Last updated on May 21, 2020
The last few weeks, we’ve talked a lot about the immune system and how it builds and maintains immunity to viral pathogens, like Covid-19. This week, I’d like to shift a bit to a different form of immunity that doesn’t have anything to do with the coronavirus (I know, a blog post that’s not about Covid-19—shocking) but one that has had major implications in the field of genetic engineering: bacterial immunity to viral infection. I mentioned briefly in my post about viruses that a large subset of viruses infect bacteria, called bacteriophages. Although bacteria are far less complex than humans are, they also evolve much faster than we do, allowing them to build adaptive immunity to a virus they have encountered. One of the most efficient ways that bacteria build immunity is through the CRISPR Cas9 system (CRISPR stands for clustered regularly interspaced short palindromic repeats and Cas9 refers to the CRISPR-associated protein 9, the main enzyme). This system allows bacteria to keep a library of information about viral invaders directly inside the bacterial genome. This information can be accessed later on to recognize and destroy new viruses.
When a new bacteriophage injects their DNA into a bacterial cell, the cell will mount a generalized defense, utilizing a slew of anti-phage tools they have developed throughout evolution. If they fail, then the bacteriophage replicates and explodes the cell to release the new virus particles. But if the defense strategy is successful, the bacteria cell wants to maintain a “memory” of that particular bacteriophage, in order to fight it more efficiently the next time. This “memory” takes the form of CRISPR DNA.
It may seem strange to refer to a cell having a “memory,” but memories are really just encoded information. In the human immune system, although the brain is only tangentially involved, we form a “memory” of a virus that’s encoded in our memory B-cells. These cells encode information about how to defeat the virus in the form of specific antibodies. As long as there are cells in the body that know how to create these specific antibodies, the immune system “remembers” the virus.
In the case of bacteria, the “memory” of a viral invader is stored in the bacteria’s own DNA. DNA is the most fundamental way living things store information. We may be accustomed to thinking of memory and information as being encoded by precisely firing neurons in the brain, but none of that would even be possible without the fundamental genetic memory within cells. The beauty of DNA is in its simplicity. With just two pairs of complementary molecules (A+T and G+C) it stores vast amounts of information that a living cell can access, read, and translate into the specific molecules it needs. A reliable system of replication allows DNA to be passed from cell to cell during replication. While controlled aberration and recombination make evolution and genetic diversity still possible. The intricacies of DNA are far too broad for me to go into detail here (I’ll certainly circle back to it in a future post), but the important concept to remember, in terms of bacterial immunity, is that DNA is information that can be stored and accessed later on.
In bacteria, this information is stored in the CRISPR DNA. I mentioned above that CRISPR stands for clustered regularly interspaced short palindromic repeats, but what does that actually mean? Well based on the name alone, CRISPR is a cluster of short palindromic repeats separated by spacers. A palindrome is a word that reads the same forwards as it does backwards (like “mom” or “race car”). In terms of genetic information, a palindrome is a sequence whose complement reads the same backwards. For example, the complement of ACCGGT would be TGGCCA, which is just the first sequence backwards.
In the case of CRISPR, a particular palindromic sequence is repeated backwards and forwards, separated by a spacer. The spacers are actually the part that contains the information. Bacterial cells collect viral DNA from the bacteriophages they have defeated and insert it between these palindromic regions in their own DNA. Later, when the virus returns, this DNA can be transcribed into RNA. Going back to our war analogy, the CRISPR DNA is intercepted enemy intel telling the “general” how and where to attack. The CRISPR RNA is the messenger that conveys that information to the front lines.
The CRISPR RNA (crRNA) gets processed and identified by CRISPR-associated (Cas) proteins. In some cases, the crRNA is identified by the presence of a hairpin loop that forms when the nearby palindromic sequences stick together. The Cas protein recognizes the hairpin structure and picks up the crRNA. In other cases, another CRISPR-associated element called trans-activating CRISPR RNA (tracrRNA) sticks to and identifies the surrounding palindromic sequence. This tracrRNA acts as a flag that recruits the Cas protein to bind with this RNA complex (this is the mechanism utilized for CRISPR Cas9 genetic engineering).
The Cas protein-crRNA complex is able to find and recognize the invasive viral genetic material. The complex binds to the DNA, and the protein induces a double-strand break that prevents the DNA from replicating or creating more virus particles.
The CRISPR-Cas system is a highly efficient mechanism for bacteriophage immunity that bacteria have perfected over their millennia-long war with viruses. It can also be hijacked by scientists to perform incredibly precise genetic engineering. Next week, I’ll talk more about how CRISPR was adapted into a scientific tool, and what that might mean for the future. Comment below or email me at contact@anyonecanscience.com to let me know what you think about this week’s blog post and tell me what sorts of topics you want me to cover in the future. And subscribe below for weekly science posts sent straight to your email!
