The book by Isaacson, The Code Breaker, is a
difficult one to review.
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.
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.
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. 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.
Lander, The Heroes of CRISPR, Cell, 164, January 14, 2016, p. 18-28
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