By Isabel Vincent, University of Glasgow

Female scientists often struggle disproportionately compared to their male counterparts, but every now and then a woman will manage to break through the misogyny and show the world the potential that is often missed. Youyou Tu received the Nobel prize for medicine/physiology in 2015 for the discovery of the anti-malarial drug artemisinin – a remarkable achievement for a woman with no medical degree, no doctorate and no overseas experience.

Born in Ningbo in Zhejiang province in December 1930, Tu was the only girl in a family keen on education for all. As a result, Tu attended the best private schools in the region, gaining a foundation in botany, literature and medicine that would prove critical to her future successes. At Peking university, Tu studied for a pharmacology degree, which included the origins of medicinal plants and how to categorise and identify them. She also learned to process drugs to reduce side effects and increase potency – skills which would later come in handy as she developed dihydroartemisinin, an improved derivative of the initial plant-derived artemisinin.

Tu was working at the Academy of Traditional Chinese Medicine, and was married with two daughters, when she was asked to participate in a mysterious new project for the Chinese Government.

Project 523

It was January 1969. Mao’s cultural revolution was in full swing: intellectuals were being persecuted and scientific funding was cut dramatically. Tu was approached by Chairman Mao’s representatives to find a drug that would cure malaria under project 523. Malaria was decimating Vietnamese troops fighting in the jungles of South West China and the only treatment at the time, chloroquine, was failing due to high levels of resistance. Hundreds of thousands of potential compounds had been screened by the US with little success, and China had been making slow progress since the malaria unit was set up in 1967.

Descriptions of malarial fevers can be found throughout recorded history. Tu believed that clues to its cure might lie in the archives of ancient Chinese texts. Tu’s team spent three months scouring manuscripts, collecting more than 2,000 herbal, animal and mineral prescriptions dating back to the Zhou dynasty (1,100-220 BC). A shortlist of 640 prescriptions was made and tested. Many texts suggested the use of the herb Qinghao (Artemisia auunua) for malaria but lab results were inconsistent. Tu hypothesised that the active compound was heat labile and tested alternative extraction solvents at lower temperatures.  Eventually “sample 191” – an ethyl ether extract – was shown to be 100% effective against rodent malaria and a new treatment was born.

From herb to drug

Refining the extract to find the active compound was straightforward for a scientist as meticulous as Tu. First, she separated the neutral and acidic portions, finding most activity in the neutral portion while the acidic part had higher toxicity. The neutral fraction gave conflicting results in terms of toxicity and the delays were frustrating for the team as the malaria season was coming to an end. Tu and two of her colleagues therefore decided to take the drug themselves to prove its safety in humans. Luckily, they didn’t suffer any side effects and further tests on the team proved its safety at higher doses. Clinical trials followed as Tu focused her attention on identifying the active compound.

Tu found that the compound could be crystallised from the ethyl ether extract then purified by silica gel column chromatography. She identified the molecular formula before finally getting the structure using x-ray crystallography.

 

Tu didn’t stop there. In 1973, she carried out structure-activity relationship studies, modifying each functional group in turn seeking compounds with more potency or better interactions with the host. Reducing a carboxyl group to a hydroxyl group using sodium bromohydride, for example, yielded dihydroartemisinin – a compound 10-fold more active than artemisinin.

 

 

Decades later, more than 200 million people have taken artemisinin, either alone or in combination with other anti-malaria drugs. Tu Youyou has saved millions of lives but said in 2007 “I do not want fame. In our day, no essay was published under the author’s byline”.

Drug discovery from the natural world

Many antibiotics in use today are derived from natural products and have evolved within plants and fungi as defence mechanisms against infections and herbivores.

Could there be other cures hiding in the diversity of plants and animals around us?

Tu’s team trawled through thousands of texts and tested hundreds of prescriptions before recognising A. annua as a contender warranting further investigation. Now there are research institutes around the world testing natural products from anything from plants to venoms, hoping to find the next artemisinin.

We don’t know how artemisinin developed in plants or how it acts on malaria, but there are efforts to find out. Mass spectrometry of malaria extracts treated with drugs can give tell-tale signs of disruption of normal metabolism within the parasite. The same techniques can analyse the plants’ own biosynthetic pathways and how they change during their growth process and under stress, providing clues as to why A. annua developed such a useful compound.

Further reading

• Phillips T. Tu Youyou: how Mao’s challenge to malaria pioneer led to Nobel prize. Guardian 2015.
• Hatton C. Nobel Prize winner Tu Youyou helped by ancient Chinese remedy. BBC 2015.
• Youyou Tu – Biographical. Nobelprize.org. Nobel Media AB 2014.
• Haynes RK, Vonwiller SC. Extraction of artemisinin and artemisinic acid: preparation of artemether and new analogues. Trans R Soc Trop Med Hyg. 1994 ;88 Suppl 1:S23-6.

About me

I am a biochemical data analyst at Glasgow Polyomics (@polyomics) and a specialist in analysing drug modes of action using mass spectrometry metabolomics. I am also Chapter Lead of ScienceGrrl Glasgow (@SciGrrlGlasgow) where I lead activities hoping to ‘normalise’ female scientists, making scientific careers more accessible to everyone.