The Code Breaker by Walter Isaacson

I’ve listened to a handful of Walter Isaacson’s podcasts but this is the first of his many incredible books that I’ve been able to sit down and read. He’s truly a magician as a writer, telling the story of the discovery of CRISPR, a gene-editing tool based on a virus fighting trick used by bacteria, which have been battling viruses for more than a billion years. The main subject of the book is Jennifer Doudna, a renowned biologist who was the principal discoverer of CRISPR in 2012, although she had been researching RNA — the molecule that actually does the work in a cell by copying some of the instructions coded by the DNA and using them to build proteins — for many years prior. It’s really a wonderful story of patience, perseverance, discovery, competition, curiosity, and the wonders of science and nature, but Isaacson is careful to point out and analyze the implications and potential perils of this magnificent discovery as well. We now have the ability to clone animals, change the genetic makeup of a new baby, eliminate diseases such as Sickle Cell Anemia and Tay-Sachs, and do many other wondrous things, but the question remains: when and how should we interfere with thousands of years of human evolution? It’s a bit of a rhetorical, unanswerable question in 2021, but sooner rather than later it will be a reality, as this technology becomes readily available to the general public and anyone who is willing to shell out a few hundred bucks on Amazon. But what if CRISPR can get rid of COVID-19 and spare us months and months of more misery? I think I’d be ok with that, and CRISPR could be used in the future to see to it that something like COVID never happens again. Only time will tell, but the impending questions surrounding this astonishing breakthrough might indeed guide us into a wonderful unknown.

• Jennifer Doudna and CRISPR: a gene-editing tool that she and others developed in 2012, based on a virus fighting trick used by bacteria, which have been battling viruses for more than a billion years
• in their DNA, bacteria develop clustered repeated sequences, known as CRISPRs, that can remember and then destroy viruses that attack them
• an immune system that can adapt itself to fight each new wave of viruses
• CRISPR could be used to engineer inheritable edits in humans that would make our children, and all of our descendants, less vulnerable to virus and infections
• could permanently alter the human race
• figuring out if and when to edit our genes will be one of the most consequential questions of the 21st century
• Einstein was driven by physics, later in the century we were driven by bits, now we have entered the life-science revolution
• RNA = molecule that actually does the work in a cell by copying some of the instructions coded by the DNA and using them to build proteins
• by 2020, CRISPR was being explored to detect and destroy the coronavirus
• the key to innovation is connecting a curiosity about basic sciences to the practical work of devising tools that can be applied to our lives
• importance of basic science — quests that are curiosity driven as opposed to application oriented
• the key to true curiosity is pausing to ponder the causes
• The Double Helix by Watson (DNA founder): shape and structure of a chemical molecule determine what biological role it can play
• gene: entity inside of living organisms that carries the code of heredity (Mendel)
• nucleic acids are the workhorses of heredity
• from an evolutionary perspective, both the simplest coronaviruses and the most complex human are essentially protein wrapped packages that contain and seek to replicate the genetic material encoded by their nucleic acids
• phages = bacteria eaters
• Watson and Crick appropriated Rosalind Franklin’s findings — she was never properly recognized for her impact
• they found a copying mechanism for genetic material (suggested)
• discovered how instructions for building every cell in every from of life were encoded by the four letter sequences of DNA
• life was made up of molecules, the chemical components and structure of these molecules governed what they would do
• the men who sequenced DNA taught us how to read the code of life, but the more important step would be learning how to write that code
• DNA’s primary activity is protecting the information it encodes and occasionally replicating itself; RNA, on the other hand actually goes out and does the real work
• it makes real products, such as proteins
• enzymes serve as catalysts — spark and accelerate and modulate the chemical reactions in all living things
• RNA’s costars and dancing partners in the book
• moving from DNA to RNA to the building of proteins is the central dogma of biology
• RNA could be enzymes; RNA molecules can split themselves by sparking a chemical reaction
• how did life begin? simplest answer may be that the early earth contained the chemical building blocks of RNA (hypothesis)
• Doudna and her team eventually explained how RNA could be an enzyme and was able to slice, splice, and replicate itself
• implication was that they might be able to cure or treat people with genetic defects
• RNA interference: small proteins find a way to mess with messenger RNAs
• hope for drugs based on this might someday be a good option for treating severe viral infections, including from new coronaviruses
• CRISPR = clustered regularly interspaced short palindromic repeats
• Mojica — discovered that bacteria have an immune system and they’re able to remember what viruses have attacked them in the past
• almost from the beginning of life on the planet, there has been an arms race between bacteria, which developed elaborate methods of defending against viruses, and ever evolving viruses, which sought ways to thwart those defenses
• Monica found that bacteria with CRISPR sequences were immune from infection by a virus that had the same sequence
• could adapt to new threats
• acquired immunity to that new virus
• CRISPR was an immune system that bacteria adapted whenever they got attacked by a new type of virus
• cut and paste new memories of viruses that attack the bacteria
• Cas enzymes (CRISPR associated) create short segments of RNA, CRISPR RNA, that can guide a scissors like enzyme to a dangerous virus and cut up its genetic material
• Vannevar Bush — argued that basic curiosity driven science is the seed corn that eventually leads to new tech and innovations
• basic research is the pacemaker of technological progress
• National Science Foundation
• started a dance among basic scientists, practical inventors, and business leaders
• when you add sequences from the virus into the CRISPR locus, the bacteria develops immunity to that virus
• CRISPR system targeted the DNA of the invading virus — could be turned into a gene editing tool
• Genentech, genetic engineering technology, began making genetically engineered drugs such as insulin to treat diabetes in 1978
• Doudna was very pushy to get articles submitted and published — papers by women are cited less frequently and they are much more reluctant to espouse the value of their own work, use positive and self promotional words
• launch of Genentech shifted the focus of commercialization from chemistry to biotech
• researchers were encouraged to patent their discoveries, partner with venture capitalists, and create businesses — Doudna started her first company in 2011
• Bush argued that america’s innovation engine would require a three way partnership of government, business, and academia
• recommended that the government should fund research at universities and corporate labs
• this government to university partnership propelled the economy in the postwar period, lead to transistors, microchips, computers, graphical user interfaces, GPS, lasers, internet, search engines
• philanthropic foundations were also added to the mix
• in person meetings can produce ideas in ways that conference calls and zoom meetings can’t
• Cas9 was discovered by Doudna and her team — can be programmed to find viruses and cut them up — programmable, could become an editing tool
• over billions of years, bacteria evolved a weird and astonishing way to protect themselves against viruses, and it was adaptable, because every time a new virus emerged, it learned how to recognize it and beat it back
• HOW CRISPR WORKS:
• a Cas9 protein, which can act like a scissors, hooks up with a piece of RNA, which guides it to the targeted DNA sequence
• Cas9 then cuts both strands of the DNA in the targeted spot, potentially chopping out a gene
• a new piece of DNA, programmed to contain a preferred gene, can be inserted where the cut was made
• a means to rewrite the code of life
• by studying a phenomenon that evolution had taken a billion or so years to perfect in bacteria, they turned nature’s miracle into a tool for humans
• first time researchers had isolated the essential components of the system and discovered their biochemical mechanisms
• gene therapy involved delivering into the patients cells some DNA that had been engineered to counteract the faulty gene that caused the disease
• invention of gene editing required that researchers had to find the right enzyme that could cut a double strand break in DNA; then they had to find a guide that would navigate the enzyme the precise target in the cell’s DNA where they wanted to make the cut
• competition drives discovery, gets a bad rap
• Zhang, Church and Doudna were in a race to get their papers published in 2012; Doudna and her partner, Charpentier, published in June of that year showing the essential three components of the CRISPR Cas9 system
• Church and Zhang ended in a virtual tie in showing how CRISPR Cas9 could be engineered for use in human cells
• results established RNA as a guided editing tool
• invention of microchip and application of CRISPR to editing human cells were accomplished by many groups around the same time
• programmed DNA molecule to target specific genes and change them was, for humanity, a momentous step into a new age
• we recall vividly our own contributions to the discussion; we’re a bit hazier when recalling the contributions of others, or we tend to minimize their significance
• Eric Lander: “Scientific breakthroughs are rarely eureka moments. They are typically ensemble acts, played out over a decade or more, in which the cast becomes part of something greater than what any one of them could do alone.”
• 1980 = Bayh Dole Act: made it easier for universities to benefit from patents, even if the research was funded by the government
• problem with patents is that they prod people to be less generous in sharing credits
• Doudna and her colleagues had identified the essential components of CRISPR Cas9 and engineered a technique to make it work using components from bacterial cells; their contention was that it was then “obvious” how it would work in a human cell
• Zhang and the Broad Institute (Lander) countered that it was not obvious that the system would work in humans
• they started in competition and still are today — went to court for years
• they could have shared the patent rights like Texas Instrument and Intel who agreed to share over the microchip by cross licensing their intellectual property to each other and splitting the royalties, which helped the microchip business grow exponentially and define a new age of tech
• business maxim: don’t fight over divvying up the proceeds until you finish robbing the stagecoach
• uses of CRISPR today that are common and welcome are used to edit some, but not all, of the body (somatic) cells of a patient and make changes that will not be inherited
• can be done by taking the cells out of the patient, editing them, and returning them (ex vivo) or by delivering the CRISPR editing tool into cells inside of the patient (in vivo)
• sickle cell anemia is a good candidate
• oxygen does not get to tissues and organs, causing severe pain and, in most cases, death by age 50
• Gates and NIH funded 200M for the Cure Sickle Cell Initiative
• most patients in the world are African or African-Americans
• fight against cystic fibrosis, which affects primarily white Americans and Europeans, has received eight times more funding from government, charities, and foundations
• CRISPR can also fight cancer — using CRISPR to edit the gene, patient’s T-cells become more effective in killing cancer cells
• used as a detection tool to identify precisely what type of cancer a patient has
• congenital blindness, pandemics, cancers, Alzheimer’s, other diseases
• tech is on the verge of becoming easy enough that it will not be confined to well regulated labs
• contact tracing and data collection could be crowdsourced
• military is the largest single source of money for CRISPR research
• Anti-CRISPR’s also discovered — could be engineered to regulate gene-editing systems; or as a defense against systems created by terrorists or malevolent enemies
• lots of moral questions — heritable human genome editing might in the future provide a reproductive option for couples who have genetic diseases
• in the wake of COVID, the idea of editing our genes to make us immune to virus attacks began to seem a bit less appalling and a bit more appealing
• for the first time in the evolution of life on this planet, a species has developed the capacity to edit its own genetic makeup
• germline edits could make a fix in all of the cells of the body; thus it holds a lot more promise, and a lot more peril
• preimplantation genetic diagnoses — couples can, if they are able, produce multiple fertilized eggs and have them tested in a lab dis, before they get implanted, for genetic characteristics
• germline involves engineering a genome rather than nurturing one that was produced naturally, and it introduces a change that will be inherited by all future descendants
• which cases, if any, should cause us to cross this germline?
• treatment vs. enhancement — big issue
• Miles Davis had sickle cell — drove him to drugs and drink
• would Miles Davis had been Miles Davis without sickle cell?
• FDR had polio, was forged by it, transformed his character
• using gene editing to prevent disabilities may make society less diverse and creative
• how do we distinguish between traits that are true disabilities and ones that are disabilities mainly because society is not good at adapting for them?
• almost every champion runner has what is known as the R allele of the ACTN3 gene
• produces a protein that builds fast twitch muscle fibers, and it is also associated with improving strength and recovery from muscle injury
• absolute improvement vs. a positional improvement? beneficial to you even if everyone gets them (absolute)
• height is a positional good, while enhanced resistance to viruses is an absolute good
• favoring enhancements that would benefit all of society over those that would give the recipient a positional advantage
• new eugenics — liberal of libertarian eugenics, one based on free choice and marketed consumerism
• diversity is good not only for society but for our species
• like any species, our evolution and resilience are strengthened a bit by randomness in the gene pool
• editing could exacerbate inequality and even permanently encode it in our species
• evolutions primary guide is reproductive fitness — what traits might cause an organism to reproduce more — which means it permits, and perhaps even encourages, all sorts of plagues, including coronaviruses and cancers, that afflict an organism once it’s childbearing use is over
• exercising mastery over nature rather than accepting the unbidden as a gift
• eschewing attempt at complete mastery over the unbidden
• all medical advances attempt to correct something that happened “naturally”, Doudna eventually realized
• “I’m an American, and putting a high priority on personal freedom and choice is part of our culture”
• any IQ differences between black and white arise primarily from environment, not genetic, differences
• fast forward to COVID
• viruses are just a tiny bit of genetic material, either DNA or RNA, inside a protein shell
• when they worm their way into a cell of an organism, they can hijack its machinery in order to replicate themselves
• by Feb. 2020, there were dozens of hospitals and academic labs, including at Stanford (Doudna) and Broad of MIT and Harvard, that had developed testing capabilities, but none had managed to win FDA authorization
• with the failure of the Trump admin to carry out widespread testing, university research labs began taking on a role that has normally been performed by the government
• using CRISPR as a diagnostic tool seemed to be a worthy endeavor
• as opposed to PCR tests, these could deploy RNA-guided enzymes that had been programmed to detect the genetic material of the virus — adapt CRISPR systems that bacterial had been deploying for millions of years
• Doudna and Zhang became more willing to share their work during COVID
• CRISPR based tests developed by them were faster and cheaper than conventional PCR tests
• home testing kits could become the platform, the operating system, and form factor that will allow us to weave the wonders of molecular biology more into our daily lives
• Pfizer/BioNTech vaccine: instead of delivering deactivated components of the targeted virus, like traditional vaccines do, it injects in humans a snippet of RNA
• vaccines work by stimulating a person’s immune system
• a substance that resembles a dangerous virus (or any other pathogen) is delivered into a persons bed
• kick the persons immune system into gear
• when it works, the body produces antibodies that will fend off infection
• new vaccines deliver a gene or piece of genetic coding that will guide human cells to produce, on their own, components of the virus
• the goal is for these components to stimulate the patients immune system
• COVID vaccine: mRNA instructs cells to make part of the spike protein that is on the surface of a coronavirus
• RNA does its work in the outer region of the cells
• RNA vaccine simply needs to deliver its payload into this outer region
• BioNTech — vaccine based on RNA sequences that would cause human cells to make versions of the coronavirus’s spike protein
• took Moderna only two days to create the desired RNA sequences that would produce the spike protein, and 38 days later it shipped the first box of vials to the NIH to begin early stage trials
• did not have to be stored at extremely low temps
• more citizen involvement in science is a good thing
• lightening fast triumph of human ingenuity, based on decades of curiosity driven research into one of the most fundamental aspects of life on earth: how genes encoded by DNA are transcribed into snippets of RNA that tell cells what proteins to assemble
• long range solution to our fight against viruses is the same as the one bacteria found: using CRISPR to guide a scissors like enzyme to chop up the genetic material of a virus, without having to enlist the patient’s immune system
• next steps are microfluidics: channeling tiny amounts of liquid in a device, and then connecting the information to our cell phones
• test our saliva and blood for hundreds of medical indicators, monitor our health conditions on our phones, and share the data with doctors and researchers
• if COVID doesn’t kill us, Zoom will — ideas are born out of serendipitous encounters
• important in brainstorming ideas and forging of personal bonds
• urgency of COVID sped up the process of building on each new finding and allowed the public to follow the advance of science as it happened
• most of us will someday have detection devices in our home that will allow us to check for viruses and many other conditions
• instead of being ivory towers, universities will be engaged in tackling real-world problems, from pandemics to climate change
• project oriented collaborations among disparate labs
• collaboration across generations
• are we right to think we can now come along and edit that genome to eliminate what we see as imperfections?