Malaria on Mind - II
Welcome back! ?? After a bit of a delay I am bringing this second part in the series to you and if you have missed the first part, then do read it here .?It is about how and why I got interested in Malaria, history of Malaria research, scientists who helped establish cause of Malaria, transmission cycle and first widely known antidote, from the Andes mountains.
Even though humans are suffering from and fighting against malaria for thousands of years, it remains a major global health challenge, specially with drug resistant strains and spread of Anopheles?Stephensi, an urban mosquito, extremely adapted to urban living conditions and able to breed almost anywhere including sewage water. Couple of months back WHO approved a Malaria vaccine RTS,S?(Mosquirix), which has efficacy of 30% against severe malaria.
Here in this part, I have dwell on to other important aspects of Malaria, search for it’s cure and turn of events because it.
Malaria, Colors, TB and Chemotherapy
Beginning of 19th Century, the Dutch were controlling 95% of Cinchona supply through plantations in Java and remaining minority was controlled by the British through plantations in Nilgiris & Eastern Himalayas. Malaria weighed heavy on WWI troops and the race was on to look for Quinine alternative(s). Monopoly in a very valuable commodity was going to be challenged by advances in Organic and Synthetic Chemistry.
French chemist duo Pelletier and Caventou had isolated quinine in 1820. In 1865 William Perkin, then 18-year-old student of Chemistry in his effort to synthesize Quinine, synthesized an organic purple dye which he called as “Mauve”. This aniline dye gave rise to entire organic dye industry. Many medicines derived from dyes such as sulfa drugs, antidepressants, tranquilizers, anti-diabetic drugs revolutionized and formed the basis of modern medicine. ?
Early 18th century fabric dyeing relied on natural dyes which British and other colonial powers had in abundance whereas Germany relied on imports. Thus Germany took keen interest and established synthetic dye plants and factories and soon became the leading player in synthetic dye industry with companies like Bayer, Agfa and BASF, (by the way A in BASF stands for Aniline). In WWI Germany lost as many soldiers to Malaria as to allied forces. Post war the Dutch were prohibited from supplying Quinine to Germany. Having learnt the importance of controlling Malaria to gain better control on war outcome, Germany chemical industry took on the challenge and delivered synthetic dye derived antimalarial drugs such as Quinacrine. These dye derived drugs had several side effects including turning skin color to blue, yellow or red depending on the dye, also not to forget depression, fatigue, seizures etc.
What makes discovery of synthetic organic dyes special and important is that it immensely helped various scientific pursuits. Walther Flemming first observed and described in detail the behavior of chromosome in the nucleus during cell division, a process called “Mitosis”. He used aniline dyes to visualize cell structure. Way ahead of its time, Flemmings’s discovery was fully appreciated only after couple of decades. ?Another great scientist Robert Koch applied aniline dyes to stain bacteria to better see and study them under microscope. He discovered the bacteria Tubercle Bacillus, responsible for Tuberculosis or TB, another giant of killer diseases. Robert Koch received Nobel in 1905 for this discovery. So many Nobles related to Malaria already! Another great mind of the times, Paul Ehrlich among many of his other significant contributions also applied dye staining method for cancer research, paving way for chemotherapy. Ehrlich received Nobel Prize in 1908, for his contribution to Immunology.
Polaroid and a Dog
Meanwhile efforts were on for total synthesis of Quinine, but it remained a challenge till 1944 when Woodward and Doering achieved formal total synthesis. Woodward worked as a consultant for Polaroid, yes Polaroid! Polaroid was interested in Quinine due to its light polarizing properties. Edward Land the owner of Polaroid used powdered Heraphite, extruded with polymer film to create the polarizing sheet in 1929. In fact, the discovery of Heraphite or Iodoquinine sulfate is as serendipitous as it can get. It was discovered by a physician and toxicologist of Royal Society of England who was studying Quinine when one of his students added iodine salt to urine of a dog who was administered Quinine!
In Germany, Karl Zeiss chemist Ferdinand Bernauer independently grew large single crystals of Heraphite between two glass plates which were sold as polarizing filter under trade name of Bernotar. How Bernauer grew such big single crystals is still a mystery. If we can decipher how he did it, it could be a breakthrough in organic electronics. Detailed crystalline structure of Heraphite was unknown and was only uncovered in 2009. So next time you look at your smart phone, wear sunglasses or watch 3D movie think of Malaria and that dog ??.
Resochin to Hydroxychloroquine: From Germany to America via France
Chloroquine, an alternative invented at Bayer by Hans Andersag in 1934, did get away with the side effect of color staining but other side effects still lingered. Germans invented Chloroquine but made a mistake of writing it off initially. Bayer at that time branded Chloroquine as Resochin for commercial purposes. This mistake has become an idiom of sort, “Resochin Error”, where actual (good) value is not realized due to evaluation mistake. During WWII, the leftover stash of Resochin by Germans in one of the captured posts by the French, landed in American hands who tweaked the formula to give us the now famous Hydroxychloroquine as a treatment for COVID- 19. Hydroxychloroquine was equally effective with lesser side effects.
There were some other anti-Malarial drugs that were invented in the 40’s and 50’s however most had serious side effects including hallucinations and severe nausea.
Purple Decade
Let’s just take a moment to appreciate the original “Mauve”, invented by Perkin.
?Original publication screenshot with fabric dyed with Perkin’s Mauve, Credit: Courtesy of Science History Institute
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Prior to the chance discovery of “Mauve”, purple color was obtained with natural dyes and available only to royalties. After Perkin’s discovery it became widely available to commoners. Europeans took liking to the new color so much so that the 1890’s is known as the “Purple Decade”. I want to and will write about links and associations between Fashion and Science, both are my interests even though I know neither..
Malaria Fights back, Vietnam War and China
By the 60’s, Malarial parasite had developed resistance against most known antimalarial drugs. It was again war which pushed for antimalarial drug discovery. In mid 60’s, it was again war which pushed for antimalarial drug discovery. During the Vietnam war, North Vietnam sought China’s help to fight against Malaria which was resistant to known treatments.
Taking up the challenge, China gave the world much needed effective, tolerable, and safe antimalarial drug. When Prof. YouYou Tu. was tasked with inventing new antimalarial drug, she turned to old traditional Chinese medicinal texts for help. She successfully extracted the active ingredient, Artemisinin from the bark of Sweet Wormwood and demonstrated its efficacy. She became the first mainland Chinese researcher to receive Noble Prize in 2015 for discovery of Artemisinin, which has saved countless lives. One more Malaria related Nobel and counting! ?ACT( Artemisinin -Combination- Therapy) has been a WHO recommended ?and widely practiced therapy against Malaria.
Control & Eradication of Malaria
Much before advances in synthesis of antimalarial drugs, nature was conferring some protection against Malaria, either by natural compounds and natural selection! A couple of years ago, I read “Survival of the Sickest” by Dr. Molem, wherein he talks about Sickle Cell Anemia offering protection from Malaria. The deformed shape of red blood cells in Sickle Cell, happens to be non conducive for Malaria. Prevalence of Sickle Cell Anemia and Malaria Endemic areas overlap, suggesting Sickle Cell genes were favored during evolution. This was one of the evolutionary biological responses to Malaria.
Another method is vector control where the parasite vector i.e., mosquito is eradicated. DDT (Dichlorodiphenyltrichloroethane) was synthesized in 1874, it was only till late 30’s it was discovered and used as an insecticide by allied force in WWII for Malaria control. Another Nobel Prize goes in Malaria related category. Paul Hermann Müller received Nobel in 1948 for discovery of DDT!
There are many aspects and debates about continued use of DDT as a vector control method as it may have serious adverse effects on humans and many mosquito vector types have become resistant to DDT since 1960’s. Agricultural use of DDT is banned in many countries including India however public health use continues. ?It was with help of DDT, India almost eradicated Malaria in the 60’s but due to combination of various factors, Malaria staged a powerful comeback in India in the 70’s. India has set the target of 2030 to become Malaria free.
Mystery that is Malaria
It has been known for long that co infection with Malaria often confers advantage in fight against other diseases.
It goes way back in history where relationship between fever and mental afflictions was noted and studied as well. Hippocrates of the famous Hippocratic oath had observed effect of fever on epileptic patients, while working in an asylum. ?Austrian physician & physiatrist Julius Wagner-Jauregg also had observed this effect on senile patients and studied it further. He induced fever by means of artificial bacterial infection as well as Malarial infection. He concluded that Malarial fever was most effective in treating Neurosyphilis. This method was acceptable as Malaria had definite cure and it can be intervened at any point. His treatment method for treatment of Neurosyphilis was popular well into the 1950’s. It was later displaced with broad spectrum antibiotics after discovery of Penicillin. Dr. Wagner received Nobel Prize for this discovery in 1929, another Nobel connection with Malaria. It was Paul Ehrlich who used synthetic organic dyes to find bacteria responsible for TB, also found cure for Syphilis in 1909!
Author Amitav Ghosh in his novel “Calcutta Chromosome” has given this Malaria-Neurosyphilis connection a wonderful treatment and given a us a masterpiece. Set in New York and Calcutta with intertwined timelines, it is a must read. Written in 1997, the book has some interesting take on AI and its applications as well. In fact, it is the routine inventory check by AI which starts the whole story ??. I am deeply impressed by the novel and want to see it on screen, preferably as a series. Amazon Prime, Netflix, Disney, HBO and everybody else, are you listening?
It is observed that co-infection of Malaria and Ebola increases chances of survival by a significant degree.?Children with respiratory disease fare better if there is Malaria co-infection, as observed in a study in Tanzania. Also once infected these parasites also seem to affect the behavior of mosquito hosts. It makes them more aggressive in terms of number of bites and ferocity of bite they inflict on humans.
Truth & Fiction
Now think of this, Plasmodium Falciparum, the protozoa responsible for Malaria has done something rather strange. Millions of years ago ancestors of this class of protozoa snacked on an algae and instead of digesting it completely decided to retain and some of its DNA. This mysterious DNA group can be key to Malaria treatment. Algae and all plant species committed similar DNA robbery and acquired photosynthesis capabilities by swallowing light harvesting bacteria millions of years ago!
Truth is stranger than fiction and our individual and collective lives are shaped by many things beyond our control. Seemingly unrelated things can have deep connection and in the post-pandemic world, need of the hour is curiosity and open mindedness to tackle the new challenges our society is facing.
References
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