The Code Breaker -- Walter Isaacson -- 481 pages (536 with notes and index)
The Code Breaker is the latest book written by Walter Isaacson that extends themes covered in many of Isaacson's recent books on Leonardo da VInci, Ben Franklin, Albert Einstein, Steve Jobs, et al related to specific technical innovations and the mindsets of the people leading those innovations. His da Vinci book focused on synergies between medicine, mechanics and art that da Vinci leveraged in his works. His Jobs book explained how conceptual technology background and a mix of liberal arts combined with a maniacal and often mean / arrogant personality became instrumental in three different companies leveraging computer technology for consumers and entertainment. The Code Breaker uses the same blended analysis of personalities and sciences to explain how COVID vaccines were created in such a short time and provide different ways of thinking about the ethical questions raised by the underlying technology.
The Book Review
The full title of the book is The Code Breaker - Jennifer Doudna, Gene Editing, and the Future of the Human Race, reflecting the three key areas of focus within the book. However, Isaacson spends relatively little time on "wayback machine" narratives about the lives of key figures as they were growing up, etc. Unlike other authors writing similar books, there is no prose that recounts inner dialog in people's head as they prepare to cross the street to head into a crucial meeting (in other words, complete fabrications the author could not possibly know or verify). Isaacson writes predominately in the present tense but he does often break the "fourth wall" of the book and state his own opinion in the first person. He is also not one to rely on subliminal foreshadowing. When a term or technology is introduced that will come back later, he states directly, "we will come back to this later." He also writes in very short chapters with subsection headings within them, making it easier to remember how the content will be tied to the larger outline. In general, Isaacson is a very concise writer and the technical explanations tend to click.
The areas where first person prose comes into play most heavily involve discussions about the societal concerns about the technologies being discussed and the ethical questions raised by their use. The book covers debates held in the medical and scientific community over the years at a variety of locations covering these topics but this material only accounts for roughly 160 pages of the larger 481 page book, including Isaacson's own personal opinions which are well separated from those of the figures in the narrative.
In general, the book is well organized and provides a clear explanation of how unique study and career choices by Jennifer Doudna to focus on RNA biochemistry produced insights that leveraged decades of work in multiple disciplines to provide the treatments needed to contain what is still a huge medical threat to the world. The material also explains how a different type of managerial intelligence exhibited by Doudna as her career involved from a gifted individual contributor in a lab to a lab director responsible for selecting team members with the best mix of intelligence, competitiveness and collaboration was VITAL to the success she and her teams experienced.
All worth $21.49 and a few hours of time to read.
But -- as they say -- that's not why I'm writing...
The Real Value of The Book
The real value of reading The Code Breaker is it provides a clear understanding of the science involved in the COVID vaccines that came from nowhere and by describing that work, makes it clear that the technology wasn't rushed out of nowhere but builds upon nearly 35 years of work dating back to 1984. It isn't likely reading this book will change the mind of a militant anti-vaxer. However, it summarizes the vocabulary, technology and milestones that make the process easier to understand for average citizens and explains why the mechanisms are essentially programmable, making it MUCH simpler to match on new virus threats with less regression testing in clinical trials. Having more laypersons with this vocabulary and understanding might raise the level of debate enough to provide a better starting point for the next pandemic -- or even the next wave of the current pandemic.
The book explains the components of "gene editing" capabilities and resulting vaccines in three related areas:
Biochemistry -- Studying underlying biochemistry allows the behaviors and interactions of various biochemicals to be analyzed with less variability and more certainty about causes and effects. There are dozens of proteins acting as information bearers and dozens of enzymes acting as catalysts to trigger specific reactions which can be tested rapidly and accurately outside the context of actual living cells.
Crystallography -- Knowing the atomic composition of a protein or enzyme isn't enough to deterministically identify its function. The SHAPE of the material and arrangement of atoms within the overall structure affects how it interacts with other chemicals. Crystallography simplifies studying the physical topology of biochemical components by freezing them. As they freeze, the chemical topology triggers crystal lattices in the material around them to form that is easier to see than the underlying chemical structures but uniquely identifies the underlying structures. Imagine a complex protein suspended in water at room temperature. You can't see the protein clearly at room temperature in a liquid. If you slowly freeze the water and the ice structure takes on a cubic lattice, that might signal an underlying structure of something in flat strands. If the lattice takes on a parallelogram pattern, that might signify a strand with two folds in it.
CRISPR - Clustered Regularly Interspersed Short Palindrommic Repeats are a term for a pattern identified in the DNA of many strains of bacteria which repeat a common pattern on a regular basis throughout the larger DNA strand. Additional research also found specific enzymes located adjacent to these repeating rungs on DNA helixes not found anywhere else. These were termed CRISPR-associated or Cas enzymes. By analogy, imagine a DNA strand as a roof ladder with 3 billion rungs with each rung consisting of a pair of proteins from a universe of four proteins. Genes represent combinations of maybe thousands or millions of rungs in a group. In that ladder of 3 billion rungs of UNIQUE information, CRISPRs are collections of rungs scattered throughout the larger ladder whose A/B pairs act as the chemical equivalent of "unused memory" with a signature that tells other processes that the space is available if needed.
How did these areas of research coalesce?
In 1996, Doudna published a paper with her team at Yale (including her husband) describing their use of crystallography to identify every atom in an RNA thread and explain how it creates the ability to "cut" itself at specific links and attract nearby compounds to self-replicate. Until then, it was not clear that a RNA strand could perform cut and splice operations without the influence of outside enzymes. This finding essentially showed that RNA demonstrated the most flexibility for driving reactions throughout cells, not just in the nucleus.
CRISPRs were first discovered in 1986 then triggered additional research between 1990 and 1997 and were more officially described in papers published in 2001 and 2002. The first scientist who discovered CRISPRs noted them in his paper but because they appeared tangential to the core purpose of his research, they were not pursued. Another scientist independently studying bacteria found the same pattern, initially thought his data was wrong, then kept finding the pattern and eventually found the 1986 paper. At that point, he realized nature would not "waste" encoding capabilities in DNA for no reason. Subsequent research found that bacteria containing CRISPR in their DNA would fend off infections of specific viruses. Bacteria without CRISPR "blanks" would not fend off infections by the same test viruses. As more research was conducted, scientists found that the CRISPRs acted as placeholders and actually allowed the bacteria to learn new DNA patterns from incoming viruses and encode that information into the "blank" CRISPR sections. The Cas enzymes next to the "blank" CRISPR sections allowed the new encodings to be surgically spliced into the DNA for future use and the sides of the DNA helix to be reconnected after inserting the new encoding.
By 2008, additional research conducted by Doudna and her team found not just one variety of CRISPR associated enzyme but many (eventually, more than 12). Each Cas enzyme demonstrated different capabilities for cutting and slicing DNA and RNA components. Most importantly, this research found that a specific Cas variety tagged Cas1 was found in nearly every variety of bacteria and had a unique fold that allowed it to target CRISPR areas and fold in proteins from invading viruses, allowing the CRISPR areas to be turned into "memory" to allow cells to defend themselves from future infections of the same virus. Research also found that these same enzymes create shorter strands of RNA with special enzymes attached that essentially seek out viruses matching their "programmed" pattern. When encountered, the Cas enzyme variant (termed Cas9) on these abbreviated "CRSPR RNA" strands (called crRNA) interact with the virus and essentially chop it into pieces, rendering it harmless.
Interestingly, much of this progress was aided by research conducted by two scientists working to improve quality for a yogurt manufacturer. The manufacturer had detailed records on its bacteria cultures back to the 80s showing exact dates on which samples had been taken, allowing the scientists to trace how the cultures reflected changes in DNA in CRISPR areas that came from a common branch, thus confirming how flexible the underlying biochemistry was.
(You can see where this is going...)
Two additional keys to the puzzle are tracrRNA ("tracer") and cas9. The term tracrRNA was created to describe a different type of RNA strand called a trans-acting crRNA that creates the main crRNA compound and also helps attach the crRNA to matching viruses to allow the cas9 enzyme to chop up the virus. By 2011, the behavior of these components was well understood and researchers led by Doudna realized the process was driven by DNA patterns so simple to identify that the process could be arbitrarily rigged to target ANY arbitrary DNA target.
The final technical optimization devised by Doudna and others involved reviewing the structure of both the crRNA (containing the target encoding) and the tracrRNA (providing the binding mechanism to allow the Cas9 enzyme to chop up the attracted virus DNA) and combining them into a single RNA strand they termed the single-guided RNA or sgRNA. Doudna's team devised a way to create this single RNA component and the results were published in 2012.
As of 2012, the biochemistry of this capability was well understood and could be replicated at will on proteins in a lab. The next step was proving the technique would work on genes within the nucleus of human cells. The logistics of getting a modified RNA component into a CELL are not necessarily the same as getting it into a NUCLEUS within the cell. Competing teams in multiple labs across the US conducted additional experiments and confirmed the sgRNA approach would work within cells. By 2019, CRISPR based technology was being used in trials for gene therapy for sickle-cell anemia.
When COVID-19 hit, the technology was used first to devise testing capabilities that could produce results faster than older PCR (polymerase chain reaction) techniques first devised in the 1980s. By 2020, an additional Cas enzyme dubbed Cas12 had been identified that not only "attacked" matching DNA signatures of viruses but would chop up any other single strand DNA components nearby. Scientists realized that other "tracer" DNA compounds unrelated to the virus could be combined with the "programmed" sgRNA containing the "target encoding" and the "hatchet" mechanism. If the sgRNA found a target virus, it would not only destroy the target virus DNA in the sample but cut up the "tracer" DNA compounds. The team chose a DNA compound that would fluoresce if cut up, providing an easy visual signal of a positive match.
The net-net of all of this boiled down is this...
In the mid 1990s, scientists identified simple DNA based memory functions in bacteria that lack sophisticated immune systems that allow bacteria to update their own DNA to remember patterns of viruses and create compounds that can chemically seek out such virus patterns, attach to those viruses and shred their DNA. These "blank memory" areas in DNA were termed CRISPRs.
Biochemical research conducted between 2001 and 2008 solidified understanding of the core protein and enzyme chemistry that drove CRISPR behavior for virus detection and disarming.
Research between 2008 and 2012 confirmed the biochemical behavior could be used in human cells with equal targeting specificity.
Research between 2012 and 2019 confirmed the technology could be used to alter human genes, not just DNA of unwanted external viruses, and the technology was incorporated into initial therapies for multiple diseases.
COVID-19 broke out in December of 2019 in China. It was first detected in America by January 2020 and by mid-January 2020, leaders at both Moderna and BioNTech were contacted by officials watching the spreading of COVID-19 and both committed to using RNA based technology already under development to model the spike protein of the SARS-CoV-2 virus to trigger an immune response. In the case of Moderna, Isaacson states that Moderna had the RNA pattern identified and recreated within TWO DAYS after getting a sample of the SARS-Cov-2 virus. Within 38 days, they had test doses ready to ship for clinical testing.
After reading The Code Breaker, the impact of an outbreak like COVID prior to this technology being available is sobering to contemplate. In America, the number dying of COVID prior to vaccine availability has been eclipsed by the number dying SINCE vaccine availability. When those vaccines have been verified to have 99% efficacy at avoiding hospitalization and death from infection and 0.0022% death rates as vaccine side effects, the argument that people "don't trust the science" is simply appalling. And correctable.
WTH
