CRISPR Part 3
find, cut, copy, paste
Part 1 was a Preview. Part 2 was DNA and the introduction of CRISPR. Today we will explain what scientists found that led to practical gene editing. If you missed the beginning here's a link.
Just because you see something in E. coli and streptococcus (says the scientist), doesn’t mean it applies to fixing my problems. How is it possible for our immune system to adapt to new dangers? The story gets more interesting and it is time to return to our ridiculous acronym for CRISPR. What were the strange repeating patterns that scientists observed throughout nature? The patterns were always next to snippets of DNA that our immune system needs to fight off to survive. The repeating pattern acronym translates to Clustered Regularly Interspaced Short Palindromic Repeats.
Even though this sounds pretty intimidating, it is helpful. Imagine a biology teacher saying to you let’s pretend you are an immune system. Yours is pretty good and knows what to do when subjected to measles, and the mumps. The way it does it is it knows the formula for what these look like and kills it when it sees it in your body. Diseases are nothing more than a recognizable sequence of DNA. Since some diseases are simple and others are complex imagine something like :
VIRUS | MEASLES | VIRUS | MUMPS | VIRUS
Now imagine the purpose of the word VIRUS in the text above is to show where the disease begins and ends (what it looks like is always in between). If a new bad disease comes into our body (let’s call it COVID) and we develop immunity our body wants to remember it so it revises the list to look more like this:
VIRUS | MEASLES | VIRUS | MUMPS | VIRUS | COVID | VIRUS
The word VIRUS in the text above is a string of DNA words that reads the same forward and backward. That is the definition of a palindrome from our crazy acronym above! Our bodies use a simple and familiar bookmark in our DNA to mark the beginning and end of a virus. Whatever is in between is the bad stuff we want to fight. Time for a palindrome tangent.
A MAN A PLAN A CANAL PANAMA
Palindromes are unusual words or phrases which can be read forward or backward and read the same such as Mom and Dad. A while back in my book club we read a great book titled “The Path Between the Seas”. It was the story of the construction of the Panama Canal. We owe much to Theodore Roosevelt and have rightly honored him with a spot on Mount Rushmore.
The silly subtitle above is my favorite palindrome. It became a slogan when the United States took over from France and completed the Panama Canal under President Roosevelt’s leadership.
Now here is a shorter than real example of a DNA palindrome which I will explain. Remember from Part 1, DNA only has four words in its vocabulary (AT, TA, CG, GC):
GC-CG-AT-CG-GC-TA-GC-CG
The order of the first character in each word / base-pair (think of them as left and first to last) GCACGTGC
The order of the last character in each word / base-pair (think of them as right and last to first) GCACGTGC
This may seem like a silly exercise but the beauty AND simplicity of a palindrome pattern like the one above makes it VERY EASY TO FIND since you can look for it seeking forward or backward! In fact it is so easy to find, E. coli can do it! Whichever base you look on as the double helix twists, the bookmark will ALWAYS be the same! This is the sort of bookmark our bodies use to mark their entries in their immune system to-do list.
Nature evolved to keep it simple and made it so easy, even E. coli can do it!
Nature is built on repeating patterns and a snippet of DNA that reads the same forward and backward is a perfect bookmark. This is what scientists found in E. coli, streptococcus and later in us!
Just as we like to use bookmarks to remember where we stopped reading a book, our bodies had a bookmarking system to identify important stuff for our immune system. These bookmarks are adjacent to anything our adaptive immune system thinks is worth fighting.
Even though we have begun to use CRISPR for something different than its original use (an immune system), the immune system will help us understand what is going on.
After watching a few videos and trying to describe it in a way I can understand, here goes:
An adaptive immune system means as new threats present, our immune system needs to keep track of what to look for. I am going to refer to the list of stuff our immune system watches out for as “the vault”
The vault is a list of bad stuff that can come into our bodies and what we should do about it (like mumps and measles and COVID). I think a vault is a pretty good analogy. Unrecognized cells are what our immune system cares about and respond one of two ways. Method 1 is for dealing with bad stuff it DOES recognize. Method 2 is dealing with stuff behaving badly that it DOES NOT recognize.
Mission 1:: If it has a profile sitting in the vault, it constructs an assembly that finds that pattern to match, cuts out that snippet of DNA, loads it into a larger carrier, and then kills it. Then it just inactivates the leftovers as junk. End of story. This is how our immune system prevents the disease from spreading.
Mission 2:: If it sees something foreign and doesn’t recognize it, it sends out an empty assembly, snips the invader DNA, and encapsulates it. Then it goes back and places the new weird bit of DNA and adds it to the vault. How do we know this is a bad thing to look out for? It also leaves our handy bookmark next to it so it can find the list of bad stuff in the future. This is ingenious, it is simple, and can scale to protect us continuously in a blade of grass or me. Life is amazing.
Our immune system, to a large extent, can search, cut, copy, and paste. This is all we need to edit life if we have a frontal lobe and are prone to inspiration and like making new tools!
Our immune system is remarkably similar in all living things and we can even find this very similar behavior in E. coli bacteria. It doesn’t get more primitive than bacteria in a discussion of living things.
What good is writing stuff down randomly if we cannot find it later? CRISPR managed to unlock nature’s secret of how to keep a list and not forget where we put it. It was all about when we want to keep track of something, it leaves a DNA palindrome bookmark. Amazing!
Every time we want to add stuff to the vault we put what is important next to our palindrome. The number of consecutive palindromes is the length of the list. That way our list of bad stuff for our immune system to watch out for can be managed like a grocery list and we can adapt to a dangerous world. How is it possible that we can identify and understand our commonality with E. coli? Our stories are encoded as a sequence of four words. Some living things have a longer story and others a shorter one. The human genome is about 3 billion base pairs. E. coli is about 4.6 million base pairs.
The basis of the immune system and its emergence in all living things is the pattern we have described here. In a dangerous world, the immune system was inevitable and is common to so many living things in largely the same way. It turns out that while it is hard to grasp the connection between lower-order organisms and us, the proof lies in the genetic record of our DNA. It turns out the basic and elaborate living things in this wonderful world all seem to do it in the same way. I’ll never think of a fruit fly the same again.
Lots of work by wonderful scientific research and a couple of Nobel Prizes later and we have arrived at a world wherein we can edit the genome. We are on the brink of so much and it remains the best of times to be alive.
If I have not bored you to tears, our immune system has a (1) way to compare stuff to a list (find it), (2) has a way to snip/cut bits of DNA and place it in a list, and (3) has a way to delete garbage (keep its list up to date). Once you can find, cut, paste and delete, you have the makings of a nifty word processor. Being able to snip DNA into manageable pieces is why we will call the tool science has brought forward “molecular scissors”.
Gene editing applies the steps and principles our immune system performs to instruct our bodies to find almost anything, cut it out and replace it with the DNA of our choosing. This is gene therapy in a nutshell.
Tonight’s song might give each of you a fighting chance to remember the palindrome part of CRISPR. Before you start the song, think of Teddy Roosevelt.
WHAT’S NEXT
We are finished with part 3 of 4. Tomorrow we will finish with “CRISPR Part 4” and my sabbatical begins from this writing adventure. It was a joy exploring this new hobby and I hope frequent readers enjoyed consuming it as much as I did the creation. I hope that my passion can return someday soon. In the meantime be kind to each other and find something else to read.