story of mustard gas didn’t end there. And it has a brighter ending than you might think.

 “In the middle of difficulty lies opportunity”- Einstein

Two decades later, with World War II looming, researchers on the side of the Allied Forces feared a repeat of the mustard gas attacks of the Great War. So they tried to create antidotes.

What they discovered led them into a very different battle.

Two doctors at Yale University, Louis Goodman and Alfred Gilman, delved into the medical records of soldiers affected by mustard gas, and noticed that many of them had a surprisingly low number of immune cells in their blood – cells that, if mutated, can go on to develop into leukaemia and lymphoma.

Goodman and Gilman hypothesised that if mustard gas could destroy normal white blood cells, it seemed likely that it could also destroy cancerous ones.

After successful animal trials, Goodman and Gilman looked for a human volunteer with white blood cell cancer to test mustard gas as a cancer therapy. They found a patient with advanced lymphoma, known today only by his initials: J.D.

A massive tumour on J.D.’s jaw meant he couldn’t swallow or sleep – he couldn’t even fold his arms across his chest because the tumours in the lymph nodes in his armpits were so big. He was encased, front and back, by cancer. His doctors tried everything they could, but his outlook was considered hopeless.

With nowhere else to turn, J.D agreed to try the new experimental drug. At 10am on the 27^th of August 1942 he was given the first injection of what they called “synthetic lymphocidal chemical”. This was in fact nitrogen mustard, the compound used to make mustard gas. Because of the war, J.D.’s treatment was a secret and it was referred to in his records only as “substance X”.

He received a number of treatments with substance X and with each one he became a little better. He could sleep, he could swallow and he could eat. He was much more comfortable and the pain faded away.

This was a monumental moment in the history of medicine. It was the beginning of what we now know as chemotherapy.

Mustard gas to modern medicine

Back in the UK and after WWII, another brilliant chemist, Professor Alexander Haddow, became Director of the Chester Beatty Research Institute – an Institute funded by one of the founding charities that merged to form Cancer Research UK. He was working on compounds that could block the growth of tumours and treat cancer.

All he needed to make a breakthrough in cancer treatment was a lead – an effective molecule to start from. Mustard gas gave him that much needed and crucial starting point.

In 1948, Haddow published a ground-breaking piece of research in the journal Nature, showing exactly which bits of the nitrogen mustard molecule were needed to kill cancer cells. Perhaps more importantly, he also found out how to make the chemical less toxic, but with more potent cancer-killing activity.

The molecular structure of chlorambucil

Haddow began by showing that nitrogen mustards could stop the growth of tumours in rats. Then in experiments akin to tinkering with Lego, he altered bits of the molecule, replacing them with different ‘bricks’. Replacing certain bits, in particular either of two chlorine atoms, rendered the molecule useless and it no longer blocked tumour growth in his rats.

This was an important finding, showing that the molecule needed both chlorine atoms to work. And replacing certain other parts of the molecule altered its activity too. Through this molecular puzzle Haddow worked out which pieces were needed to make a treatment that would benefit cancer patients across the globe.

He continued his research, showing how these chemicals actually worked – it was by somehow linking together other molecules inside the cancer cell, ultimately leading the cell on a suicidal path. Other researchers then went on to show that these linked molecules were in fact strands of DNA. This triggered the cell’s self-destruct mechanism – causing the cell to shut down and break apart, destroying it.

The future is changing

And so mustard gas went from the very real battleground of the WWI trenches into the frontline of cancer treatment. But for J.D, the treatment came too late. Although it worked initially, giving him an immensely important extra few months with less pain and greater comfort, he lost his life six months after his experimental treatment was started. There is just one entry in his medical records from the 1st of December 1942. It simply says “Died”. J.D passed away unaware of the impact that his life and death would go on to have.

But Haddow’s subsequent work launched the start of a new era of cancer treatment – chemotherapy. All of the drugs that followed worked in the same basic way as Haddow described. And in fact, nitrogen mustard derived chemotherapy is still used to treat some cancers today.

The chemical structure Haddow published is only a few atoms away from the structure of the drug chlorambucil, which is still used to treat a type of leukaemia called chronic lymphocytic leukaemia and another blood cancer called non-Hodgkin lymphoma (NHL). Survival from NHL has nearly trebled since the early 1970s and now over 60 per cent of people survive for at least 10 years, thanks in part to this drug. And work continues on these sorts of treatments to make them kinder, with fewer side effects.

Haddow’s research led to the development of more chemotherapy treatments that have completely changed the outlook for other types of cancer. Cisplatin and carboplatin work in a similar way to the nitrogen mustards. Cisplatin even has two critical chlorine atoms, the same as mustard gas. And it’s largely responsible for the fact that 96 per cent of men with testicular cancer now survive the disease long term.

But chemotherapy is just one of the ways we treat cancer at the moment. And anyone who’s been through it knows that, despite decades of evolution away from the trenches, chemotherapy is still, for many, a very difficult and unpleasant experience.

So we have developed, and will continue to develop, more and more targeted treatments designed to pick out specific cancer targets – like a sniper selecting precisely who to ‘take out’. And immunotherapies – designed to switch on our own defences against cancer – acting like the Black Ops of cancer treatment.

But for now there’s still a place for chemotherapy – one of the first chemical weapons in our ever-growing arsenal against cancer.

Sarah

• With many thanks to the BBC, in particular Giles Harrison – Producer of the series Pain, Pus and Poison: The Search for Modern Medicines for allowing us the use content for the Poison episode.

Reference:

• HADDOW, A., KON, G., & ROSS, W. (1948). Effects upon tumours of Various Haloalkylarylamines Nature, 162 (4125), 824-825 DOI: 10.1038/162824a0
• Images via Wikimedia Commons (trenches, poppies, chlorambucil)