Natural Firewalls in Bacteria
Sometimes it seems as if information is the most important commodity in our technological age. Information, of course, can be put to good or bad uses. We would all agree, no doubt, that computer viruses are a bad use of information. In that situation, a small piece of computer code (information), once it is inside your computer, can take over the whole operating system, with disastrous results for your interests. Of course such problems are nothing new. The term “virus” comes from natural phenomena that do the very same thing to living cells. Invading information occurs to even the smallest cells, bacteria. In fact, some of the bacteria that most threaten our health, are themselves the victims of invasive information from outside unrelated sources. Consider the case of the infamous Escherischia coli 0157:H7, cause of potentially fatal hamburger disease and in some isolated situations, contaminated water.
E. coli (short for Escherischia coli), is a normal component of human intestines and dairy animal intestines. In the past, E. coli has not been known to cause disease. There are some other similar bacteria which live in the intestines, but which cause nasty diseases, at least some of the time. Salmonella typhimurium, for example, lives happily in the intestines of birds and mammals, but should some of these bacteria contaminate human food, these microbes can cause food poisoning in human consumers. Another similar organism, Shigella dysenteriae, causes dysentery. This organism produces a particularly dangerous poison. In our society with closely enforced standards for cleanliness, we have not had to worry much about dysentery at least, and most people are pretty careful about the possibility of food poisoning from animal sources.
Our complacency concerning dysentery however, ended with a bang in 1982. In that year, some people in Oregon and Michigan, who had consumed fast-food hamburgers, became very ill with hemorrhagic colitis. Some of them died. Scientists soon discovered that the causal agent in undercooked hamburgers, was none other than E. coli itself. But this particular strain was slightly different. It contained a gene for the Shiga toxin, previously known only in Shigella dysenteriae.
The next pressing question was how did E. coli 0157:H7 become possessed of the Shiga toxin. It so happens that bacteria, even unrelated bacteria, are able to link together by means of thin tubes. Then some genetic material is able to move from one cell to the next through the tiny tube. The process is called “conjugation”. Usually the transferred information consists of a small ring of genetic information and this ring is called a “plasmid”. Since 1982 we have had to deal with a strain of E. coli which can live in cow intestines without problem, but when it contaminates meat which is ground up, or water contaminated by manure, some terrible outbreaks of hemorrhagic colitis have resulted in people.
The question arises obviously, if bacteria can become invaded by a toxin producing gene, what else could bacteria acquire through conjugation? Genes for drug resistance spring to mind and not surprisingly, this process is a major source of antibiotic resistant superbugs (bacteria).
It appears that some bacteria have long possessed genes which confer resistance to antibiotics, even long before the use of these drugs came into common use. Many antibiotics, after all, are natural products produced by other microbes. It is not surprising then that bacteria can pass on antibiotic resistance through the process of conjugation. In hospitals where some patients are being treated for various infectious diseases, the opportunities for diverse strains of bacteria to come into close contact, is high. Thus in 1961 the first superbug appeared in a hospital in the United States. MRSA or methicillin resistant Staphlococcus aureus is a much feared bacterium which crops up in many hospitals today. In 2002, strains of Staphlococcus resistant to the antibiotic of last resort (vancomycin) began to appear in hospitals. Apparently VRSA had also acquired its resistance through conjugation from a less dangerous pathogen.
Obviously conjugation is a major problem. Bacteria themselves also usually do better when they are not loaded down with extra information which they must express. Recently scientists have discovered that some bacteria have been endowed with amazing systems for eliminating invading pieces of information in the form of plasmids or phage (bacteria infecting) viruses.
Once scientists were able to figure out the order of the genetic code in microbes, then they were able to carry out extensive comparisons between various organisms. Soon scientists noticed a curious pattern in a number of these bacteria. What they observed were repeating blocks of highly distinctive code with unique brief pieces of code in between. The pattern is like an arrangement of beads such as: striped bead, unique red bead, striped bead, unique blue bead, striped bead, unique yellow bead, striped bead, unique green bead etc.
In 1987 the above strange arrangement of coding was described in E. coli. It featured an arrangement along the DNA molecule of short highly organized pieces of DNA. These were stretches of code that read the same in opposite directions. For example “Madam, I’m Adam” can be read in opposite directions. This is called a palindrome, and these pieces of code observed in the E. coli, were palindromes. Sandwiched between identical palindromes, were other pieces of code, each different from the others. These unique spacers separating the palindromes were brief, for example from 21 – 72 “letter characters” long. Thus there was palindrome, spacer A, palindrome, spacer B, palindrome, spacer C, palindrome, spacer D etc. Scientists have named these collections of information CRISPRs, short for “clustered regularly interspaced short palindromic repeats” of genetic code. Trust the scientists to come up with such fancy terms!
Twenty years would pass before scientists had any good ideas as to the significance of these pieces of code. It now appears that this fancy section of the total bacterial DNA, provides an amazing system for acquired immunity for the bacteria. This system enables many bacteria to maintain their genetic integrity from becoming corrupted by invading genetic elements like plasmids and bacteriophage.
So how does the system work? In the bacterial DNA molecule, the CRISPR system comes complete with a leader sequence at one end, to initiate activation of the system, and a collection of genes for associated proteins at the other end. When a piece of foreign DNA invades a bacterial cell, the leader section causes the CRISPR part of the DNA to be copied into the related information bearing molecule RNA. Then CRISPR associated proteins cut up the long RNA chain into fragments each of which consists of one palindrome with attached unique spacer. It is as if the bead chain mentioned above, were chopped into two bead sections consisting of one striped bead with one coloured bead attached. So there would be a couplet of striped bead with red bead, another couplet of striped bead with a green bead and so on. Each unique spacer is an exact code replica of a part of some foreign DNA that invaded the cell in the past. The spacers remind me of children’s adventure stories where a pagan has a string of scalps along his belt to remind him of past foreigners vanquished. The cell next compares each unique spacer with the order of code in an invading plasmid or phage DNA. If there is a match, the associated proteins then chop up the invading DNA. And behold, the invading information has been quickly destroyed!
The short interspaced pieces of unique DNA provide a memory of past invaders into the cell. If there is a match with the invading plasmid, the plasmid is destroyed. What happens however if there is no match? In many cells, the invader goes unchallenged and manages to stay. However occasionally, a cell will manage to capture a piece of the DNA of the invader and incorporate it into the CRISPR apparatus. After that, none of these invaders will be successful.
The other interesting aspect of the CRISPR system is how much variety there is in the system design in different bacteria. It is in the associated proteins that we see the greatest variety, and they direct the operations of the system. Various bacteria exhibit different combinations of associated proteins so that the apparatus and process for matching invader with memory code may be quite different, but the end result is the same.
What an elegant system! It appears so minimalist and simple, yet it manages to carry out such sophisticated and highly precise technical tasks. We see information capture, memory storage, memory retrieval and information matching, with the end result of destruction of unwanted damaging information. Who designed this system? Who designed the many similar systems in bacteria to produce the memory, hardware and operating systems which constitute a firewall against hostile invasions of information code? All praise to the Creator of all things great and small!
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