The Big 3: Tuberculosis Part 1

Welcome to the first disease post of TB Honest. If you haven't already, I recommend you take a look at the introduction.

This post took me some time to get together because TB is complicated and I'm figuring out how I want to format my disease posts. I'll keep refining this as I go, but I realized that the original post was way too long so I'm cutting into multiple, more digestible posts. The next part should be up in a couple days.

Well, here we are talking about our very first disease. One of the oldest and most feared infectious diseases on the planet, it has been called the White Plague, phthisis, and consumption. It holds epithets such as the robber of youth, the graveyard cough, and Captain of all these men of Death.(6) It's the namesake for this blog. It's tuberculosis.

Along with HIV and malaria, TB is one of the top priorities for public health. Of all infectious diseases in the world, it is the number one killer. In 2015, tuberculosis killed 1.8 million people and infected another 10.4 million.(2) As of today, the world population stands at around 7.5 billion people. One-third of them have tuberculosis.(2)

No, I did not mistype that. One out of three people is infected with tuberculosis. But that's from a global perspective. If you look at the United States, the case incidence rate comes out to about 3 people per 100,000 persons.(2) It joins Canada, Australia, New Zealand, and the nations of Western Europe as one of the countries with the lowest TB burden. Indonesia and India have the most TB cases in the world.(14) [Edit: after reviewing the numbers, I realized Indonesia has a much higher TB rate than China. Corrected.] The point I'm trying to make is that the distribution of tuberculosis worldwide is not equal. We are going to talk about why that is. However, tuberculosis is a global, complex topic and I will not be able to cover everything in this one series of posts. So we will be revisiting this topic from time to time with supplemental posts. We're covering the basics right now.

So let's talk about where TB came from.

A brief history of TB

Tuberculosis is nothing new. It is an ancient disease. We found traces of it in the mummies of Ancient Egypt. (18) References to the disease are in the Bible, the Vedas, Hammurabi's Code, and Homer's Odyssey.(4,6,11) Now, the question of how long tuberculosis has been a part of the human experience is a matter of debate. Some experts say 40,000 years, while others put it around 6,000.(1,16) Regardless, TB has a rich history that spans multiple volumes, so there is no way a humble blog post can cover everything. Remember, we're going shallow here.

As for how tuberculosis first found its way into humans, studies seem to suggest that it may have been a cross-species hop from animals to humans when we started taking up agriculture. Tuberculosis is a disease that does not confine itself to one species. We see that nowadays when it infects animals such as cows and elephants. So it shouldn't be much of a surprise that there is a study that suggests tuberculosis may have crossed the Atlantic Ocean and came to the Americas through seals.(1)

Throughout human history, tuberculosis made its way through societies and civilizations and racked up an impressive death toll. Towards the close of the 19th century, some European officials believed that the infection rate in their cities was close to 100%. There was a strange period in the 1800s when the disease was romanticized by poets and writers (because it killed a lot of them), and the pale, thin figure common in TB patients became a standard of beauty for the time. That trademark, wasting pallor is why the disease was known as consumption and may be where its name the White Plague came from. The literary tradition for describing vampires and their victims, which started in this time period, probably came from the common sight of individuals with tuberculosis.(7) So next time you see a vampire or Tim Burton movie, remember TB.

March 24, 1882 was an important date for tuberculosis because that was when Dr. Robert Koch, a legendary physician and hero for the field of infectious disease, discovered the bacteria that causes it: Mycobacterium tuberculosis. (There are other bacteria that cause tuberculosis, but M. tuberculosis is the main species and we don't need to get into that nuance right now.) This day is now memorialized by the World Health Organization as World TB Day. As technology steadily advanced, we became better equipped at detecting and preventing the spread of tuberculosis. 1895 was the discovery of the X-ray, which helped us detect TB infection of the lungs. In 1900, a pair of French scientists began developing a vaccine against tuberculosis. This became the Bacille Calmette-Guérin (BCG) vaccine which is still in use today.

However, the biggest development was the discovery of streptomycin, the first effective antibiotic against tuberculosis. The guy who discovered the drug, Selman Waksman, was also the person who coined the term "antibiotic." In countries with the infrastructure and resources to implement effective public health policy and treatment options, tuberculosis, our old scourge of antiquity, began to drop off. Countries that did not have access to antibiotics nor the public health infrastructure did not see the significant drop off with tuberculosis. Yet, those countries that started to bring their TB cases under control became confident in their medicine. This was that nice optimistic period I mentioned in my introductory post where we began to dream of a world without infectious disease.

Then the 1980s arrived, and along with it came the AIDS crisis. As it turns out, tuberculosis is a major opportunistic infection for HIV patients, so the number of tuberculosis cases exploded. Then we noticed that the bacteria that causes TB was becoming resistant to our antibiotics. And that brings us to today.

So now that we've covered a small portion of the rich history of tuberculosis, we are going to some basic biology to talk about bacteria.

Image credit to U.S. Centers for Disease Control and Prevention - Med Illustrator. Provided by CDC/ James Archer.

What are bacteria?*

*A Caveat Concerning Biology

Of the three basic sciences, biology is the most complicated. That is because physics is the cornerstone: it attempts to understand the physical laws of reality. Chemistry examines how matter is composed, interacts, and changes. Biology then studies how living organisms survive as they abide by the laws of chemistry and physics.

When I said "law" back there, I'm referring to a scientific law which is a little different from our concept of law in day-to-day society. In science, a law is a statement that describes or predicts natural phenomena. A lot of times those laws can be written out as math equations. Physics has Newton's law of gravity, Kepler's law of planetary motion, and plenty of others. Chemistry has the laws of thermodynamics. These laws were developed by empirical study and experimentation, and they are used to predict the behaviors of the known universe. If a law has an exception, then it is not a law. And the problem with biology is it is full of exceptions because it deals with life. Life is diverse. This makes biologists cautious when they go about naming the rules of their field. You have probably heard about Darwin's Theory of Evolution. It is the most groundbreaking and revolutionary concept in biology because it affects every subset of biology. Yet, we are still figuring out the mechanisms behind evolution, so scientists are not comfortable with making it Darwin's Law of Evolution.

The reason I spent time talking about the laws of science is to warn you, dear reader. The science behind biology is extremely complicated, and I am not going into that level of detail. I will generalize. For every generalization I am about to give you, there's probably at least one exception. Tuberculosis itself breaks a few nice, easy generalizations I will attempt to make about bacteria. So keep that in mind.

Bacteria

Bacteria are some of the smallest and most successful forms of life on this planet. Look under a microscope and you'll see circles, rods, cones, spirals, helixes, and all sorts of squiggling shapes. The largest bacterium on the planet is three-fourths of a millimeter wide and lives in ocean sediment. The smallest bacterium is between 200 and 300 nanometers, lives in the human urogenital tract, and is a cousin of chlamydia. They are a diverse group of life forms. And they are everywhere. They live inside of us and on everything we touch. We use them to make cheese and yogurt. And then, of course, there are some that make us sick.

So why are bacteria so successful?

Let's compare a human cell to a bacterial cell. If we want to throw scientific terms around, we would say that a human cell is eukaryotic and a bacterial cell is prokaryotic and leave the discussion there. However, that doesn't mean anything to most people, so let's dig a bit. The very first difference is in size. A human cell is typically at least ten times bigger than a bacterium. If you compare the two, the human cell is also much more complicated. A human cell has to work together with the other cells in your body to break down your food, tell your muscles to move, be your muscles, or whatever task it's been assigned. It has tiny organs, called organelles, that help facilitate whatever task that cell is made to do. The human cell has a nucleus, the "brain" of the cell if you will. When you look at DNA, the human genome is about 60 times larger than an average bacterial genome. Human cells are so much more complicated than bacteria.

If you look at bacterium, you will see a much starker structure: smaller, no organelles, less DNA, no nucleus. That's why bacteria are so successful: they're simpler so it's easier for them to replicate. It takes nine months to make a human. If you look at us at the cellular level, our fastest dividing cells are in our skin and intestinal lining. It takes 20 hours to make a new cell to line your colon.

Now, what about bacteria?

If you want to look at a "typical" bacteria, we look at E. coli. Yep, that's the same E. coli you hear about in the news when it gets in your lettuce. An E. coli cell replicates every 20 minutes. That is one-sixtieth of the time it takes your fastest cells to divide. E. coli is so good at replicating itself that it will start copying its DNA for another division as it is in the process of dividing. Human cells can't do that (and if they did, they'd be cancer cells).

The strategy of bacteria for surviving a harsh world is to make so many copies of themselves that their species will survive simply because it's so hard to kill them all. Give them 40 minutes and they're grandparents. And since they're producing so many of themselves, you see a much faster rate of natural selection and adaptation to a changing environment. If you want to generalize this even further, bacteria emphasize quantity over quality.

...except for tuberculosis. One of the reasons why tuberculosis, HIV, and malaria are a part of the big three is because they do not adhere to our typical frames for bacteria, viruses, and parasites. Here is where the distinctive personality of tuberculosis begins to shine through. TB is patient. It isn't in a hurry. Whereas most bacteria divide quickly, TB takes its time. The doubling time for a tuberculosis bacterium is 18 to 54 hours.(9)

That slow division time is a feature for the Mycobacterium genus. Whenever you see a scientific name, it is a way to classify how related different organisms are and are written Genus species. So remember, humans are Homo sapiens. What I'm saying is that tuberculosis has some pretty slow cousins. One of those cousins is the bacterium that causes leprosy.

The biggest effect that this slow growth has is on research. One of the reasons why E. coli is the "typical" bacteria in science is because it's easy to grow a ton of it and do tests. If you are researching tuberculosis and trying to grow your own bacteria, it's going to take a while to do anything. There are some implications to this which will come later.

Gram Staining

Bacteria are small, and they are transparent. Consequently, they're hard to see. So one of the very first steps to researching any bacteria is to visualize them on a microscope slide. The way we do that is called a Gram stain. We wash the bacteria with a couple of different chemicals, and when we look at them under a microscope we can see them because they've been stained a certain color. What color bacteria turn is a result of their membrane, the part of a cell that divides the cell from everything else. You can just think of a membrane as like skin.

So if a Gram stain turns a bacterium red, we'd classify it as a Gram positive. If the bacterium is blue, it's Gram negative. The reason this is important is that this is one of the basic ways we sort types of bacteria.

...except for tuberculosis. Gram stains don't work.

The reason why Gram stains don't work is that the tuberculosis bacterium is surrounded by a thick layer of fat which prevents the chemicals from staining. Mycobacterium tuberculosis is what is known as an acid-fast bacteria because before it can be visualized on a microscope slide, you need to dissolve the fat with an acid.

Okay, so I'm cutting this post off right here. The next post we will be going into the transmission and pathophysiology of tuberculosis infection. See you in a few days.

Part two is now up.

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