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Saturday, January 24, 2004

A Bird In The Hand


Dr. Lester CN Simon

This is not a political article. The title came to mind because of the outbreak of avian influenza (bird flu), which has spread from birds to humans. It also represents a comical look at some of our sayings and nursery rhymes. For example, I never expected to see the day (or night) when the cow jumped over the moon. But cows have made the lunar leap. They have become stark raving, non-grazing lunatics, as Mad Cow Disease shows us.

The basic science of influenza tells us that there are three types of influenza viruses. Type A, type B, and type C. Wild birds are the natural habitat of influenza A virus. From wild birds it can spread to chicken, pigs, whales, horses, and seals. On the surface of the influenza A virus, there are two proteins called protein H (hemagglutinin) and protein N (neuraminidase). There are 15 types of protein H (H1, H2 ….H15) and 9 types of protein N (N1, N2…..N9). Hence there are 135 (15 x 9 = 135) subtypes of influenza A viruses. Two subtypes of influenza A found in humans are A (H1N1) and A (H3N2). Influenza B and influenza C viruses are found only in humans.

Pigs can be infected with two different subtypes of influenza A virus. In the pig, the genes responsible for making protein H and protein N can become assorted and then they can re-assort. This can result in the formation of a new virus. For example, subtypes H3N4 and H5N6 viruses in a pig can swap genes to produce a third virus subtype, H3N6.

The pigs are crucial because pigs are susceptible to infection from both avian and mammalian viruses, including human influenza subtypes. Pigs act as “mixing vessels” for the creation of new subtypes. Recent research suggests that humans can serve as “mixing vessels” just like pigs. The danger with new subtypes is that most people may have little or no protection since they were never exposed to the new subtype, either by natural infection or by vaccination. This may allow for an epidemic or a pandemic.

Over the past 100 years, there have been 3 flu pandemics. In 1918-1919 the Spanish flu was caused by influenza A (H1N1). About 20 million people died worldwide.
In 1957-1958 the Asian flu by influenza A (H2N2) caused 98,000 deaths. In 1968-1969 about 46,000 people died from the Hong Kong Influenza A (H3N2) pandemic.

The flu (influenza) and the common cold affect the respiratory system. They are caused by different viruses. The flu is worse than the common cold. People with the cold have a runny or stuffy nose. It may be difficult to tell the difference, but the flu is usually more intense, with fever, body aches, extreme tiredness and dry cough. The flu may be complicated by pneumonia and can result in hospitalization, especially in high risk groups such as the elderly and the chronically ill.

Bird flu (avian influenza) is caused by influenza type A. Bird flu runs a spectrum from mild illness to rapidly fatal disease in birds. Fifteen subtypes of influenza A infect birds. Subtypes H5 and H7 are highly contagious among birds, and are rapidly fatal.

Bird flu in wild birds can spread to domestic poultry such as chickens and turkeys. Live birds markets in Asia play an important role in spreading epidemics of bird flu.

The control of an outbreak of influenza A (H5N2) among the poultry population in USA during a 1983-1984 epidemic cost US$65 million. More than 17 millions birds had to be destroyed. More than 13 million birds died or were destroyed in Italy during the 1999-2001 bird flu epidemic caused by influenza A ( H7N1) epidemic.

Can humans get bird flu? Yes. The bird flu viruses more often infect other birds and pigs. But in 1997, bird flu caused by avian influenza A (H5N1) infected humans. This was the first documented case of transmission of avian influenza from birds to humans. It took place in Hong Kong where 6 of 18 humans infected, died.

This first case of direct transmission of influenza from avian to humans was alarming to health authorities worldwide. In Hong Kong, destruction, in 3 days, of some 1.5 million birds, the entire poultry population, averted a pandemic.

The alarm bells went off again in 2003 with an outbreak of avian influenza A (H5N1) in Hong Kong. It caused 2 human cases with 1 death. Then there was avian influenza A (H7N7) in the Netherlands in 2003 with the death of a veterinarian. Mild cases of avian influenza A (H9N2) occurred in 2 children in Hong Kong in 1999 and in 1 child in 2003.

The most recent alarm bells rang out loudly this month. First, there was an outbreak of avian influenza A (H5N1)in the poultry population in Vietnam in December 2003. Then laboratory tests confirmed the presence of avian influenza A (H4N1) in humans in Viet Nam. Children died. It is thought that they became infected by playing in yards where chickens were kept. They probably made contact with infected avian faeces, a good source of influenza A. Two birds in the bush may be better than one bird in the hand.

There is no evidence yet of direct human to human spread of the recent avian influenza A (H5N1). Nonetheless, H5N1 is of particular concern because it can mutate into subtypes rapidly. Its genes can re-assort with others easily to form new subtypes. WHO notes that H5N1 has the unique capacity to cause severe disease, with high mortality, in humans.

The relationship between humans and animals is in the spotlight as new diseases emerge. The vegetarians should not laugh. Do we know what is going into plants and vegetables for human consumption?

If we worry about meat and other cattle-derived products, pigs, chicken, turkey and other avian products, what will be left to eat? The little dog laughed to see such fun, and the dish ran away with the spoon.

Tuesday, January 6, 2004

The Cow Jumps Over


Dr. Lester CN Simon

In a previous article, we looked at the basic science of a group of degenerative, spongiform brain diseases in which the brain in reduced to a sponge. In this article, we look at the full spectrum of these diseases with emphasis on the more important ones.

There are at least 6 transmissible spongiform brain diseases that affect animals. For over 200 years, shepherds have recognized a spongiform brain disease called scrapie, in sheep and goats. It is called scrapie because the animals degenerate and itch to the extent that they rub against any object and scrape off their wool.

Chronic wasting disease of mule deer and Rocky Mountain elk is a spongiform disease seen in Colorado and Wyoming, USA. Scrapie and chronic wasting disease are the only 2 spongiform brain diseases that appear to be spread directly from animal to animal.

A third disease, transmissible mink encephalopathy, was discovered in Wisconsin, USA in 1947. Encephalopathy simply means brain disease. Ingestion of contaminated food stuffs is thought to be the mode of infection.

The remaining three spongiform brain diseases in animals include exotic ungulate encephalopathy, identified in British zoos in the mid-1980s. Ungulates are hoofed mammals including antelopes, cheetahs and others. Feline spongiform encephalopathy in domestic cats was discovered in 1990. These two spongiform diseases in ungulates and cats are thought to be due to the same infectious agent that causes Mad Cow Disease, the sixth and most notorious of animal spongiform brain diseases.

Mad Cow Disease or Bovine Spongiform Encephalopathy (BSE) was first discovered in Britain in November 1986. The cows’ mental state ranged from initial apprehension to frank madness. Since the 1940s, cattle feed was enriched with meat and bone meal from other animals including sheep and other cows. Ordinary grass was insufficient for cattle.

Offal refers to the entrails and internal organs of an animal that are used as food. The enriched meal for cattle includes offal from slaughterhouses. It goes through a process called rendering. Here, the melted fat is removed as tallow. Tallow is the hard fatty substance from animals. It can be used to make some candles and soap.

After the tallow is removed, the solids comprise meat and bone meal for cattle. How did the first cows with Mad Cow Disease get infected? They got infected from the enriched meal during the winter of 1981-1982. The rendering process had been altered. The use of chemicals called organic solvents and the high temperatures used in the rendering process were stopped. The lack of these chemicals and the absence of high temperatures meant that any infectious agents in the animals used in rendering, survived and were inadvertently passed on. The infectious agents came from scrapie-infected sheep.

The next time you hear someone say they do not eat meat, just smile. Some rendering processes use spoiled meats scraps and animal carcasses. In addition to preparing meat and bone meal to enrich cattle feed, many by-products are derived from the rendering process. Some of these rendered products include high-protein base used in soaps, medicine and candy. Render unto cattle and render unto Caesar.

According to the Wall Street Journal, processed cow fats are used to make cookies and salty snacks taste rich, and lipstick to glide on smoothly. Cow proteins end up in shampoo. Gelatin from cattle hide and bones is found in ice cream, candy, marshmallows and in capsules encasing drugs. Cow lips are used in taco filling and other offal parts are found in pet food.

The manufactures claim that none of the organs that are known to transmit Mad Cow Disease are used in their preparation. If we accept this as truth, we have to also accept that the science of Mad Cow Disease is evolving. The brain and the spinal cord are known to be the areas that harbour the infectious agents called prions.

Dr. Prusiner, the discoverer of prions, noted that there are discoveries that widen the spectrum of prion diseases in mice. These discoveries are prompting a search for human prion diseases that affect the peripheral nervous system and muscles.

The spongiform brain diseases in humans include Kuru, Creutzfeldt-Jakob Disease (CJD), Gerstmann-Straussler-Scheinker Disease and Fatal Insomnia.

CJD is the most common human spongiform disease. Yet it is very rare. The estimated incidence is about 1 case per million, per year, worldwide. Before 1995, it existed in 3 forms. Sporadic or random CJD (about 85%), familial CJD, and CJD from use of infected medical organs or products. Familial CJD means that bad genes are passed on to an offspring.

Sporadic CJD is rare in people under 30 years of age. There is progressive mental deterioration and death occurs in less than a year. In late 1995, a new form of CJD was observed in Britain. It was called new variant CJD. In retrospect, the first case was probably in 1994, some eight years after Mad Cow Disease was discovered. It was called new variant CJD because the patients were teenagers or younger than classic, random or spontaneous CJD patients. New variant CJD (nvCJD) patients survived longer.

Kuru is due to cannibalism among the Fore people of New Guinea. Industrial cannibalism in scrapie-enriched cattle feed is the cause of Mad Cow Disease and nvCJD is due to humans eating infected beef products.

Canine, ovine, bovine, asinine? Respectively: tooth, sheep, cow, stupid or foolish?

Monday, January 5, 2004

Mad Food

Eat This. But Not In Remembrance of Me!

Dr. Lester CN Simon

The title of this article is aimed at linking two crucial aspects of the basic science of Mad Cow Disease. Mad Cow Disease is the lay person’s term for Bovine Spongiform Encephalopathy (BSE). BSE is only one of a list of spongiform brain disorders in animals and humans in which the brain is literally reduced to a sponge.

To get a clear grasp of the basic science so that we can apply it to public health, we have to understand a peculiar set of diseases caused by agents called prions.

When we think of the causes of infections, parasites, fungi, bacteria and viruses readily come to mind. The first three agents contain many sophisticated, genetic chemicals including DNA and RNA. These three infectious agents grow, reproduce, make and use proteins once nutrients are available. Viruses, on the other hand, are not as sophisticated. A virus possesses either DNA or RNA, not both. Viruses cannot grow, reproduce and make or use proteins unless they inhabit living cells.

As important as proteins are, it was not considered possible that a protein could cause infection by itself. Infection means that the causative agent sets up shop in the host and multiples therein. Proteins should not be able to do this since they do not have the chemical genetic machinery in the form of DNA or RNA.

Enter the prion. In 1980, Dr. Stanley Prusiner evoked a good deal of scepticism when he proposed that the infectious agents causing spongiform brain diseases in animals and, more rarely, in humans might consist of protein and nothing else. At the time, Dr. Prusiner was considered a heretic. His work was revolutionary. He realised that dogma held that the conveyers of transmissible diseases required genetic material, DNA or RNA, in order to establish an infection in a host. Fifteen year later, Dr. Stanley Prusiner was awarded the Nobel Prize in Medicine for his work on prions.

The name prion (pronounced "pree-ons" by Dr. Prusiner), is an acronym. Actually you may say it is a prionic acronym, as you will see later. It comes from the words: proteinaceous infectious particle, using the first three letters of proteinaceous (pro) and the first two letters of infectious (in). Obviously, this would lead to the name, proin but it was decided to call it prion instead of proin, because prion has a better sound.

But even if prions cause diseases, they are proteins; and all proteins are made by genes (DNA and RNA). So how do the prions reproduce when they cause infections? Do they have a piece of genetic material attached to them? No. The genes that make prions are where all genes are: inside the cell. They make prion proteins (PrP) all the time without necessarily causing any sickness. This suggests that prion proteins exist in two states, a normal, innocent state and an abnormal, corrupted, sinister state.

Good prions are easily degraded by the usual protein-degrading enzymes in all cells. Unfortunately, bad prions resist this degradation. Hence, bad prions will always win and the good ones will lose. The concept of good prions is relatively new. When prions were first discovered, they were thought to be intrinsically bad. Just recently, in December 2003, it was considered that one sort of prion has a vital role to play in how memory can be stored in the brain. Hence the name of this article.

Shape or conformation is very important to proteins. Change the shape and the function can change. The bad prion acts as an infectious agent by somehow causing a change in the shape of the good prion, which then becomes a rebel prion and damages the body. The derivation of the name prion is itself prionic in that the name was changed from proin to prion.

The shape of a protein is only one aspect of its structure. There is a more basic building block comprising a sequence of amino acids. The closer 2 prions are in their basic structures, the easier it is for a bad, rebel prion to corrupt a normal prion by forcing it to alter its shape and become a rebel too. Birds of a feather do all sorts of things together.

This raises the concept of species barrier. Species barrier refers to the difficulty of prions made by one species causing disease in another species. The cause of this difficulty is unknown but it is important in light of Mad Cow Disease in which bad prions from other animals such as sheep and cows were part of the feed for cows.

The close genetic link between sheep and cows allows for the transformation of “Mad Sheep Disease’ to Mad Cow Disease. “Mad Sheep Disease”, known for over 200 years is called scrapie because the sheep have a terrible itch and scratch against a fence until they scrape off their wool.

Kuru is a prion disease that was found in 1957 among the Fore tribal population of Papua New Guinea. Transmission was due to the practice of ritualistic cannibalism. With the cessation of this social custom, Kuru has essentially disappeared. Kuru is the Fore word for shivering, trembling or “laughing death”.

Sheep and cow prions differ at 7 positions. Alternatively, cow and human prions differ at more than 30 positions. Because of this greater variance, Dr. Prusiner thinks that the likelihood of transmission of prions from cows to people is low. But low does not mean impossible because it does occur. Maybe only a small area of similarity is required for corruption of the human prions by the bovine prions. Additionally, other types of proteins called chaperone proteins may assist in the alteration and corruption of the good prions.

In genetic and other terms, are we humans far from the madding cow?