The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race, by Walter Isaacson

Category: Non-fiction; Rating: 4 out of 5; Tags: Biography, CRISPR, Gene Editing, Jennifer Doudna; How I learned about it: review in The Economist

Jennifer Doudna, with Emmanuelle Charpentier, shared the 2020 Nobel prize in chemistry for the development of the CRISPR-Cas9 gene editing tool.  Walter Isaacson’s book The Code Breaker is more than a biography of Jennifer Doudna; it’s also a wide-ranging story of curiosity-driven research involving many scientists over many decades.  From the discovery of the structure of DNA by Crick and Watson using the X-ray crystallography of Rosalind Franklin, to the implementation of CRISPR in the cells of mammals and its potential uses to detect and combat Covid-19, Isaacson applies his excellent writing skills to the history of genetic research.

A quote attributed to Isaac Asimov goes, “The most exciting phrase to hear in science, the one that heralds new discoveries, is not ‘Eureka!’ (I found it!) but ‘That’s funny …’,” and that’s what happened with the discovery of CRISPR and it’s adaptation as a gene editing tool.  In 1986 groups of repeated DNA sequences were found by PhD student Yoshizumi Ishino in the genes of E. Coli bacteria, but he had no idea what they were for.  Francisco Mojica, another PhD student, found similar sequences in his research, and became fascinated with the DNA that separated the repeated sequences.  In 2003 he discovered they helped the organism resist attack from viruses.  Curiosity-driven research led to the discovery of a whole new kind of immune system, one that needs no white blood cells, no antibodies or T-cells, just DNA.

We’re introduced to some quirky and complex characters in this book.  Eric Lander, director of the Broad Institute (an MIT and Harvard research group focused on genomic medicine), criticized Doudna for rushing a paper through review, but cheerfully admitted he’d done the same to be first in print with his research results.  James Watson, for all his brilliance, voiced repugnant views on race.  Harvard scientist George Church, with his rumpled white hair and wild beard, looks like a mad scientist, and has “the amused demeanor of a time-traveler who is eager to get back to the future.”

CRISPR is an amazing tool, and now that the hard part has been done, it’s easy to use.  Isaacson even does a little gene-editing himself.  With a bit of mixing and incubation, presto, he’s edited DNA in a test tube.  And if Doudna’s lab hadn’t provided the materials, he could have ordered genome editing kits online for under $100.  Editing DNA inside a human cell is a bit trickier, but he manages that, too, deliberately making it glow green.  Now imagine what could be done by a rogue scientist or gene hacker.  CRISPR has great potential for treating and curing diseases, but also carries great risk if misused.

For a thorough discussion of the ethics and dangers of editing the germ-line cells of humans, see CRISPR People, by Henry Greely.  For more on the philosophical implications of the human race becoming a species able to control its own genome, see Yuval Harari’s Homo Deus.  The Code Breaker is a good source for the history of research on genes and gene editing, for the details of CRISPR technology, and for its description of the motivations, challenges, and lives of scientists.

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CRISPR People: The Science and Ethics of Editing Humans, by Henry T. Greely

Category: Non-Fiction.  Rating: 3 out of 5.  Tags:  CRISPR, DNA, Ethics, Gene Editing, Human Genome

CRISPR stands for “Clustered Regularly Interspaced Palindromic Repeats”.  It refers to a gene editing technology that makes it much easier to edit DNA.  Coupled with a protein like Cas-9, CRISPR makes it possible to snip out a targeted section of DNA and replace it with something designed to have a desired effect, like repairing a genetic defect or reducing susceptibility to disease.  The “CRISPR People” in the title of this book by Henry Greely are those who use CRISPR technology to edit genes, not humans whose genes have been edited using CRISPR.  The latter would properly be called “CRISPR’d people” in a distinction characteristic of Greely’s careful, lawyerly thinking.

Take, for example, Greely’s definition of “human germline genome editing”.  He takes care to explain that human means a person; we’re not just talking about changing the DNA of human cells in a petri dish.  The germline consists of those cells of an organism that create the next generation; in humans, they are the egg and sperm cells, and changes to them are passed on to the next generation.  And it’s genome editing, instead of DNA editing, because it affects a whole person, not just the string of DNA that’s changed.

There are a few funny slips in Greely’s careful writing.  I get tangled up in my own words sometimes, so I can’t complain too much, but here’s an example:  in a biographical aside about biochemist Paul Berg, Greely says, “Born in June 1926 in Brooklyn, after military service in World War II…”.  I didn’t think this was a a book about time travel paradoxes.

The book was inspired by the announcement in 2018 of the use of CRISPR by researchers in China to edit the DNA of human embryos.  The edited embryos were implanted into the wombs of several trial participants, resulting in the birth of three genetically edited babies.  The announcement raised very troubling questions for several reasons, one of which was that the Chinese scientists had engaged in human germline genome editing.  The goal of the gene editing treatment sounded good – to change genes in an embryo to reduce or eliminate the susceptibility to AIDS.  But CRISPR is far from perfect.

It’s tempting to think of CRISPR as being like a word editor, in which you can automatically search for a word in a document and replace all occurrences of that word with another.  CRISPR is more like a word editor that finds and replaces only half of the instances of the word you want to change, and some of the words it does find aren’t changed to the new word that you specify, but to something random.  And just to make it even more interesting, it also makes changes to other words than the ones you wanted to change; in CRISPR, these are called off-target effects.  With such uncertainties, we shouldn’t have to worry about designer babies for quite some time.

Using a tool like this on embryos that will become living humans, let alone making genetic changes that will be passed along to their offspring, is obviously something that should be done with great care.  Tests for harmful off-target effects should be rigorous; alternative treatments should be considered; the risks of gene editing should be balanced against the severity of the condition being treated.  Informed consent from the participants and approval from an ethics review board should be required.  Chinese scientist He Jiankui did these things carelessly, fraudulently, or not at all, and is currently serving a three-year prison term in China.

 

 

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The Gene: An Intimate History, by Siddhartha Mukherjee

Rating: 4/5

This is a masterful treatment of the history of the science of genetics.  At nearly 500 pages, it is long, but the detail is worthwhile and the material intensely interesting.  It’s an intimate history because Mukherjee has a family history of mental illness, and naturally wonders about the chances that he has inherited a gene for madness.

 

It starts with Darwin’s theory of evolution, goes through Mendel’s extensive experiments with peas, to the identification of DNA as the carrier of genetic information and the discovery of the double helix structure by Watson, Crick and Franklin.  The field has advanced rapidly, as illustrated by the ability to identify genes and their functions, the sequencing of the complete human genome, cloning of complex organisms, and the creation of trans-genetic organisms – living creatures artificially created to contain DNA from other animals.

 

However, knowing what a gene does and even knowing how to modify it does not mean that a genetic disease can easily be cured.  Some diseases are caused be multiple genes; some are influenced by the environment.  Simple figures show how our thinking about genes have evolved.  Starting from the idea that a gene encodes a message to build a protein, we now know that it’s more complicated than that, and that the environment can influence the expression and regulation of genes.

 

The ability to manipulate human genes raises serious ethical questions, and Mukherjee helpfully contributes to the discussion with a list of facts and historical lessons to guide our decisions.