CRISPR enables, for the first time ever, relatively controlled, precise, and efficient genetic engineering.

A Primer on Genetic Engineering

Genetic engineering is nothing new. We've been doing it for thousands of years, through the practice of selective breeding, ever since primitive people modified the development of plants and animals via trial and error.

Farmers selectively bred richer, more productive crops, and stockbreeders bred more useful animals, like docile, wooly sheep.

Only thousands of years later, in 1857, did the study of genetics take off, with an experiment by Gregor Mendel. He selectively bred pea plants, discovering that something in male and female plants determine various traits, called genes.

To understand genes, and ultimately genetic engineering, we need to dive a bit deeper.

Later advancements in microscopes led to the discovery of the cell, and its components. In short, cells are made mainly of six elements (Carbon, Hydrogen, Nitrogen, Oxygen, Phosphorus, and Sulfur), which join to form molecules, like water or sugar.

A Primer on DNA & RNA

These molecules together form macromolecules, including nucleic (in the nucleus) acids, like RNA and DNA, which are chains of nucleotides (a sugar, a phosphate, and a base), with the bases A, C, G, T, and U forming a set of instructions (like the 1s and 0s in a computer) for a cell, enabling the synthesis of amino acids (subunits of proteins, which are mainly enzymes) as needed, ultimately determining what happens in that cell. All the cells in an organism together yield, well, the organism.

TLDR: DNA is the info our cells use to replicate.

DNA replication is interesting to look at here, because it actually uses a lot of the same mechanisms and concepts that we hear of when talking about CRISPR.

For instance, DNA replication starts when a "snipping enyzyme" cuts the DNA strands at the "origin." As it's cut, whenever a free nucleotide meets a complementary base on the DNA, it sticks, and a "clipping enzyme" puts them together.

The sequence of base pairs can be thought of as a series of “words” determining the order of amino acids in each protein. However, to translate those “words” into amino acids requires three things:

A “messenger molecule” copied from DNA A family of “translator” molecules to connect the “message” to amino acids A body which holds things in place and helps two amino acids form bonds

Protein synthesis starts when a region of DNA is snipped open, and a molecule of RNA is built along one strand by an enzyme called RNA polymerase (this is called transcription). As in DNA replication, matching base pairs meet up.

RNA is used here because, unlike DNA, it is much shorter and also single-stranded.

This RNA is called the messenger RNA (mRNA), as it carries the genetic message from the DNA to the protein factory. This message is triplets of bases (e.g. AUG), known as a codon, with each codon standing for a single amino acid, and the whole mRNA strand encoding a protein.

Together, these codons form the genetic code.

Supposedly meaningless sequences of codons were found within DNA, called “junk DNA,” or introns.

"Junk DNA": The Misnomer That Led to Discovering CRISPR

It turned out that these sequences weren't actually "junk," some of which came to be known as CRISPR.

CRISPR consists of repeating sequences of genetic code, interrupted by "spacer" sequences. These are code remnants left by past invaders, serving as a genetic memory to detect and destroy returning invaders ("bacteriophages").

This genetic memory let cells target bacteriophages by cleaving their DNA molecule with CRISPR-associated ("CAS") enzymes.

From Discovering CRISPR to the Patent War

Ever since the discovery in the late 1900s, the field has been rapidly advancing. Here are some select early events:

Date Event December 1987 The CRISPR mechanism first published 2005 Jennifer Doudna and Jillian Banfield started investigating CRISPR April 2012 First commercialisation of CRISPR-Cas 9 technology May 2012 First patent application submitted for CRISPR-Cas 9 technology 12 Dec 2012 Fast track application for CRISPR-Cas 9 technology submitted to US patent office.

As you'll note, research began around 1987, and it wasn't until 25 years later that attempts were made to patent CRISPR.

You can see this visualized in an HGF graphic below:

"Patenting tends to get people's juices flowing when you put the word 'gene' and the word 'patent' in the same sentence... This is stuff we're carrying around - all of us - inside all of our cells. Should somebody be able to lay claim to it?" - Francis Collins

However, since 2012, the patent war has ramped up fiercely. In fact, just in 2020, the European Patent Office has made decisions affecting the foundational CRISPR IP of The Broad Institute and UC Berkeley (two major CRISPR players).

As a result, The Broad Institute's lead EP (European Patent) was revoked, and UC Berkeley's was maintained.

The hottest area in gene editing, and thus also patents, is in eukaryotic cells, with applications including developing human disease cures and genetically modifying plants and animals.

What Are The Patents For?

Two evolutions of the original CRISPR editing technique are known as base-editing and prime-editing, which are licensed by The Broad Institute to Beam Therapeautics and Prime Medicine.

One challenge with CRISPR (the original editing technique is known as non-homologues end joining homology-directed repair) is achieving an accurate, desired effect, without off-target effects.

Base-editing requires a Cas9 nickase (or other Cas nickase), and changes the sequence base by base to be more accurate. Because it uses a nickase to cut the non-edited strand, the original CRISPR IP is still relevant.

Prime-editing uses a Cas9 nickase (fused to a reverse transcriptase instead of a deaminase) for also more subtle and accurate editing.

Patents over these, and other techniques, are being disputed.

WHY Patent?

With a technology that promises to change the world for the better, from therapies to modified crops to mosquito control, and more, you may ask why anyone would ever want to restrict or control it.

Unfortunately, therein lies the answer: CRISPR is such a powerful technology, with billions of dollars at stake, that patenting it would yield huge financial returns.

In fact, there are several publicly-traded companies in the CRISPR realm, including CRISPR Therapeutics (NASDAQ:CRSP), Editas Medicine (NASDAQ:EDIT), and Intellia Therapeutics (NASDAQ:NTLA). Other investment vehicles include CRISPR Therapeautics' partner Vertex Pharmaceuticals (NASDAQ:VRTX), which announced encouraging preliminary results from clinical studies for a CRISPR gene-editing therapy.

The companies that win the most patents have the most to gain, since any company that wants to use that technology will have to license it from them.

As the saying goes: "Follow the money."