Staggers and Downers

The kuru epidemic reached its height in the 1960's (Lindenbaum, 1979). Between 1957 and 1968, over 1,100 of the South Fore died from kuru (Lindenbaum, 1979). The vast majority of victims among the South Fore were women. In fact, eight times more women than men contracted the disease (Lindenbaum, 1979). It later affected small children and the elderly at a high rate as well. This is to be expected, since women were the prime participants in mortuary cannibalism (Lindenbaum, 1979). It is currently believed that kuru was transmitted among the South Fore through participation in such cannibalism. Upon the death of an individual, the maternal kin were in charge of the dismemberment of the corpse (Lindenbaum, 1979). The women would remove the arms and feet, strip the limbs of muscle, remove the brains, and cut open the chest in order to remove internal organs (Lindenbaum, 1979). Lindenbaum (1979) states that kuru victims were highly regarded as sources of food, because the layer of fat on victims who died quickly resembled pork. Women also were known to feed morsels such as human brains and various parts of organs to their children and the elderly (Lindenbaum, 1979).

Misinterpretations of Kuru

Scholars who first studied the disease among the South Fore initially had two major misconceptions concerning the nature of the disease. They first incorrectly postulated that it was a genetic disorder. After this possibility was ruled out, scientists next asserted that kuru was the manifestation of a slow virus. Genetic disorders can be fully understood through application to population genetics. Mutations provide variation and fuel natural selection. A genetic disorder is one that is caused by a mutation that is passed on to subsequent offspring. Since kuru had a tendency to occur among family members (Lindenbaum, 1979), the original notion that it was a genetic disorder seems somewhat appropriate. This possibility was eventually ruled out, because kuru was too common and too fatal (Lindenbaum, 1979). A completely lethal genetic disorder would drastically reduce the fitness of a population. Sooner or later it would die out of the gene pool. This fact led scholars to seek additional possible explanations to describe the dynamics of the disease.

Studies on chimpanzees injected with brain material from a victim led scientists to believe the agent was a slow virus, because the chimps developed a very similar condition after a long incubation period (Gadjusek et al., 1966). Gadjusek was responsible for conducting these tests on chimps. He defined a slow virus as a viral disease with an abnormally long incubation period (Gadjusek et al., 1966). In humans, kuru had an incubation period with a minimum of two years and maximum of 23 years (Lindenbaum, 1979:26). Gadjusek's results also confirmed the infectious, transmittable nature of the prion. Mestel (1996:185) writes, "Since then, his [Gadjusek's] team has shown that CJD [Creutzfeldt-Jakob disease] and GGS [German-Straussler-Scheinker syndrome] are also infectious..." With kuru, there was no evidence of an immune response or an antibody. It will become evident later that both of these hypotheses were incorrect. For now, the specific symptoms of kuru are relevant in gaining a more complete understanding of the disease as a neurological disorder.

Symptoms of Kuru

Gadjusek studied kuru, and he found the condition of kuru victims to be an upsetting sight. He explains, "...to see them, however, regularly progress to neurological degeneration in three to six months (usually three) and to death is another matter and cannot be shrugged off" (Gadjusek, 1996:10). Gadjusek (1973) reported three main stages in the progression of symptoms. The first stage is called the ambulant stage, and it includes unsteadiness of stance, gait, voice, hands, and eyes; deterioration of speech; tremor; shivering; in- coordination in lower extremities that moves slowly upward; and dysarthria (slurring of speech) (Gadjusek, 1973). The second stage is also known as the sedentary stage, and Gadjusek (1973) defines it with the following symptoms: patient can no longer walk without support, more severe tremors and ataxia (loss of coordination of the muscles), shock-like muscle jerks, emotional lability, outbursts of laughter, depression, and mental slowing (it is important to note that muscle degeneration has not occurred in this stage, and tendon reflexes are usually still normal) (Gadjusek, 1973). The third stage is the terminal stage, which is marked by the patient's inability to sit up without support; more severe ataxia (loss of muscle coordination), tremor, and dysarthria (slurring of speech); urinary and faecal incontinence; difficulty swallowing (dysphagia); and deep ulcerations appear (Gadjusek, 1973). Cerebellar dysfunction is the cause of these conditions. Symptoms are generally common among prion diseases, as a comparison with Creutzfeldt-Jakob disease will demonstrate.

Comparison to CJD

Creutzfeldt-Jakob disease displays striking similarities to kuru in regards to symptoms displayed and organ damage (mostly to the brain). Comparisons and parallels are evident between these two prion diseases. By inspecting an in depth case study of CJD from Massachusetts General Hospital, it is possible to gain a more complete understanding of prion diseases.

At age 47, a woman feeling depression sought professional help at Massachusetts General Hospital (Scully et al., 1993). She became hypoactive, noticed impairment of her recent memory, and had urinary incontinence (Scully et al., 1993). Within a few months she became dizzy and had an unstable gait (Scully et al., 1993). At this point a computed tomographic scan (CAT scan) of the brain showed slight cerebral and central atrophy; delusion began to set in (Scully et al., 1993). According to Scully et al. (1993), by age 50 the patient's cranial-nerve functions were still normal, as well as motor power, sensation, and coordination. The next symptom to appear was the occurrence of inappropriate laughter, and her replies to questions became irrelevant and incorrect (Scully et al., 1993). Mild tremor was noted, although the cranial-nerve functions, strength, coordination, and sensation were still intact (Scully et al., 1993). At this time another CAT scan was performed, and the results were the same as the year before (Scully et al., 1993). Within a week after this scan, she was readmitted with shaking spells (Scully et al., 1993). There was a constant alteration between laughing and crying, but reflexes were still normal (Scully et al., 1993). By the age of 51 and a half years, her speech had deteriorated rapidly, and a new CAT scan showed marked cerebral and cerebellar atrophy (Scully et al., 1993). According to Scully et al. (1993), gradual deterioration continued up until her death four months prior to her fifty-fourth birthday.

Important similarities occur between Creutzfeldt-Jakob disease (CJD) and kuru. Both prion diseases cause tremor and inappropriate laughter. Depression was expressed early in CJD and in stage two of kuru. Unsteadiness in gait and sporadic muscle jerks were observed in both ailments. Dysarthria occurred in kuru during the initial stages of the diseases and in CJD more towards the end, and the exact same situation is seen with the condition of urinary incontinence as well.

The Prion Protein

The exact nature of kuru perplexed scholars for decades after the discovery of the ailment, until Prusiner identified and defined prion diseases in 1982 (Prusiner, 1995). Prusiner (1991) classified a prion as an infectious particle composed of a protein that causes neurodegenerative disorders. According to Cashman (1997), prions are infectious agents by biological and medical criteria. However, they are also fairly unique, and properties of prions differ from those of conventional microbes. All known prion diseases are fatal. Such diseases are often called spongiform encephalies, because they frequently cause the brain to become spongy and riddled with holes (Prusiner, 1995). Well known prion diseases include scrapie, bovine spongiform encephalopathy (mad cow disease or BSE), and Creutzfeldt-Jakob disease (CJD). Less well-known prion diseases include the following: transmissible mink encephalopathy, chronic wasting disease, feline spongiform encephalopathy, exotic ungulate encephalopathy, German-Straussler-Scheinker syndrome (GSS), and fatal familial insomnia (Krakauer et al., 1997). Of these infirmities, four affect humans: Creutzfeldt-Jakob disease, Gertsmann-Straussler-Scheinker syndrome, fatal familial insomnia, and kuru. The most common form of prion disease is scrapie, expressed in sheep and goats (Prusiner, 1995). According to Cohen et al. (1994), prions cause a variety of degenerative neurologic diseases that can be infectious, inherited, or sporadic in origin. The cause of the sporadic forms is unknown; inherited forms are caused by up to twenty different mutations of the human PrP gene; and the infectious forms are transmitted through contact with or consumption of previously infected tissues (Prusiner, 1997).

PrPC is the normal, cellular prion protein, and it is converted into PrPSc (Prusiner, 1997). Mutations in the 102nd codon of this gene have been linked to neurodegeneration, which is the main, encompassing attribute of the prion diseases. Prusiner (1995) identified 15 amino acids at one end of the PrP protein. Using this knowledge, molecular probes were constructed and used to study the sequences of the normal verses the mutated form of the gene (Prusiner, 1995). Specifically, Prusiner discovered that the amino acid leucine is substituted by the amino acid proline (Prusiner, 1995). An incident of this type is commonly known as a point mutation. In the case of prion proteins, this mutation encodes additional copies of an octapeptide repeat toward the 5' end (Krakauer et al., 1997). The normal protein consists of mainly alpha helices with a spiral backbone, but the new, mutated prion protein is predominately formed by beta strands with a fully extended backbone (Prusiner, 1995). This alteration in tertiary structure provides evidence for post-translational modification of the protein.

Subsequent to the publication of this article, thousands of scientists tried to figure out the prion puzzle. According to Prusiner (1995), extracts from scrapie-infected brains were subjected to ultraviolet and ioninzing radiation (Prusiner, 1995). Such treatments usually destroy nucleic acids, but these tissues remained infectious (Prusiner, 1995). Prusiner (1995) concluded that the scrapie agent was indeed nucleotide-free, like a protein. This means that a prion does not contain DNA or RNA, which disproved Prusiner's first hypothesis (that the prion could possibly be a virus). Furthermore, the prion was inactivated by extreme treatments that destroy or denature proteins, such as chaotropic ions or denaturing detergents (Cashman, 1997). After discovering these clues, scientists began to question the prion's method of replication.

Cashman (1997) has suggested that the same nucleic acid and amino acid sequence gave rise to the two, different proteins. Further studies indicated the structural differences between the normal protein PrPC and the abnormal prion protein PrPSc. To summarize, the normal protein (PrPC) dissolves in nondenaturing detergents and breaks down easily with exposure to proteases, but PrPSc does not dissolve and is partially resistant to proteases (Prusiner, 1997). PrPSc can inhabit various acidic or basic environments, because it is stable between pH 2 and 10 and has survived two year immersions in formol saline (Mims and White, 1984). The last important feature to note with respect to the pathogenic prion particle is that the prion protein gene (PrP) in laboratory mice controlled the incubation time, neuropathology, and prion synthesis within the infected organism (Prusiner 1991).

Prion Replication

Scientists believe that the replication of a prion particle occurs almost exactly as the duplication of a virus. The mechanism of replication involves the synthesis of polypeptides in the absence of nucleic acid templates and the post-translational modifications of cellular proteins (Prusiner, 1991). A polypeptide is a chain of amino acids, and a nucleic acid template is a group of DNA or RNA molecules that carry information to direct cellular functions. For the prion, replication involves converting conventional proteins into prions. The resulting PrPSc is a four helix bundle protein with four regions of secondary structure, numbered H1 through H4 (Prusiner, 1997). Mestel (1996) explains that prions replicate by recruiting normal proteins to their cause, "flipping" them into a rogue prion-like shape that can go on to infect other cells and animals. This change initiates a chain reaction, and newly converted prions convert other proteins which they come into contact with on the interior of their respective cell membrane (Prusiner, 1995). In cell cultures, the conversion occurred inside neurons. The PrPSc accumulated in lysosomes and eventually filled the lysosomes until they exploded, releasing the prions to attack other cells (Prusiner, 1995). Future understanding of the operation of the PrP gene could possibly lead to a manipulation of these conditions in patients with a prion disease.

Development of Therapies

Currently, Prusiner (1995) believes that a more comprehensive understanding of the three-dimensional structure of the PrP protein will lead to the development of therapies. According to Prusiner (1995), experiments with laboratory mice were conducted. The PrP gene was targeted, and mice lacking the gene were created (Prusiner, 1995). In this case, the animals did not display any noticeable side effects or abnormalities (Prusiner, 1995). This is encouraging: if further studies show the PrP gene to be inessential, then physicians may be able to inject antigene therapies to patients with prion diseases in the future (Prusiner, 1995).

Recently, prion infections have been termed amyloidoses (Serpell et al., 1997). Serpell and colleagues state, "Amyloidoses are diseases...in which soluble proteins are deposited in a specific, highly stable, fibrillar form" (Serpell et al., 1997:871). Amyloid fibrils have three diagnostic characteristics: under the electron microscope, the fibrils are straight and unbranched with a smooth surface; amyloid fibrils can be stained with Congo Red and subsequently exhibit an apple-green birefringe; and they have a distinct X-ray defraction pattern, indicative of the beta sheets found in the PrPSc formation (Serpell et al., 1997). Understanding the process of amyloid formation may aid in the development of therapies for such diseases.

Since the 1950s, scientists have worked on the prion puzzle. Microbiologists and epidemiologists have been confused by the prions. Advancements have been made, especially in the 1990s. This can be evidenced by Prusiner's reception of the Nobel Prize in 1997. However, it has still been difficult to detect prion infection, track its transmission, and type the different strains (Cashman, 1997). The Fore experienced a long struggle with kuru, which serves as a poignant example.

Conclusion

Since the discovery of the kuru epidemic in New Guinea, a vast amount of knowledge has been gained concerning prion diseases. The specific dynamics of the kuru disease are important to realize in order to better understand all prion diseases. Scientists admit that there is still a lot of ground to cover in this area of research. Numerous questions have been answered, yet many puzzles still remain to be solved. A large amount of the work done in the name of understanding prion diseases was carried out by anthropologists in the field studying the Fore. Their contributions to this research have played an enormous role. Fortunately, kuru has disappeared in New Guinea, but many prion diseases remain that can attack humans and animals. Although the case may be closed for kuru, the other prion diseases must continue to be studied in the hopes of conquering these illnesses.

References Cited

Cashman NR (1997) A prion primer. Canadian Medical Journal Association, 157(10):1381-1386.

Cohen FE, Pan K, Huang Z, Baldwin M, Fletterick RJ, and SB Prusiner (1994) Structural clues to prion replication. Science, 264:530-531.

Gadjusek DC (1996) Kuru: from the New Guinea field journals 1957-1962. Grand Street, 15:6-33.

Gadjusek DC (1973) Kuru in the New Guinea Highlands. In Spillane JD (ed): Tropical Neurology. New York, Oxford University Press.

Gadjusek DC, Gibbs CJ, and M Alpers (1966) Experimental transmission of a kuru-like syndrome to chimpanzees. Nature, 209:794.

Krakauer DC, de Zanotto PM, and M Pagel (1998) Prion's progress: patterns and rates of molecular evolution in relation to spongiform disease. Journal of Molecular Evolution, 47:133-145.

Lindenbaum S (1979) Kuru Sorcery. Mountain View, Ca, Mayfield Publishing Company.

Mestel R (1996) Putting prions to the test. Science, 273:184-189

Mims CA and DO White (1984) Viral Pathogenesis and Immunology. Boston, Blackwell Scientific Publications.

Prusiner SB (1991) Molecular biology of prion diseases. Science, 252:1515-1521.

Prusiner SB (1995) Prion diseases. Scientific American, 272(1):48-56.

Prusiner SB (1997) Prion diseases and the BSE crisis. Science, 278:245-251.

Scully RE, Mark EJ, McNeely WF, and BU McNeely (eds) (1993) Case records of the Massachusetts General Hospital. N Eng. J. Med., 328:1259-1266.

Serpell L, Sunde M, and CCF Blake (1997) The molecular basis of amyloidosis. Cellular and Molecular Life Sciences, 53:871-887.

The Guardian

The US government was yesterday scrambling to calm public fears over its food supply after America's first recorded case of mad cow disease was found in a sick animal in Washington state.

Ann Veneman, agriculture secretary, said the positive test for BSE (bovine spongiform encephalopathy) was "presumptive" and would be confirmed in a British laboratory. But she said the administration was confident that the finding was accurate and had already implemented measures to curb its spreading.

A sample was believed to be on its way to the World Reference Laboratory in Pirbright, Surrey, where a sample was sent from Canada in May after a BSE alert there.

The US was last night notifying the country's trading partners and Ms Veneman was not sure how they would react.

However, she assured Americans: "The risk of spreading is low based on the safeguards and controls we have put in place." She said the risk of the disease entering the human food chain was minimal. "I plan to serve beef for my Christmas dinner and we remain confident in our food supply," Ms Veneman said, in an echo of the then British agriculture minister John Selwyn Gummer's ill-fated ploy to have his young daughter eat a hamburger on behalf of British beef in 1990.

The infected cow identified yesterday was a Holstein which was tested because it was a "downer", unable to walk, when it arrived at a Washington state slaughterhouse. The meat from the cow was nevertheless sent to a processing plant.

Agriculture department investigators were yesterday urgently trying to track it down.

Ms Veneman said that only the "muscle cuts" had been sent for processing for human consumption and there was no record of the disease being transmitted through the meat. The brain and spinal column had been sent to a "rendering facility" elsewhere, but she did not specify how it had been used.

The news hit an already nervous American public, entering the Christmas holiday under a high state of alert because of the risk of a new terrorist attack. Ms Veneman felt it necessary to stress there was no evidence of terrorism in the BSE incident.

However, her assurances that the outbreak would be contained were questioned by public health activist, John Stauber. He called them "ex tremely disingenuous", and pointed out Ms Veneman was a former lobbyist for the cattle industry. "I suggest this cow is the tip of an invisible iceberg," Mr Stauber, co-author of a book about the threat of the disease, told CNN last night. "My presumption is mad cow disease is spread throughout North America at some level, but because our testing programme is so inadequate we have not identified it."

He said the US livestock industry, unlike its European counterparts, continued to practise "animal cannibalism".

That appears to have happened with the Washington cow. Yesterday, Elsa Murano, under secretary of agriculture for food safety, said its brain and spinal column had been sent to such a plant, to be turned into protein feed, oils and other products. It is the brain and spinal cord that are the most likely to be infected with prions, the misfolded proteins that can lead to a mad-cow-like disease in humans.

This does not guarantee that infected matter will never make its way into the human food supply, critics noted yesterday.

Under Food and Drug Administration regulations issued in 1997, it is illegal to feed protein made from cows, sheep, deer and other so-called ruminants to other ruminants. But it is still legal to feed the rendered protein to pigs, chickens and other animals. Those animals in turn can be rendered and fed to cows or sheep. Also, beef blood and beef fat can be fed to calves.

"You can go into any feed store and buy Calf Starter or calf milk substitute," said John Stauber, co-author of "Mad Cow U.S.A.," a 1997 book that warned that the disease could reach this country. "We're weaning calves on cattle blood proteins, even though we know blood plasma can carry the disease."

Also, said Sheldon Rampton, Mr. Stauber's co-author, questions have been raised about how effective the F.D.A. bans on feeding across species are.

If an animal becomes infected, the incubation period of the disease is three to eight years, so the detection of one animal with the disease suggests that others may have been infected by the same source but have not yet been found.

Mr. Stauber said an F.D.A. memorandum in 1997 predicted that if a single case of encephalopathy was found in the United States and a total ban on all feeding of animal protein to animals was immediately enacted, it was still possible that as many as 299,000 infected cows would be found over the next 11 years.

December 24, 2003
WASHINGTON -- Although the United States Department of Agriculture insisted the U.S. beef supply is safe Tuesday after announcing the first documented case of mad cow disease in the United States, the agency for six months repeatedly refused to release its tests for mad cow to United Press International.

The USDA claims to have tested approximately 20,000 cows for the disease in 2002 and 2003, but has been unable to provide any documentation in support of this to UPI, which first requested the information in July.

In addition, former USDA veterinarians tell UPI they have long suspected the disease was in U.S herds and there are probably additional infected animals.

USDA Secretary Ann M. Veneman announced late Tuesday during a hastily scheduled news briefing that a cow slaughtered Dec. 9 on a farm in Mabton, Wash., had tested positive for mad cow disease. The farm has been quarantined but the meat from the animal may have already passed into the human food supply.

The slaughtered meat was sent for processing to Midway Meats in Washington and the USDA is currently trying to trace if the meat went for human consumption, Veneman said.

The fear is mad cow disease can infect humans and cause a brain-wasting condition known as variant Creutzfeldt-Jakob disease that is always fatal. More than 100 people contracted this disease in the United Kingdom after a widespread outbreak of mad cow disease in that country in the 1980s.

An outbreak of mad cow disease in the United States has the potential to dwarf the situation in the United Kingdom because the American beef industry is far larger and U.S. beef is exported to countries all over the globe.

"We're talking about billions of people" around the world who potentially have been exposed to U.S. beef, Lester Friedlander, a former USDA veterinarian who has been insisting mad cow is present in American herds for years, told UPI.

The USDA insisted the case is probably isolated and the US beef supply is safe. "I plan to serve beef for my Christmas dinner," Veneman said, "and we remain confident in the safety of our food supply."

Responded Friedlander: "She might as well kiss her (behind) goodbye, then."

Veneman went on to say she had confidence in the USDA surveillance system for detecting mad cow and protecting the public, noting the agency has tested more than 20,000 cattle for the disease this year.

This represents only a small percentage of the millions of cows in the U.S. herd, however, and experts say current procedures are unlikely to detect mad cow.

The Washington cow was tested because it was a so-called downer cow -- a cow unable to stand on its own -- which is a sign of mad cow disease. However, the United States sees approximately 200,000 of these per year or about 10 times as many animals are tested for the disease.

USDA officials told UPI as recently as Dec. 17 the agency still is searching for documentation of its mad cow testing results from 2002 and 2003.

UPI initially requested the documents on July 10, and the agency sent a response letter dated July 24, saying it had launched a search for any documents pertaining to mad cow tests from 2002 and 2003.

"If any documents exist, they will be forwarded," USDA official Michael Marquis wrote in the letter.

Despite this and a 30-day limit under the Freedom of Information Act on responding to such a request, the USDA never sent any corresponding documents. The agency's FOI office also did not return several calls from UPI placed over a series of months.

Finally, UPI threatened legal action in early December if the agency did not respond.

In a Dec. 17 letter to UPI from USDA Freedom of Information Act Office Andrea E. Fowler, the agency wrote: "Your request has been forwarded to the (Animal and Plant Health Inspection Service) for processing and to search for the record responsive to your earlier request."

To date, the USDA has not said if any records exist or if they will be sent to UPI.

"It's always concerned me that they haven't used the same rapid testing technique that's used in Europe," where mad cow has been detected in several additional countries outside of the United Kingdom, Michael Schwochert, a retired USDA veterinarian in Ft. Morgan, Colo., told UPI.

"It was almost like they didn't want to find mad cow disease," Schwochert said.

He noted he had been informed that approximately six months ago a cow displaying symptoms suggestive of mad cow disease showed up at the X-cel slaughtering plant in Ft. Morgan.

Once cows are unloaded off the truck they are required to be inspected by USDA veterinarians. However, the cow was spotted by plant employees before USDA officials saw it and "it went back out on a special truck and they called the guys in the office and said don't say anything about this," Schwochert said.

Veneman said the Washington case "does not pose any kind of significant risk to the human food chain."

Friedlander called that assessment, aptly enough, "B.S." Referring to the USDA's failure to provide their testing documentation to UPI, he said, "The government doesn't have records to substantiate their testing so how do they know whether this is an isolated case." The agency also cannot provide any assurance that this animal did not get processed for human consumption, he said.

Schwochert agreed with that, saying the USDA's sparse testing means they cannot say with any confidence whether there are additional cases or not.

Both Schwochert and Friedlander said the report of a mad cow case would devastate the U.S. beef industry.

"It scares the hell out of me what it's going to do to the cattle industry," Schwochert said. "This could be catastrophic."

Only hours after Veneman's announcement, Japan -- the biggest importer of U.S. beef -- and South Korea both banned the importation of American meat.

The American Meat Institute, a trade group in Arlington, Va., representing the U.S. meat and poultry industry, maintained the U.S. beef supply is safe for human consumption.

"First and foremost, the U.S. beef supply is safe," AMI spokesman Dan Murphy told UPI. "We think its safe for U.S. consumers to eat."

This is because infectious prions, thought to be the causative agent of mad cow and vCJD, are not found in muscle tissue that comprises hamburgers and steaks, he said. They are generally located in brain and spinal cord tissue.

However, recent studies have suggested prions may occur, albeit in smaller numbers, in muscle tissue, and bits of brain and spinal cord tissue have been detected in hamburger meat.

Other protective measures have also been put in place that should protect consumers, Murphy said.

Mad cow disease is thought to be spread by feeding infected cow tissue back to cattle -- a practice that was common in the United Kingdom and is thought to have contributed to their widespread outbreak. The practice has been banned in the United States by the Food and Drug Administration since 1997, which should help ensure this is "an isolated case," Murphy said.

A report from the General Accounting Office issued just last year, however, found some ranchers in the United States still violate the feed ban and do feed cow tissue to cattle.

The GAO concluded: "While (mad cow disease) has not been found in the United States, federal actions do not sufficiently ensure that all (mad cow)-infected animals or products are kept out or that if (mad cow) were found, it would be detected promptly and not spread to other cattle through animal feed or enter the human food supply."