TTMTO #2 – Proteins Are Tiny Robots

I am currently taking an university course on the biochemistry of proteins. And proteins might not get you very excited, but they started exciting me because holy crap are proteins amazing.

In short, proteins are the the smallest biomolecules that do things in living organisms. They are the most complex and interesting biological building blocks, with others (water, fats, minerals, DNA and other organic compounds) being there to support proteins and their function. All cells have some proteins in them, to perform a huge variety of functions. There are gatekeeper proteins, attacker proteins, defender proteins, walking proteins, holding proteins, bendy proteins, slidy proteins and the list goes on.

Now, the fact that proteins are just chains and clusters of atoms is precisely what makes them so amazing. They’re essentially very tiny, very specialized atomic robots engineered by nature. You may not think, that a molecule being able to trap an element, say iron, is too exciting – it just happens to be shaped right to be a good fit. If it does get you excited, you either are or should consider being a biochemist and should also look up Hemoglobin. Nonetheless, you should really be impressed by this penis-with-feet protein named Kinesin.

Kinesin, gracefully strolling across a microtubule

Kinesin is an absolutely awesome protein with the sole function of walking and dragging other molecules with it. Dragging robot! Kinesin primarily spends time dragging organelles (micro-organs of cells, if you will) to where they need to be. Kinesin usually drags them from the centre of a cell to the outer regions along molecular tubes called microtubules. It has a cousin called Dynein, which drags cargo from outer regions of the cell towards the centre.

Where do proteins come from? Well, they are made by protein factories, of course. Every cell stores DNA as strands of sugar in chromosomes. DNA is also referred to as the genome and is the description of what an organism is. To be more precise, DNA dictates how chemical interactions occur within cells and some of the DNA encodes how proteins should be made. When proteins in a cell are needed, a fraction of DNA is copied onto a messenger RNA (a relative of DNA) and taken to the ribosome. The ribosome is a very special complex molecular protein factory made out of some 50 or more proteins and ribosomal RNA. It uses the code to produce a long chain of amino acids, which folds into a protein. The ribosome is a construction robot! The process is kind of hard to explain with text, you should probably watch this video:

The whole DNA and ribosome thing raises an interesting question related to the origin of life itself (proteins are a rollercoaster ride, I know!). If the ribosome is made out of proteins and it is the thing that makes proteins, where did the proteins to make the ribosome come from? Chicken and egg! Some people say it must have been aliens, seeding life on the planet, or it could have been God. Wikipedia cites like 9 articles which have some good ideas about its origin, but a lot of it is speculative. Therefore it’s aliens. But maybe not.


While the ribosome is really cool and useful, there also exists really destructive horror proteins like Amyloid beta (Aβ). Aβ is the protein believed to be the primary cause of Alzheimer’s disease, which is a form of dementia where you slowly but surely lose braincells, go crazy, forget who you are and then die. Killer robot :( . According to current statistics, 1 in 6 people over 80 get the Alzheimer’s disease, which is a really large number.

death_causes
The exciting colourful chart of death causes.

Essentially, dementia is what gets you if you don’t die from doing stupid things in your twenties and avoid getting cancer throughout your adulthood. There are a lot of smart people in the world, trying to figure out how to combat the disease, but their efforts have not found any strong-evidence based cure or even remedy so far. Not least because Aβ is a very deceptive protein. See, most proteins fold into a specific shape, a 3D structure and stay that way. If we gather a whole bunch of them, crystalize and perform crystallography (which is a fancy word for shining light through crystals and seeing which way it goes) we can figure out that 3D structure and from it – the protein’s function. This cannot be done for Amyloid beta, because it is intrinsically unstructured, meaning that it refuses to form a single 3D shape we can measure.

The 3D structure of potassium channel protein - essentially a door that allows potassium into neurons some times, but not other times.
This is what 3D structures look like when we can figure them out using crystallography. This is a potassium channel protein – essentially a door that allows potassium into neurons some times, but not other times.

The unstructured nature of Aβ is probably the reason that allows it to cause so much damage. It can pack really tightly and form insoluble plaque layers on human brains which are believed to cause braincell death. In fact, Aβ is believed to be closely related to prions, the protein version of disease. Prions are some of the nastiest biomolecules, which infect other proteins, causing them to misfold and impairing their function. Even worse, prions are impossible to remove from surgical tools with traditional decontamination methods like heat or spirits, which means that you could get contaminated with someone else’s prions during a surgery, unless very extreme measures are taken during decontamination, as extreme as remelting the tools completely. Nigthmare!

The monster of Frankenstein is upset, not least because he’s a bit demented.

Thankfully, the fight against many diseases is not as hopeless. In fact, life has impressively intricate and complex systems in place, to deal with all kinds of terrors. For example, most bacteria and archaea have a really awesome set of proteins called Cas9 used in cellular warfare. This protein has been discovered very recently and allowed to develop a really powerful and cheap technique for genetic modification called CRISPR. Genetic modification is a topic worth an article of its own, so for now let’s instead focus on how the Cas9 protein works.

So you know how bacteria usually go about their lives and then OH MY GOD IT’S A VIRUS INVASION. It is fine, the bacteria doesn’t panic, it simply starts making simple land-soldier proteins. These tiny molecular robots try and chip away at viruses to kill them.

bacterial-viral-warfare
Land-soldier proteins – restriction enzymes – charge into a glorious battle against evil viruses. Also, I can’t draw robots, so just pretend that stickmen are robots.

Most of the time the land-soldier proteins aren’t strong enough and the bacteria dies. However, sometimes the land-soldiers prevail. The bacteria then deploys the specialist protein Cas9, which takes the DNA remains of the dead viruses and stores them in the DNA of the bacteria itself. In fact, the bacteria has a whole bulletin board of wanted virus posters.

bulletin-board
A bacteria stores known viral DNA in its own DNA. It’s like a molecular wanted bulletin board. This genetic information is passed on to the offspring, granting immunity to future generations of bacteria.

Whenever a virus attack happens, the bacteria also deploys Cas9 carrying DNA snippets of wanted viruses. If it manages to identify one of these viruses, it unwinds and snips its DNA chain, destroying it in the process. It’s a serial killer robot!

bacterial-viral-ninja
The bacteria deploys Cas9 proteins, which snip and unwind viral DNA with ease if they can recognise it.

Cas9 is completely ridiculous – how do you have serial killer proteins in a cell!? And now that it’s been figured out, people are using it to perform cheap genetic modification. The complexity of this work is beyond my understanding, aside from that it has some amazing as well as terrifying implications. With the CRISPR technique, the cost of DNA editing has gone down between 10x and 100x, depending on where you read about it, which is great. We can try to cure more diseases, grow more and better food and similar. But then you have the Chinese, who said “fuck others thinking it’s immoral. We will test this on human embryos” (the quote may be made up) and now the scientific community is all like “genetic engineering on humans is now a thing, we should stop debating whether it’s moral and start debating what we will do about this”.


Before wrapping up, there’s one more thing I find fascinating. So DNA is stored in chromosomes, right? Humans have 46 chromosomes. A potato has 48 – 2 more than humans. Why does the potato need so many chromosomes? Oh wait, a carp has 104. Maybe their DNA is nothing like our DNA? Well, there are 4 nucleotides (DNA alphabet) which encode 20 amino acids (protein alphabet), which encodes about a thousand protein folds (proteins that are kinda similar and tend to do similar things), which means that all life shares the same molecular robot parts. So where is all this complexity coming from?

The answer as of 2016 is “we have some ideas, but we’re not really sure”. See, only about 1.5% of the genome encodes proteins. It used to be thought that non-encoding DNA (not containing protein definitions) was just noise or redundancy. New organisms are born by copying and multiplying cells and their DNA information. Sometimes some of the information is copied incorrectly, so having some meaningless parts in the DNA would be beneficial as they would be more likely to get corrupted. However, over the last 15 years with more research in the field we have some new ideas. For example, it is now known that certain sequences of DNA are markers for transcriber factor proteins, which they lock on marking which parts need to be synthesised.

Transcriber factor protein locks on to string of DNA indicating which parts to copy onto RNA
Transcriber factor protein locks on to string of DNA indicating which parts need to be synthesised into a protein.

So yeah, proteins are kinda crazy. This kind of complexity makes sense on the macro level, but proteins are just a bunch of atoms that interact with other atoms. Atoms are the smallest thing in the universe you could possibly build complex function from. As the world slowly inches towards robotic automation future, like driverless cars, remember that the nature designed, engineered and deployed driverless protein robots about 4 billion years ago. Nature’s got engineering down! However, humans are getting pretty good at reverse engineering so it’s looking out to be a promising 21st century for biochemists. Look out for the headlines of new genetic discoveries!


Read the previous TMMTO.

This Post May Be an Expression of Free Will.

I was thinking about free will the other day. I like to believe I have control over my life and my choices, but how would I know, if I didn’t? My brain might make me believe that I have free will, because it is evolutionarily advantageous or something and I wouldn’t know (whatever that even means; I am my brain, who’s this me that my brain is making believe things?) The other day I got really curious, about the mental workings of walking. See, making robots that beat us at chess is fairly easy, but making robots that can walk like us is really really hard. You have to do a whole bunch of calculations on how to move the legs, where to shift the body weight, the stability of the surface, etc. For a contrast, I’d like to ask you to stand up and walk a few paces back and forth. Notice, how that just sort of happens. Even though there is a tremendous amount of complex calculations going on, you probably don’t feel like you have to do much. Your muscles just kind of figure it out for you. When I do this, I begin believing that I am being carried by somebody else, like my legs are not really a part of my body or myself. They are meant to be within the jurisdiction of my free will, but the sensation of walking feels supernatural occasionally. Even worse, sometimes my legs will do their own thing completely, like bouncing under the desk while I focus on something (see RLS, aka. “I’m sorry I can’t stop them from moving, you’ll have to deal with this” or “I’m tired today, my legs decided to run a half marathon while I was sleeping”).

Interestingly, there is about 35 years worth of neuroscientific research and experimental data done on free will focusing precisely on physical movements. Pretty much all of this research is a variation on an experiment by a guy called Benjamin Libet in 1980s, who tried to measure the difference between performing an action and deciding to perform it. The experiment is simple, you sit in a room with a clock, and a bunch of wires attached to your head. You are told to randomly decide to tap your finger and take note of the precise time at which you made the decision to start moving. This is done a number of times with lots of different people. Their reported times of decision are plotted against when their brainwaves indicate signalling to finger muscles.

1_eeg

Now, how do you measure movement brainwaves? A special bit of the scalp has been discovered back in 1965, which during Electroencephalogram (EEG) reveals Bereitschaftspotential. Bereitschaftspotential, is otherwise known as readiness potential. It peaks just before some physical movement occurs, thus we can (maybe) use it to figure out, when the brain sends signals to muscles to contract and move. Bereitschaftspotential (don’t just skim over it again, actually try to pronounce it this time) is fun to say!

Typical recording of a Bereitschaftspotential
Typical recording of Bereitschaftspotential

Anyway, Libet’s data indicated that people think they decide to tap their fingers before they start tapping their fingers. He then went on to make a (slightly excessive) conclusion, that free will does not exist and rather, that free will is an illusion our brain creates for us.

2_libets_experiment

Now, I must say this. The experimental methods of this study are not exactly impressive. Neuroscience has discovered some amazing things using EEG, like figuring out that there are two major parts to a sleeping cycle (divided to a bunch smaller subparts). However due to its crudeness, EEG is very limited in pinpointing any more specific brain functions – we are not even sure whether Bereitschaftspotential (don’t skim over it, come on!) indicates intent, action or is simply a side effect of the two.

Following the unimpressive methods, the conclusions drawn are, well, ridiculous. If based on this experiment our bodies moved before we willed them to, we would probably end up being carried around by our legs to places we have no intention going to (for exceptions, see sleepwalking), because they would have their own minds. In fact, the publication drew lots of criticism pointing out various problems to the method, not even related to how ridiculous the conclusions are, including people’s perception and reaction times being unaccounted for.

There is a really curious mental disease, called alien hand syndrome. When certain parts of the brain get damaged, say after a stroke, limb paralysis is often observed. However, sometimes patients may develop a condition, where they have no control over a limb, say a hand, yet it involuntarily performs actions, like moving around, grabbing hold of objects, wiping the face or rubbing the eyes. How do you even perform the Libet’s experiment on people with alien hand syndrome? Does that mean these people have no free will at all?

Spongebob’s may be a different hand syndrome, but no less impressive.

Many neuroscientists attempted to recreate and modify Libet’s experiment since the 1980s and get a better estimate of when people actually decide that they want to tap fingers, however they didn’t ever veer too far off from the original experiment. Different alternations have been tried, including:

  • Tapping a finger rhythmically
  • Tapping a finger, but stopping if a tone plays
  • Tapping a finger when a green card is shown and stopping when a red one appears

To everyone’s surprise, all these tappy experiments produced data, which indicated an even bigger gap between a person’s initial movement and their perceived decision to move, sadly, concluding that there’s definitely no such thing as free will. And all of them sparked even more criticism and controversy.

The conclusion is sad, because it is a very far fetched conclusion to draw from such data. And even sadder yet – there have been very few studies that had more rigorous methods and analysed things like reasoning and active mental choices. I guess coming up with good experiments is hard. Being a neuroscientist and making sense of the brain is really hard.

One of the worst things about science being unable to explain something is that we still end up forming an opinion about it (talk about the lack of free will, huh). We may still need to act on things that science has no idea about. Say, even if you choose to never choose anything again because you think free will does not exist, that is still a choice of its own. Contradictions!

Where contradictions arise, philosophy and religion shortly arrive too. Philosophers have not been very helpful on the topic, mostly being confused about how to even define what free will is. Some say it is the ability to do something differently if you want to, some believe that free will is about being able to direct your actions based on some sort of mental reasoning, and others have even more contrived definitions still. When philosophers agree on definitions, they are quick to come up with labels, choose camps and have long boring conversations about who’s camp sucks the least. In short – nobody is sure, but some people are more morbid than others.

Screenshot from 2016-01-29 23-04-22
Philosophical camps of free will (also, ugly gradients).

Religion is not much help either. The Christians and Jews share an all knowing, all controlling god that gives Adam and Eve free will. They then go on to do a very bad thing in god’s eyes and are told off. God then allows them to keep their free will and continue doing very bad things, even though he could stop it because he’s got the power. Hinduism is all about “everything is predetermined”, but then they keep insisting that karma is a bitch. Predestination is actually one of the six holy articles of Islam, but then that’s only some schools of Islam and even the main Sunni view has some leeway.

Do well and Hindu gods may grant you an afterlife as something graceful and amazing. Like a baby goat.

I invite you to notice that you blink and breathe and how weird it is that last time it captured your attention was probably like a month ago, even though you have been doing it all this time. If you want, however, you can blink three times in succession right now. Or out of free will, you may choose not to, I don’t control your life. Over the past month, though, were you blinking out of free will or without any control?

In a way, I feel too trapped in my own body to even begin to reason about this in any sensible way. Ironically, everyone makes a choice on what to believe regarding free will. I can’t help but contradict myself – my gut feeling keeps telling me I am the owner of my actions, yet every scientific attempt to quantify the idea say I have no control.

One of my housemates saw me writing this post and posed the question about whether I was doing it out of free will. Talk about meta. Well, I hope this was a result of choice. After all, I didn’t choose to browse reddit all day again!

What do you think about free will?