A History of Bugs and Resistance

A little over seventeen years ago around this time I started coming down with flu-like symptoms. My father already had similar symptoms, and my mother developed them shortly after. After a week our symptoms only got worse. So, we went to our doctor. He suspected a bacterial infection and prescribed an antibiotic: tetracyclin. This helped: within four days most of the infection cleared, and within two weeks all lingering symptoms disappeared.

The Ancient

Antibiotics may conjure up an image of people wearing white coats in a modern laboratory. However, traces of that same antibiotic we used, tetracyclin, were found in ancient mummies. How could this be?

We often think of medication as something made in a lab. However, antibiotics, stuff that either kills or slows the growth of bacteria, are all around us. Humans have been consuming antibiotics for a long time, though without knowing the actual mechanism behind their curing effects.

Antibiotics found in the soil are a natural byproduct of warfare at a tiny scale. As bacteria compete with other bacteria to survive, producing something that kills the competition is a highly effective survival strategy. The result of this small-scale chemical warfare can both help us and harm us.

The Great War

Anyone who went to Sam Mendes’s 1917, a film about the first World War, got at least an inkling of what it was like back then. However, while brilliantly shot, some of the trenches looked a bit too clean.

In reality the hygienic conditions in the trenches of World War I were abysmal. The spread of disease made worse by decaying corpses, poor sanitation and prolific bugs such as lice and flies. Combined with the soldiers’ own weakened immune systems and the transport of livestock near the front-lines, the environment formed the perfect breeding ground for existing diseases to flourish and new ones to emerge. While the macroscopic trench warfare was characterized by stand-offs, the microscopic germ warfare was continuous.

The Spanish Flu

Near the end of the war a new kind of flu emerged in northern France, one with an unusually high mortality rate. To maintain the morale of the troops, the news of this novel flu was mostly kept under wraps. However, as the infection spread to Spain, not subject to this censorship, reports of its devastating death toll started to spread more widely. This owed the disease its popular name: The Spanish flu.

The Spanish flu quickly spread to Ireland through returning soldiers. Saved from the brutal war, some of them would become the carriers of death for the home front. The disease spread throughout the United States and the rest of the world and killed about two people for every ten infected. In total it would go on to claim at least fifty million lives worldwide.

No antibiotic existed yet, but none would have helped directly against this flu either, since antibiotics combat bacterial infections not viral ones. Nevertheless, antibiotics could have saved the lives of many soldiers during World War I. Especially those with infected wounds and diseases like typhoid. However, it would take another decade for the first antibiotic to be found.

Fungi Fighters

In 1928 Alexander Fleming discovered this first antibiotic more or less by accident: penicillin. During the second World War, the availability of penicillin saved many lives. However, while useful for resolving and preventing bacterial infections, it was ineffective against fungal diseases which many came down with. Hence, focus shifted from bacteria to fungi. The race was on to find something that would kill those fungi.

Elizabeth Hazen, a bacteriologist, dedicated years of her life to the search for an antifungal producing microbe. She scouted soil samples and mailed them to Rachel Brown, a chemist, for purification. The pair searched for several years and during that time discovered many molecules that proved lethal to both fungi and animals. One day Elizabeth found a promising micro organism in a soil sample of a friend’s dairy farm.

Elizabeth Hazen and Rachel Brown (1955)

Fortunately, the organism produced a molecule that killed only fungi and not animals. Hazen and Brown marketed it as Nystatin, the world’s first antifungal drug. It saved countless lives since its introduction. The patent on the drug made them millionaires. Money which they donated to a nonprofit that went on to conduct similar research.

The Modern World

In recent years we have seen outbreaks of several high-profile influenza viruses with a higher than usual mortality rate. Think of SARS (2003), MERS (2012) and recently COVID-19 (2019). Like the Spanish flu, outbreaks like these have the potential to wreak havoc. However, while public awareness concerning the emergence of novel viruses is high, the risks of infections with mutated resistant bacteria, and fungi, are understated. After all, we already have antibiotics and antifungals to combat and defeat those, right?

Unfortunately, that has not been the case for many years. The best known example is MRSA: methicilin-resistant Staphylococcus aureus. Dairy cows serve as a reservoir for this family of mutated strains of the common and normally harmless Staphylococcus aureus bacterium.

The overuse and misuse of penicillin in the fifties contributed to the evolution of resistant strains of Staphylococcus aureus. Methicillin was then used instead to fight it, but over time resistant strains emerged: MRSA. Nowadays, the treatment for it is Vancomycin, but there are already mutations for which that treatment no longer seems to be as effective.

The circumstances that gave rise to widespread bacterial infections during World War I, still exist. There are plenty of overcrowded places with poor sanitation, proximity to animals treated with antibiotics which harbor resistant microbes, and lackluster medical facilities and dismal containment procedures. The ideal breeding ground for the next fatally resistant mutation. This risk is thus not restricted to viruses, but extends to bacteria and fungi alike.

These resistant microbes spread and thrive in places where people gather or pass through like hospitals. Their presence there can turn routine operations into risky procedures.

In conclusion

While the discovery of antibiotics is fairly recent, they have existed for many years in the soil. This continues to be a source for development of new drugs, so too for antifungals.

Poor hygienic condition provide a breeding ground for new bacteria, fungi, viruses and other pathogens to mutate into something more deadly. Finding an effective treatment can take many years, if one can be found at all.

While viral mutations are risky, so are mutations of bacteria and fungi. The treatments that we currently have for them can lull us into a false sense of security. This is why we should take care to protect our most potent antibiotics and antifungals. We should do this by using them judiciously, limiting their applications in agriculture, and incentivizing work on continuously finding new ones.

I conclude with the jarring realization that if there had not been antibiotics available, effective against the bacterial infection my family contracted, we might not have experienced the past seventeen years at all.

References

  1. McCarthy, M. (2019). Superbugs: The Race to Stop an Epidemic.
  2. Jackson, P. (2019). They shall not grow old.
  3. Jacobs, A. (2019). U.N. Issues Urgent Warning on the growing Peril of Drug-Resistant Infections.

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Compound Effects

Why do we have a poor intuition for processes that unfold non-linearly? How can we leverage compound effects in order to spiral ourselves upwards in terms of health, wealth and knowledge? Let’s explore.

Physical World

Many of our intuitions are rooted in the physical world. When we roll a ball gently across the floor, and it disappears behind a couch we know it will reappear on the other side. It may roll a bit slower and come to a halt eventually. However, we certainly don’t expect that ball to continue to accelerate and shoot through the outer wall, across the yard into the house of an adjacent neighbor.

It’s not that we never expect something to accelerate: if you jump out of a plane you expect to accelerate initially, falling faster and faster. However, that only last for a dozen seconds. After this you reach terminal velocity after which you keep hurtling towards the earth’s surface at a constant speed.

Miracles and Catastrophes

We don’t possess a good intuition for things that keep accelerating, for the simple reason that this does not happen in the physical world in a way we can easily observe or experience directly. When we do observe the outcomes of such accelerated processes, we often refer to its outcome as either a miracle or a catastrophe.

Consider our main building block: a single cell. It divides and after twenty generations of dividing gives rise to a million cells in total. Add to that another twenty generations and there are enough cells to make a human being like yourself. Although this process is, to an extent, scientifically explainable, many label this a miracle when they observe it.

In contrast: we can create nuclear energy by a controlled chain reaction of splitting the nuclei of atoms. When left uncontrolled this can lead to a nuclear explosion, which we label a catastrophe.

In both cases the outcome, a human being or an explosion, is an outcome that we observed and can reason about. Nevertheless, even knowing the facts, the outcome still feels surprising. It does not feel intuitive.

A Rational Example

To explore this a bit further, let’s look at a practical example to test your intuition. Let’s say that I gave you a choice between three options: (a) I give you ten euro’s now, which I guarantee will grow with five percent every day for the next four months, or (b) I give you ten euro’s now and ten euro for every day during the next four months, or (c) instead I give you a thousand euro’s and well: that’s it. Think about it for a moment: what would you do? Read back, reason and pick option a, b or c.

Now that you have picked, let’s take a look at what your best option really was. Starting with the last (c) option, the 1000 euro in your hand, that really is the best choice during a little more than the first three months of the time proposed. However, this is surpassed by the middle option (b) for getting ten euro for every day which tops out after about four months at 1200 euro. Spectacularly, the linear growth of (b) is passed even a couple of days earlier by option (a) with an exponential growth of five percent every day. In fact the first option literally explodes and balloons to nearly 3500 euro after the four months have passed! Was this in line with your expectations?

Interestingly the best option in the end performs quite poorly during the first three months. In fact: quite a bit worse than both other options. It is only after quite some time that the exponential approach starts to really pay off, and when it does: it pays off big time.

Seeing exponential effects plotted this way can help to foster a more intuitive grasp for them, which is much more difficult to infer from only a description. Let’s dive a bit deeper into applied implications of this exponential curve.

Money

The effect of making more money with some money is called compounding. The idea is that you start with some initial amount, called the principal, and then get some interest over this at the end of a time period, when you add that interest back to the principal it is called compound interest, as you can keep repeating this cycle like we did in the graph above.

Whether you know it or not, you are heavily relying on this effect if you take part in any sort of pension scheme, have money in a savings account or are holding onto investments. The idea is that if you have money you can lend it out to others. For this you get compensated: either by interest paid on the loan you provide, or with dividends or increased stock value in case of investments. Either way: you are making money with money.

It is important to realize that the flip side also holds: if you borrow money, you pay interest to whomever is providing you with it. In turn that means you can spend less. Thus, the exponential curve can bend upwards, but it can similarly bend downwards. This also explains the fact that people that have a lot of debt, more easily spiral downwards into a situation with even more debt.

So far we have covered familiar territory, but now I ask you to consider that the same thing that applies to money, also applies to your habits and skills.

The Direction of Habits and Choices

Let’s look at two simple habits. Firstly, brushing your teeth. Spiraling downwards: if you forget to brush your teeth for a day, you’re probably okay. However, if you don’t do it for a year, the exponential effect of bacteria feasting in your mouth, will likely cause significant decay of your teeth. In addition to that direct negative effect, there are others collateral ones too. Just think of the social implications of not brushing your teeth for such a long time. A spiral downwards thus pulls down other things in its wake.

Spiraling upwards: if you read in a book every day, you’re likely to read quite a few books in a year. There is knowledge acquisition even if you remember only a fraction of what you read. Though, the real impact comes after, where if you keep doing this consistently, you can make connections between concepts that you learned previously yielding non-linear gains in knowledge.

Skill Acquisition: A brief diversion into learning

Interpreting a post like this requires the skill of reading. While you probably don’t remember it, reading was incredibly difficult at first. The foundations for this skill were created from the very first time you heard anything. Further growth relied heavily on your environment. You only later learned to link sounds to symbols. Learning to do this consistently and growing a vocabulary large enough to read a text like this took many years. However, currently you are probably not exerting conscious effort to read the letters, or to understand the sentences.

Most adults find learning something new very challenging. One reason for this is that initial progress is usually slow which can be quite discouraging. However, this slow growth is entirely to be expected: like the ten euro’s growing very slowly during the first month in our money example.

Unfortunately, many people simply give up too early, perhaps being thrown off course by their linear expectation of returns. This happens especially for the effort they put in early in the process, where the return on the time spend is still fairly low. After all: when picking up something new you first need to master the basics. Getting through that stage can be though. There is no quick fix for this.

The Shape of Learning

When you are learning something new, you should not expect linear gains for the time you put in. Rather, when you are consistent and stick with it, you will see some large jump in competence every so often. This is somewhat similar to the compound interest effect. Let’s look at an example learning curve.

As I alluded to, learning curves share some similarity with the compound effect, but they are certainly not identical. Learning is not a smooth process that continues forever for a specific skill. Rather, as shown in the example graph above: it is full of plateaus, regression and tapers off at certain point. Beyond this point more and more time needs to be invested to get the skill to a higher level. We can see this if we ignore the details and look at the curve at the distance. This reveals an S-shaped curve. The learning plateaus form smaller S-curves inside a larger S-curve.

Looking at learning through these curves is useful, as they reveal both accelerating and decelerating effects visually. However, they are also limited to specific skills that have a clear path towards mastery. The interplay between different skills and the fluidity in many fields makes their real-world application limited. After all, even if you can identify a letters on a page flawlessly, that does not mean that you can actually understand what you read. And, even if you do understand a text at some level, you may not understand it at all levels the author intended to convey.

After this brief diversion into learning, let’s return to the topic of habits and choices and how we can more practically apply compound effects there.

Choices

We are continuously presented with the challenge of making decisions. The effect of all the small choices we make can lead us to either remain level, spiral upwards or downwards.

Consider three areas: things that you are, things that you have and that you know. In all these areas you can make choices daily, that snowball you in a direction with a positive or negative outcome. An important precondition for this is that you own the outcome itself. After all, outcomes are the result of many small decisions that you yourself made in the past.

These choices really are moment-to-moment things. Do you go to the gym or stay at home? Will you impulsively buy something you see in an ad, or stick to your financial plan and budget? Do you stay at the mediocre job you have or find a better one where you can develop new skills?

What is right for you is what aligns with your personal goals. These goals can be in the areas of physical and mental health, financial and job security, and acquisition of knowledge and skills.

Goals

Once you decide on some area to improve, it is time to make a plan and stick with it. Here is were most people are too ambitious about what they can achieve in the short term. They choose process goals that are hard to keep up. Like going to the gym every day, living in an unusually spartan way, or overloading their brains with information.

Instead it may be better to choose very modest process goals that you can keep up over a long time. Go to the gym twice a week and eat hundred calories less per day, transfer five percent of your income to a savings account automatically, choose one on-line course and spend an evening per week to complete it at most. As we have seen many exponential effects are the result of doing something consistently over a long period of time.

Conclusion

If you start doing something consistently, your progress at first will be slow. However, after some time the effect of whatever you do will start compounding. This process is not intuitive. The outcome will surprise you, even if you understand the concept of compounding rationally.

The effect of compounding is that you will either start to spiral up, or down, in any given area based on the many small choices that you make. Setting modest process goals helps in creating long term consistency which will in turn lead to a noticeable compound effect in your outcomes.

If you are not satisfied with were you are with respect to some specific areas of your life: find places where you can leverage compound effects by making small consistent process changes. Take ownership of the result by setting clear goals and tracking your progress. Then enjoy your outcomes spiral upwards.

References

  1. Hardy, D. (2010). The Compound Effect.

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Sleep

If you do not sleep you will die within months. Though, it’s unlikely that you would voluntarily stay awake twenty four hours for days at a time, modern society with its many distractions, makes it tempting to trade a little bit of sleep for a little bit of something else every day. Is this a wise trade-off to make? To answer that question: let’s dive deeper into sleep.

Rhythm

A decade ago I visited the music festival Sziget in Budapest. I camped there with a group of friends near the northern tip of the ‘party island’. After several days, thanks to a combination of staying up very late and sleeping with an eye mask and earplugs, my usual waking time had settled around noon. Despite the intense heat buildup in my tent during the morning hours, I still had an actual, though shifted, sleep rhythm. Where does this rhythm come from?

Living for several days on a music festival terrain, while an unforgettable experience in many ways, was not very convenient. Nevertheless, this inconvenience does not remotely come close to that of living in a cave without exposure to daylight for a month. This is what the father of modern sleep research, Nathaniel Kleitman, did in 1938 together with one of his students. Experimenting on himself was not new to Kleitman, as he also kept himself awake on benzedrine for up to hundred-eighty hours at a time just to measure the effect [2]. Little did he know that a form of this would later become a popular party drug at festivals for staying awake and boosting energy: speed.

Student Bruce Richardson (Left) and Nathaniel Kleitman (Right) in the cave

Back to Kleitman’s cave experiment: it revealed two important things. Firstly, if there is no sunlight, our bodies can still self regulate sleep and wakefulness. Secondly, our sleep cycle is not exactly twenty four hours, but a little bit longer. This observation gave rise to the concept of what we nowadays call rhythm of approximately (circa) a day (dian): the circadian rhythm.

The presence of sunlight resets the rhythm, and keeps it from shifting. This is quite similar to the way that your computer, whose clock is not entirely accurate and suffers from drift, synchronizes its time at regular intervals by contacting computers with more accurate clocks using the Network Time Protocol. Indeed, some alarm clocks are equipped with radio signal based synchronization which essentially does the same thing.

Pressure

The first few days at the Sziget festival, when my rhythm had not shifted as much yet, I felt very sleepy near the end of the day when I stayed up late. But I noticed that when I stayed up long enough, there was a moment, usually in the early morning, where I got over the sleepiness and started feeling more alert again. Since my rhythm had not shifted yet: what caused this?

Besides the circadian rhythm our bodies have an other mechanism to regulate sleep. As long as you are awake your sleep pressure rises through the buildup of the neurochemical adenosine in your brain. The higher the sleep pressure, the more you actually feel like sleeping. This pressure is referred to as the sleep drive, whereas the circadian rhythm is called the wake drive.

If you were ever in a lecture where another student fell asleep on their desk with a loud thud you know what high sleep pressure can do: it will make you nid-nod, falling in and out of slumber, even if you really want to consciously pay attention. While this is fairly harmless during a lecture it can be extremely dangerous in other situations, for example: when driving.

Rising sleep urge as result of staying awake. The arc is the rising sleep pressure (sleep drive). The dotted line is the circadian rhythm (wake drive). The distance between the two represents how sleepy you feel, expressed in words as the urge to sleep.

The interesting thing is that the circadian rhythm and sleep pressure are independent ‘systems’. As your sleep pressure continues to build up, your circadian rhythm may already be swinging back up, making you feel awake and more alert: exactly what I was experiencing the first couple of days at the festival. The figure above shows this: once you stay awake long enough the distance between the sleep pressure arc (top) and the circadian rhythm (bottom) becomes less, only to hit you much harder again as the circadian rhythm comes back down, resulting in a very strong urge to sleep.

Reset your brain

A good night consists of seven to nine hours of sleep opportunity, subtract from that half an hour to an hour to get the actual time slept. Back to the Sziget festival: not everyone had the fortune of being able to obtain a good night’s sleep. One evening we met a group of girls that had set up their tent next to the twenty-four hour DJ booth. I probably don’t need to tell you that setting up their tents there did not bode well for their sleep opportunity. Hence, we spent the night socializing with them. As we sat and talked on a set of wooden benches time flew by and before we knew it the sun came up again. The festival terrain was nearly silent, until we heard a loud rumbling sound.

It was around six in the morning, and the cleaning crew rolled in. A literal wall of people that moved from the front to the back of the festival terrain picking up garbage, followed by truck mounted water sprayers that cleaned the streets. An impressive sight.

Using water to clean and cool down the streets at Sziget [3]

In the deep stages of sleep something similar to what that cleaning crew did happens in your brain. Electrical waves sweep from the front to the back of your brain. This consolidates what you experienced and learned the previous day, and at the same time helps you prepare for sponging up new things the next day. In fact, not sleeping for one night reduces your ability to form new memories the next day by a whopping forty percent.

Better sleeping through chemistry?

Sitting on those benches at the festival, pulling an all-nighter, was not good for retention of memories, but also not good for overall wakefulness. The next day I had serious problems staying awake, thanks to the before mentioned buildup of sleep pressure. As a quick fix I turned to coffee: the stimulant of choice to keep one awake under such circumstances.

The caffeine in coffee blocks the binding of certain chemicals in the brain. This makes you feel more alert while your body is still tired. A negative effect is that once you do sleep after having coffee, you will have problems reaching the deep stages of sleep and thus will acquire less deep sleep overall. Ironically, this lack of deep sleep can trap you in a dependency cycle where you actually need coffee in the morning to feel refreshed after poor quality sleep.

It was a festival, so not only did we drink coffee. There was also plenty of cheap alcohol to go around. Beer, wine, shots, you name it, they had it. This stuff had the opposite effect of coffee: it made me feel sleepy. Alcohol, after all, is a depressant.

Alcohol makes you fall ‘asleep’ faster by sedating you, but as a side effect it heavily fragments your sleep. You wake up much more often than you usually would, though you do not consciously register this. This is the reason why the day after an evening of drinking a lot, you feel extremely drowsy. A secondary effect is that you do not reach the REM stage of sleep, which is vital for learning and memory formation. The debilitating effect of alcohol on memory formation is similar to that of not sleeping at all.

Consequences

Regardless of the cause: what else, besides memory and learning problems, really happens when you do not sleep enough? When I came back from the festival I had a throat infection. Not surprising: sleeping just one night for only four hours, instead of eight, reduces the presence of natural killer cells by over seventy percent. Doing this repeatedly left me much more vulnerable to infections, and there were plenty of germs floating around there. For such a short time, and the great fun I had there, that was an acceptable trade-off. However, that luxury of choice does not always apply to everyone. Involuntary chronic sleep deprivation incurs a heavy toll.

A chronic lack of sleep increases risk of physical diseases, like cancer, heart disease and diabetes, and also of mental diseases, including depression, anxiety and suicidality. Sleeping too little generally means that your life expectancy will go down dramatically. The evidence for this is strong enough that we know that if you were to actually sleep consistently for only 6.75 hours per night, you will likely live only into your early sixties.

Conclusion

What can you do to improve sleep? Three tips: firstly, maintain a regular schedule, which means: go to sleep and wake up at the same time every day, also during the weekends. Secondly, take care of your sleep ‘hygiene’: make sure your room is sufficiently dark and cool, around eighteen degrees Celsius, and avoid screens before you go to bed. Thirdly, avoid drinking coffee and alcohol, especially shortly before you go to bed, but also in the late afternoon and early evening.

Going to a music festival and losing some sleep by choice like I did is not a big deal. The real problem is that two thirds of all adults worldwide structurally fail to get the recommended minimum amount of sleep opportunity of seven to nine hours per night. Please, don’t be one of them. Sleeping is the single most important thing you can do to reset your brain and body health every day. Trading a little bit of sleep for a little bit of something else is not worth it in the end.

Sources

  1. Walker, M. (2017). Why We Sleep.
  2. Levine, J. (2016). Self-experimentation in Science.
  3. Forbes, G. (2008). Sziget Festival Photos.

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