CRISPR Part 2

a healthy checklist

This story was a challenge to write. I hope that I make it easy to understand. Maybe well enough to talk about it at a party when someone is eating something bacon wrapped. Today we start with DNA and what the researchers found.

When we encounter something we do not understand, an analogy to make it simpler to understand is a blessing. When I hear the term CRISPR I just think of molecular scissors.

Today we dig into the amazing story of a man with a pig heart we started in “CRISPR Part 1” last night. The story starts in a lab. We can connect the dots directly from scientific work begun in Spain in 1993 to the successful editing of a pig heart to make it suitable for implant into a human being. All of this is built on faith in the scientific method to reveal the secrets of the natural world.

In Part 1, I just let you know what you were in for. Today we are just going to talk about just enough DNA to explain what the researchers found. The story begins in Spain, in 1993 in the lab with Francisco Mojica, at the University of Alicante, Spain observed an unusual repeating pattern in the DNA snippet of E. coli bacteria. Continuing research saw similar or exactly the same repeating pattern in streptococcus. What did he see?

It turns out that anything that wants to live for a while needs an immune system, even lowly bacterias we associate with food poisoning and strep throat. My theory is Francisco must like doing puzzles of some kind because he is good at seeing patterns. Francisco noticed a pattern in the bacterias that seemed to repeat an awful lot. These patterns need a little explanation so we will start there. By the way, it eventually becomes clear and practical to do all sorts of things when we realize that lowly E. coli and well-differentiated mammals have very similar approaches to fighting off disease and preparing for a return, an adaptive immune system that keeps a list of stuff to watch out for and marks its entries with a CRISPR tag.

While it is all well and good for an advanced specialty scientist to conclude they see a pattern, what the heck does that really mean?

So far, if we are paying attention, we know that CRISPR is a new way of editing our genes (or the genes of any living thing). That sounds amazing but could turn out to be creepy also. Our genes are just some special segments of our DNA. Everything that lives on this earth contains DNA and it all works about the same way. That seems absurd to think that a blade of grass and Shaquille O’Neal both grow and became what they are with the same building blocks.

As crazy as it sounds, that is the story of how it all works. We need to start this story with DNA. Since CRISPR is a method to edit genes (our underlying DNA), we will first go through some information about DNA.

For me, color makes things easier. Think of the alphabet of all living things (DNA) to be merely four letters long. The four amino acids that define the recipe of life in all its detail are shown in color above. Note that the green and red pair up. The same is true for blue and yellow.

Our human language (at least English) gets along with 26 letters in the alphabet. Nature, at first blush, is a little simpler. When it comes to DNA and the making of some sort of language, there are only 4 letters in the alphabet; A, C, G & T. The four letters of the alphabet are shorthand for four chemicals (amino acids) with the names Adenine, Cytosine, Guanine, and Thymine. For me, it is easier just to think of the four letters. From here on out we will stick with A, C, G & T. Once you have an alphabet, the words you can make come next. In the language of DNA, AT sticks together and CG sticks together. The whole dictionary of POSSIBLE WORDS in the DNA language is comprised of only four words AT, TA, CG & GC.

Now it is time for another confusing phrase, specifically base-pair. Instead of calling our four combinations in our DNA language words, biologists went with base pairs. This is mostly because the pairs of letters attach to two strips that are wound together (the bases). The way the bands twist together is called a double helix to describe the shape.

The picture above is great because it is color-coded. The four amino acids always mate up in pairs. If you look at the picture red and green stick together as do blue and yellow. Before we talk about what each of these four words might mean, it is good to know how long the book is. A human being and their DNA is about 3 billion base-pairs (words). A fruitfly is about 180 million base pairs. If it makes you feel powerful, that means our story is almost 15 times as long as a fruit fly and about 700 times as long as an E. coli bacteria. Take that bug/bacteria!

Now here is some context because it always helps with big numbers. I decided to compare the “word-count” to a couple of books. The long book War and Peace is about 600,000 words long (about 1/8 of a fruit fly). I confess that I have not read it and likely never will. Another that I have read and recommend is Infinite Jest by David Foster Wallace which comes in around 540,000 words so even though I think the book is GREAT, it doesn’t have much to offer compared to E. coli.

Returning to DNA for now. Any one of the four base pairs is valid and in all of nature, we have never found ANY exceptions. This IS the common denominator for every living thing on this Earth. While science is always searching for new refinements, we have never found an exception and we’ve been looking hard. This is a pretty simple language and hopefully, that makes this easy to follow.

So a pretty reasonable question that I would ask is how can such a simple set of letters and words (base-pairs) lead to all of the amazing living things on earth? So each living thing has sequences of base pairs that make up a gene. I think of genes as the recipe for an important feature any organism expresses. The more complex the thing means more genes and the overall length grows and grows. A number of genes are typically grouped into chromosomes and finally, the content of your chromosomes is the recipe book for you. Humans have 20,000 to 25,000 genes crammed into their 23 pairs of chromosomes. All of the base pairs in between used to be referred to as junk DNA. Only about 1-2% of our genome is chromosomes. A lot of the rest is a mystery. The truth was, we discounted the parts we don’t understand.

I am sure a biologist out there will correct me but here is a simple way to see things

Four letters A, C, G & T in the alphabet

Four words AT, TA, CG, & GC aka base-pairs in the dictionary

A long sequence of base-pairs comprise a gene

A group of genes comprise a chromosome

A group of chromosomes provide the cookbook for a living thing

Two living things (A&B) mix their chromosomes together and you get offspring that are a little bit of A and a little bit of B

Sometimes mistakes in the copying (mutations) introduce unexpected changes and a living thing can slowly start changing aka evolving

There is a lot more to our DNA than just our genes though. There is a whole lot more to our genome. One of the mysteries of how things work has always been our immune system. How does our body keep track of what the bad stuff is they need to look out for? What does our body do when it finds the bad stuff? Finally, and most important to today’s discussion, is what do you do when you have more than one thing to remember and watch out for? How does our body deal with something completely new to worry about? It is easy to go to the store when you only need one thing. Once the number of items grows, it becomes time for a list. Our immune systems are amazing and they aren’t just looking out for a cold. They have a lot of things on their list of stuff to watch out for.

The hypothesis was that an adaptive immune system had been found! Imagine the surprise that the same basic concept was common to most living things. It is humbling when something as significant as an immune system also works similarly in bacteria and viruses (and us). Subsequent research and refinement identified the details of how immune systems work and how their methods could be adapted to edit genes. I think, for many of us, such an observation is difficult to wrap our heads around. Can something as “significant” as an adaptive immune system be the result of a dynamic list of things to fight in a simple four-letter alphabet? The Nobel Prize in Chemistry recognized the breakthrough in 2020, awarding the prize to two women (the first time that has happened) Emmanuelle Charpentier and Jennifer A. Doudna. Mankind Womankind has been making tools since the Stone Age. This is the coolest set of scissors you might ever imagine. So what did they find and why did they call it CRISPR?

We will continue with that part of the story next Saturday in “CRISPR Part 3”. However, it only seems fair that we at least explain what CRISPR stands for. After all, I’ve been blathering on for two nights.

So what is CRISPR? This is undoubtedly the most ridiculous acronym we have discussed in my posts thus far. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats. Yikes. I think this will be fun! I have NO EDUCATIONAL background in biology and genetics. As the joke goes, perhaps I stayed at a Holiday Inn Express last night. I am not in the crowd that needs to be convinced about life on this planet and its evolution in place of another explanation. Whenever I delve into the topic, I always emerge amazed at the elegance and simplicity of the patterns. It helps to know it works in E. coli bacteria. Here’s the video I watched on YouTube that was my primer on CRISPR. I had to watch it twice which made for 6000 steps on the treadmill. That was about all I could manage that day after feeling under the weather the previous few days after New Year’s.

Here’s a song that captures my background in biology as I soldier through this series of posts. I hope this is an inspiring story and you will return for the rest. I was playing this song in the middle of my writing and thought it fit with my mood.

WHAT’S NEXT

We return to regular posts next time. The next one is titled Arnolds and is inspired by “The Terminator” and former California Governor Arnold Schwarzenegger.