Weird Life: Viruses and Prions
January 26, 2004

• Starr, pages 317-319: Viruses and Prions
• Commonly Asked Questions About BSE January 14, 2004 by FDA's Center for Food Safety and Applied Nutrition (CFSAN)
• The Prion Diseases by Stanley Prusiner, discoverer of prions and Nobel Laureate (1997). From Scientific American, January 1995 (Optional)
• Guardian Unlimited Web Special on BSE - great articles - read a few if you get a chance

Viruses are non-cellular infectious particles that consist of a genome (DNA or a related molecule RNA) wrapped in a protein coat or shell. Occasionally, viruses are surrounded by an envelope that consists of a piece of the the plasma membrane of the host cell that the virus picked up on its way out of a host cell.

Since viruses are cannot grow or replicate on their own, they are considered to be obligate intracellular parasites and generally not considered to be alive; but it is important to note that viruses have both living as well as non-living characteristics (a definition from one of the major textbooks in Biology). [Image of SARS virus]

Viral Diseases:

Viruses cause disease when they enter cells and 'hijack' the cell's own protein-making machinery, causing the cells to STOP production of normal cellular proteins, and START making viral proteins and copying viral DNA or RNA. Once the cell makes enough of the viral proteins and DNA, the cell even assembles these parts to make complete viruses in cells! At this point, when there are up to a few hundred mature viruses in the cell, the virus often bursts out of the cell, causing destruction of that cell, and an avenue of escape to spread to neighboring cells. Some viruses (like the Herpes viruses) also have the ability to insert their DNA into the DNA of their host, and exist as a "latent" virus until environmental conditions are right for the virus to exit cells.

There is an IMPRESSIVE array of viruses on Earth - even bacteria become infected with their own viruses! This is a great website for all kinds of cool electron microscope pictures of viruses, and lots of information on how viruses are classified and grouped: The Big Picture Book of Viruses. The main classification of viruses is usually based on what type of genetic material they carry into cells:

DNA viruses: These viruses carry their DNA into cells, and uses the cell's machinery to make viral proteins.

• Herpes virus (cold sores),
• Adenoviruses (common cold)
• Pox-viruses (Chicken pox, smallpox, etc),
• Parvoviruses (common cold)
• Human Papiloma Virus (HPV; involved in the development of cervical cancer; a new vaccine for HPV is currently being developed)
• [Image of adenovirus]

RNA viruses: These viruses carry RNA into cells, which is copied into DNA by an enzyme called reverse transcriptase and then made into viral proteins.

• Coronaviruses (SARS) ,
• Flaviviruses (hepatitis C),
• Picornaviruses (polio,common cold),
• Paramyxoviruses (measles and mumps),
• Influenza viruses, (the flu)
• Retroviruses (HIV-AIDS)
• [Image of Flu virus]

Viral Diseases of humans from A (adenovirus) -Z (varicella zoster)!! They're all here...!

A few notable pandemic viral diseases:

Influenza viruses - the subject of our first Good For!  CL

• To read more, please see: "Flu : The Story Of The Great Influenza Pandemic" by Gina Kolata. A fascinating story of the greatest pandemic known in human history - -more than 20 million people died in just a few years.
• Chilling thought "Are we ready for pandemic influenza?" . November 28, 2003: Science. 2003 Nov 28; 302(5650): 1519-22. Richard Webby and Robert Webster
• The latest from the CDC and the WHO on Vietnamese Bird Flu: (highly virulent H5N1strain spread between chickens and humans)

The AIDS pandemic: AIDS, first described in the late 1970s, has killed more than 22 million worldwide in the last 20 years. Nearly 40 million people world wide are infected by the virus, and currently, over 1 million people die every year.

• Worldwide, 16,000 people become infected with HIV every day and about 3.2 million are children younger than the age of 15.
• In the US, 900,000 people have HIV and 40,000 new infections appear annually. More than half those infected are people of color, and half of all new cases are people under 25, according to the National Institute of Allergy and Infectious Diseases.
• For a chilling history of the disease, a great book is "And the Band Played on: Politics, People, and the AIDS Epidemic", by Randy Shilts "
• HIV destroys the body's T-helper cells, the cells that normally protect us against viral attack. HIV is so devastating to the immune system because it carries a protein on its outer surface, named CD4+, that allows it to 'dock' and gain access to the CD4+ receptor (a protein in the lipid bilayer) on the T cell. Once inside the T cell, HIV uses the enzyme reverse transcriptase, to copy its RNA into DNA, and the inserts itself into the T cell's chromosomes. The HIV DNA then 'hijacks' the T cell to direct the synthesis of proteins for new HIV viruses. These new viruses 'bud' from the cell to infect (and kill) other T cells. [Image of HIV exiting cell]
• This eventually results in an almost complete destruction of the body's T cells and immune system. Once there are less than 200 CD4+ cells in the body, most people develop AIDS and succumb to opportunistic infection from normally harmless bacteria or fungi that the body has lost the ability to fight off, including PCP (Pneumocystis carinii pneumonia), a lung infection; Candida, a fungal infection; KS (Kaposi's sarcoma), a skin cancer; or CMV (Cytomegalovirus), an infection of the eyes.
• New anti-retroviral HIV drug 'cocktails' can reduce the 'viral load' in T-cells, and extend lives. Many are based on inhibiting the viral enzyme reverse transcriptase. Several drugs are given at a time in each 'cocktail' because the virus mutates so rapidly that it quickly becomes resistant to most drugs.
• Where did HIV come from? "Most likely HIV is the human version of a related virus called SIV (simian immunodeficiency virus) that infects chimpanzees (and was probably picked up from chimps eating monkeys infected with two different monkey viruses that recombined to make a hybrid virus - SIV.) Humans probably first became infected in Africa by butchering chimpanzees for bushmeat."
• Hardest hit by HIV-ADIS is Africa; over 70% of all cases in the world - nearly 30 million people in Africa have the AIDS virus, including three million children...yet, due to poverty, war, lack of cooperation from drug manufacturers, and lack of education, only 50,000 Africans receive the medicine they need....During his State of the Union speech on January 28, 2003, President Bush pledged $15 billion to Africa for AIDS relief over the next 5 years (The President's Emergency Plan for AIDS Relief ), and at about the same time, the Bill and Melinda Gates foundation pledged $100 million to the global AIDS fund . Stay tuned!

See the CDC for information on West Nile Virus, SARS, smallpox, and other viral diseases...

5 January 2004: SARS returns to southern China. "The World Health Organization (WHO) has confirmed a new case of SARS (Severe Acute Respiratory Syndrome) in China. Chinese authorities announced plans to slaughter thousands of civet cats, ferret-like animals that are a delicacy in China's food markets and are suspected of transmitting the SARS coronavirus to humans." The SARS virus is an unusual entirely new virus related to the common cold virus that is part-animal and part-bird virus in origin. In the last 2 years, SARS has infected over 3,000 people in over 30 countries and has killed over 700 people by causing a severe pneumonia-like infection. [Image]

Prions: a newly discovered infectious agent

What are Prions? The term prion was coined by Dr. Stanley Prusiner to describe a "proteinaceous infectious particle". Dr. Prusiner started studying these proteins in 1972 after one of his patients died of Creutzfeld-Jacob Disease (CJD), a rare, fatal brain disease that occurs spontaneously in a few people per year.

Dr. Prusiner found two interesting things:
(1) CJD was very similar to a number of known brain disorders in animals called spongiform encephalopathies ('spongy brain' diseases), like scrapie - described below.
(2) CJD, as well as other spongiform encephalopathies, appeared to be spread in an unusual way - by abnormal proteins transmitted from organism to organism. These abnormal, infectious proteins - prions - have the ability to cause a mis-folding of a normal protein counterpart in brains.

• Dr. Prusiner was surprised to discover that the mis-folded shape appeared to be 'contagious', with one abnormal prion having the ability to convert normal cellular proteins to abnormal prion forms.
• A 'domino effect' follows infection with a prion, with the abnormal prions collecting in large clumps, plaques, or "holes" in the brain, causing the fatal spongiform encephalopathy. [Image]
• Dr. Prusiner hypothesized a NEW class of infectious agent that he termed prions that were able to convert normal, cellular proteins to abnormal proteins - without the need for new proteins to be made from DNA (the standard way infectious agents- bacteria, viruses, parasites - usually do their work!)
• The discovery that proteins alone could transmit an infectious disease was a big shock to other scientists, since at the time all known infectious agents did their 'dirty work' through DNA or RNA. Many scientists shunned Prusiner's work for years until the evidence for prions became overwhelmingly clear (if you get a chance, read Prusiner's autobiography where he discusses this reaction from the scientific community!).

The Prion (or "Protein only") hypothesis:

'Benign' (normal) PrP-c + the infectious 'scrapie form', PrP-sc ====> conversion of PrP-c to PrP-sc ====> spongiform encephalopathy

Prions are definitely infectious: when brain tissue from scrapie sheep is used to isolate the PrP-sc protein, and PrP-sc is injected into healthy animals, spongiform encephalopathy eventually results.

In October, 1997, Stanley Prusiner was awarded the Nobel Prize in Medicine "for his identification and characterization of the Prion and the association of this protein with neurological disorders." Press Release

Prion disorders of non-human animals:

• Scrapie: (transmissible spongiform encephalopathy): sheep -farmers have reported cases of scrapie since the early 1700s in England, Scotland, and the US.
• BSE (bovine spongiform encephalopathy): cows - first noticed in 1986 in England. Due to the similarities in the behavior of the infected cows, BSE was suspected to be linked to the common practice of feeding cattle with remnants of tissue from slaughtered sheep.
• TME (transmissible mink encephalopathy): mink - found in the US
• CWD (chronic wasting disease): deer, elk - found in the US
• FSE (feline spongiform encephalopathy): housecats!

Prion disorders of humans (there are others, but these are the main ones):

• CJD: Creutzfeld-Jacob Disease - a rare disorder first reported in the 1920s - dementia, followed by death.
• Kuru: first reported in 1957. Existed only among a single tribe of Fore Highlanders in Papua New Guinea. The likely cause of Kuru: ritual cannibalism - the practice of honoring the dead by eating their brains. Once ritual cannibalism was stopped, by the urging of the WHO, kuru virtually disappeared from the tribe.
• FFI: Fatal familial Insomnia: first described in 1986. Long periods of insomnia, followed by dementia and death.
• vCJD: Shortly after British cattle started developing BSE symptoms in 1986 (and government officials said the disease posed no threat to humans) people started dying of an unusual (variant) strain of CJD. It appears that the variant strain came from eating BSE infected beef.

Mad Cow disease in England - 1986 and on

BSE first appeared in England in 1986, and scientists soon after realized that the disease BSE was strikingly similar to scrapie in sheep - the brains of BSE cattle clearly had spongiform encephalopathy.

How were the cows infected with BSE? Cattle with BSE had been fed a protein-rich feed made from the carcasses, bone meal, and the offal - slaughterhouse remains - of slaughtered sheep. This practice, common in modern factory farms, seems 'efficient' in that it makes use of carcasses as well as provides a protein-rich feed to encourage rapid growth of cows, BUT, it also provides an easy way for a prion to cross the species barrier from sheep into cattle, and then from cattle into the humans who eat beef. Scientists have evidence that the first cases of BSE were likely due to cattle being fed high-protein supplements from sheep infected with scrapie. [Image]

How humans were infected: In 1986, Government ministers in England reassured the public that beef was safe to eat. However, in the early 1990s, about 20 people in England were diagnosed with a new spongiform encephalopathy - called variant Creutzfeld-Jacob disease (vCJD), making health authorities suspicious that BSE had perhaps been transmitted to humans from BSE-infected cows slaughtered for human consumption. Tests indicated that this strain of CJD came from eating BSE-infected beef. Millions of cattle suspected of being infected with BSE in England and Europe were incinerated, but not before millions of hamburgers were, in fact, made from BSE-tainted beef. The beef industry in England still continues to suffer today. Currently over 110 people in Europe have contracted vCJD from BSE-tainted beef.

BSE in the USA: (From CBS's Mad Cow Disease interactive)
In the US, safety of meat is monitored by the USDA, who has set up a special website to track BSE in the US.
They also have a site on Actions to Prevent Bovine Spongiform Encephalopathy (BSE)

• "The US banned imports of cattle and bovine products from countries with BSE beginning in 1989.
• The FDA and USDA in 1997 instituted a ban on feeding ruminant-derived meat and bone meal supplements to cattle. This is the 'firewall' that would limit the spread of BSE if it were present in the U.S. Note: IF all meat producers comply with the ban....
• May 20, 2003: In the first case of Mad Cow affecting cattle born in North America, a cow in Alberta, Canada, is diagnosed with the disease. A previous case in Canada, in 1993, involved an animal born in Britain that was imported.
• Dec. 25, 2003: The first U.S. case of mad cow, an infected Canadian Holstein slaughtered Dec. 9 in Washington state, is confirmed by a British lab. More than 30 nations ban U.S. beef imports, and transactions on the Chicago Mercantile Exchange are temporarily frozen after live cattle prices plummet.
• Dec. 29, 2003: Eight states and Guam scramble to find tons of meat that may have been processed along with a cow with mad cow disease. Dr. Ron DeHaven, USDA Chief Veterinarian, tells CBS's The Early Show any recall actions are being taken out of an "abundance of precaution."
• 30 December 2003: Mad cow found in America: "US beef imports were banned by Japan and other countries after the USDA announced the diagnosis of bovine spongiform encephalopathy (BSE), or mad cow disease - in a 'downer' dairy cow, unable to walk yet still sent for slaughter and human consumption". Beef producers in the US have lost their biggest export market, worth ~$1 billion / year. [Image]
• Jan. 6, 2004 - Genetic testing confirms that the U.S. cow diagnosed with mad cow disease was born in Canada. The results allow investigators to intensify their search for the source of infection, most likely from contaminated feed in Alberta, where the Holstein cow was born in 1997.
• Jan. 12, 2004: From the Guardian Unlimited: Culture of indifference leaves America open to BSE
• NEW! This just in: Thursday, Jan 22, 2004: CDC investigating CJD cluster in NJ - United Press International

Fortunately, the risk of developing a TSE from eating BSE-tainted beef is very low. While between one and two million European BSE cattle were eaten by humans from the 1980s on, a relatively small number of people - 110 people at last count - are believed to have been infected with vCJD due to eating BSE-tainted beef. (It is still NOT known how many people will eventually become infected, though).

Unfortunately, there are no obvious symptoms of TSEs until the animal is in the advanced stages on the disease. The US 'Mad Cow' was a 6-year old dairy cow, and she had lived long enough to show symptoms of BSE. However, most cows are killed before they turn 2 years old, many years before they might show symptoms of BSE. The USDA currently tests only about 20,000 of the 40 MILLION cows slaughtered annually; this may have to increase if we want to assure safety as well as please our major beef exporters like Japan.

About time, or what!?! 'Downer' Cows Banned As Food. (12/ 30/ 03) Over 130,000 downer cows enter the human food supply every year, and only 1 in 5 is tested for BSE. Why are downer cows in the food supply anyway? Could politics have anything to do with it? Hmmmmm....

AND, LETS END ON A GOOD NOTE!
A new role for Prions: 12/26/03: A normal role for prion proteins in the brain - human memory! WAY COOL!!! Scientists at the Whitehead Institute have recently found that the normal prion protein may be a 'storage device' for human memory. Prion-like proteins would be perfect for switching into different states to 'hold' memories for long periods of time. Stay tuned!

Optional: Do you really want to know? NOT for the squeamish... Grab a Boca burger and read on!
What is rendering? by Griffin Industries. More than 150 million pounds of waste animals by-products are discarded daily. Here's one company that makes the best of these useful by-products. Bonus:... free pick-up!
Advanced Meat Recovery: A technology for removing the last bits of meat from those ol' cow bones. Hold the sausages, please.....
What's really in pet food? You may never buy L'il Friskies again....
Dairy cows, hamburgers, and the Inefficient Efficiencies of Modern Farming; the sad and strange life of a modern Holstein milk cow. Originally from the New York Times, January 5, 2004

Objectives:
1. Describe ways in which viruses share characteristics of living cells.
2. How do viruses replicate? What is meant by the term 'obligate intracellular parasite'?
3. Compare and contrast DNA and RNA viruses - and give 2 examples of each.
4. Describe how the HIV virus causes the destruction of immune cells. How many people worldwide, and in the US, are infected with HIV?
5. What are prions and how do they cause brain diseases? What is a spongiform encephalopathy?
6. How are scrapie, mad cow disease, and vCJD related?
7. What might be the normal function of prion proteins?