I wanted to learn what CRISPR is and what it can do. I should have previewed the book before buying, because it’s a long-winded story of every person involved in the journey of discovery and development of CRISPR. What they look like, where they grew up, what they said, who they met and when, on and on and on. When I was done with the book, I watched a 15-minute Kurzgesagt video about CRISPR and learned better than I did from this long story-telling book.
CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats
We can now exercise control of heredity.
We can erase or rewrite disease genes.
We can change the genomes of livestock, plants, and parasites.
DNA is not just a genetic code, it is also a moral code.
A molecular cursor can scan the 3 billion letters that make up the human genome for a specific sequence, cut it, then repair or change it.
We can design and engineer the DNA sequence of organisms big and small, from viruses and bacteria to plants (crops, flowers, trees), worms, fish, rodents, dogs, monkeys - and humans.
There are already enhancements to CRISPR, even more precise versions called base editing and prime editing.
What can CRISPR do?
Treat cancer and thousands of genetic diseases.
Simple, cheap, mobile diagnostic tools to detect outbreaks of deadly infectious diseases.
Design heartier, more nutritious strains of crops to feed the world.
Create new breeds of disease-resistant livestock and animals for organ transplantation.
Conjuring the notion of “de-extinction,” a way to resurrect extinct species such as the woolly mammoth, while providing a new tool for conservationists to save endangered species.
Shape evolution to control or even eliminate the scourge of infectious diseases.
Our genome contains barely 20,000 genes.
CRISPR doesn’t require expensive lab instruments. Most of the reagents can be ordered over the Internet and handled in the lab without any special safety precautions.
There are half-a-dozen different flavors or types of CRISPR system.
One of the simplest arrangements - Type II - features an enzyme called Cas9. This nuclease makes a clean break on both strands of the DNA double helix like a pair of nail clippers, but not indiscriminately. It grabs an RNA tag, holding it like a mugshot, searching the incoming DNA for a match. Once encountered, Cas9 will latch onto the viral DNA and cut it, neutralizing the threat. When Cas9 polices the intracellular neighborhood for invasions, it literally carries a copy of that most wanted poster with it. Asking everyone that comes in: “Excuse me, do you carry an exact match to this little most wanted poster that I’m carrying? Yes? Then I’ll cut you.”
We have hijacked a bacterial enzyme a billion years old and repurposed it into a 21st-century molecular scalpel.
Bacteria boast an army of potent enzymes that recognize and attack specific motifs in any foreign DNA.
CRISPR is a small subsection of the bacterial genome that stores snippets of captured viral code for future reference, each viral fragment (or spacer) neatly separated by an identical repetitive DNA sequence.
Whether we want to edit the genome of a hamster or a human, a mosquito or a mouse, a redcurrant or a redwood, the process essentially is the same.
That’s because all organisms in nature use the same inert DNA code, composed of the same four-letter alphabet.
90 percent of Archaea contain CRISPR elements, but only 40 percent of bacteria.
100 percent of all commercial yogurt cultures are enhanced using CRISPR screening.
Whether you have yogurt, a bite of cheese, whether you put that on your nachos or pizza or cheeseburger, you are consuming a fermented dairy product that was manufactured using a CRISPR-enhanced starter culture.
We should have ethical objections to the way that natural evolution does things.
The apparent total indifference to animal suffering, to any kind of notion of right or wrong.
Evolution is amoral. Not immoral, because it is a physical process.
But the fact that it does not care about or optimize well-being is a fundamental flaw in the universe.
Evolution has no moral compass. We do.
To edit mosquitoes, harness gene drive systems that occur naturally, probably originating hundreds of millions of years ago.
The cow genome, for instance, is littered with genetic elements from snakes that spread via a gene drive.
Prior to the development of CRISPR, nobody had contemplated being able to edit an entire wild species.
Don’t worry about the ethical risks of a gene drive potentially running amok and crossing over into other species.
CRISPR is powerful enough that you cannot really build a gene drive that cannot be targeted with CRISPR, meaning whatever one person does, another person can override.
There are many technologies that are irreversible. But genetics isn’t one of them.
The screwworm was eradicated across North America in the late 1960s using the sterile insect technique.
By irradiating and releasing millions of sterile male flies - a factory in Florida was producing 50 million infertile flies a week - the population was halted in its tracks.
Mark Lynas was a proud environmental activist, but the more he researched the science underlying genetically modified organisms (GMOs) and climate change for books such as Six Degrees, the more he realized his blinded ignorance. Indeed, the evidence overwhelmingly supports the safety of GMOs. In 2016, the National Academies of Science, Engineering and Medicine published a major report concluding that GMOs did not harm animals nor cause any health problems in humans in the food supply. A group of more than one hundred Nobel laureates called on Greenpeace to end its opposition to GMOs. Lynas admitted his own mistakes during a keynote speech in 2013 at a major farming conference before a shocked audience. He apologized for ripping up GM crops and helping to demonize a technology with profound environmental benefits.
The most profound thing we’ll see in terms of CRISPR’s effects on people’s everyday lives will be in the agricultural sector.
The CRISPR craze has swept through plant biology.
In the mid-1950s, Borlaug, an expert at interspecies hybridization, developed semi-dwarf wheat, which probably saved millions of lives after it was introduced to India in 1962, earning him a Nobel Prize. It now makes up 99 percent of all wheat planted around the world.
Half a century ago, scientists used a nuclear reactor to shoot gamma rays at barley seeds, inducing a plethora of random mutations in the DNA.
One result was “Golden Promise,” a high-yielding, low-sodium barley variety popular with (ironically) organic farmers and brewers.
Before CRISPR, they had to treat seeds with chemicals that randomly mutagenize the DNA and then manually search for desirable mutations by scouring row after row of tomatoes.
They spent four years compiling a toolkit of new mutations, where several mutations worked collectively to build a higher-yield tomato plant.
There had to be an easier way.
CRISPR technology is not about introducing foreign DNA, but working with the plant’s own DNA and enhancing natural repair processes.
For example, a desirable trait in tomatoes is called jointless, in which the stem leading to the fruit lacks a knuckle or joint. Fresh market tomatoes crossbred with the jointless trait enables high-throughput production and less damage during handling.
They used CRISPR to engineer a jointless line of tomatoes without having to cross different strains, and can apply this to any variety.
There are about a billion people in the world who are obese, and a billion people who are hungry.
If we were able to cure all diseases, we wouldn’t all live forever - we’d die of starvation.
Gene editing does not introduce a foreign gene, as happens in GMOs - but introduces a specific change to the DNA, usually to a sequence that already exists in nature. Besides speed and specificity, gene editing offers another benefit. Traditional selection leads to a loss of genetic diversity as lines are crossed and back-crossed. Gene editing can introduce traits without backcrossing, preserving or reintroducing lost variation.
The wheat genome is three times larger than the human genome.
The banana industry was saved from collapse by the Cavendish variety, derived from plants grown in the 1830s at Chatsworth House, an English stately home.
The Cavendish is an inferior fruit in most respects but became a commercial mainstay thanks to its resistance to the Panamanian fungus.
The enormous promise of CRISPR for food production will be crushed unless gene editing is decoupled from GMOs.
African swine fever (ASF), bovine respiratory disease, pig influenza, and chicken influenza are just a few of the other pig diseases that CRISPR can help.
The classic CRISPR technology will only work therapeutically in a fraction of genetic diseases
The best genome editing would be to modify a single letter of the genetic code without cleaving the DNA in the process.
That’s base editing — the latest power upgrade to the CRISPR toolbox.
The first two base editors offer a means to edit “all the easy mutations,”
These molecular machines have to search the genome for a single target position, open up the DNA, perform chemical surgery directly on a base to rearrange the atoms - then do nothing else [except] defend the edit from the cell’s fervent desire to undo them.
There’ll be a library of base editors and you’ll pull out the book that matches exactly what you need.
In each of your 10 trillion cells, the genome is constantly mutating.
Hundreds of times a day, a C is mutated to a U, which if left unchecked, would become a C-to-T mutation.
There are more than 75,000 known disease-causing mutations in the human genome - about half of those are point mutations - but most can’t be targeted by CRISPR-Cas9 or base editing.
While base editing’s strength is its ability to make a class of base substitutions known as transitions, they only account for four of the dozen possible base changes.
The CBE would in principle fix 14 percent of known point mutations; the ABE accounted for a higher fraction, some 48 percent.
The full range of prime editing’s prowess - 175 different edits, including 100 point mutations of all possible types; repair of known disease mutations in human cells; insertions and deletions in the forty to eighty base range; and simultaneously deleting two bases while converting a G-to-a-T a few bases away.
Prime editing could in theory address 89 percent of the categories of human disease mutations.
Whether it takes five years or fifty, it seems inevitable that we will be able to engineer bespoke variants into the genome precisely and safely.
The prospect of rewiring the genetic code to cure deafness or diabetes, sickle-cell or schizophrenia, is getting closer all the time.
If we really care about avoiding cases of genetic disease, germline editing is not the first, second, third, or fourth thing we should be thinking about.
In preimplantation genetic testing (PGT), we already have a method to reduce the transmission of disease genes.
Hsu scornfully dismisses criticisms, shocked that human geneticists have virtually no idea what their colleagues in livestock or corn breeding are doing.
Germline editing offers three intrinsic advantages.
First, it is more effective than other delivery systems at reaching all cells in the body.
Second, after administering the edit, every future child and descendant would receive the edit free rather than costing millions of dollars for their own somatic gene therapy.
Third, germline editing goes through a single cell, whereas somatic therapies impact millions of cells.
There is nothing ethically superior in leaving things be if it is possible to change them for the better.