Not long after the Second World War, Australian colonial officials assigned to the remote plains of Papua New Guinea noticed an unusual disease among the members of a small tribe called Fore. The locals called the ailment “kuru” which, in their language, means “to tremble”. That is because those affected by the disease gradually became unable to control their muscles, started to shake and sometimes even laugh or cry uncontrollably. Once the first symptoms of the disease appeared, the sufferer’s death would follow in a matter of months.
The unusual diet of the natives
In 1957 when Carleton Gajdusek, at the time a 33-year-old doctor, arrived to New Guinea, the stories about the mysterious disease, told by the colonial officers, immediately caught his attention. He set out to visit the tribe and began conducting a thorough analysis to discover the true cause of the illness. In order to research the disease Gajdusek had to gather samples of the tissue belonging to the diseased natives. Most of the time he managed this by buying a dead body and doing an impromptu autopsy, sometimes right on the kitchen table in his hut, and then saving the tissue samples in a shared refrigerator.
When, after carrying out different tests, he eliminated the possibility that the disease was being caused by viral or bacterial infections, he started examining all the environmental factors that could have contributed to the outbreak of the disease. He analyzed the food that the members of the tribe ate as well as the surroundings of their dwellings, but he was unable to discover the cause of the disease. Even worse: he failed to classify kuru by any of the main medical categories into which diseases are usually sorted. By all appearances, kuru was neither a genetic disease nor an infection, nor a psychosomatic disorder; and neither was it caused by the environment.
After long years of research, which he continued in the USA, Gajdusek succeeded in proving that the disease was transmitted through brain tissue. He used a sample of a kuru patient’s brain tissue to infect the brains of a healthy monkey and it fell ill with the disease. In 1976 he received the Nobel Prize for Medicine for his research on this “completely new form of infection”.
It soon became clear why the disease was spreading even more rapidly among the women and children of the tribe. It turned out that the kuru disease epidemic was caused by ritual cannibalism adopted by the tribe from their neighbors. It was typical of the tribe not to cook and eat their enemies, but their own people who had passed away. This culinary ritual represented a part of their custom of bidding farewell to the dead. Symbolically, the funeral was compared to digestion and the tribe shared different parts of the cooked corpse according to the hierarchical structure of their society; only feeding on the members of the inner family circle was forbidden. If a woman died, for example, her daughters-in-law would get her arms and legs while her sisters-in-law would get her buttocks and her intestines. If a man died, his testicles were given to their uncles’ wives.
Cannibalism disappeared from New Guinea four decades ago after being successfully eradicated by the missionaries soon after their arrival. However, a few of the older female members of the Fore tribe still die of kuru each year, which indicates that the incubation period can last very long. According to evaluations, the disease has caused the death of almost 3000 natives.
Has the central dogma of molecular biology been violated?
However, Gajdusek is not the only researcher to have received the Nobel Prize for work in this interesting field of medicine. In 1997 the prestigious scientific award was also given to Stanley Prusiner, who succeeded in substantially developing Gajdusek’s findings and discovering the mechanism that explains how kuru and similar diseases actually work on a molecular level. (Gajdusek also became known for being one of the few Nobel laureates to have been sentenced to prison at an old age. In 1997, while living in the USA, he was sentenced to 18 months’ imprisonment for child molestation. He found out about Prusiner’s Nobel Prize while serving his sentence.)
In 1972 Prusiner, then a young neurologist based in San Francisco, lost a patient to Creutzfeldt-Jakob disease, which is well known today on account of the “Mad Cow” disease. As he did not know much about the disease at the time, he buried himself into literature and found out that it had been proved through tests on animals that Creutzfeldt-Jakob disease, along with scrapie (a disease of livestock) and the exotic kuru disease from Papua New Guinea, were all transmitted by the infection of healthy brain tissue with a sample taken from a diseased organ.
As the only research material he could get in sufficient amounts were infected sheep, he decided to try and isolate the agent that causes scrapie, a disease of the central nervous system which affects small cattle (sheep, goats and pigs). The method required for isolating such an agent was complicated because different types of molecules had to be extracted from the infected tissue. These molecules then had to be tested in order to determine whether they caused the disease or not. Or, to give a more detailed description of the process: a sample of brain tissue was taken from a diseased animal and put into a centrifuge in order to separate individual molecules. The further separated samples were then injected one by one into a mouse to determine which part was still infected. The process was then split into further phases to observe and determine which parts were still causing the disease.
The first hypotheses suggested the existence of so-called “slow viruses”, but it turned out that the extract obtained from diseased brains could still cause an infection, even if all the nucleic acids which contain the viruses’ genetic material were destroyed with radiation. It was also found, however, that by adding enzymes that deform proteins the sample did become less contagious, which meant that proteins were most probably the main cause of the disease.
Proteins are very important molecules in our bodies, often called nature’s robots. They perform many kinds of different tasks in our cells. They are built from long chains of amino- acids which do not crawl around cells like long snakes, but form complex structures as soon as they come into existence. It is only in this form that they become active and capable of performing their various tasks. The protein called hemoglobin, for example, carries oxygen through blood.
Nobody was able to understand, though, how proteins multiplied in the absence of the DNA or RNA which contain the instructions for their production. According to the classical theory, the foundation of all modern biology, genetic material is stored in DNA molecules which provide the basic information cells need to produce the proteins which then perform different tasks in our bodies. According to this theory, also called “the central dogma” of molecular biology, the transfer of information is only possible from DNA to proteins and in no way in the opposite direction. A protein cannot create instructions for its own production and write them into the cell genome. It is rather always the cell that produces the proteins, keeping their blueprints stored inside its genetic code.
Quite a few hypotheses attempting to solve the riddle of the mysterious infectious proteins were made, but in the end the most unusual one turned out to be the most accurate, and it was this theory which won Pruisner his Nobel Prize. As he was aware of the fact that publicity and promotion of a discovery is an important part of science, he needed an attractive name to suit his innovative idea. He wanted something simple, easy to remember, that would sound like already established scientific terms such as quark, proton, neutron, electron … And so, the prion was born.
Usually, only one form of a protein is stable. Prions are special among proteins because they have two stable forms. The common, natural form can be found in healthy organisms while the other one causes the disease. The most extraordinary thing is that the “bad” prion has a great ability to recruit and convert the prions around it. If it meets a “good” prion it will most probably turn it into a “bad one” when they come into contact. The consequence of this conversion is that in the presence of merely a few “bad” prions the majority of the “good” prions eventually turn “bad”. And this is exactly what happens in the case of prion diseases. Prions are, in fact, proteins that can multiply without the participation of genes.
In the case of a spontaneous occurrence of Creutzfeldt-Jakob disease, the first “bad” prions appear by coincidence and they immediately start their mission of conversion. In about a year after the first symptoms occur, the patient succumbs to the disease. Some families, fortunately there are no more than a hundred in the world, are genetically prone to suffer from this disease due to their slightly different genetic code. Nevertheless, others can be infected by “bad” prions as well. In some cases, people were infected while having their brains examined because doctors repeatedly used the same electrodes, transferring the diseased patient’s “bad” prions to the healthy patient’s brain, where the evil proteins set out on their deadly mission.
A mutation in the part of the genetic code responsible for the production of prion proteins can also cause an unusual disease, named fatal family insomnia. It was first noted in the 1980s in a respectable Italian family whose ancestors, upon reaching middle age, have for centuries died of unusual symptoms which were always accompanied by insomnia. Sometime between their 35th and 60th year of life some of the family’s members found themselves suddenly unable to fall asleep normally. The problems could not even be remedied with potent sleeping pills and they continued to grow worse with every month until the patient, terminally exhausted, fell into a coma which was followed by death less than a year after the first symptoms occurred.
A cure for treating prion diseases has yet to be found. This is due to the fact that it is extremely difficult to prevent “bad” prions from leading other prions astray once they have entered a body. The usual kinds of drugs successful in fighting viruses and bacteria are powerless here. A prion inside a living body practically cannot be “killed”.