The Code Breaker

by Walter Isaacson

The gene-editing tool that Doudna and others developed in 2012 is based on a virus-fighting trick used by bacteria, which have been battling viruses for more than a billion years.

In November 2018, a young Chinese scientist who had been to some of Doudna’s gene-editing conferences used CRISPR to edit embryos and remove a gene that produces a receptor for HIV, the virus that causes AIDS.

The invention of CRISPR and the plague of COVID will hasten our transition to the third great revolution of modern times. These revolutions arose from the discovery, beginning just over a century ago, of the three fundamental kernels of our existence: the atom, the bit, and the gene.

The first, second and the third modern revolution, respectively

Children who study digital coding will be joined by those who study genetic code.

the key to innovation is connecting a curiosity about basic science to the practical work of devising tools that can be applied to our lives—moving

Curiosity-driven research into the wonders of nature plants the seeds, sometimes in unpredictable ways, for later innovations.

The key to true curiosity is pausing to ponder the causes.

X-ray crystallographers do something similar: they shine an X-ray on a crystal from many different angles and record the shadows and diffraction patterns.

Sir Lawrence Bragg,

Youngest Nobel laureate ever

three strands swirled in the middle, and the four bases jutted outward from this backbone.

The incorrect, but first attempt at visualising the DNA structure.

the twisting backbones had to be on the outside, not inside, and the proposed model did not contain enough water.

Rosalind Franklin played a pivotal role in finding the structure, as she was the one who rectified the duos' miscalculation, as well as producing the X-ray diffraction image of the DNA (Photo 51).

It had two sugar-phosphate strands that twisted and spiraled to form a double-stranded helix. Protruding from these were the four bases in DNA: adenine, thymine, guanine, and cytosine, now commonly known by the letters A, T, G, and C. They came to agree with Franklin that the backbones were on the outside and the bases pointed inward, like a twisted ladder or spiral staircase.

Thus was produced one of the most significant sentences in science: “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.”

The flow of history is accelerated when two rivers converge.

The key aspect of his intellect, she realized, was his ability to make unexpected connections between different fields.

Shows the flexibilty and adaptability of Jack Szostak's mind

Human Genome Project, and its goal was to figure out the sequence of the three billion base pairs in our DNA and map the more than twenty thousand genes that these base pairs encode.

That drove me to lead the Human Genome Project.

James Watson's son was diagnosed with schizophrenia, and hence motivated him to drive the Human Genome Project, as genes were responsible for his son's misfortune.

Watson enlisted Lander to help reorganize the public effort and speed up its work.

There were two rivals at this time; Collins' goverment funded HGP and Craig Venter's private firm, Celera.

$3 billion dedicated to the Human Genome Project was worth it.

More than four thousand disease-causing DNA mutations were found. But no cure sprang forth for even the most simple of single-gene disorders, such as Tay-Sachs, sickle cell, or Huntington’s. The men who had sequenced DNA taught us how to read the code of life, but the more important step would be learning how to write that code.

RNA (ribonucleic acid) is a molecule in living cells that is similar to DNA (deoxyribonucleic acid), but it has one more oxygen atom in its sugar-phosphate backbone and a difference in one of its four bases.

DNA doesn’t do much work. It mainly stays at home in the nucleus of our cells, not venturing forth. Its primary activity is protecting the information it encodes and occasionally replicating itself.

RNA, on the other hand, actually goes out and does real work. Instead of just sitting at home curating information, it makes real products, such as proteins.

“ribozymes,”

Nucleic acid derived enzyme.

Never do something that a thousand other people are doing.

Ask big questions.

One breakthrough came as a result of the random things that often happen in science: a slight blunder,

RNA is made up of very few chemicals, so it accomplishes complex tasks based on the different ways it is folded.

“One possibility is that we might be able to cure or treat people who have genetic defects.”

the structure of RNA.

Jennifer Doudna et al.

Many viruses are composed of DNA, but SARS was a coronavirus that instead contained RNA.

officially known as SARS-CoV. In 2020, it had to be renamed SARS-CoV-1.

RNA interference does just what the name implies: small molecules find a way to mess with these messenger RNAs.

“Dicer.”

A enzyme which converts RNA into small hostile fragments, that disintegrate the genetic information of mRNA (RNA interference).

By studying the Dicer structure, Doudna showed that it acted like a ruler that had a clamp at one end, which it used to grab on to a long RNA strand, and a cleaver at the other end, which it used to slice the segment at just the correct length.

The scientist does not study nature because it is useful. He studies it because he takes pleasure in it, and he takes pleasure in it because it is beautiful. —Henri Poincaré, Science and Method,

“clustered regularly interspaced short palindromic repeats.”

In most organisms that had CRISPRs, the repeated sequences were flanked by one of these genes, which encoded directions for making an enzyme.

“spacers,” those regions of normal-looking DNA segments that were nestled in between the repeated CRISPR segments.

their spacer segments matched those of viruses that attacked that bacteria.

longest-running, most massive and vicious war on this planet: that between bacteria and the viruses,

Mojica found that bacteria with CRISPR spacer sequences seemed to be immune from infection by a virus that had the same sequence.

Maybe the spacers use a form of RNA interference to dice the viral genetic material?

When new viruses came along, the bacteria that survived were able to incorporate some of that virus’s DNA and thus create, in its progeny, an acquired immunity to that new virus.

Mojica recalls being so overcome by emotion at this realization that he got tears in his eyes.8 The beauty of nature can sometimes do that to you.

the role of the CRISPR-associated enzymes was to grab bits of DNA out of the attacking viruses and insert them into the bacteria’s own DNA, sort of like cutting and pasting a mug shot of dangerous viruses.

They speculated that the CRISPR defense system worked through RNA interference.

Got my answer to my previous note ;)

It’s an all-rounder in the world of biomolecules!”

RNA can: 1) Perform catalysis (Ribozyme) 2) Fold into 3D structures 3) Retain genetic information

adjacent to the CRISPR sequences in a bacteria’s DNA. These CRISPR-associated (Cas) enzymes enable the system to cut and paste new memories of viruses that attack the bacteria. They also create short segments of RNA, known as CRISPR RNA (crRNA), that can guide a scissors-like enzyme to a dangerous virus and cut up its genetic material. Presto! That’s how the wily bacteria create an adaptive immune system!

crRNA (produced by Cas enzymes) deploys enzymes that have the ability to chop up a virus and embed its genetic material into the bacteria's own DNA.

they were standardized into names such as Cas1, Cas9, Cas12, and Cas13.

Cas1 has a distinct fold, indicating that it is the mechanism that bacteria use to cleave a snippet of DNA from invading viruses and incorporate it into their CRISPR array,