Saturday, February 17, 2018

The Flu

This winter (2017/2018) has been a particularly bad flu season around the world, and as of mid-February, it continues to get worse in the United States. One in ten deaths last week in the US were caused by either the flu or from pneumonia, a complication from the flu. As of February 1st, it was widespread across Canada and the United States and there are serious widespread outbreaks in Japan, the Koreas and in Europe. More than one strain of influenza appears to be responsible for these outbreaks. Here in Canada and in the US, the main culprits appear to be a strain of H3N2 as well as type B influenza, both of which are spreading at the same time. The current season's flu vaccine is estimated to be about 55% effective against type B influenza but only about 15% effective against the H3N2 type A virus.

What Is the Flu (Influenza)?

Both the common cold and the flu are caused and spread by viruses. Sometimes it is hard to tell the difference between flu and cold symptoms, especially if the flu is mild. According to webmd.com, with either the flu or a cold, you typically feel congested. You have a sore throat and tend to sneeze. These symptoms as well as headache, coughing and chest discomfort are common to both the flu and the cold. If you also have a high fever and experience extreme fatigue and muscular weakness, you more likely have the flu. Young children might also suffer from vomiting as well, according to the CDC webpage on influenza. Another aspect that sets the flu apart is its symptoms tend to come on very rapidly. You feel hit by a bus. Neither virus is any fun but the flu is the one that tends to put us out of commission for 1-2 weeks, in bed, almost unable to get up. It can also be deadly, especially for those of us in high-risk groups, which I will detail.

While an ordinary bout of the flu is generally just awful, the flu can also become dangerous when complications develop as a result of the original viral infection of the upper respiratory tract. Anybody can become severely ill with the flu but most often complications from the flu strike the very young, the elderly, people suffering from chronic medical conditions and pregnant women. These complications can range from sinus or ear infections to pneumonia or inflammation of the heart or brain or muscle tissues. The latter complications can be life-threatening, and they obviously require hospitalized care. Severe inflammation of body tissues can be very dangerous, possibly leading to multi-organ dysfunction syndrome. In rare cases, the body's immune reaction to the virus rather than the virus itself can trigger an inflammatory response so severe that it leads to sepsis, which can rapidly (within hours) lead to death. It is difficult to square the fact that influenza, an annoying illness that always seems to wreck havoc with Christmas plans, is also the same virus that killed about 50 million people in 1918, some of them in matter of a day or two after contact with the virus.

This 4-minute National Geographic video offers a rather-sobering primer on how the influenza virus attacks:



I hope that this article will offer you the power of knowledge against this common and nasty virus. I found this to be true for myself, after doing the background research. There is hope that influenza will be eradicated once and for all, like small pox was and polio will soon be.

Flu Treatment

Antibiotics do not treat influenza or the cold, which are both viral infections. However, antibiotics can be used to treat flu complications such as bacterial pneumonia, an ear infection (if it is caused by bacteria; about half are viral and sinusitis (if it is bacterial, most sinus infections are viral).

All of the over-the-counter medications you find in pharmacies treat the symptoms of cold and flu viral infections rather then the virus itself. There is no treatment for the cold virus, but there are a few antiviral medications that can treat influenza, such as oral oseltamivir (Tamiflu), inhaled zanamivir (Relenza), or the intravenous drug peramivir (Rapivab). There are three main reasons why doctors don't tend to use these antivirals for a common bout of the flu without complications. First, even when they are started at the first appearance of symptoms, they tend to shorten the duration if the flu by only a day or two. Second, these drugs tend to cause nausea, vomiting and/or diarrhea (which may not be worth the trade-off), and they can interfere with other medications. Third, a concern more of the cost to the health system, is the fact that these drugs are expensive. A single adult course of Tamiflu (75 mg twice a day for 5 days) costs about $100 in Canada. These antiviral drugs are, however, useful to treat those of us who are at risk of serious flu complications and those of us who have weakened immune systems. They are obtained through a doctor's prescription (in Canda).

What To Do When You Get The Flu

Your body is busy fighting a battle that requires energy so it's best to give yourself a rest. Stay home. This will do not only yourself a favour but those around you as well by preventing its spread to others. Don't visit anyone in the hospital for this reason. Stay in bed or on the couch in a comfy blanket to ease those pesky chills. A fever (and the accompanying sweats) dries you out so drink plenty of fluids. Try to avoid the caffeine that might prevent you from napping and opt for herbal teas instead. Ginger teas help reduce nausea. If you can eat, do so but try to fuel your body with healthy choices. Homemade soups (no preservatives and usually much lower in salt) do triple duty by providing nutrition/fuel, hydration and comfort. Of course you don't want to cook when you're sick so it's not a bad idea to have a few containers made up in your freezer during flu season.

Do not work out, especially if you have a fever, any dizziness, a hacking cough or body aches. While regular day-to-day moderate exercise strengthens your immune system and offers increased protection against colds and flus, once you do get the flu, it is best to stop your routine especially if you have a moderate to severe case of flu. Intense exercise causes the body to release hormones, such as cortisol and adrenaline, both of which temporarily suppress the immune system. You don't want to fight against your body's natural defenses. A shift to gentle yoga (at home, not at the studio where you can spread it) and/or walking during a very mild flu not only can boost your mood but it eases some of the muscle stiffness associated with the flu, it helps stimulate the appetite, and it helps work up phlegm, easing breathing. If you have trouble getting out of bed, stay in bed and don't feel guilty (easier said than done especially for moms).

Over-The-Counter Flu Medications: Take With Caution

Taking an over-the-counter remedy can also ease symptoms. Be careful to read the labels, especially for dosage and side affects. It is all too easy to unknowingly double or triple the dose of a powerful drug by combining different medications such as a pill with a flu drink, for example. Many flu remedies contain acetaminophen, which treats pain and fever. An overdose of this drug can lead to liver damage or even acute liver failure.

It might be tempting to make up a hot toddy or some other boozy drink to deal with flu symptoms. There is some old mythology out there that alcohol sterilizes the virus somehow. When alcohol enters the body, it quickly enters the bloodstream (within minutes). It is then detoxified in the liver and excreted through the lungs, kidneys and in sweat, over a period of hours. So, yes, you will temporarily have alcohol in your blood but recall that even at the legal limit (here in Alberta) only 0.08% of your blood consists of alcohol, hardly a sterilizing strength. Alcohol dehydrates the body and it has been shown to weaken the immune response if several drinks are consumed.

Be warned, alcohol exacerbates the liver-damaging effects of acetaminophen. The evidence is preliminary but disturbing: combining even a small or moderate drink with a regular dose of acetaminophen can damage your liver. However, some alcoholic drinks such as wine appear to offer the body some immunoprotective antioxidants, a benefit, mind you, that is undone by consuming more than one drink. A glass of your favourite wine, if you can stomach it, can be a good strategy in the evening before sleep but NOT if you are going to take a nighttime flu medication.

Alcohol in the form of alcohol-based (70% alcohol) hand sanitizers and even ordinary hand soap are very effective in removing the virus from our hands. This might be the most effective strategy of all to avoid getting the flu in the first place, and to avoid infecting others around you when you have it.

Keep in mind that antihistamines (for runny or itchy nose and sneezing) can make you drowsy so avoid driving. Decongestants should be used with caution if you have hypertension (high blood pressure). These drugs enhance adrenaline and adrenaline-like hormones in your body, which restrict blood vessels in your nose and throat, reducing swelling and mucus formation. Vessel restriction also increases your blood pressure, which is a concern if you have heart disease or hypertension. There is new evidence as well that having the flu increases the risk of a cardiovascular event such as a heart attack, an additional reason to treat decongestants with caution. Finally, it appears that over-the-counter decongestant nasal sprays can be physically addictive. Keep in mind too that the adrenaline-like action of a decongestant can keep you from sleeping. That is why this ingredient is left out of nighttime store remedies.

A Few Safe Flu Remedies

Here are some safe flu remedies to consider. Nasal irrigation using saline solution (a neti pot) is a natural and proven method to ease stuffiness. Over-the-counter lozenges, especially those that contain menthol (found in peppermint, eucalyptus and other mints) act to coat and soothe a sore itchy throat and may reduce coughing. A humidifier in the room can help you breathe more easily, especially at night. An old-fashioned saltwater gargle also helps (1/4 to 1/2 teaspoon salt in one cup of warm water) to relieve symptoms and it might even help flush out the virus.

There is much literature online touting the use of vitamin C supplements to boost the immune system and to prevent and treat infections, particularly the common cold. The scientific literature is conflicting. A large analysis of previous scientific studies done by the Cochrane Database of Systematic Reviews in 2013 reveals that those who experience extreme physical stress such as exertion or exposure to cold and who may be deficient in vitamin C can reduce their incidence of colds by about half if they take a daily supplement. Taking a daily supplement appeared in some studies to slightly shorten the duration of colds among adults and children. Like the glass of wine mentioned earlier, vitamin C is an antioxidant. Antioxidants protect cells against damage from free radicals. Both are present naturally in the body. Many foods contain high levels of antioxidants and many dieticians recommend a diet high in citrus fruits, berries and vegetables, which will supply more than enough vitamin C. However, some people believe that taking large daily doses of vitamin C (such as 1000 mg) is beneficial. It is generally harmless to take even large doses of vitamin C (under 2000 mg daily) because the excess is rapidly flushed out of the body by the kidneys. However, there are a number of possible interactions to be aware of. Of particular concern for us are some studies that suggest that a large dose of vitamin C can lower the rate at which acetaminophen is passed from the body in the urine, which means that vitamin C may a dangerous mix with many over-the-counter flu remedies, and even more so if you consume any alcohol as well.

All this cautionary advice might encourage you to seek an herbal flu remedy. According to webmd.com, there is no hard scientific proof that any herbal remedies work against the flu. Beware that many herbal remedies contain active ingredients and the strength varies from product to product. You should always tell your doctor which herbal remedies you are taking (at any time) because they can interact with prescription medications making them either less effective or too effective.

When to Call The Doctor

This is advice for adults. For children, click caringforkids.cps.ca for an excellent page on advice. It is published by the Canadian Pediatric Society. Often, a typical run-in with the flu passes in one or two weeks and you don't need to contact your doctor, as long as you don't have symptoms of flu complications as described earlier. Stay home, rest and save others from your nasty germs. But, influenza can quickly turn dangerous, so it is important to monitor your symptoms and contact your doctor if:

1) You have a very high fever, over 39.4°C (103°F), or a moderate fever that doesn't go down after 3 days
2)  You feel unusually short of breath
3) You start to cough up yellow, green or brown sputum
4) You experience a sharp pain in your chest when you breathe in
5) You have a severe ear ache
6) You feel light-headed or faint
7) You have any serious chronic disease (heart, lung, kidney disease or diabetes or you are on immunosuppressant drugs)

 (These guidelines are from Harvard Medical School's site)

A Further Caution: Know Where Your Online Information Comes From

There are now some excellent online reference websites for you to explore for information on influenza and other diseases and conditions. However, when researching health-related information online, one should check to see if the website offers accurate information backed up by peer-reviewed research (there should be links to scientific research papers). This is a task that is difficult for anyone not in a medical field so always trust the advice of your doctor, nurse or nurse practitioner first. These professionals are the real experts and they have your best interest in mind. Most informational websites, even some put out by medical schools and universities, are for-profit. This means that they make money by encouraging readers to buy certain healthcare products or drugs. Even medical advice from webmd.com, one of the top healthcare websites in the world, and a website accredited by a Washington-based non-profit accrediting organization, should be taken as a supplement to doctor's advice. It is owned by a private equity company and it is publicly traded, which means that it is obligated to its shareholders to make a profit, partly from advertising and partly from sponsorship from private drug companies. The New York Observer and the New York Times each published articles critical of webmd's reliance on drug company sponsors and how those sponsors influence content (see the reference section on its Wikipedia page here).

Types of Flu and How it is Transmitted

Influenza is transmitted by an extremely tiny microscopic particle called a virion. Each spherical or oblong virion is about 100 nanometres wide. To put this in perspective, a human hair is about 100,000 nanamotres wide. A microscopic image of several flu virions is shown below.

CDC/Dr. Terrence Tumpey;Wikipedia
Like the cold virus, the flu virus is an RNA virus. This means that its genetic material is composed of RNA (ribonucleic acid) rather than DNA (deoxyribonucleic acid). Human cells contain both RNA and DNA, following a general rule in genetics that DNA makes RNA that makes proteins. The influenza virus is an infectious agent that replicates only inside the living cells of organisms. It is composed of a strand of RNA (genetic code) housed inside a glycoprotein (a protein that has a carbohydrate attached to it) coat.

You may have heard about how fast flu viruses mutate. By the time a new vaccine is formulated, one or more of the target viruses may have already mutated into a different form, making that vaccine less effective or even ineffective. Their RNA is the reason flu viruses can do this. Influenza viral genomes, as a group, have the highest mutation rates of any genome. Compared to DNA viruses (they cause cold, warts, herpes, chicken pox, etc.), RNA viruses tend to have higher mutation rates, and single-stranded RNA viruses (such as flu viruses) have the highest mutation rates of all. Within DNA viruses, DNA-directed RNA polymerase (part of the cell's RNA-making machinery) can proofread and fix code errors in newly replicated RNA. RNA polymerases in RNA viruses lack this proofreading step. A lack of genetic proofreading would lead to life-threatening cancers in complex organisms like us but it is actually a boon to the flu virus. It allows constantly occurring minor point mutations in the genetic code to make coat proteins that subtly but constantly change, enough to fool antibodies, like a thief choosing a new mask all the time. This high mutation rate also allows it to stay one or more steps ahead of virologists desperately trying to predict each year's new vaccine cocktail.

There are three types of flu virus: Type A, Type B and Type C. These three types, or genera as they are called taxonomically, can cause influenza in many different classes of vertebrates, including humans and other mammals such as pigs, dogs, seals birds, etc. Influenza A is of most concern. This type of flu virus mutates the fastest and it is the only type associated with past flu epidemics, including the devastating 1918 Spanish flu pandemic, the 2009 swine flu pandemic, the Asian flu of the 1950's and various bird flu outbreaks. Some of subtypes of influenza A, such as H1N1, can be highly pathogenic and/or highly virulent, which means they have a high ability to cause disease and they have a high ability to infect a host, respectively. In other words, they spread quickly and they have a high mortality rate. Not all viruses of subtype H1N1 are so dangerous. Some strains of this subtype cause only mild seasonal flu. Virus phylogeny consists of type, divided into subtypes, which are further divided into strains.

The H1N1subtype is of particular interest to virologists. It is one of three subtypes that are always part of the flu vaccine cocktail. It was responsible for the deadly "Spanish" 1918 flu and for the 2009 "swine" flu pandemics, as well as others. There is currently (January 2018) a deadly epidemic of a new H1N1 strain in Pakistan that mutated from the sine flu. An epidemic is an outbreak of disease that attacks many people at the same time in the same general location. A pandemic occurs when an epidemic spreads throughout the world.

Other strains of the H1N1 subtype are commonly found in small numbers during every annual flu season. Each subtype comes in numerous different and always-evolving variants or strains. One strain of H1N1 might produce an average short-lived isolated flu outbreak. Another might only infect pigs and not humans at all, while a third could be as dangerous at the 1918 Type A H1N1 strain.

Type B influenza only infects humans and seals. Fewer hosts (fewer animal reservoirs of the virus) and a mutation rate that is 2 to 3 times lower than Type A influenza means that Type B is less dangerous. Unlike influenza A, Type B is broken down directly into strains and lineages rather than subtypes. There are only two lineages currently in circulation in the world. Each year's flu vaccine contains Type B virus. Type B flu virus can cause flu epidemics as well, but sufferers tend to have less severe flu symptoms than those from Type A viruses. Type C influenza infects humans and pigs. Outbreaks of type C are rare and they tend to cause only mild flu symptoms but there have been local epidemics. This type of virus is more difficult to isolate and study so much less is known about it than the other two types. The good news is that by the time we are 10 years old, most of us have been exposed to type C flu and have antibodies against it. It is the slowest virus type to evolve and it doesn't present a serious threat to humans.

Influenza Virion Structure

The influenza virus is crafty. It probably evolved for many millennia infecting humans and various animals, spreading back and forth between these vectors, although the first reliable evidence of an influenza outbreak was a pandemic in Asia, Africa and Europe, recorded in 1580. Technically the virus is not a living organism because it needs a living host to survive and reproduce, but has evolved many strategies to carry on its progeny from one host to the next over the millennia, adapting to new hosts and changing conditions during the process.

The diagram below helps to explain how a particular virion is labeled (for example, H1N1). A Fujian flu virus (a type A virus) is used as the example. Types A, B and C flu viruses are structurally and compositionally very similar to one another.

Burschik;Wikipedia
The squiggly purple lines inside the circle represent enclosed RNA genetic material. The glycoprotein coat is shown in red. In flu viruses, this coat is composed of two large glycoproteins: hemagglutinin (the small red "lollipop" structures, H) and neuraminidase (the rectangle-shaped structures, N. The arrow is a bit off.). Hemagglutinin, denoted as H left but elsewhere in this article shortened to HA, allows the virus to recognize and bind to its target cell. Neuraminidase (N or NA) enables new viruses made inside the target cell (or host cell) to be released. Both HA and NA are viral sites that antiviral drugs target. HA and NA are also antigens that our antibodies target during an immune response to the virus. Each antibody made by our immune system targets a specific antigen, like a lock and key mechanism, and binds to it (shown below left). Different antibodies have many different functions. Those that attack flu and other viruses usually block part of the (virus's) antigen's surface, rendering it ineffective.

Fvasconcellos;Wikipedia
Two glycoproteins, HA and NA, distinguish which subtype the virus is. H3N2 is another particular subtype of flu virus Type A. The flu vaccine almost always contains a strain of this subtype as well.

HA molecules on the surface of the flu virus envelope identify and bind to corresponding receptor sites on the membrane of an epithelial cell in the host's respiratory system. Once attached, the viral envelope fuses with the host cell membrane. The viral RNA genome then enters the host cell and commandeers its RNA-making and protein-making machinery to make new virus proteins and RNA. This process gradually weakens or kills the host cell while it sheds multitudes of new viruses into the respiratory system. See the diagram below showing how a virus attaches to and enters a host cell and how it uses the host cell's machinery to make new viruses that bud off the host cell to infect new host cells.

User:YK Times;Wikipedia
Glycoprotein coat-making machinery is on the left in the cell and RNA-making machinery is in the center, inside the cell nucleus. Steps 1 through 7 are described in detail here (under "summary").

The flu virus can be transmitted in three main ways. First, transmission occurs when viruses within the saliva and mucus (such as in a sneeze by an infected person) land directly on a new victim's eyes, inside the nose or inside the mouth. This is direct transmission. It can also take an airborne route, where someone later inhales virus-laden air sneezed or coughed out by an infected person. Third, someone can pick up the virus by touching a surface that was infected by a sick person or through skin-skin contact such as shaking hands. The flu virus can live outside the body for up to 24 hours on a hard surface and for more than a week in mucus. The simple message to wash your hands often and well if you are sick and if you are around people who are sick is a very effective method to avoid the getting and spreading the flu. A single sneeze or cough can spray up to half a million viral particles into the air. Two methods you can use to stop this transmission route are to sneeze or cough into the crook of your elbow or to sneeze or cough into a tissue, then throw that tissue into the garbage and then wash your hands.

Why Do I have These Symptoms?

During the first day or two after exposure to the virus, your immune system is already responding by churning out antibodies and T cells (the immune system's "soldiers"). If you got the flu shot and it matches the strain of flu you caught or if you've previously been exposed to this strain, your body already has a stockpile of antibodies. They provide an immune shortcut, a kind of a one-up on the virus. Antibodies will recognize that viral strain and stop it in its tracks, preventing illness. If your flu shot does not match but is similar to this strain or if you were already exposed to a similar but non-matching flu in your past, you likely still have a advantage; your flu will likely be milder than it would have been otherwise.

By around day three or four after being infected with the flu virus, your immune system, good as it is, is no longer keeping up with the viral onslaught. You go from feeling normal to feeling like you've been hit by a train, often over a period of hours. You have a fever, chills, headache and all of your muscles feel like you just did some kind of beast race. The root cause of your exhaustion, fever, headache, chills and muscle aches is your immune system. It's gone into code red emergency mode, creating a body-wide inflammatory response, with these unpleasant symptoms as side effects.

Your entire body is now in flu-fighting mode and that is why it is wise to rest and fuel it for the war it is waging against the viral invasion. Dead epithelial cell debris clogs up your breathing passageways - you develop a dry cough. Your throat is sore; your nose is red, itchy and runny. The flu essentially blows infected epithelial cells apart. These are the cells that normally protect your respiratory tract. The virus causes tissue damage, felt as soreness, swelling and inflammation. It is this damage to the lining of the respiratory tract, and the detritus left behind, that can set up the stage for complications from the flu such as a possible secondary bacterial infection such as bacterial bronchitis or bacterial pneumonia.

Although it isn't much of a concern for healthy adults infected with mild to moderate seasonal flu, you should seek medical help if you start to feel worse after you've already started feeling better. Bacterial pneumonia comes on slower than flu symptoms do. Serious chills, serious sweating, a high fever, trouble catching your breath, faster breathing and faster pulse are signs that you may have pneumonia as a complication of the flu. Go to emergency because it is a potentially very dangerous and rapidly evolving situation.

It is going to take about a week before your immune system starts to get the upper hand. In the meantime, there is a risk that bacteria and other viruses can invade you in your weakened state. It usually takes about two weeks before you can confidently feel recovered, and during this whole time, your body continues to shed the flu virus, although at a constantly decreasing level after the first few days when viral shedding peaks. This means that you are contagious throughout the whole time you are sick, and you are particularly contagious even before your first symptoms.

How the Flu Virus Makes Us Sick (Its Pathophysiology)

One factor that makes it hard to contain the transmission of flu is the simple fact that you are contagious before the symptoms hit you. The virus has entered your nose, throat and lungs. It is getting right to work taking over the cellular machinery in your epithelial cells lining these airways so that it can copy itself and multiply. At this point you are contagious but you don't know it yet. Every sneeze and cough hurls new viruses into the air, and onto surfaces around you, and onto your hands as you politely try to cover your mouth and nose. A deeply ingrained regular hand-washing habit can avoid having others around you come down with the flu too.

When a flu virion enters the respiratory tract, its hemagglutinin, the glycoprotein on its surface membrane, recognizes and binds to sialic acid-containing receptor proteins on the membranes of epithelial cells. Once the virus binds to the epithelial cell, the cell engulfs it as well as the bit of cell membrane that was stuck to it, to make an endosome inside the cell that is filled with the virus. An endosome is depicted in the right side of the cell in the cell diagram earlier. The cell then does what it is programmed to do when a foreign body enters it. It acidifies the inside of the endosome and then begins to digest the contents. However, the virus is quite ingenious. As soon as the pH falls below 6, the HA molecule partially unfolds, releasing a peptide that acts like a grappling hook. Then the HA molecule refolds into a new low-pH-stable structure. It uses the "grappling hook" peptide to come up to and fuse its endosome membrane with the epithelial cell's inner membrane. Once done, it spills its contents, including its RNA, into the cell's cytoplasm and gets to work using the cell's replication machinery.

There are at least 18 different subtypes of HA: H1 through H18. Several of these only infect specific animal species. H1, H2 and H3 are human viruses. Of each subtype there are numerous continually evolving strains. Antibodies made in the body usually attack the specific subtype/strain hemagglutinin that the virus presents on its surface. Hemagglutinin (HA) is a lollipop-shaped structure. It has a head, which binds to sialic acid on target epithelial cells. It also has a distinct stalk. The head structure changes subtly but continuously thanks to frequent mutations in the RNA coding for it. Most antibodies bind to the HA near its "lollipop head," preventing it from attaching to sialic acid receptors on the epithelial cells. To a lesser extent, antibodies are also made to recognize and attach to the stem part of the HA molecule instead. These antibodies stop the virus by inhibiting the membrane fusion machinery, most of which is located in the stem part. The stem will become important later on in this article.

Why Are Some Flu Epidemics So Deadly?

Each subtype of flu (such as H1N1, for example) can come in many different strains. A specific strain of H1N1 caused the deadly 1918 flu (about 50 million deaths) pandemic while another strain of H1N1 is currently a mild seasonal flu. Some strains are far more pathogenic than others. Viruses that contain avian (bird) hemagglutinins, such as H1, H6, H7, H10 or H15, appear to cause low-pathogenicity illnesses in birds but when these particular genes for the HA glycoprotein cross over into human strains of flu, they can potentially do far more damage in human lungs and they can be far more deadly than they are in birds. Avian subtype flu viruses also seem to cause a far more intense inflammatory immune response in humans, a physiological response that, in itself, can be deadly. In a 2014 study by Li Qi et al., mice (with respiratory systems and epithelial cell receptors very similar to humans) injected with H1, H6, H7, H10 or H15 avian HA viral subtypes rapidly lost weight and some died from primary viral pneumonia (pneumonia caused by the flu virus itself) within a week. Other (non-avian) subtypes (H2, H3, H5, H9, H11, H13, H14 and H16) caused no significant disease in the rodents.

The 1918 flu appears to have been one of these avian/human crossovers. Normally, the immune system is immediately activated after exposure to a mild seasonal flu virus. Cells of the immune system (white blood cells) such as macrophages, cytotoxic T cells and neutrophils recognize, target and kill virus-infected cells. This 3-minute video animation describes how these and other immune cells carry out an immune response:



However, for not entirely understood reasons, avian-like flu viruses, such as the 1918 epidemic virus, stimulate an exaggerated immune response that can be as damaging as the virus itself. Even healthy cells of the respiratory tract are targeted and killed, leading to life-threatening events such as acute respiratory distress syndrome and multiple organ dysfunction syndrome. These events can kill a person within hours of infection with the virus. The 1918 flu virus, and other avian-type flu viruses appear to target not just pulmonary epithelial cells but also the cells lining the alveoli deep in the lungs. The body has epithelial receptors for this particular avian-like strain of HA glycoprotein not only in the nose, throat, and upper respiratory tract but the lower tract as well.

By attacking not only the throat and nose but also deep inside the lungs, infection with the 1918 viral strain led to serious consequences such as rapid fluid and dead cell detritus buildup in the lungs. Unlike mild to moderate seasonal outbreaks, the 1918 flu targeted young healthy 20-35 year olds (although illness rates were highest among school age kids). This flu was contagious but not unusually so. Still, those who were infected with it suffered greatly. Within hours some victims experienced intense fatigue, and a cough violent enough to tear abdominal muscles. They turned blue as they coughed up foamy blood and many victims suffocated to death within two to three days of getting sick. It is important to note, however, that most victims died later on, approximately a week after getting sick and they died from secondary bacterial pneumonia, rather than the deadly acute immune reaction just described.

The types of casualties revealed a puzzle. Previously healthy victims with robust immune systems died partly because their immune system turned against them. In most 40 year olds, the immune response begins to weaken and it is simply unable to match such deadly intensity, and in the very young the immune system is not yet completely developed. Careful studies of the victim's histories also revealed another clue. These young healthy victims were not exposed to a similar flu in their youth, but older people living then were exposed, and some researchers suspect that this prior exposure is what saved many in the older group. Antibodies to a similar flu virus will lessen the severity of a flu infection. People born before 1875 were around 43 when the epidemic hit. These people had been exposed to a variety of subtypes of influenza A that some researchers suspect that exposure led to partial immunity against the 1918 flu strain. This, in addition to a less robust immune system that cannot run amok, might have offered older people some protection.

Understanding the unusual pathophysiology of the 1918 flu epidemic offers clues about how to avoid a similar flu deadly pandemic in the future. Knowing how our immune systems evolve over time, how different strains attack the body, where in the world and in what species new strains could originate from, and how previous exposure to past similar flu strains can moderate our immune response all help the world's health organizations zero in on what to watch out for as each new season takes shape.

 Avian Flu Cross-Over: A Concern for the Future

H5N1

While the 1918 deadly H1N1 flu strain appears to have been a cross-over from an avian flu virus, this and similar strains may be much less likely to cause a future deadly pandemic. In recent years, outbreaks of H1N1 have been fairly mild and it makes the rounds often enough that most humans have antibodies against at least a few strains of this subtype. Those who get the flu shot will also have antibodies against various strains of the H1N1 subtype. Virologists now have their eye on a different avian flu subtype, H5N1, a subtype commonly called "bird flu" (even though there are many subtypes of avian influenza, see above). It is currently one of two most likely candidates for a future deadly flu pandemic. Even though mouse studies, exposing mice to avian H5N1, did not result in serious illness, it doesn't mean that this virus has not been deadly in humans.

Bird flu is largely a south Asian disease of birds but it can infect a wide range of other hosts species as well such as pigs, cats and humans. There are low pathogenic (LP) strains of H5N1 (these are also found in North America) and high pathogenic (HP) strains of H5N1. Virologists are particularly concerned with a high pathogenic strain called HPAI H5N1. It was discovered in China in 1996, isolated in a goose, and the first human outbreak of this strain was in 1997. The rate of infection has been increasing since then, with several hundred cases of this strain in humans now reported to the WHO (World Health Organization). WHO announced that between 2003 and 2013, 630 cases have been confirmed and of those, more than half, 375 people, have died. H5N1, at least currently, doesn't easily spread from birds to humans but when it does, the disease is often unusually pathogenic, and deadly. In a 2006 outbreak, limited human-to-human transmission was confirmed as well, which is even more worrying.

What makes all avian influenza subtypes a concern is where they tend to attack the body. As mentioned earlier, viral HA recognizes and attaches to sialic acid receptors in respiratory epithelium cells. There are two kinds of sialic acid receptors: 2,3 linked and 2,6 linked. Flu viruses that originate in birds tend to prefer the 2,3 linked type of sialic acid receptor, while flu viruses that originate in humans tend to prefer 2,6 linked receptors. 2,6 linked receptors are mostly found in the upper respiratory tract, such as in the throat, the nose, and in the upper trachea. Humans also have 2,3 linked receptors and these tend to be most numerous deep in the lungs. This means that when avian-type viruses infect humans, there is a higher risk that deadly primary viral pneumonia can set up deep in the lungs, and this accounts for its high mortality rate. An upside to this is that because the site of attack is deeper in the body it is more difficult to sneeze or cough out viruses, making these infections less likely to spread through airborne contact. So far, there has been no recorded instance of a highly pathogenic avian influenza outbreak that is transmitted through airborne contact. However, a  2008 study found evidence that the H5N1 subtype, in addition to infecting deep lung tissues, can infect the gastrointestinal tract, the brain, the liver, the blood cells, and in one case it even crossed the placenta into the fetus of a pregnant woman, which means it could cause damage to and weaken various regions of the body.

H7N9

Another avian influenza Type A virus, H79N, has recently also appeared on WHO's radar, and this subtype might be considered even more worrisome than H5N1. There have been about 1200 confirmed cases of H7N9 so far, and about 40% of those have died. Not as much is known about the transmission and pathology of H7N9, but it also appears to attack the lower respiratory tract, leading to viral pneumonia. It also appears to overload the immune system causing a cytokine storm, which in some cases led to acute respiratory distress or multiple organ dysfunction syndrome. A cytokine storm acts like a dangerous positive feedback loop. It occurs when various immune cells are activated in large numbers. These cells release cytokines, which in turn activate even more white blood cells.

In 2013, virologists reported that it did not transmit easily from birds to humans and that person-to-person transmission was unlikely. Therefore it was unlikely to cause a pandemic. However, since then they walked that back. While H5N1 causes illness in birds, making it fairly easy to identify and monitor, H7N9 doesn't appear to cause any visible signs of disease in birds. This makes it virtually impossible to monitor in bird populations such as poultry farms. Since birds don't get sick, it also means that there could be a large sustained pool of the virus in the bird population. There is no evidence yet for person-to-person spread of this subtype, but there is concern that the virus could mutate and gain that ability.

The Flu Shot: What Does It Do and Is It Worth It?

The annual flu vaccine typically reduces your risk of getting the flu by about 50% on average year over year, and if you do get the flu, the symptoms tend to be milder. Aside from taking antiviral drugs, it is the only action you can take to prevent the flu. Here in Alberta, the annual flu shot is provided free of charge through Albert Health Services. They provide it through immunization clinics or you can get it at your local pharmacy (like I do every year). It is generally available at the start of flu season, some time in October. Protection starts about two weeks after you get the shot. In the United States and In Canada, the flu shot is recommended for everyone aged 6 months and older. Vaccination rates in Canada have been steadily increasing over the past two decades. According to a Canadian report released four years ago (2014), about 30% of all Canadians got the flu shot annually, with a high of about 67% for seniors and a low of about 20% for people between 12 to 17 years old. By 2016, vaccination rates increased to about 42% for all Canadians, 59% of which were children aged 6 months to 17 years. Every accredited medical website I checked online recommends that you get the annual flu shot.

A unique flu vaccine is formulated each year to protect against three or four of the most likely virus strains to show up. These strains are determined by the World Healthcare Organization (WHO), usually some time in February, for each upcoming year.

What's In the Flu Vaccine? Is it Safe?

I know a lot of friends and family who resist getting the annual flu shot, and the reason varies from a fear of needles to a belief it is ineffective to worries about the safety of the vaccine. Side effects from the flu shot can occur and that is why you are told to wait 15 minutes after your shot before leaving the pharmacy. The side effects are usually minor, with the most serious possibility being an allergic reaction, and that is primarily what the pharmacist watches for during those 15 minutes. Symptoms such as swelling around the eyes or lips, hives, a racing heart beat, dizziness or trouble breathing indicate that you are having an allergic reaction to the flu shot. Severe allergic reactions to the flu shot are very rare (there are just 1.31 reported cases of anaphylaxis per million doses given, according the CDC in the United States). If you have a severe allergy to eggs you should talk to your doctor before getting the flu shot. However, the flu shot is recommended even for those with moderate egg allergies, provided they are monitored after the shot for symptoms. Most flu shots and the nasal spray are manufactured using chicken eggs so they contain a small amount of egg protein such as albumin.

Another possible avenue for allergic reaction is thimerosal, a preservative that is added to multi-use vials of flu vaccine. Prefilled syringes and the nasal spray do not contain it. Thimerosal exposure can trigger rare and mild allergic symptoms such as itchiness, redness and swelling around the injection site. Thimersol is also present in make-up, soaps, some contact solutions and ointments. Thimerosal contains ethylmercury and some people worry about mercury exposure. Our body eliminates ethylmercury so it cannot build up in our tissues and cause damage. Methylmercury, however, does build up in the body (it is the molecule that builds up in fish tissues and can be toxic). You can choose a thimerosal-free vaccine dose if you are concerned.

The vaccine also contains stabilizers such as sucrose (table sugar), sorbital (artificial sweetener) and monosodium glutamate (MSG). These additives prevent the vaccine from losing potency when exposed to heat and light. Even if you are diabetic or are sensitive to sorbital or MSG, the amount in your dose is far too small to cause any reaction. Antibiotics are also added to the vaccine, again in extremely small amounts. A small amount of emulsifier, polysorbate 80, is also added. This is the stuff in purchased salad dressings and sauces. The shot vaccine also contains formaldehyde, which is used to deactivate the virus. Formaldehyde, found in wood glues and adhesives, can cause eye and throat irritation and it is a carcinogen with long-term large-dose exposure. As a water-soluble gas, almost all of it is removed from the vaccine before packaging. The amount that is left in the vaccine is less than the amount found in your body naturally, and so is not a concern.

The flu vaccine causes approximately one in one million elderly people to get Gullian-Barré syndrome. This is a very rare disorder in which your immune system attacks your nerve cells, and it can occasionally lead to paralysis. You are more likely to get the syndrome after the suffering from the flu itself than from the flu vaccination. People with a history of Gullian-Barré syndrome after receiving a previous flu shot, however, should talk to their doctor before getting the current season shot.

If you do not feel well, you should talk to your doctor before you get the shot. You want to have a robust immune reaction to your flu shot to maximize antibody production. If your immune system is already taxed, your body is less likely to develop good immunity against the flu strains in it.

Shots and Nasal Sprays

As you suspect, the flu shot contains the flu virus, or viruses to be precise. Side effects from the flu shot include soreness, redness or swelling at the injection site, headache, mild fever, nausea and muscle aches (I usually experience a sore arm, the most common side effect, for a few days). You might experience a runny/stuffy nose for a few days after the nasal spray. These symptoms might sound familiar after reading this article. They are symptoms of the flu itself, albeit much milder. They are far easier to live with than the symptoms of the full-on flu itself. It is important to note that the vaccine viruses themselves DO NOT cause these symptoms. These are signs that your immune system is being activated. They are the immune response to the disease but not the disease. You CANNOT get the flu from the flu shot or the nasal spray.

The flu viruses in the flu shot are inactivated (dead). Formaldehyde inactivates the virus, while leaving the surface HA glycoproteins intact to trigger an immune response. The viruses in the nasal spray are live but they are attenuated, or weakened. First made available in 2003, some American studies have recently shown it to be less effective in reducing cases of the flu, and the reasons for that are not yet understood, which is unfortunate for children and others who fear needles. In the United States, the CDC did not recommend the nasal spray for this flu season (2017/2018) while Canada's National Advisory Committee on Immunization still recommends it, based on Canadian studies that show that it works. That being said, Alberta and Saskatchewan stopped offering the nasal spray for free last fall, although it is available at a cost.

Because the nasal spray contains a live (but weakened) virus, it can cause a mild flu infection. The virus in this case is grown in a cold setting, which means it can survive and reproduce in the cooler nasal passages but it cannot live elsewhere in the warmer (deeper) respiratory tract. Sniffles and a stuffy nose means that it is triggering an immune response and making antibodies. You DO NOT actually get the flu. It is not the cascade-like invasion of virus that is the hallmark of a bout of influenza. However, the nasal spray could lead to complications in people with already weakened immune systems. Wikipedia lists those who should not get the flu nasal spray here. People who receive the nasal spray may also shed small amounts of live virus for about a week afterward, which means it could lead to transmission of the viruses in the vaccine, although it is a very minimal risk.

Soreness, redness or swelling at the injection site, headache, mild fever, nausea and muscle aches are all good signs that your immune system has recognized the viral invaders and is launching a counter-attack. Your immune system will remember those flu strains. If it encounters any of those strains in the future it will be able to attack the virus without delay.

How Long Does Immunity Last?

How long does immunity last against a particular flu strain? You need a flu shot every year not primarily because your immunity wears off but because flu viruses mutate into new strains every year. Each year, a new collection of three or four of the "worst and most likely" viruses is used to make vaccine. One or more of these viruses can and often will mutate before the vaccine is manufactured and distributed, which will make the vaccine less effective or even ineffective against that particular strain. It's a frustrating game of Russian roulette or maybe whack-a-mole.

Is there a side benefit from the yearly shot, such an ever-increasing arsenal of antibodies and memory B cells against various flu strains? I would like to think this is a bonus of getting the shot every year, but the evidence for this is not yet solid. It is unclear whether yearly vaccination produces a strong enough immune response to provide a lasting year-over-year memory B cell population that is large enough to provide strong immunity to each strain we receive. However, there are hints that this could be the case, at least for past exposures to wild strains of the flu. Evidence from studies on the 1918 flu pandemic suggests that antibodies to a similar viral strain can reduce the severity of a current infection. That work also suggests that memory B cells created in response to a flu infection, especially while the immune system is young and robust, can lead to decades and perhaps even a lifetime of immunity against that strain as well as similar future strains.

How long you retain antibodies and memory B cells depends on how powerfully your immune system reacted to the virus. For the best antibody production you need a healthy and mature immune system. A baby is born with an immature but highly adaptive immune system. It acquires immune memory in the form of long-term memory B-cells as the child grows and comes into contact with various antigens over the years. Memory B-cells migrate to the bone marrow after an immune response, where they live for up to several decades. These are the cells that produce (shorter-lived) antibodies in response to a repeat invasion of foreign material such as a virus. B lymphocytes make antibodies to an antigen (the naive B cell shown below). At the same time, they also make memory B cells, which remember that antigen and launch a faster antibody response the next time the body is infected with virus "A."

Hazmat2;Wikipedia
As you get older you develop an expanding repertoire of memory B-cells to various antigens. Your immune system reaches its peak function at around age 30 and then goes into slow decline. At around 50, we have noticeably weaker immune systems in general but our overall health at this age makes a big difference. Although memory B-cells persist, the immune response in general declines with age as fewer immune cells are made after exposure. The equilibrium of the immune system is also weaker after around 50. Tolerance to self-antigens goes down, which means we experience more autoimmune diseases, our bodies experience increased overall inflammation, and our systems no longer recognize and eliminate cancerous cells as efficiently.

All of this suggests that exposure to many strains of flu virus when we are young and healthy could build up a good arsenal of memory B-cells to help protect us against various strains of flu well into our declining years. It might mean that starting the yearly shot with its ever-changing cocktail of viruses as young as possible (at six months for the shot) and getting immunized every year might be the best long-term strategy against the flu. A couple of studies, however, show just the opposite - that getting the yearly shot might actually diminish one's immunity against the flu, a perplexing finding. One possibility for this is negative interference. For example, if identical or very similar viral strains are present in the shot two years in a row, the antibodies produced in year one might neutralize the virus in the year-two vaccine before it can trigger a full immune response. In this case, infection with the strain in year two must rely on a two-year-old repository of antibodies/memory B cells to attack it. While the presence of antibodies should lessen the severity of the flu, they might not be as effective as antibodies made more recently. In other years, the opposite (positive interference) might occur, which could provide enhanced protection instead. Researchers need to determine if negative interference exists and what to do about it. One possible solution is a higher dose vaccine in year two, which would elicit a stronger response.

Some of my friends/family claim it might be better for kids to actually contract the flu each year rather than to get the shot or spray. It is possible that a full-blown bout of the illness could elicit a more robust immune response than the shot or spray, making a better arsenal of antibodies for the future, and some researchers suspect this is the case but there is a price. Getting a full-blown flu is massively unpleasant and it has significant risk associated with it, and vaccination does not. The yearly shot, I think, is the more logical and kinder strategy for your kids, and it might add that bonus of a broadening immunity against the flu.

I have found conflicting evidence in various research papers about how long the flu shot affects future immunity against the flu. One study, based on the 2009 H1N1 outbreak, for example, suggests that after immunization, immunity against that strain was lost within a year. Another study suggests that we could gain immunity against a strain of the flu that could last a lifetime. Importantly I think, this was based on a prior infection with the flu, not exposure from vaccination. 90 years after the deadly 1918 flu epidemic, 32 elderly volunteers still contained memory B cells circulating in their blood that readily secreted antibodies after exposure to hemagglutinin (HA) glycoprotein from the same strain.

Even though questions remain about how long immunity from the flu shot or nasal spray lasts, evidence that the annual flu shot offers some protection against the flu is clear. Even during years when the shot's effectiveness is low, it may still offer protection by reducing the severity of the illness, and therefore reducing the risks associated with serious and sometimes deadly flu complications.

The first flu vaccines were developed in the 1930's. Flu vaccines have been widely administered throughout the world for well over 50 years, but there is still much to learn about how the vaccine works and how to maximize its effectiveness. Researching the effectiveness of flu vaccines is very difficult. The pool of test subjects is almost impossible to control for. Individuals have unique and highly variable immune system function, which depends on health history, exposure history, sex and age. The effectiveness of the flu shot varies based on two central things: how closely it matches current circulating viral strains, which are always in the process of changing, and second, on the particular immunity of the person being vaccinated (which can often be a black box).

How The Flu Vaccine Is Made

Over a hundred national influenza centres across over more than a hundred countries collect flu data all year long. They monitor which strains are making people sick and how those strains are spreading, and then they pass that data along to the World Health Organization (WHO) and other centres. The data is gathered and analyzed to determine which strains are most likely to spread and cause illness during the year ahead. Usually three strains and sometimes four are selected: most often they are an H1N1 strain, an H3N2 strain and a B strain. This link lists the viral compositions of past (back to 2010) and present WHO-recommended flu vaccines.

Egg-based Flu Vaccine

The egg method has been used since the first flu vaccines were made, and it is still the method almost exclusively used. Each strain in the flu vaccine is produced separately in fertilized chicken eggs that are 11 to 12 days old. The following brief 2-minute video from McMaster University in Hamilton, Canada illustrates the basic procedure:



This fairly low-tech method is currently how most live attenuated and inactivated vaccines are made. This 2015 article outlines the protocol very clearly and is easy to follow. The candidate viruses are injected into eggs and incubated for two days so that the viruses can replicate. Then the virus-containing fluid is collected. The viruses are inactivated (for the shot), and then purified and tested before they are released. Attenuated viruses are also manufactured using eggs but the process is different and relies upon some modern genetic tools. In this case, a universal master donor virus is used. This master virus is made to be cold-adapted and temperature-sensitive by being cultured at progressively colder temperatures. It is then used as a vehicle to combine with the genes for the current virus, and then it is attenuated. Specifically, the genes used are those that encode the virus strain's unique hemagglutinin (HA) surface glycoprotein.

Although it has been used for many decades, the egg system in general is not a perfect system for several reasons. One problem with egg incubation is that it takes a long time. Even though the actual viral replication time is short (a few days) the entire process from start to end takes several weeks to obtain a sufficient amount of virus. Growing human viruses in an avian environment also presents a problem. Recent research reveals that it prompts the (human-adapted) virus to adapt to its foreign (avian) environment. This means that by the time the viruses are harvested, there is a chance that the immunologically important HA structure has mutated away from that of the original virus. The altered-HA virus in the vaccine now matches a different antigen, not the one causing people to get sick. This is a problem found especially with H3N2 strains of type A virus, and there are some questions about this happening with H5N1 as well. These two subtypes are part of most yearly vaccines. The H3N2 subtype in particular, for unclear reasons, grows poorly in eggs. Some years the virus grows so poorly that egg incubation fails altogether. When it does grow, it often means that its HA glycoprotein has mutated to help it replicate better (another function of this HA molecule). In this case, the HA either no longer matches the original antigen or its mutation reduces the ability of our antibodies to attach to it. Either mutation makes the vaccine less effective against H3N2 viruses. A fourth problem is that the timeline between virus identification and vaccine availability is 4-6 months, plenty of time for the "wild" virus itself to mutate within the human population so that the vaccine no longer targets it. A fifth worry is that because these are avian-type viruses that could also make chickens sick and die, a sudden pandemic of a virulent H5N1, H3N2 or other avian-type virus could come on scene without a ready supply of eggs. These are the primary reasons why we sometimes get frustratingly low success rates with the yearly flu vaccine, and why we need a better method soon.

Cell-based Flu Vaccine

In 2012, Flucelvax was the first flu vaccine manufactured using cell culture technology to be approved by the FDA in the United States. In this case, the virus was cultured in mammalian (dog kidney) cells) instead of a chicken egg, an environment that is more similar to a human host environment. Dog kidney cells (a cell line called MDCK) are a uniquely suitable epithelial cell substrate for culturing the influenza virus. Not only are they very similar to human epithelial cells, avoiding mutation pressure, but the virus also replicates readily in these cells. You might wonder why human cells aren't used. The canine version of an interferon-induced protein doesn't resist viral replication as it would in a human cell line.

Using mammalian cell culture technologies has several advantages over the egg method. There is hope that viruses cultured in mammalian cells do not experience as much pressure to adapt and mutate during culture. Importantly, while egg technology depends on having an egg supply (millions upon millions of eggs) ready, these culture cells can be frozen and banked, immediately ready for use, when a vaccine is needed quickly such as during a pandemic of a new strain. It also avoids possible allergic reactions against egg proteins and, finally, cell lines such as MDCK can be grown in a (supplemented) synthetic medium rather than commonly used fetal bovine serum. By avoiding bovine serum, the accidental transmission of some diseases such as spongiform encephalitis can be avoided. Since this method has been established now for a few years, why aren't most or all vaccines made this way, I wonder. Pharmaceutical companies appear to be reluctant to invest in switching over their technology.

DNA-based Flu Vaccine

A new and exciting approach currently underway goes even farther. The idea here is to isolate part of the particular virus's genetic code and inject that into the body, rather than the virus. The code will also contain special DNA code that allows it to enter our cells and direct them to make a flu antigen. Rather than a whole virus, this antigen could be the HA receptor itself or another viral segment. This approach would mean isolating a particular segment of the viral RNA and replicating it in large numbers in a cell culture. Like the cell-based method, this high-tech process takes much less time than isolating the virus and growing it in chicken eggs. Because the isolated genetic code remains identical to the virus's original RNA code throughout the process, there is no longer any problem with genetic drift (mutation away from the original). The vaccine is always an exact match to the virus. As long as the "wild" virus doesn't mutate in the human population during manufacturing time, it will match the virus making people sick. This shorter process reduces the window of time when that can happen as well. One problem encountered so far, however, seems to be getting the body to make a strong enough immune response. For unknown reasons, isolated parts of the flu virus (such as the HA receptor glycoprotein) do not stimulate as vigorous a response as an invasion of the whole virus does.

A Universal Flu Vaccine

Flu viruses are notorious for their mutation rate. This is probably the biggest hurdle faced when each yearly vaccine is created. By the time the vaccine is made, the virus has changed again. Some parts of the virus mutate at faster rates than other parts, and this can be exploited to make a universal flu vaccine. Our immune system naturally recognizes the HA receptor glycoprotein as an antigen and makes antibodies against it. As mentioned earlier, the HA receptor has two parts - a head and a stalk. Both the head and the stalk contain antigenic proteins but the immune system prefers to focus on the immunodominant head and makes antibodies against it. The problem is that head part of HA receptor mutates very often, meaning that antibodies induced by a flu vaccination often miss the mark. The stalk part, however, doesn't change much over the years. These proteins are encoded by conserved components of the viral genetic code.

In 2009, researchers discovered that the body also makes antibodies against the HA stem but not in as high a titre. The stem contains most of the virus's membrane fusion machinery. An antibody that binds to it blocks it and prevents the infection of epithelial cells, stopping the flu infection in its tracks.

If one can make a DNA vaccine against this conserved part of the virus, one can target the flu virus no matter what new strain it has mutated into. That is how a universal vaccine can be made against all influenza strains. The trick is to get the body to make a lot of stalk antigen and then to make a lot of antibodies against it, which it doesn't naturally do. The immune system tends to go for the HA head and ignore the stalk. One approach being investigated is to attach part of the stem to another protein called ferritin. The ferritin serves as a kind of glue that sticks a bunch of stem parts together and highlights their presence to the immune system. Another approach is to chop off the heads of the HA molecules and modify the stem so antibodies can attach to it more effectively.

A robust immune response against the flu viral HA stalk means the body will launch a rapid offensive against any future flu virus it encounters. If the researchers are lucky, it could even be a one-time vaccination if the production of memory B cells against it is robust enough, doing away with the hassle, significant expense and uncertainty of coming up with new yearly vaccines. Perhaps most importantly, it could protect us from the next highly pathogenic "pandemic" virus to come along, saving countless lives. It is frustrating for us to sometimes come down with the flu even after we've been vaccinated and to worry about the next inevitable deadly flu epidemic. It may seem that too little is being done to improve things but there are many lines of research underway that are focused on a new and better flu vaccine. It takes time, however, because each promising approach must be tested in preclinical (test animal) trials and if they show promise, and are proven to be safe, they can move on to clinical (human) trials, a process that generally takes several years. Still, what I've read makes me hopeful. I can imagine a day when my personally dreaded "Christmas flu" (even more dreaded than fruitcake) will be just a story from the scary old days. More importantly for all of us, we may soon never have to worry about a horrifyingly deadly pandemic like the1918 Spanish flu ever again.

Thursday, January 4, 2018

The Laws of Thermodynamics PART 4

The Laws of Thermodynamics PART 1 click here
The Laws of Thermodynamics PART 2 click here
The Laws of Thermodynamics PART 3 click here

The Third Law of Thermodynamics

The last in this four-part series of articles explores the third law, which focuses on the properties of  systems that approach absolute zero. The eerie quantum behaviour of matter becomes observable in extremely cold systems. At much warmer temperatures, molecules and atoms have so much kinetic energy they cannot form the chemical bonds that hold liquids or solids together. However, as absolute zero approaches, such random particle motion is quieted down enough to begin to reveal matter's underlying quantum nature. A tremendous amount of research is underway to explore how how ultra cold matter behaves. New and exotic behaviours, such as superfluidity, emerge as the system's thermal energy approaches zero. The third thermodynamic law is all about the energy of matter as it approaches absolute zero.

This law can be stated a few different ways. Put most simply, the entropy of a pure substance approaches zero when its temperature approaches absolute zero (0 K, -273.15°C, -459.67°F). It is a statement about the limits of temperature and entropy in a system. What is absolute zero? A substance, if it could reach exactly 0 K, would have no thermal energy left at all. Although it is theoretically possible, 0 K doesn't exist in nature, and this law really explores the reason why that is so. The coldest measured object in the universe is the Boomerang Nebula, which contains gases cooled to just 1 K. These gases are even colder than the empty space around them and that initially presented a puzzle. Background microwave radiation warms empty space to 2.73 K, so how is it possible to cool an object down more than the space around it? This posed a mystery to scientists until recently. They think that the Boomerang Nebula was created when a dying red giant star exploded as a smaller-mass companion star crashed into it, creating an exceptionally powerful explosion that ejected stellar gases outward at such velocity (10 times faster than a single exploding red giant of comparable mass) that the gas adiabatically expanded into an ultra-cold gas. The gas cloud would then gradually absorb heat from the microwave radiation bathing the space it occupies, until it reaches equilibrium with it, at 2.73 K

As matter approaches 0 K, atoms lose thermal energy. The electrons in atoms eventually fall down into low energy states. Does zero thermal energy mean that a system has zero entropy as well? Not necessarily, and this is the key point. When many substances freeze, they settle into a three-dimensional lattice-like arrangement. Crystallography is the science that explores those arrangements that atoms assume when a substance freezes into a crystal. Only a perfect crystal of a pure substance could actually reach absolute zero. Only in such a flawless atomic arrangement could atoms lock into such a perfect alignment that has zero thermal energy. Atoms in it would not have any kinetic energy. They would not move about slightly in the lattice or undergo any translational or rotational movements. Even at 0 K, however, each atom would still vibrate (in its lowest energy state) about its equilibrium position within the crystal, but this motion is not transferable as heat. Individual molecules and atoms can never be totally frozen. They are quantum clouds that are always in motion associated with the uncertainty principle, and electrons by their nature are never stationary. None of this motion is thermal motion.

A perfect crystal would have to contain only one kind of atom or molecule. Otherwise there would be entropy associated with the mixing of two or more microstates (you can also say there is more than one microscopic configuration possible). We are reminded that entropy is also about the multiplicity of possible states in a system.

A perfect crystal, though impossible to create, is useful because it offers a benchmark we can use to describe what happens to entropy as real substances are cooled to absolute zero. Microscopic imperfections always form when substances crystallize, no matter how controlled the procedure is. Any imperfection in a crystal lattice adds disorder and therefore entropy. Even the most flawless diamond, for example, is never perfect. Defects inevitably get frozen into a crystal that pull the lattice pattern out of alignment. If just a single boron atom replaces a carbon atom in a diamond crystal, for example, it will shift the whole alignment microscopically, reducing the microscopic order and increasing its entropy. All pure substances that in theory would condense into perfect crystals have, in reality, point defects. Such a defect could be a single replacement (like boron for carbon) or a hole created by a missing atom. It could be a linear defect or a planar defect. These are all called crystallographic defects. Every crystallographic defect adds residual entropy to a crystal, and would prevent it from ever reaching 0 K.

Some pure substances, even if they could be entirely defect-free, will still never settle into an absolutely perfect lattice formation. These substances cannot reach 0 K because of their atomic makeup. They will always retain a certain amount of residual entropy. A classic example is carbon monoxide (CO). A CO molecule has a small dipole moment, which means it has a slightly lopsided charge (it has "a left" and "a right"). When the gas is cooled down far enough it will eventually form crystals. Those crystals will not be perfect because each CO molecule can be oriented CO or OC. The dipole moment is too small to assure that all align in one direction so there is a chance that CO could crystallize in another pattern such as CO:OC:CO instead of CO:CO:CO, for example. We can estimate this contribution to the crystal's entropy by calculating how many possible microstates a crystal sample of a certain number of molecules can achieve. For carbon monoxide we know there are two ways each CO molecule can exist in the lattice so we can give a value w = 2. For an N number of CO molecules in the crystal, there are wN ways, or 2N ways in this case, that the CO molecules can be arranged. There are 2N different microstates possible, and entropy, we now know, is all about the number of possible states a system can be in.

When carbon monoxide freezes into a crystal, it becomes locked into one of many possible ground states, each of which corresponds to a specific microscopic configuration. It therefore must have residual entropy even at 0 K. Put more scientifically, carbon monoxide has a degenerate, or asymmetrical, ground state. Asymmetrical ground states are very interesting to study. Times crystals, mentioned earlier, show that an asymmetrical ground state can be one in space (as with the carbon monoxide crystal) or one in time and space (as in a time crystal). These crystals have a very unusual property. While ordinary crystals, such as carbon monoxide, have an atomic structure that repeats in space, time crystals repeat in time as well: they maintain a constant perfectly regular atomic-level oscillation while in their ground energy state. Researchers thought this was impossible - the atoms in substances at ground state should be locked in place and shouldn't change because there is no energy available to change. Yet a time crystal changes from moment to moment, leading researchers to wonder if it is doing work without any input of energy, a microscopic sort of perpetual motion machine that (gasp!) breaks the second law of thermodynamics.

Technically a time crystal is indeed a system with no thermal energy available to do work. It was also assumed to be an isolated system, where no thermal energy is transferred into the system. Upon close study, however, physicists discovered that a time crystal system is not closed. Even though it is in its ground state and remains in its ground state, it is actually an open non-equilibrium system (and the first non-equilibrium ground state system ever discovered).

Proposed theoretically in 2012, time crystals were recently created in the lab. One way to create a time crystal is to line up a set of ytterbium atoms, all of which have quantum-entangled electrons, that is laser-cooled to its ground state. Then it is deliberately kept out of equilibrium by hitting the atoms with two alternating lasers. It is open to the environment and energy is continuously being supplied to the crystal. If the lasers are turned off the crystal stops oscillating. The fine point here is that it's not a transfer of thermal energy because the atoms stay in ground state. If even very slight changes were made to the magnetic field or to the laser pulses, the ytterbium line "melted," changing its phase of matter, a clear signal that thermal energy was absorbed by the atoms. The time crystal therefore does not convert thermal energy into mechanical work. To make the time crystal "tick," one laser sets up a magnetic field that the electrons respond to and the other one flips the spins of some of the atoms. All the atoms are entangled so they all settle into a perfectly stable repetitive spin-flipping pattern that, strangely, is exactly half the rate of the laser pulses. There is no heat exchange or change in entropy because it is in only one ground state at a time. Rather than being a thermodynamic process, this motion, without thermal or kinetic energy, appears to be the first example of broken time translation symmetry observed in nature. Time translation symmetry is the fundamental assertion that the laws of physics don't change over time, and the conservation of energy in nature depends on it. Scientists make the distinction that if time symmetry is broken explicitly, then the laws of nature can no longer be counted on. In a time crystal, however, the symmetry is broken spontaneously, which means that, only in a specific case, nature chooses a state that doesn't obey time translation symmetry. This exception to the rule is analogous to the breaking of CP and time symmetry observed by the weak force mentioned earlier.

Conclusion

The laws of thermodynamics have an all-encompassing scope. They preside over every other science from biology, to geology, chemistry, astrophysics and quantum physics, to name just a few. They outline the basic rules that every process within the vast universe to the sub-atomic realm must follow, which means that these rules must work to explain the extremes of nature, such as black holes. Every scientific discipline from engineering to the applied chemistries to quantum computing must take thermodynamics into account when systems are designed. The laws can also be harnessed as a tool to probe into the mysteries of space-time and quantum behaviour.

Thermodynamics impacts us all personally. It underlies everything we do in life. It is essential to understanding how all life processes work, and how life evolved on this planet. It will be an essential component in our search for efficient energy sources of the future. It will even help us look for and recognize life on other worlds, as scientists imagine all the ways living systems could utilize exotic sources of energy. Anytime energy is converted from one form into another, or into work and vice versa, in any process, thermodynamics determines what can happen and what can't happen and why.

Wednesday, January 3, 2018

The Laws of Thermodynamics PART 3

The Laws of Thermodynamics PART 1 click here
The Laws of Thermodynamics PART 2 click here

The Second Law of Thermodynamics

The concepts of heat, internal energy and thermal energy we just explored can easily be confused. We still casually but incorrectly talk about heat as if it is something that an object contains, or as a property of that object. Internal energy and thermal energy are sometimes incorrectly used interchangeably even in textbooks (they are interchangeable only in a theoretical ideal gas, where there is no potential energy - the particle-particle interactions considered are perfectly elastic collisions between atoms which are treated as small hard spheres). Despite these challenges, the second law is no doubt the most misunderstood law in thermodynamics. Even by experts. We could look at it as something to be feared, but we can also see this law as the source of high quality mental fun. Borrowing from physicist Lidia del Rio once again this is where the village witch lives and it is where she does her best magic.

The second law introduces another term called entropy. This law states that entropy can never decrease over time in an isolated system. Unlike energy, entropy is not conserved in an isolated system. Remember, an isolated system is one in which neither energy nor matter can ever enter or leave. As a possible consequence, the universe as an isolated system might eventually suffer an ultimate fate called heat death, which is based on the second law of thermodynamics. The universe's entropy will continue to increase until it reaches a state of maximum possible entropy, or thermal equilibrium, where heat exchange between molecules and atoms is no longer possible. All thermodynamic processes die as a result. Entropy is an interesting and far-reaching concept. It does not always relate specifically to the internal energy of a system. Sometimes, entropy is (too-broadly) defined as the level of disorder in a system. It can also be defined as the number of possible microstates within a system. Often, entropy is a measure of the amount of information in a system.

Is the universe actually hurtling toward heat death? Is it truly isolated? Considering that highly organized structures evolve in the universe over time, the notion of increasing entropy in the universe presents some controversy. Wikipedia's brief "controversies" entry on heat death offers arguments against even assigning entropy to the universe as a whole, and there are many more arguments for and against to be found online. One question I find intriguing is whether a gravitational field itself has entropy. Gravitational fields have a way of keeping objects out of thermal equilibrium with the space around them. This idea is explored in the controversial theory of entropic gravity. Here, gravity is treated as an emergent and entropic force: at the macroscopic scale it is homogenous but at the quantum scale it is subject to quantum disorder, that is, from quantum entanglement of bits of space-time information. This disorder is expressed as a force we define as gravity. It agrees with both Newtonian gravity and general relativity and it offers an explanation for "dark energy," as a kind of positive vacuum energy within space-time.

A common way of phrasing the second law is to say that a system always tends toward disorder over order, but this statement can be misinterpreted. In physics, entropy is closely related to the concept of multiplicity. I think it is probably the easiest way to think of entropy. Take as an example a system of 20 books. There are many more ways (a multiplicity of ways) to accomplish a jumbled pile (no rules) than to stack them up neatly (specific rules). We can say that the randomly jumbled mess of books has higher entropy than the neat stack does. What happens when we come along and straighten up the books? Does the book "system" go against entropy's natural tendency toward disorder? No, because we were involved in the process we became part of the system. We did work on the system to decrease its entropy. Overall, the entropy of the "us plus the books" system increased.

The second law also states that systems tend toward a state of equilibrium. To explain this, let's take a different example. We have two volumes of gas separated by a movable wall inside a really good Thermos bottle, a bottle so well made we can consider the system isolated. The wall itself is also made of a perfect insulating material so no heat transfer can happen. We can think of this arrangement as two systems in mechanical contact with each other. To start with, we have one gas that is hot and the other one is cold. The hot gas will exert thermal pressure and push the wall into the cold side. We will assume that the wall movement is frictionless. The hot gas will expand and cool and the cold gas will compress and warm up (this is another example of an adiabatic process). The system does mechanical work (the expansion and compression of gases as well as the movement of the wall). The wall will stop moving when both gases reach the same pressure. If it is the same type of gas on each side, the compartments will also reach the same temperature. The two systems will come to rest at a state of thermodynamic equilibrium, and in this state, no part of the two-gas system can do any more work on the other part. This system still has thermal energy but that energy can't be used to do any work (within the system). This state has the highest entropy it can have under these circumstances. In this case, it is not self-evident that the system has reached a state of maximum disorder, or even that it has achieved the greatest multiplicity of possible states. We do know, however, that it has evolved toward an end state of thermodynamic equilibrium, which is also an evolution toward maximum achievable entropy.

As we can see, there is more than one way to look at entropy, like looking at a magic trick from different angles. No one angle gives it completely away.

The system's movement toward equilibrium is an irreversible process. It can't return to its original state of disequilibrium unless work is done on it. We could set up a real system of two gases as close as we can to the one just described and we would discover why this move toward equilibrium is irreversible. It might seem that we could restart the experiment over and over forever. Each time we would do exactly the same mount of work to heat and cool our gases to their starting temperatures. But even the best insulating material is imperfect and only superfluids are truly frictionless. Some heat will be lost to the outside of the Thermos, and some energy will be lost as heat loss through friction by the wall as it moves. If the experiment was repeated over and over using the same Thermos and the same initial work input, the overall thermal energy available to the system would eventually decrease and the entropy of the system (which now includes the room into which the heat dissipates and the mechanism we use to heat/cool the gases) would increase.

Another way of defining an irreversible process considers the role of chaos in systems. Any system of interacting molecules will include interactions between them that are chaotic in nature. We often think of chaos as what our kids do to their rooms but it is also a scientific theory. Systems are very sensitive to initial conditions, so even very tiny deviations in conditions at the beginning of a process can result in significant differences in how that system progresses over time. A hurricane is a chaotic system and that's why its strength and path are impossible to predict with certainty even a few days out. Almost every real process contains one or more chaotic elements. If we try to reverse a process back to its initial conditions we cannot rely on a series of predictable step-by-step transformations to arrive at exactly the same starting state. The specific process is irreversible and the outcome is not repeatable.

Is there any truly reversible process in thermodynamics? Even an atomic clock, which relies on extremely stable microwave cavity oscillations, shows minute frequency drift over time. In these clocks, laser-cooled atoms "tick" back and forth between an excited state and ground state. The energy difference between the states is always perfectly precise because it is quantum in nature. However, even the NIST-F1 cesium clock loses a second every 300 million years. Rather than heat loss per se, this system loses energy because the field transitions dissipate energy (they do work at the quantum scale just to keep going). The clock's entropy increases, albeit very slowly.

A process that doesn't generate entropy is a reversible process. The second law of thermodynamics (that entropy tends to increase in systems) is a consequence of the irreversibility of processes. Maxwell's demon was once held up as a theoretical system in which entropy could hold steady during a thermodynamic process. But under close scrutiny, even this famous thought experiment devised by James Clerk Maxwell, is not a reversible process. The idea itself though is intriguing: A microscopic demon guards the gate between two halves of a room. He lets only slow molecules into one half and fast molecules into the other half. Eventually you expect one half of the room to be warmer than the other half. This reduces the randomness of the molecular arrangement of gases and therefore reduces the entropy of the room (system). Looked at another way, it takes a system in equilibrium out of equilibrium. The argument seems rock-solid until you realize that the entropy of the demon itself (all that sorting work it is doing) actually increases the system's entropy overall more than it decreases it. In nature, many systems appear to have decreasing entropy. In all living systems, molecules are ordered into, and maintained as, intricate arrangements. Highly ordered galaxies appear to form from disordered clouds of gas. Disordered water vapour molecules flash-freeze into beautiful crystal patterns on a winter window. The key to all of these systems, living and non-living, is that they are open to some extent to their surroundings, like any real system is. In each case, surrounding entropy increases by an even greater amount, leading to a net entropy increase overall.

Scientists can only approximate a perfectly reversible process. An example is a process that is reversed by introducing an extremely tiny change to some property of a system that starts at equilibrium with its surroundings. If the tweak is small enough, the system remains so close to equilibrium that any deviation from it cannot be accurately measured yet the process itself does reverse.

In an ideal system designed to do work, such as a theoretical engine that has 100% efficiency, none of the work performed would be lost to heat transfer. The efficiency of a real engine, however, is always less than 100%, significantly less. If it is a piston engine or a steam engine, its efficiency can be analyzed quite easily by plotting a pressure-volume curve as it goes through a compression/expansion cycle. The area bound by the curve is the work done. The more efficient the engine is, the more closely that curve will follow an ideal equilibrium curve for that engine. An efficient engine never deviates far from its equilibrium state. A Carnot heat engine, mentioned earlier, is a theoretically ideal thermodynamic cycle, in which no energy is lost as "waste" heat transfer and there is no net increase in entropy. It represents an engine with 100% efficiency. An irreversible (real) process always strays away from that ideal equilibrium curve.

An example of a process that strays far from equilibrium is the carbon dioxide fire extinguisher once again. When you trigger the fire extinguisher, the carbon dioxide gas sprays out of the canister so fast that the air/carbon dioxide system has no time to reach equilibrium at first. The carbon dioxide cools adiabatically. The original amount of thermal energy is now spread over a large volume of gas cloud. Almost all of the potential energy of the pressurized system is lost through the work of adiabatic expansion. Even more work would be required to compress that gas back into the canister, much more than the work originally done because this process is now far from equilibrium. It is definitely not reversible and there is a significant increase in the system's entropy. However, entropy is also a statistical concept. Even in this case there is a chance, an infinitesimally small chance, that all the carbon dioxide molecules could spontaneously re-arrange themselves back into the canister (against their pressure gradient) through purely random molecular movements, reducing the system's entropy, and reminding us that the second law itself is statistical in nature. In a macroscopic system full of billions of atoms, it is vanishingly unlikely, but in a system of just a few atoms, the random chance of them all doing something together goes up. A triggered extinguisher, like all thermodynamic processes, proceeds in one direction only, and that is in the direction of increasing entropy. This direction, in turn, implies a forward arrow of time.

Thermodynamic Arrow of Time

The universe follows the second law of thermodynamics, where all real processes are irreversible, with the consequence that time must flow in one direction only. The increasing entropy of an evolving system gives us an impression of time and means that we can distinguish past events from future ones. The exception is a system that is in prefect equilibrium. In this case, the entropy remains the same and it is impossible to distinguish a past state of that system from a present state. The arrow of time would have seemed self-evident to Rudolf Clausius, who coined the term "entropy" in the mid 1800's, defining it as heat that incrementally dissipated from heat engines. The fact that time moves forward then seemed obvious but that confidence wasn't about to last. In just a couple of decades, quantum field theory was formulated to allow for charge, parity and time reversal (CPT symmetry). At around the same time, the idea that space and time are sewn together into a four-dimensional fabric was quickly becoming accepted science. General relativity and special relativity (which preceded general relativity) both treat time as something that is malleable and part of the system rather than outside of it. These theoretical developments brought our assumptions about time, and the second law of thermodynamics itself, into question.

Time, as we experience it, is a broken symmetry; there is no mirror in which time flows backward. Broken eggs can't reassemble. Aging doesn't reverse itself except in The Curious Case of Benjamin Button. Why this is so is actually a deep mystery in physics. Charge, parity and time reversal (CPT symmetry) is a fundamental symmetry of physical laws (except thermodynamics). The implication of this symmetry is that there is no theoretical reason why a "mirror" universe, one with an arbitrary plane of inversion (which you could think of as a vast three-dimensional mirror), with reversed momenta (complete with time running backward) and populated with antimatter (carrying opposite charges), couldn't evolve under our very same physical laws. It might even start from a vast Big Bang and shrink in volume rather than expand as ours does. Entropy in such a universe, we might assume, would tend to decrease rather than increase. However, even this assumption might be too simple. A number of physicists speculate that even in a universe that oscillates - it expands and contracts over and over - entropy might continually increase.

We might think that CPT symmetry, a mathematical theorem particularly useful in quantum physics, is a violation of the laws of thermodynamics. It should dissolve the one-way arrow of time and the rule that entropy never decreases in an isolated system. For example, we know that antimatter particles exist in our universe and we might assume that they travel backward through time. This assumption is wrong but it is not so easy to understand why. We can take the positron, the electron's antimatter twin particle, as an example. According to a theory called quantum electrodynamics (QED), an antimatter particle, mathematically speaking, travels backwards in time. If you look at a Feynman diagram of particle interaction, backward time travel by particles is commonly depicted. Below, we can see that an e+ (positron) and an antiquark (the q with the line over it) both travel backward in time in this depiction of electron/positron (e-/e+) annihilation (see the black arrows angled toward the left).

Joel Holdsworth; Wikipedia
Positrons are used everyday in large hospitals and we know that positrons are never emitted before a PET scanner is turned on in the hospital (thankfully). Why? A positron is exactly the same as an electron, but with positive charge. "Flip" time and you have an electron. A perhaps unsatisfying way to understand this problem is to treat time as a mirror-like parity that is flipped in a dimensional kind of way (think of four-dimensional space-time) rather than as the continuous forward flow we experience.

Even though all of our physical laws (except thermodynamics) display a fundamental CPT symmetry, it doesn't mean that all processes obey it. Three of the four fundamental forces of nature, the strong force, the electromagnetic force and gravitation (which, as general relativity, is not formulated in terms of quantum mechanics) obey CPT symmetry but the weak fundamental force occasionally violates both parity and charge symmetry at the quantum level. Recently, researchers discovered that this quantum process also sometimes violates time symmetry as well. Oscillations between different kinds of B-meson particles during the weak interaction happen in both directions of time but the rates are slightly different - this disparity doesn't have anything to do with the thermodynamic reason for time's broken symmetry however. An article from SLAC National Accelerator Laboratory at Stanford University offers an excellent technical comparison between broken T-symmetry at the macroscopic and quantum scales. For a thorough discussion of what this means philosophically, try this 2017 article posted by the Journal of General Philosophy of Science. I found it a good read.

As we've seen, at the quantum scale, processes are time-reversible (with the weak force exception). Quantum processes, according to the Copenhagen interpretation, are governed by the Schrodinger equation, which has T-symmetry built into it. Wave function collapse, however, does not. This is a mathematical framework that links indeterminate ("fuzzy") quantum particle behaviours to the determinate macroscopic behaviours of substances. Therefore, it finds itself at the epicenter of how time symmetry in the quantum world breaks down at the larger scale we experience.

Mathematically, a quantum system is laid out as a superposition of several equally possible states (technically called eigenstates (https://en.wikipedia.org/wiki/Introduction_to_eigenstates)), which reduce to a single eigenstate when the system is observed or measured. How this happens, and even if this happens, physically, is up for debate. It is simply a mathematical description, which means that the process itself is a black box, but it does provide a link between quantum indeterminacy and determinate macro-processes, thermodynamics being one of them. Somehow, inside the "black box," time switches from reversible to irreversible. How do two well established and experimentally proven but mutually exclusive theories (thermodynamics versus quantum mechanics) co-exist? This problem is encapsulated in Loschmidt's Paradox. No one knows the solution to Loschmidt's Paradox, although theorists have been working on it for decades.

What is known is that the second law of thermodynamics (and its arrow of time) is a statistical principle based (somehow) on the behaviors of countless quantum time-symmetrical particles. If we keep the statistical nature of these descriptions in the front of our minds and go back to the simple example of a stack of books, we could add that, yes, there are countless more ways those books can fall into a messy pile than there are ways to stack them up neatly BUT there is no rule against the books spontaneously falling into a nice neat stack either. It's just extremely unlikely. If this happened, it would not mean that the second law of thermodynamics just broke. It means that the underlying statistical nature of the arrow of time is revealing itself. A puzzle appears, however, when we think again about the increasing entropy of the universe. We could assume from that that the universe initially had very low entropy. There were no indistinguishable particles or forces at the very beginning. Through a series of symmetry-breaking processes, four distinct fundamental forces and all the myriad particles of matter emerged as the universe expanded and cooled. The question is, if the universe started with very low entropy wouldn't it have been extremely unlikely as well?

We might wonder if the arrow of time is an aspect of dynamics that emerges at the macroscopic scale. Emergence might not be the best description because at the subatomic particle level, time seems to exist but it runs in either direction. Time's one-way arrow only emerges within a large collection of molecules. Time's arrow might be better described as a symmetry that breaks at the macroscopic scale.

All these questions, I hope, point out that our understanding of time itself is a problem when we think about the second law of thermodynamics and entropy. Time is not a unified concept in physics. Depending on the theoretical framework you chose - quantum mechanics, classical dynamics or even general relativity - time can be reversible. Or it can be a one-way arrow. Or it can be illusion altogether, because general relativity treats time as one dimension in a four-dimensional stretchy fabric where all past and future times are equally present and our present time is non-important.

Black Hole Entropy: Testing Thermodynamics

A black hole tests all of our scientific laws and it is especially interesting when viewed as a thermodynamic object, which it surely is. A black hole is a region of space-time bent so severely by gravity that nothing, not even electromagnetic radiation such as light, can escape. Once energy or matter crosses the black hole's event horizon, it is lost from our observations. Black holes can be directly observed when in-falling matter is heated by internal friction, creating an accretion disk external to the event horizon, and it can be extremely bright. A black hole also gradually emits radiation, called Hawking radiation, and it has a temperature, which means that these objects should be subject to the same laws of thermodynamics as any other object.

Entropy, as we've explored already, can be understood in several different ways. Some physicists might argue that entropy is best understood as a statement about information rather than about order or disorder. Generally the various descriptions of entropy agree with each other but under specific circumstances, individual weaknesses with each approach become evident. Theorists appear to be best equipped to tackle the question of black hole entropy by interpreting entropy as information. More information encoded in a system means it has higher entropy. As an isolated system's entropy can never decrease, the information encoded by an isolated system can never decrease. This is a slightly different take on the idea of entropy as a multiplicity of microstates.

Black holes are wonderfully mysterious objects. Inside a black hole, matter becomes inaccessible to our observations. But, the momentum and charge of that matter is conserved, and its mass remains to bend space-time around it. Most black holes, especially those formed by massive collapsing spinning stars, are expected to have not only charge but also significant angular momentum. According to the second law of thermodynamics, we expect that matter disappearing into a black hole should increase the black hole's entropy. This implies that a black hole has non-zero entropy. A number of theoretical physicists are currently working on how entropy works with black holes and how to measure it. The new methodologies they have come up with so far are surprising. We immediately realize how unusual a black hole is when we learn that instead of using volume to calculate the entropy of what we assume is a spinning spherical object, we must use the area bound by its event horizon instead. In 1973, Jakob Bekenstein calculated black hole entropy as proportional to the area of its event horizon divided by the Planck area (the area by which a black hole surface increases when it swallows one bit of information). In 1974, Stephen Hawking backed up this work and additionally showed that black holes emit thermal radiation, which means they have a specific temperature. So how does the second law of thermodynamics enter? It has actually been rewritten for black holes to say that the total area of the event horizons of any two colliding black holes never decreases. This is part of the closely analogous set of laws for black hole mechanics.

How do we get an intuitive picture of how black hole entropy works? We can start by looking at a black hole's entropy statistically. Each of all the countless billions of particles that have fallen down the gravity well of a black hole will be in a specific thermodynamic state. Each microstate will contribute to what should be an enormous number of possible microstate arrangements. Microstates in a macroscopic system are all the different ways that the system can achieve its particular macro-state (which is defined by its density, pressure, volume, temperature, etc.).

By treating these microstates statistically, we can come up with an approximation of the black hole's overall entropy. This would be straightforward if black holes didn't present us with a unique and bedeviling twist: the no-hair theorem. The no-hair theorem argues that this approximation cannot be done. Aptly named, it tells us that a black hole can be described by only three classical parameters: its mass, its charge and its angular momentum. All the particles that fell into a black hole do not contribute to any kind of unique character to it. A black hole that swallowed up a cold hydrogen gas cloud looks the same as one that swallowed an iron-dense planet. Instead, the no-hair theorem treats a black hole as a ubiquitous and enormous single "homogenous" particle. A possible analogy might come from another housekeeping chore. The vacuum cleaner sucks up all the stuff off the floor. A CSI investigator could look in the canister afterward and determine, through skin flakes, hairs and other debris, who lived in the room, and perhaps even what they were doing over the week. In the case of black holes, the "canister contents" appear to become generic once they cross the event horizon. You can't tell what particular atoms fell in, when they fell in, and what their velocities, etc., were. The no-hair theorem is a mathematical theorem: it is the solution to Einstein-Maxwell equations of electromagnetism in curved space-time. It turns all different forms of matter/energy into a generic electromagnetic stress-energy tensor, which bends space-time. What this theorem implies is that all of the information encoded by the special quantum characteristics of each matter particle, such as baryon number, lepton number, colour charge, and even whether it is matter or antimatter, is annihilated when it falls into a black hole. More specifically, it implies that the black hole as a system will have much less entropy than the ordinary matter originally had. Matter and energy being lost in a black hole, if treated as an isolated system, appears to represent a process that decreases entropy, and that is a violation of the second law.

We can't just toss out the no-hair theorem as a mathematical curiosity that might well prove invalid in nature. d. Its validity is backed up by recent observations of black holes by LIGO, a gravitational wave observatory. To add to this entropy problem we could draw the additional, and no less astounding, conclusion that the no-hair theorem suggests that a black hole is actually just one a single microstate (just one "particle"), which means it should have not just low entropy but zero entropy, if we interpret it as there's only one way to assemble a single microstate.

According to quantum mechanics, the quantum information encoded in a particle (its spin, angular momentum, energy, etc.) must be conserved during any process, which is a variation on the first law of thermodynamics, except that the focus here is on information rather than energy. Where does that information go inside a black hole? Hawking radiation, which leaves the black hole system, is a natural place to look, but Hawking's theory suggests that this radiation is "mixed," which means that it is generic; it doesn't contain any of the specific particle information that went into it. To make things even more interesting, there is some serious debate about whether Hawking radiation, as described using quantum theory, actually is a form of thermal radiation. The conclusion that a black hole has a temperature comes not from direct observation (which could be understood using classical statistics). It is based, instead, on quantum mechanics. Thermal radiation, emitted from a black body (a physical object that absorbs all incoming electromagnetic radiation), contains information about the body that emitted it. Hawking radiation contains no such information. It is based on the law of conservation of energy only. In space-time, virtual particles pop in and out of existence all the time everywhere. They exist because space-time has a non-zero vacuum energy, which is a consequence of the uncertainty principle. Close to the very high-energy space-time environment around a black hole, some theorists suspect that virtual particles, as particle-antiparticle pairs, have enough energy to become real particle pairs, with mass. If one of the pair falls in, it must have negative energy (according to an outside observer) in order to preserve the conservation of energy law. This also means it has negative mass (there is a mass-energy equivalence), which means that the black hole itself loses mass and appears to emit a particle (again, as observed by an outside observer). Hawking radiation has not been observed yet, but by using an analogue acoustic black hole made in a lab, scientists have found strong evidence that suggests Hawking radiation exists around real black holes.

Good evidence for the existence of black hole radiation, whether it is thermal or not, might solve the issue of conservation of energy but it doesn't appear to conserve information. Information can be lost by one of a pair of entangled particles when it falls into a black hole and is lost. Entangled particles are thought to be very common in space-time and they can also be physically very far apart in space, across the universe in fact. Distance is irrelevant to quantum entanglement. Because of quantum mechanics, an entangled pair or a group of particles can be described by a singular unique quantum state (spin, angular momentum, energy, etc.) just as a single particle is. From a quantum mechanics point of view, the pair or group becomes a single particle (some theorists think that matter inside a black hole might be quantum-entangled). If one of a pair of quantum entangled particles falls into a black hole and loses its quantum signature, does its entangled partner pop out of existence somewhere else in the universe at the same time? It seems that this process would continuously decrease the entropy of the universe as a whole. The dilemma this presents is called the black hole information paradox. One could argue that because time slows down to a stop in the infinite gravity well at the event horizon of a black hole, nothing really ever goes in. Its quantum information remains somehow encoded, smeared somehow across the event horizon, scrambled up and out of reach. Newer models of quantum gravity suggest that the particle left behind remains entangled by whatever form of matter/energy its partner is now in inside the black hole, thus dissolving the paradox. Another argument emerging among physicists is also exciting. It actually uses quantum entanglement to solve the black hole paradox. It uses wormholes to link the paradox phenomenon with the Einstein-Rosen Bridge (or wormhole), described by two previously unrelated theories. It is laid out in this Quantum magazine article. Entangled particles inside and outside a black hole could remain connected through the continuous space-time that would exist inside a wormhole, solving the information paradox. No one's sure yet if that idea holds up theoretically.

The holographic principle, which is gaining momentum in theoretical physics, is yet another way to explore the information paradox. It suggests that a black hole encodes all of the particle information just outside the event horizon as statistical degrees of freedom. Degrees of freedom are a measure of information, closely related to the idea of multiple microstates. How this information is stored, and what form it is in, is impossible to visualize, however, because a black hole is treated theoretically (in almost all theories) as a four-dimensional (space-time) object. Although a black hole should appear as a sphere to an observer, it is not a three-dimensional sphere we can relate to. It is a singularity of mass. The event horizon, likewise, is not a physical two-dimensional barrier shell around a black hole. It is the last distance from which light can escape the gravitational well, measured as the Schwartzchild radius. For example, Earth has a Schwartzchild radius of about 2 centimetres, which means that if Earth's mass was compressed into a sphere of 2 cm radius, it would be so dense that it would spontaneously collapse into a black hole singularity.

From our perspective, information is last observed at the event horizon of a black hole. This approach helps us understand why entropy is a measure of event horizon area, rather than volume. It also implies that a black hole, rather than being a zero-entropy object, is a maximum entropy object. Depending on how we look at it, generic information can be thought of as equivalent to maximally mixed information, an equilibrium state.

No matter how we look at the information paradox, information inside a black hole seemingly must get back out through black hole evaporation (as Hawking radiation). A black hole that doesn't feed on matter should gradually shrink and eventually disappear, meaning that somehow, the quantum information of all that matter must get back out. If the information is irretrievably lost from our universe, then black holes either do no obey thermodynamics or they represent some kind of door into some other entity and the universe is not an isolated system after all. It could even mean that ordinary matter and energy as we know it is actually an illusion. It could be information encoded on a surface area, making the universe, by extension, a hologram of that data.

Black hole entropy has also recently been calculated based on a supersymmetric black hole in string theory. This technical 2007 review by T. Mohaupt describes the reasoning and process. This solution ties in with the holographic principle (which is also based on string theory) and its solution closely matches that of Jakob Bekenstein (who based black hole entropy on the area of the event horizon). The fact that the two calculations match up closely gives a number of theorists hope that string theory could be a route to ultimately solving the information paradox.

Based on all of these and other developments, physicists Brandon Carter, Stephen Hawking and James Bardeen have formulated a series of black hole mechanics laws, which are analogous to the laws of thermodynamics. While thermodynamics is a classical science, these laws attempt to integrate general relativity, quantum mechanics and thermodynamics together. As I hinted at earlier, these mechanical laws offer up some seemingly odd conclusions. Uniform gravity at the event horizon is analogous to thermal equilibrium (the first law of thermodynamics). Entropy is analogous to the increasing surface area of the event horizon (the second law of thermodynamics). New theories about black hole entropy offer some serious food for thought because we approach entropy not just through the lens of classical mechanics but through the lenses of general relativity and quantum mechanics as well. Being a universal rule of nature, shouldn't entropy find its expression there too?

One of the most interesting approaches to black hole entropy was done under a specialized mathematical framework. It is laid out by physics theorist Sean Carroll in one of his blog entries from 2009 (I wholeheartedly recommend his blog). As a black hole's rotation and charge increases, its entropy approaches zero. This statement is analogous to the third law of thermodynamics, which will be explored next. According to this law, no system can have exactly zero entropy, so this means there is a limit to the spin and charge of a black hole. The third black hole law of mechanics might represent the deepest puzzle yet for theorists.

A black hole at the spin/charge limit is called an extremal black hole. It is a black hole that has the smallest possible mass at a given charge and angular momentum. It is therefore the smallest possible mass black hole that could theoretically exist while rotating at a constant speed. If these objects existed, they would be microscopic, but they are only theoretical. In theory, an extremal black hole could be created in which all of its energy comes from the charge, or electrical field, and none from matter. Such a black hole is a product of Euclidean quantum gravity, a theory of space-time in which time is treated exactly like another spatial dimension. The entropy of such a black hole can be calculated by using string theory, and it comes out to be exactly zero, which is forbidden by the third law of thermodynamics. A first reaction could be, well, that's the end of that thought-stream, and Dr. Carroll suggests that this is exactly what the authors of the original paper thought. But then the idea was revisited because it seemed to hint at something very interesting.

In an extremal black hole, entropy discontinuously drops as charge is increased, and eventually its hits a limit where the mathematical solution the researchers used splits into two different space-times! Part of this mystery includes the fact that the mathematics of all charged black holes gives them not one but two event horizons. The outer event horizon is the one you expect - a point of no return. The inner event horizon is located between that point of no return and the singularity itself. What's unique is that an object between the two horizons isn't forced to crash into the singularity. Inside the black hole, moving forward in time means moving inward toward the inner event horizon. That part is inevitable. However, outside the black hole and inside the inner event horizon, time moving forward looks normal and an object in either of those spaces isn't forced anywhere.

As you increase the charge and keep the mass the same, the two horizons come together.  You are moving toward an extremal black hole. You would expect that the region of space-time between the horizons will eventually disappear, but it doesn't. It reaches a finite size and stays there, until you reach an exact extremal black hole, and which point it suddenly and discontinuously disappears. The entropy, when calculated, decreases smoothly alongside the increasing charge until exactly when an extremal black hole is reached and at that point it suddenly slips to zero. This asks the question: is there a theoretical problem here or does the entropy suddenly escape into some new and different space-time (as space-time itself appears to split as well)? Does it offer a clue about where matter (and all that missing entropy) goes inside a real black hole? This new space-time is a mathematical solution called two-dimensional anti-de-Sitter space-time on a two-dimensional sphere. Dr. Carroll himself wonderfully refers to this hidden space-time as "Whoville" In his fascinating post on this mysterious theoretical journey. You can download a pdf of the scientific paper he and the original authors written on it here.

Although we might not know exactly what kind of space-time black hole particles find themselves in if that's what they finds themselves in, black hole physics seems to be a great tool to use to search out the limits of the second law of thermodynamics. Black holes go an additional step by demanding that all of our disparate laws of nature come together to describe them. Dr. Carroll puts it well: black holes are fertile "thought-experiment laboratories" to test our understanding of thermodynamics, especially the second law.

For The Laws of Thermodynamics PART 4 click here