Bacterial Chemotaxis and Human Memory: Pete and Repeat

Many do not place ‘bacteria’ and ‘memory’ in the same sentence. Normal human perception does not connect the two concepts. However, Mother Nature seems to have a more profound perception. The past 50 years or so of scientific investigation has shown how our uniqueness as humans is actually commonplace across all forms of life on Earth. Case in point, how closely associated molecular memory is between bacteria and human.

Bacteria use adaptation to signals as memory

Swimming bacteria do not move randomly in their environment. This behavior would be futile and counterproductive. Instead, bacteria are constantly monitoring their environment in search of food and poisons. Moving towards the former and away from the latter. This observation was first published in the late 19th century. Bacteria, like the famous and infamous E. coli, use molecular antennae to receive these important ‘signals’ as the basis in the decision of which direction to swim. What if the bacteria find a great place to reside with lots of food but still need to receive signals to ensure they remain there? The antennae have sections that can be modified easily and reversibly. These modifications, in the form of methylation, alter the sensitivity of the antenna protein to subsequent signals. Methylation allows these antennae not to receive the number of absolute signals but relative signals. In other words, the antenna protein through fine-tuned methylation detects changes in the number of signals now versus some time in the past. This is the basis of molecular memory.

These antennae are proteins called methyl-accepting chemotaxis proteins, or MCPs. MCPs accept methyl groups from the essential cofactor S-adenosylmethionine (aka SAM or AdoMet). AdoMet is essential to both prokaryotes and eukaryotes like humans. The methyl groups are added by a protein called CheR (pronounced ‘key R’) which transfers the methyl from AdoMet to very specific amino acid side groups of glutamate. The process, called O-methylation adds the methyl group to the single-bonded oxygen on the carboxyl.

O-methylation reaction
O-methylation reaction. Courtesy of www.brenda-enzymes.org.

The length of a bacterium’s molecular memory is very short in comparison to how we perceive memory at only a few seconds. But, to bacteria it is long enough to successfully navigate the environment with similar precision when concentrations of food or poison vary (up to several orders of magnitude, or ~1000x).

Does the basis of molecular memory in humans mimic bacteria?

Eukaryotes, including humans, use a very similar mechanism in signal transduction to bacteria. Phosphorylation (transferring a phosphate group from ATP or GTP to a protein amino acid) is the basis of all signal transduction and cell regulation. Bacteria use histidine kinases and response regulators, as do plants to some degree. However, the majority of regulation through signal transduction in eukaryotes is through two types of proteins, RAS proteins and the heterotrimeric G-proteins. G-proteins interact with membrane receptors that regulate their activity. What determines which surface receptors G-proteins interact with? Isoprenylcysteine methyltransferase, or ICMT, is one of two methyltransferases that regulate signal transduction activity. ICMT is a membrane protein that uses AdoMet to add methyl groups to isoprenylcysteine, a post-translationally modified cysteine residue on both heterotrimeric and RAS-related G proteins. Methylation regulates which receptors the G-proteins interact with, thus playing a major role in connecting the initial signal to downstream regulatory pathways. The carboxyl methylation essentially modulates G-protein signalling globally.

G-protein carboxyl methylation is regulated by GPCR signaling and, as seen above, GPCR signaling is regulated by G-protein carboxyl methylation. This feedback/feed forward loop could be seen as a form of molecular memory stored in methylation patterns. Within the brain, ICMT activity is almost exclusively found in the region controlling coordination of movement. Thus, methylation could be used to modulate certain neuronal signaling pathways which result in learned patterns of sensory-motor skills.

The only other major methyltransferase is from a protein known as PPMT. PPMT interacts with a major enzyme in signal termination, the protein phosphatase PP2A. PPMT adds methyl groups to the backbone carboxyl of a specific leucine in PP2A. This carboxyl methylation helps determine which B subunit PP2A interacts with and where in the cell PP2A can be found. PPMT structurally resembles CheR in bacterial memory. Moreover, the enzyme that removes the methyl group from PP2A, PME, structurally resembles the bacterial enzyme that removes methyls from MCPs, CheB.

PP2A is one of the major regulators of pathway coordination to maintain synaptic plasticity in the brain. Interestingly, methylation defects and PP2A-PME complexes are suggested to play a role in the cause of Alzheimer’s Disease and memory loss. Methylation defects leading to defective phosphatase activity of PP2A leads to accumulation of a phosphorylated subunit of the structural protein microtubule. In this phosphorylated form, the filaments used to keep axons structurally sound collapse and lead to loss of normal synapses. Therefore, molecular memory in the form of methylation plays a vital role in promoting normal brain activity and its disruption can ultimately lead to dementia. 

Chicken, meet egg. Egg, meet chicken.

So, from bacteria to human, carboxyl methylation is necessary for memory. Did these pathways evolve individually in parallel, or did the memory we have today originate in the predominant lifeforms found within us?

 

Suggested Reading

Li and Stock. (2009) Biol. Chem. 390: 1067-1096. DOI 10.1515/BC.2009.133

Telling the Scientific Method Story

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The scientific method as a bucket filled with Mother Nature’s water with an ever -changing hue.

The science gap is huge. One of the biggest misconceptions hindering the advancement of scientific literacy in society is also one of the most crucial – the scientific method. And no wonder. Most people would look back at primary and secondary school and cringe when thinking about all the facts and concepts they had to memorize in science classes. I cringe when I think of the public concluding science is static and just the sum of all data gathered through the centuries.

The scientific method is dynamic and so is the collection of accepted scientific knowledge

Nothing in science is certain. In the words of the great Richard Feynman:

We absolutely must leave room for doubt or there is no progress and no learning. There is no learning without having to pose a question. And a question requires doubt. People search for certainty. But there is no certainty. People are terrified — how can you live and not know? It is not odd at all. You only think you know, as a matter of fact. And most of your actions are based on incomplete knowledge…

The idea that scientific knowledge is like a statue is a horrible, infectious disease in society. Consider this…

The scientific method is a bucket. This is not just any bucket; it holds all the scientific knowledge gathered throughout history. The bucket is just a utilitarian tool for collecting knowledge. Luckily, this bucket has a hole in the bottom. The scientific method is a two way street and is objective just like a bucket is just a bucket. At the beginning of it all, the bucket was filled with crystal clear water. Mother Nature had filled it for us but all its contents were a complete unknown. As human inquiry began, discoveries were like drops of color that allowed us to have a glimpse of the contents as it dispersed like food coloring in a glass of water. Each new discovery or observation adds a touch of color to the bucket. Nature’s true color will not be observed in our lifetime or possibly at all. Our curiosity and practice only adds to the hue within the bucket.

Sometimes we don’t know the hue of the water is wrong until new knowledge is obtained and added to the large bucket. With addition of the new color, drops of discolored water pour from the hole in the bucket. Soon the prevailing knowledge is uniform within the bucket. Science never sleeps so this constant increase in knowledge and data get us one step closer to the true color of the universe, or so we think until we find out the hue is all wrong as the hole opens and a novel color drops in.

8

Science: Solving Mysteries One Clue at a Time

This past Tuesday, something mysterious and amazing happened. My wife noticed a strange deposit into our bank account; a large deposit: $1,400. She asked when I was supposed to be paid for something I was working on and I told her not until later. This deposit piqued both our curiosities. What was it? Why was it in there? Who put it there? I started investigating; researching as much as I could. I was able to find out it was $1,400 cash, which bank branch and what time the money was put in. Paranoid it was some scam perpetrated to clean out our bank account, my wife wanted me to call the bank to inquire. So, Wednesday morning, I called. Long story short, my wife received a call Wednesday afternoon from a bank employee saying someone anonymously deposited money in our account because they thought we should have it. What? To say the least, we were humbled and astonished. The curiosity has not gone away. We are still trying to figure out who this saint(s) is.

This mystery made me think; it is eerily like the field of science. The path to discovery in any science discipline begins with something very simple, an observation. My wife observed a strange deposit into our bank account. Observations lead to curiosity and ultimately yield questions. What was this deposit? Why was it there? Who put it there? Explanations or answers to the questions are developed. These explanations, or hypotheses, have their validity tested through experiment or some action. My wife’s initial explanation was that someone deposited it to somehow gain access to our account to clean it out. My action of calling the bank to report the deposit as not originating from the wife or myself was partly to make sure the deposit was legitimate and not some clever scam. Through experiment or action, facts are gathered to support the explanations or rule them out. The fact a bank employee called to let us know the deposit was from an anonymous ‘Good Samaritan’ ruled out the hypothesis of the scam. Scientific discovery ultimately leads to more observations, curiosity, questions, and hypotheses.

For my wife and I, the discovery that someone thought so highly of us to give us any amount of money has only fueled the mystery. The main question now is, who did it? Unlike any good mystery, or science for that matter, we may never find out.

This post is dedicated to my family’s ‘Good Samaritan’. Thank you…

STORYTELLING IN SCIENCE: THE CELL AS YOUR FAVORITE RESTAURANT PART III

<img alt="Storytelling in science visualized through bacteria"      src="open-for-business.png">
Storytelling in Science visualized

Perhaps a running list of metaphors so far:

Restaurant: bacterial cell

Building: cell membrane

Doors: channels and transporters

Patrons: metabolites/compounds/substrates and products

Employees: proteins/enzymes

Managers: two-component proteins to regulate gene transcription

Employee list: genome

Copy machine: DNA replication machinery

So, in the last part our restaurant was going great and we opened up a new restaurant with the same employee list among other things. The two restaurants are now independent of each other and are free to act accordingly.

What if things change and times are not going as well? The overall number of patrons drastically decreases, not enough electricity (ATP) to run the restaurant or running water (redox potential)? What if disaster is about to strike? How can the restaurant prepare all the managers, employees, the building, the doors, the patrons for it?

Luckily the restaurant has a monitoring system that can quickly make sure the restaurant will be ready for anything that comes its way. The monitoring system can take snapshots of all data generated by the restaurant: power supply, water supply, patron count, employee count, conditions outside the restaurant like weather or competing restaurants. The monitoring system is the bacterial second messenger systems. With the support of the managers, the monitoring system can instantaneously keep track of all variables and make changes as needed.

The system is detecting the start of a drought. This drought will lower the number of patrons coming and going from the restaurant. The drought will also change the available electricity and water supply of the restaurant. The monitoring system sounds the alarm, a message is sent over the intercom for all the managers and employees to hear and react to. The intercom message alerts some managers to call in additional employees while telling others to stop their work. Some employees take on a new job in preparation for the drought. The intercom message is the bacterial second messenger cyclic-di-GMP. The entire restaurant begins preparations for the drought so it can survive until better times are present. Other than changes to managers and employees, some new employees are called in to prepare the building itself. Perhaps to change the number of doors. The employees may also change the exterior of the building to better withstand the drought like changing a wood exterior to a brick or stucco one. The brick or stucco are the exopolysaccharides, complex sugars on the exterior of the cell that can serve as protection or to help cells adhere to each other to ride out the hard times together. 

When times change, the restaurant has to be able to change with them. That is why these restaurants have been in business for ~3 billion years and still going strong.

First Order of Business When Rich: One Microscope Per Child

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Azospirillum brasilense cells swimming in an oxygen gradient. Magnified 40X

It is really sad humans (that seem so determined to destroy this planet) show little regard to the majority of species, most of which are invisible to the naked eye. Most people go through life without knowing the splendor of Mother Nature in all its glory.

It’s hard to believe now the accepted knowledge of society before invention of the microscope around 1590 by Zacharias Janssen (disputed). Everyone had  to rely on their own eyes, while exquisite in their own right, but these are only reliable down to the size of a human hair width. Imagine a world where flies and maggots were thought to spontaneously generate from items such as rotting meat. This was the common knowledge and understanding. After human observation was enhanced by wonderful inventions such as the compound microscope, only then could the true understanding of all things small or distant be studied in acceptable depth.

Imagine if you will looking through a microscope for the first time. You have been told, and believe, you live in a clean world in which if you can’t see it, it does not exist. With true curiosity and virgin eyes, you place a drop of water on a small glass slide and focus upon it with a microscope. Small particles that appear to be moving as if they were swimming come into view. Suddenly, your whole world changes. At the intersection of ignorance and knowledge, powerful things happen.

Today, microscopes have evolved and improved to the point where we can visualize hydrogen bonds in molecules at the atomic scale. The invention of the electron microscope helped usher in the field of virology just as Antonie van Leeuwenhoek did so much for microbiology with his improvements to the light microscope. The gifted van Leeuwenhoek discovered red blood cells, cell vacuoles, and bacteria (among other things). Thanks to him, the use of a microscope became a useful technique in various types of research.

It is said that ignorance is bliss. However, I believe ignorance is…ignorance. The less a person knows and understands, the smaller their world and the less their ability to imagine and perceive new ideas. Seeing is believing and what better way to see beyond your means than with a microscope.

Now, imagine giving this enormous ability to see the unexplainable to the most curious and imaginative of us, children. Their innate curiosity and unobstructed ability to use their imagination makes the power of the microscope exponentially greater. Giving a child this portal to the unseen opens their eyes to endless possibilities, probing questions, and the ability to answer the questions themselves.

I support the One Laptop Per Child movement. Opening up the entire world of information to a child can open up new possibilities and lead to a better life. The laptop opens the world to the child, but a microscope opens the child’s world in which they live. The knowledge gained is not flat and two dimensional; it is in real 3D.

Yeah, when I’m rich, One Microscope Per Child is my first action.

Friend and Foe: Illustration of common blue-green algal species Microcystis

Sometimes in nature it’s not what you are but who you are. A great example of this is the cyanobacteria (blue-green algae) from the genus Microcystis. They are common in freshwater habitats. Some of these are showing bright potential as a source of biofuels. However, some of these have less benevolent potential. I have heard much lately about algal blooms. Some are harmless while others have potential to harm wildlife and unsuspecting humans who eat poisoned seafood.

Some species, like Microcystis aeruginosa, can produce microcystins, or toxins, that can cause major damage to a person’s liver.

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Illustration of Microcystis