Pioneering thinker - then and now: Methylene blue
Heinrich Caro, a German chemist, first synthesized methylene blue in 1876. The French-born scientist Claude Wischik discovered the synthetic dye’s potential as a treatment for Alzheimer’s.
Making dyes is one of the oldest human activities. Since ancient times, dye recipes have been handed down across generations. Until the mid-19th century, the basic ingredients came from plants. But with the advent of the industrial revolution and the rapid growth of the textile industry, natural dyes could no longer satisfy growing demand.
This was the world in which Heinrich Caro started his career. Chemistry was an exciting, fast-developing area. After the first synthetic coal tar dye, mauve, was obtained by William Perkin in England in 1856, chemists throughout Europe discovered a huge range of synthetic dyes, whose brilliant colors attracted high prices. Science and industry were at the beginning of their close and profitable cooperation.
Born in 1834 in Posen, Prussia (today, Poznan in Poland), Caro trained at the Gewerbeinstitut in Berlin as a textile colorist, at the same time attending chemistry lectures at the university. He got his first job in 1855 as a colorist at a calico printing company in Mülheim an der Ruhr, where natural dyes were still in use. The company sent him to England to learn the most up-to-date techniques, including advances in the use of steam. He eventually took up employment there for the Manchester chemical company Roberts, Dale & Co. Gradually he made the transition to becoming a fully-fledged industrial organic chemist, and made a series of discoveries, including a more efficient synthesis of mauve.
Caro was drawn back to Germany in 1866, where the new chemical firms provided exciting opportunities. He brought with him, from his time in England, an approach that fused academic, research-based science with an understanding of the commercial needs of industry. This proved highly fruitful in his position as the first head of research of the Badische Anilin- & Sodafabrik (BASF) in Ludwigshafen.
It was here, in 1876, that, while experimenting with a new intermediate product, he succeeded in synthesizing a pure blue dye for cotton, methylene blue. A year later, BASF was awarded Germany’s first patent for a coal tar dye for methylene blue.
Caro went on to become a leading spokesman for the German chemical industry, helping to develop patent law to protect chemical inventions, and his groundbreaking work at BASF played a key role in the foundation of the German coal tar dye industry. He joined BASF’s Board of Executive Directors in 1884 and, six years later, transferred to the company’s Supervisory Board. He died at the age of 76 in Dresden in 1910.
And methylene blue has gone on from playing an important role as a dye to having a wide variety of uses in medicine and hygiene.
When Claude Wischik arrived at Cambridge University in 1980 to do a Ph.D. under Professor Sir Martin Roth, scientists around the world were trying to work out the cause of Alzheimer’s – a disease that affects tens of millions, but for which no effective treatment exists.
Dr. Alois Alzheimer, who first described the disease in 1906, had identified thick fiber tangles in the brains of sufferers. Decades later, Roth established a correlation between the formation of tangles and the degree of dementia. He gave Wischik the task of finding out what the tangles were.
Wischik, born in France and raised in Australia, did not set out to play a pivotal role in Alzheimer’s research. His first degree was in mathematics and philosophy. He only came to medicine, he says, because meeting his wife-to-be made it clear to him he “needed a proper job”. “The trouble was,” he says, “I found myself becoming increasingly interested”.
Working in the lab at Cambridge, Wischik had to isolate the tangle before he could identify it. Colleagues suggested using the dyes alcian blue and dimethyl-methylene blue on the samples. To Wischik’s surprise, they blew the tangle fibres apart. As unexpected as this was, it gave him the idea – if you could create a drug that would dissolve the tangle, could this be the basis of a treatment for Alzheimer’s? “I was intrigued,” he says. “I spent a night in the library looking up compounds. That’s when I hit upon methylene blue. The key was, it also dissolved the tangles and had already been used psychiatrically – that meant it got into the brain.”
Wischik discovered that the tangles are made of tau, a protein normally present in the brain but which, in Alzheimer’s patients, folds back on itself and aggregates into oligomers which propagate themselves. His hope was that he had found a way to prevent tau aggregation. The theory now had to be put to the test.
Together with investors, he founded the company TauRx and set about launching a phase 2 clinical trial. By now, he had taken up the Chair of Mental Health at Aberdeen University, in Scotland. Here he met organic chemist, Professor John Storey. “Storey’s role was crucial,” explains Wischik. “Methylene blue is a fairly impure dye. Although it had been used as a pharmaceutical, it had not been manufactured to the standard required for long-term dosing. With Storey’s help, we were able to create a suitably pure form, called rember®.”
The phase 2 trial results were impressive: The drug arrested the progression of Alzheimer’s for two years. The team is now carrying out a global phase 3 trial, this time using a novel stable, reduced form of the drug, called LMTX™, that is more easily absorbed and better tolerated.
“Methylene blue is the scaffolding we used to get to where we are,” says Wischik. “Our hope is that LMTX™ will be the first disease-modifying treatment of Alzheimer’s.”
Methylene blue revealed its medical talent in 1886 when the budding doctor Paul Ehrlich noticed a curious phenomenon during his experiments: methylene blue, a dye recently synthesized by BASF, turned live neurons blue – and had the same effect on plasmodium (the parasite that causes malaria) in human blood. Ehrlich concluded that the dye might be used for selective targeting of malaria in the human body. A few years later, he tested methylene blue as a remedy to treat swamp fever – with success. For the first time ever, Ehrlich cured an infectious disease with a synthetic substance. However, quinine was already established as an antimalarial and the dye vanished into oblivion. That’s how things stayed until malaria started becoming increasingly resistant to the drugs currently in use. Then, several years ago, Professor Dr. Olaf Müller at the University of Heidelberg began looking into the blue dye. He found out that methylene blue is superior to all known antimalarial agents in important properties. In fact, it is probably the most effective drug to inhibit the transmission of infection. BASF is funding the project at the University of Heidelberg.