Of Slow Viruses And Prion

Today, we as a species cutting across barriers, face the onslaught of a virus pandemic with wave after wave of mutations and alterations.

From wet markets that satisfy the fancy appetite of humans to lab-escape from experiments shrouded in mystery, the origin of the pandemic virus remains hotly debated.

But here we present a reversal of the story — of how scientists bravely investigated into human misery to mitigate it with brilliant insights and collaborative detective team work.

Read on.

One of the major challenges to biologists today is the task of discovering not only the cause of, but also the cure for a group of diseases which slowly and irreversibly destroy the entire nervous system.

They are identified by either one or more of a wide range of symptoms such as the loss of acquired skills, the inability to perform elementary manual operations, the lack of coordination of muscles, advancing paralysis of limbs and finally, in some cases, the rapid destruction of the brain, resulting in death.

Rita Hayworth, a beauty-queen of Hollywood, who had brought delight to millions of fans, and who after a fairy tale romance, had married one of the world’s richest men, died due to Alzheimer’s disease; Ronald Reagan former President of the United States also died due to the same disease; and the legendary Stephen Hawking, the greatest English physicist since Newton, was confined to a wheelchair, till his death, having been stricken with amyotrophic lateral sclerosis.

There are a few other disorders such as Kuru, Creutzfeldt-Jacob disease, multiple sclerosis, and human spongiform encephalopathy, which also belong to the same category of debilitating or crippling ailments that have baffled medical science.

What is pathetic is the manner in which the diseases slowly drive the afflicted persons to the level of existence of a vegetable, before extinguishing their lives.

In fact, sometimes, death comes as a relief to those suffering from such diseases, towards the end, from an opportunistic infection, such as pneumonia.

Scientists had found no evidence to suggest that these diseases represent a natural aspect of the ageing process or occur due to hardening of the arteries.

Nor had there been a basis to suggest that they were being caused due to known agents such as bacteria. However, biologists had a vague suspicion that all these diseases were probably caused by some kind of viruses whose mode of transmission was yet unknown.

In 1957, a brilliant doctor from the United States, Carleton Gajdusek, visited Papua New Guinea. There, he lived among the Fore tribe, in an isolated rain forest, and studied their language and culture.

He found that mostly women and children of the tribe had a rare neurological disorder called Kuru. Gajdusek, with his uncanny observation and attention to detail, noticed that the disease ran into three stages.

In its first stage, a person with Kuru exhibited some loss of bodily control. He usually had difficulty balancing and maintaining posture. In the second stage, or sedentary stage, the person was unable to stand or walk. Body tremors and significant involuntary jerks and movements began to occur.

In the third stage, the person was usually bedridden and incontinent. He lost the ability to speak. Some afflicted persons also exhibited dementia or behaviour changes, causing them to seem unconcerned about their health.

Starvation and malnutrition usually set in at the end of the third stage, due to the difficulty of eating and swallowing. These secondary symptoms invariably led to death within a year.

Gajdusek performed autopsies on those people.

He suspected that Kuru was being transmitted during occasions of mourning when the villagers ate the brains and other tissues of dead relatives as a sign of respect (years later, he also considered the possibility of the infection having been transmitted directly into the blood through cuts and scratches during a ritual involving vigorous rubbing or massage).

The Fore were ritualistic cannibals who ate their dead. By 1950, twenty-five per cent of Fore women were dying of Kuru. The condition was observed in children of both sexes as well as a few adult men.

Put briefly, a person with Kuru progressed through three stages of increasingly intense tremors, shivering, staggering, inability to walk or swallow, till death put an end to his miseries.

After Gajdusek studied the disease in New Guinea, he later teamed up with a virologist in the United States, Clarence Joseph Gibbs, to establish what they called the Laboratory of Slow, Latent and Temperate Virus Infections.

Their theory was that the cause of Kuru was some form of slowly developing virus that was transmitted during the process of eating the brains and other tissues of the deceased.

Other deadly neurological diseases had been observed that seemed to exhibit a similar course of symptoms and brain pathology e.g Creutzfeldt-Jacob disease (CJD) in humans, and scrapie in sheep.

Gajdusek and Gibbs set about to determine the real cause of these puzzling and strange diseases.

In 1963, Gajdusek procured a brain sample from a Fore boy who had died from Kuru. He hand-carried the tissue back to the U.S to the lab run by Gibbs.

They wanted to see if an animal infected with the boy’s brain tissue would become ill. They purchased three two-year-old chimpanzees: Daisy, “George,” and an unnamed chimpanzee.

On February 17, 1963, they inoculated Daisy with the boy's tissue. On September 17, 1963, they anaesthetised Georgette, drilled a hole through her skull and injected a solution of pureed brain from the Fore boy directly into Georgette's cerebellum.

Georgette was very young at the time, weighing only about 13 pounds.

Both Daisy and Georgette developed Kuru, only after a long period of incubation. Then it progressed rapidly when it started, and was unlike any previously understood infection.

They, therefore, called the causative agent a "slow virus" and showed that Kuru in humans was related to scrapie in sheep.

As Gajdusek was returning home, an American scientist, William Hadley, was leaving for England to study scrapie, a disease mostly affecting sheep.

Hadley, who had by accident seen Gagdusek's slides of Kuru victims and their brain tissue, could not fail to see the similarities between Kuru and scrapie and had hinted in a letter to the prestigious British medical journal Lancet that the same type of pathogen might be responsible for Kuru as well as Creutzfeltd-Jacob disease.

Gajdusek was awarded the Nobel Prize for Medicine in 1976, for his researches into Kuru

Meanwhile, in England, scientists had succeeded in transmitting scrapie into mice. What was more significant was that the disease had manifested itself in mice within five months unlike in the case of sheep in whom it took a longer time.

The experiments gave useful clues about the pathway of the scrapie agent through the body and underscored the difficulty in. separating it from the membranes of brain cells.

The most startling revelation about the so-called ‘slow virus’ was the possibility that it might not be a virus at all because it had nothing in common with all other known viruses.

.1. First of all, it was unaffected by heat, radiation or and chemicals which destroy all known bacteria and viruses. It also had an amazing survival ability resisting all known sterilising procedures such as boiling, exposure to alcohol, formaldehyde and other disinfectants.

2. Unlike other viruses or bacteria, it could not be seen even under an electron microscope.

3. Its most remarkable feature, however, was its ability to multiply even though it did not have either DNA or RNA — the genetic material central to all forms of life. Hence, its very existence was a violation of the basic laws of biology.

4. When injected into susceptible animals (such as chimpanzees, guinea pigs, mice and hamsters), the symptoms took 18 months or more to appear, following which rapid destruction of the brain took place.

5.The the nucleic acids (RNA & DNA) are the means by which disease is transmitted in the case of viruses. A virus, which is merely a strand of DNA or RNA encased in a protein skin acts by getting rid of its skin and inserting itself into the DNA cell, taking over the genetic machinery and giving a signal to the cell to produce viruses.

The infected cell bursts, releasing new viruses which once again attack neighbouring cells. Scientists were, therefore, unable to explain how in the the case of Kuru (as well as Creutzfeldt-Jacob's disease), the organism in question, which has no DNA and RNA, accomplishes the destruction of cells in this fashion.

In 1974, Gajdusek decided to take up the purification and identification of the scrapie agent. A number of other scientists joined him.

The first stage in the procedure was to produce a pinkish sludge from the ground-up brains of hundreds of infected hamsters. The sludge was then placed in a centrifuge to separate it into various fractions and by using chemicals and by passing an electric current in a process known as electrophoresis the molecular components were separated.

In a tissue which was diseased a gel-coated plate used in the process showed the presence of a foreign protein.

Several years later, Gibbs and Gajdusek used brain tissue from a man who had died from Creutzfeldt-Jacob disease (CJD) to inoculate a three-year-old male chimpanzee.

Thirteen months later, that chimpanzee developed symptoms of CJD and was killed 16 months later when his symptoms became severe and unbearable. An autopsy of his brain confirmed that Creutzfeldt-Jacob disease (CJD), too, was transmissible in the same manner as the other diseases.

While matters stood thus, Stanley Prusiner, an American neurologist and biochemist and his colleagues succeeded in 1982 in preparing a protein solution in the same manner, stated above.

Prusiner postulated the existence of Prions, a class of infectious self-reproducing pathogens, primarily or solely composed of protein.

But Prusiner, in the beginning, had not been successful in determining the chemical structure of the active and mysterious particle in the solution which he believed to be a protein molecule.

Because of its lack of similarity to all other known forms of life, its precise status could not be defined.

Prusiner basically got interested in this group of brain diseases because one of his patients died of Creutzfeldt-Jacob disease which was similar to two diseases that could be transmitted by cannibalism — Kuru which affects human beings and scrapie which affects sheep.

Prusiner followed the work of Gajdusek vigorously and his persistence was rewarded.

By 1982 he concluded that the so-called slow virus was actually a proteinaceous infectious particle and christened it the ‘prion’. His theory that prion, and not a slow virurses was responsible for all these similar diseases was at first viewed by sceptics with suspicion.

Prusiner's theory that a protein which has no nucleic acids and, therefore, cannot multiply or replicate but can cause brain diseases was at first considered bizarre and new. It made no sense.

However, scientists soon came to agree with Prusiner's theory that Kuru in humans, Creutzfeldt-Jacob disease in humans , human spongiform encephalopathy, scrapie in sheep, bovine spongiform encephalopathy in cattle (mad cow disease), and chronic wasting disease in deer are all " transmissible spongiform encephalopathies", affecting the the structure of the brain or or other neural tissue in mammals.

They have the very odd characteristic of being transmitted by what is currently presumed to be a misfolded (misshapen) protein called a "prion". No bacteria, virus, or other organism was responsible for the disease. The protein solution had the ability to resist heat, radiation and chemical action and to transmit disease to other animals, as stated earlier.

Thus, general medical opinion now appears to be going in favour of Prusiner's hypothesis of the prion. His contribution was recognised as very significant and he was awarded the Nobel Prize in 1997.

Prusiner also feels that there is a possibility that the prion may even be a small virus, with a protein shell so thick that its genetic material is protected from investigative probes or, perhaps, an agent which has its own DNA or RNA hidden away where it cannot be found easily.

Many scientists are generally against the idea of asking for funds for research on specific diseases at the cost of and in preference to broader and more productive programmes in basic science.

This is because of a general belief that when a basic research is carried out, crucial information relating to the cure for certain diseases will automatically emerge as a fringe benefit.

However, in the case of prion, because of the very nature of the disease, and the humiliating manner in which it makes afflicted persons suffer, even such scientists would not, perhaps, be unwilling to advocate targeted research, i.e. directing research towards a specific goal such as tackling Kuru or Alzheimer's disease.

Justification for such goal-directed research is also provided by the fact that, at present, nothing can be done to alleviate the sufferings of these patients by medical care alone.

No reorganisation of medical programmes based on the present level of knowledge scientists have, in respect of these diseases, would in any way prove helpful to them.

All the same, it must be realised that these people urgently need help and a complete cure has to be found soon.

When the story of the discovery of Kuru comes to be written by future science historians, the pride of place would be given to Gajdusek for his painstaking researches in an isolated rainforest in a remote island , his untiring efforts and powers of observation. Prusiner would then be given credit for discovering that all neurodegenerative diseases like Kuru, Spongiform encephalopathy and Creutzfeldt-Jacob disease are caused by a proteinaceous infectious particle.( prion).

Diseases like Kuru, Alzheimer's, Creutzfeldt-Jacob's disease, amyotrophic lateral sclerosis, human spongiform encephalopathy, multiple sclerosis , and sub-acute sclerosing panencephalitis (a rare late complication of measles), seem to be cataclysms designed by nature to test the human spirit.

Those who suffer from these diseases are sidetracked from the broad sunlit avenues of ongoing life, totally deprived of the instincts, emotions, intelligence imagination, and motor activity, that make life worth living,

While death may be preferable to such an existence, finding a cure for restoration of the above basic faculties, and saving their lives, would represent one of the noblest achievements, and greatest triumphs of medical science.