Deriving Life from Venom

loading The Malayan pit viper.

One scientist’s resolve to uncover a medical mystery led to a possible treatment for stroke, but the cure comes from a most unexpected source.

It is called the “hundred pacer” because victims of its bite meet their death by the time they have taken their hundredth step. While the veracity of this local legend is questionable, many survivors are left with amputated or dysfunctional limbs. The culprit? Ancistrodon rhodostoma, otherwise known as the Malayan pit viper.

Little did Penang-born pathologist Prof. Dato’ Dr Chan Kok Ewe know that the snake’s venom can treat stroke patients.

In the 1960s Chan was instrumental in unravelling the medical mystery of why some bite victims suffer local bleeding, while others do not. He made the medical breakthrough while serving as the specialist pathologist at the Institute for Medical Research (IMR) branch laboratory of the Penang General Hospital in 1960.

“I used to attend clinical rounds with a senior medical consultant, Dr Hugh Alistair Reid, at GH Penang;” says Chan. “He was in charge of handling snake bite cases from Sungai Petani; the more severe ones were brought to Penang for treatment.

“Reid was puzzled as to why the victims’ blood was unable to clot. When blood is drawn and placed in a test tube, it normally becomes solid through clotting, but not that of these victims’, which interestingly stayed uncoagulated for up to two weeks. Not all patients whose blood did not coagulate bled, contradictory to medical expectation – in such cases, the patients should have bled to death. This was indeed a startling deviation from medical knowledge.”

Being 27 at the time and having developed a keen interest in correlating clinical laboratory findings to the state of the disease in patients, Chan was eager to find an explanation for the medical anomaly. With limited lab equipment and the existing conflicting state of medical knowledge, Chan set to work.

Six months later, and after many failed attempts, the mystery was finally cracked. “It’s a funny story actually. I was taking tea one evening when the idea suddenly presented itself, almost like an epiphany,” recalls Chan. “I thought that maybe the fibrinogen, the plasma protein responsible for forming the blood clots, was depleted.”

He decided to put the theory into practice: fibrinogen was added to the blood (of snake bite victims) that wouldn’t coagulate, which soon clotted. Electrophoresis (a technique used in laboratories to separate macromolecules based on size) of the victims’ blood plasma also confirmed the absence of the tell-tale fibrinogen band, validating Chan’s theory further.

Prof. Dato' Dr Chan Kok Ewe.

Chan continued his examination of the snake venom’s properties, though this time by studying its in vivo effects in a controlled environment. Two active components were discovered in the toxin: one responsible for the undesired local effects, and the other for depleting the fibrinogen in the body.

Fibrinogen is essential for blood-clotting and to staunch profuse bleeding; when the wall of a blood vessel is damaged, platelets in the blood come together to form a plug to stop the bleeding.1 But the plasma protein is also liable for causing thrombi formation (blood clots), resulting in medical disorders such as heart attacks and pulmonary embolism.2

Chan’s clinical findings would soon be pivotal in developing treatments for blood circulatory disorders; the removal of the body’s fibrinogen by the snake venom suggests potential in isolating its anti-clotting factor and using it to develop an anti-thrombotic drug. “I persuaded Reid to patent the venom with the National Research Development Corporation in the UK as a possible drug in thrombosis.” Its patenting, however, required the isolation of the active component from the crude venom, which was successfully extracted by leading protein chemist Dr Peter Esnouf at the Royal Infirmary, Oxford.

In 1964 Chan, along with Reid and Esnouf, patented Ancrod (Arvin), the anti-thrombotic drug used to prevent venous and arterial thrombus. Manufacturing in the UK and Germany soon began. The snake venom, as quoted by the (then) West German embassy, was credited to have changed the fate of 10,000 Germans suffering from peripheral arterial problem, who would have otherwise lost their limbs to gangrene.

“Ancrod is the drug of the future and is now also being explored as a possible treatment for ischemic stroke caused by arterial blockage to the brain,” says Chan. In the event of an ischemic stroke, the blood and oxygen flow in the brain is reduced locally, leading to hypoxia (deficiency in the amount of oxygen reaching the tissues) of the cells near the location of the original insult. This can lead to hypoxic cell death (infarction) and continued amplification of the original damage from the ischemia; however, due to increased blood flow to the brain as a whole because of reduced blood viscosity by Ancrod, further ischemic damage may be minimised.

Extracting the venom of a Malayan pit viper.

The tPA (tissue plasminogen activator) drug is currently the only FDA - approved treatment for ischemic stroke. The drug works to dissolve clots, thus improving blood flow to the affected brain area. On the flipside, the clot-busting drug must be administered within three hours (or up to four and a half hours in certain eligible patients) for better recovery chances.3

Though still experimental, Ancrod is believed to be the next best treatment for stroke; the drug not only prevents the build-up of existing clots and improves blood flow to the brain, it thins out the blood and prevents new clots from forming as well. Most importantly, it can be administered within a six-hour time frame, extending the timespan of the tPA.

For all of Ancrod’s potency, the drug is derived from venomous reptiles, which certain segments of the public might be averse to. “But if Ancrod is capable of minimising interruption to daily living, it should be given the opportunity to do so,” says Chan. “When a doctor treats a patient, there’s no guarantee the patient will pull through, but it is imperative for all possible efforts to be exhausted for the patient’s survival – that is what practicing medicine is about.”

Source: Transformation Through Invention: A Short History of MINDS

1https://www.thestar.com/life/health_wellness/2013/12/09/snake_venom_could_help_treat_heart_attacks_and_strokes_toronto_study.html

2Transformation Through Invention: A Short History of MINDS

3http://www.strokeassociation.org/STROKEORG/AboutStroke/BLS/Stroke-Treatments_UCM_310892_Article.jsp#.Wr-ovIhubIW



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