The book by Isaacson, The Code Breaker, is a difficult one to review[1]. The reason is that is appears to be four stories in one. The prime tale is the hagiography of Doudna. Namely Isaacson takes the reader along the life of Doudna, her development as a biologist, and her understanding of the Cas9 protein and the use of CRISPRs to edit genes. The second tale is that of Isaacson himself and his personal journey in the biotech world, the real world of fast movement developments and often ruthless competition. The third tale is that of the bit players who are often viewed as adversaries of his heroine but are essential to the telling of the tale. Finally the fourth tale is that of the science itself, namely CRISPRs. Since I have used some of these ideas in things I have been doing this review is not the typical one as one would find normally. I have personalized this and thus the reader should understand this personalization.
Frankly I find this a less than a balanced presentation and the battle between the four tales noted above in my opinion detract greatly from what should be told. Isaacson is neither a scientist nor a technically proficient individual, nor frankly does he seem to be aware of the often internecine wars in academia.
Now I am not a scientist, my education and training is limited to engineering and medicine. In both fields we take the results of science and use them over and over again to solve problems presented in many variants. I first heard of CRISPRs in a brief remark from Eric Lander if I recall in late 2012 while at MIT. It was almost an offhand remark that lingered for several months before I decided to see if this could be a new and useful tool. I read through Doudna's original paper and saw that there may be something there that could become a useful tool. Tools are the lifeblood of biotech. Tools such as those which are used to sequence DNA, to produce mRNA, to determine genetic pathways. The success of biotech is based on having a plethora of such tools to see inside cells and to grasp the dynamics of how cells function and interact. Thus the CRISPR to me was another tool, albeit a putatively powerful one.
I wrote a paper in 2013 recounting how CRISPRs could be used in cancer therapy. At that time, we had TVEC which was a viral vectored approach to mitigating the growth of melanomas and perhaps use of CRISPRs could be applied there as well. In early 2014 I was asked to speak to my grandchildren's fifth grade class on my work in botany. I genetically hybridize plants, the advantage of old age. In that talk, I described plants, how they can be hybridized and gave each student some seeds, planters and the like. Somehow, I then started to tell them about CRISPRs. I thought of the film The Graduate and the phrase "plastics" so to these ten year olds I whispered "CRISPRs". Perhaps some seeds may have taken root.
Tale 1: The Hagiography
It appears that Isaacson set out to write about Doudna. Possibly a parallel to Jobs and Apple but here he set the paradigm up as Doudna and CRISPR. Yet as will be seen Doudna is but one of many players in the CRISPR saga and unlike Jobs and Apple, the nexus is nowhere as tight. We see Doudna starting here interest reading Watson's book, The Double Helix, and then going on to a California undergraduate degree. She successfully goes on to Harvard for her doctorate and then through various post doc and university appointments until she ends up at UC Berkeley.
It is the fortuitous contact with Charpentier that leads her to study the CRISPR process. This means moving from the confines of biochemistry to understanding and analyzing the gene movements of RNA and the Cas9 protein. Isaacson details these steps with reasonable clarity identifying many of the background players and their contributions.
This eventually leads to the 2012 Science paper with Charpentier and others[2]. The abstract notes as follows:
Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems provide bacteria and archaea with adaptive immunity against viruses and plasmids by using CRISPR RNAs (crRNAs) to guide the silencing of invading nucleic acids. We show here that in a subset of these systems, the mature crRNA that is base-paired to trans-activating crRNA (tracrRNA) forms a two-RNA structure that directs the CRISPR-associated protein Cas9 to introduce double-stranded (ds) breaks in target DNA. At sites complementary to the crRNA-guide sequence, the Cas9 HNH nuclease domain cleaves the complementary strand, whereas the Cas9 RuvC-like domain cleaves the noncomplementary strand. The dual-tracrRNA:crRNA, when engineered as a single RNA chimera, also directs sequence-specific Cas9 dsDNA cleavage. Our study reveals a family of endonucleases that use dual-RNAs for site-specific DNA cleavage and highlights the potential to exploit the system for RNA-programmable genome editing
The paper details how CRISPR functions as well as asserting the presumptive last sentence. Namely they suggest the potential for gene editing in species other than prokaryotes. This seems to be the point at which the battle ensues. From this point on Isaacson takes the reader on the back and forth journey of Doudna, with and without her original partners.
Isaacson fails to details the public relations battle that Doudna seems to have orchestrated with such things as her book laying out her claims to primacy[3]. Then the patent battle with Zhang and the MIT patent attorneys. In my experience MIT has aggressive and assertive attorneys and the failure on Doudna's part was due to the UC Berkley attorneys as well as her apparent naivete. Again, we see Isaacson taking the Doudna side failing to fully grasp the intense battles well underway in the biotech field.
Also when Doudna is asked to joint a startup in Boston, she complains about having to fly coach to attend a meeting on the red eye. Having done this and even more, literally around the world in hours, I found that just whining. She then enters a meeting being totally unprepared and grossly unadvised and later withdraws. One would assume that coming from the Silicon Valley world of California that someone would have advised her that perhaps she was entering a lion's den with venture capitalists. Again, she is clearly a world class scientists but as so many are, a poor preparer outside of her ken.
Her erstwhile opponent is Zhang at MIT. There are many such as Zhang, as there are many such at Stanford and other centers of excellence. Zhang was just a faster mover and it was he that took the steps to mover Doudna's speculation into reality and in addition to move and file for patent primacy.Isaaacson's surprise that such competitiveness exists should not really be a surprise. It is this reflection that leads one to see that this is his story as much as it is Doudna's.
Tale 2: The Personal Journey
As noted above Isaacson takes us on this journey with Doudna and he becomes a co-participant on the way. Unlike the classic biographer who tries to separate themselves from their subject, Isaacson integrates himself with his subject, and in a sense become he biggest fan. He continues to tell us what "he" discovered, whether it is the competitiveness, the patent battles, the publishing warfare, and the start up intrigues. We get not only the facts but the personal assessments of the people and the processes.
Isaacson tells us of his meetings, lunches, etc detailing his personal but social contacts with the other parties. Yet it does appear that all countervailing interactions are presaged by Doudna interpretations.
Tale 3: The "Bit" Players
The "bit" players are very consequential. There are three of whom I am familiar. Eric Lander, now the Presidential Science Advisor, James Watson, Nobel Prize winner for his work with Francis Crick delineating the structure and function of DNA and Feng Zhang. Isaacson plays all three against his heroine in Doudna. Lander is a brilliant scientist and leader of the Broad Institute. He also is a fantastic teacher and motivator of many people. He is also from Brooklyn, and thus as with myself has that New York edge. Namely they do not tolerate fools very well, and I do not mean somewhat not considered intelligent to a great degree, but those who have a tendency to make rash assumptions and assertions. Now Watson is interesting.
My last encounter was sending some of my doctoral and pot docs to a lecture he gave at MIT. I told them to be careful since Watson can be cutting and can hold little for engineers. Upon their return they were aghast since Watson asserted to the assembled that engineers and physicians can never be scientists, and that clearly scientists were at the top of the intellectual ladder. My reply was simply that I had told them so but still Watson is always worth listening to even if he may from time to time assert something one may strongly disagree with. Finally there is Zhang, the young, smart, aggressive, academic who saw CRISPR and immediately envisioned the next fifty steps and then took them. Zhang out ran Doudna in many ways. Zhang has that classic MIT edge of competitiveness and was able both personally and with the support of Lander race along and in many ways out run Doudna.
Lander wrote what was in his opinion in 2016 a history of the CRISPR development[4]. That document, a bit surprising in view of the litigation underway at the time, is his view based upon the evidence he presents of the development of CRISPR. In a sense it is akin to an Expert Report in a contentious litigation. It would have been nice to see a rebuttal if one could be crafted and if it would have been materially different. Perhaps this book is just such a rebuttal, but aimed not at the professional community but at the public. I read Lander's paper when it was issued and it is compelling and comprehensive. It is typical Lander, namely well crafted and presenting a well-documented basis for each of his assertions.
As for Watson, he is a sine qua non. He is unique. I read his book, The Double Helix, when it came out, and checked, I even have a first edition hard cover with cover jacket! I tend to re-read it every decade or so. His thought process, along with Crick, is well presented and the competitiveness well documented. Thus, if you have read this, I dare say you get a clear glimpse into Watson. He can be irascible yet brilliant, opinionated yet sees the next steps with great clarity. His statements on racial differences is what got him into trouble. Somewhat like Shockley and his walk down that path as well, was clearly inappropriate yet in many ways it or something like it could be expected given Watson's predilection to speak his mind freely, often without sensing the consequences of his opinions. Yet Watson has done such a great deal, as evidenced by his tenure at Cold Spring Harbor Labs, that for a man his age perhaps some slack could be afforded. However in today's rather heated environment one must be especially cautious of any and all statements. Isaacson does attempt from time to time to treat Watson with due respect. Isaacson walks the fine line of rejecting Watson's statements on race while honoring his work on DNA and its expansion. It would have been useful, if not here but elsewhere to explore the Watson mindset, how he reached his conclusions, and if perhaps it is just the mumblings of old age.
Now for Zhang, it is clear that Isaacson has many backhand compliments. Rather than trying to understand Zhang he presents a person driven by scientific competitiveness lacking in the interpersonal skills Isaacson sees in his heroine. Perhaps it is cultural, perhaps it is the MIT environment. Based upon my personal experience I suspect the latter. Yet in my opinion Isaacson tells but half the story due to his continuing support of Doudna.
Tale 4: The "Science"
Here is where I can fault Isaacson. He is not scientifically astute. Telling the CRISPR tale presumes a somewhat sophisticated understanding of biology and biological systems. Yet Isaacson does not in any way explain what a CRISPR/Cas9 system was, how it functions and more importantly how it can be applied to human gene modifications.
In a simplistic sense one can state:
1. Bacteria are Prokaryotes and are cells without a nucleus. That is an important fact since in eukaryotes, such as humans, we have nuclei and a great many functions are carried on in that compartment. Bacteria, not having such a compartment, carry on all their activity in the body of the cell without compartmentalization.
2. Virus are organisms of a sort that need other organisms to reproduce. They are either of a DNA or an RNA type and thus rely upon a host organism to take that DNA and RNA and use the host proteins to replicate itself over and over until it kills the host organism. Corona viruses in COVID are an example of an RNA virus that attacks human cells. The virus enters a cell and unleashes its RNA or DNA and seeks polymerases to start reproducing.
3. BUT, and this is the important issue, many bacteria have developed an immune like system to attack this virus. The attack mechanism consists of two elements. First is a protein called Cas9. Second is a nucleotide sequence called CRISPR. This is a sequence of nucleotides, in a special format called a palindrome. A palindrome looks the same going from left to right or right to left. Thus the CRISPR may look like, AATTCGCGGCGCTTAA. This CRISPR looks at all strings of DNA and RNA from non-self and it attaches its complement, (A to T (or U) and G to C) along with the Cas9 protein. Once both are attached then Cas9 cuts the DNA/RNA at a precise spot thus destroying the virus' ability to reproduce.
4. The above was what Doudna and Charpentier had observed. The first observation was simply the gene destroying mechanism in a bacteria.
5. Now the fun begins. If one can create a CRISPR for a specific target gene sequence, which one can, then can one insert this in a nucleated cell, not just a prokaryote, and cut a gene out? Can one then replace that gene with a new one? The answer to these questions are all yes, and thus CRISPRs become a household word.
Yet there are problems. The site for the cutting may not be unique and thus one may remove the wrong gene. The list can go on. There still is a great deal of work to be done. Science is often "on the one hand, and on the other hand".
The following are some comments by page.
On p xiii and p 411, Isaacson displays his political dislike for the former President. It is not that one generally does not know this already but such comments do not age well and generally are ill placed unless one wants to ensure the reader knows what side he is on. Clearly the CDC demonstrated in my opinion the gross incompetence of Government entities, independent of Administrations. The "test kits" were procedure in gene targeting performed in the third year undergraduate program at any reputable university. The CDC however managed to stumble badly from the start. In fact as of January 28, 2020 in both The Lancet and NEJM we knew the extent of the problem and even the 30,000 long bases in the ss RNA of the virus. By February 4, 2020 I had written that a pandemic was on the way. It took six more weeks before the authorities responsible, not the President, made that recognition. Thus we has a systemic failure of the Federal employees responsible.
On p 72 he recounts a researcher looking for data and having no Google. In fact there was Dialog and Chem Abstracts, both on line and around for two decades by then! Any competent professional would have had access. In fact, my wife was in the 1980s a trainer for Dialog going from site to site enabling on line real time searching as is done today with Google or Semantic Scholar. It helps to understand the facts at the time assertions are made.
On p 133 there appears to be the only presentation of CRISPs and their functions. This is grossly inadequate and in fact lacks adequate detail to provide even the least competent with an understanding of the process. Given that CRISPRs is at the heart of this story it really would have been worth the while to have a detailed understanding and discussion, even in an appendix.
On p 223 Isaacson details the Lander Cell paper and is highly critical of his exposition of the history. The key fact here is who showed it working in humans first, Zhang or Doudna. For Lander it was Zhang.
On p 239 Isaacson again espouses his political views but this time on the Supreme Court. Namely regarding a Doudna attorney who allegedly was better than the initial one. This is an example of the ongoing insertions of the author and his journey along with his heroine.
On p 270 we have a discussion concerning the ethical issues regarding the use of human embryo gene editing. The ultimate player here is David Baltimore who played a role in the 1970s when recombinant DNA was rolling out. Ironically, Baltimore had been awarded the Nobel for his work on reverse transcription, essential for understanding HIV and more importantly for testing for corona viruses. But it was the same Baltimore who was viciously and mendaciously attacked by the Congressman from Michigan, almost destroying his career.
On p 4040 the author remarks about the ACE2 receptor. He offhandedly states it has other functions. Indeed, it does, it balances the effects of ACE, and thus its blocking can result in massive hypertension and strokes. This is a small example of how knowing a little and telling it reveals a great deal.
On p. 435 Isaacson recounts his time getting a trial vaccination. He makes the statement that the alleged physician did not want him to see the contents since it was a "double blind" trial. That frankly makes no sense since double blind means neither patient nor physician knows. Thus the vaccine and placebo would appear the same to both patient and physician. Whether that was Isaacson's interpretation or a fact is left to the reader to judge.
Overall I find this book lacking. The author's style is akin to Time magazine and his continual personal interjection makes it a personal account and not a biography. Second, the hagiography is just that, an unbalanced presentation of what occurred. In a sese this may be the rebuttal to Lander's Cell article. If so, it appears that Isaacson's argument is that Doudna is good and Zhang, Lander, and Watson are bad. Unfortunately, I could not disagree more.
[1] https://www.amazon.com/gp/product/1982115858/ref=ppx_yo_dt_b_asin_title_o04_s00?ie=UTF8&psc=1
[2] Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J.A., and Charpentier, E. (2012). A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816–821.
[3] Comfort, That’s the way the CRISPR crumbles, 30, Nature, Vol 546, 1 June 2017
[4]
Lander, The Heroes of CRISPR, Cell, 164, January 14, 2016, p. 18-28
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