Modern Prometheus Editing the Human Genome with Crispr

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MODERN PRO M ETH EUS
Editing the Human Genome with
Crispr-Cas9
Revised and updated edition
Jim Kozubek
 University Printing House, Cambridge CB2 8BS, United Kingdom

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learning and research at the highest international levels of excellence.

www.cambridge.org

Information on this title: www.cambridge.org/9781108454629

DOI: 10.1017/9781108597104

© Jim Kozubek 2016, 2018

This publication is in copyright. Subject to statutory exception and to the provisions of relevant
collective licensing agreements, no reproduction of any part may take place without the written
permission of Cambridge University Press.

First published 2016

Revised paperback edition published 2018

Printed in the United States of America by Sheridan Books, Inc.

A catalogue record for this publication is available from the British Library

ISBN 978-1-107-17216-6 Hardback

ISBN 978-1-108-45462-9 Revised paperback edition

Cambridge University Press has no responsibility for the persistence or accuracy of URLs for
external or third-party internet websites referred to in this publication, and does not guarantee
that any content on such websites is, or will remain, accurate or appropriate.

Sections of this book previously appeared in STAT, The Atlantic, The Boston Globe, Scientific
American, TIME and Nautilus.

Between 14 October 2013 and 6 May 2016, Jim Kozubek worked as a staff scientist at the
Brigham and Women’s Hospital which is affiliated to the Broad Institute of MIT and Harvard.
Although the Broad Institute is in Crispr genome editing research, development, and sharing,
this book was developed independently of the author’s Broad affiliation.
 Contents
Preface
Acknowledgements

1. Crispr, Cas and Capitalists

2. The Gene Trade

3. Asilomar

4. We Can Play God in that Cell

5. Modern Prometheus

6. Biopolitics

7. Life in a Bubble

8. To Summon a Leviathan

9. A Molecular Fairytale

10. Secrets from a Freshwater Fish

11. Gene Hackers

12. Washington

Notes
Bibliography
Index
 Preface
This is a book about Crispr. It is animated by many forces. I grew up
reading science books that could be described as instructive or didactic, but
I saw the trade begin to gradually drift into a pop science which worsened
an already existing problem that much of scientific explanation is based on
partial truths or weak causal links. To break from this trend, I set out to
write in a different style, which is the tragic vein of literature. To this end,
the book puts an emphasis on scientists as fallible agents, and is injurious
throughout, while taking few moral positions. It is not designed to attack or
damage anyone per se, but to describe a more realistic, harder and more
complicated situation which we endure.
Technology is accelerating. We have begun inserting ourselves into
evolution, using the Crispr system to modify the genetic code of plants, sea
creatures and livestock to reduce infection and promote the yields of crops.
Crispr has been used to fix recessive conditions such as kidney disease in
inbred Dalmatians, create super-strong beagles, cows without horns,
miniature pet pigs, and it has been used to disable immune-alerting genes in
pigs so that their organs can be used for human transplant. It is being used
to alter the genes of mice to stop Lyme disease in the transmission cycle
and to modify mosquitoes to stop the spread of Zika virus. Crispr is also
being used in ways that are dubious. It has been used to disrupt genes in
butterflies to affect color patterns in their wings, and as scientists suggest, it
will soon be used to create customized butterflies with pretty new wing
colors. Crispr is sold on the internet in kits, and is actively being used to do
fiddling things, such as to create fluorescent beer. Its ubiquity and ease of
use has also raised concerns about “biohackers,” who view gene
modification as a right and alter microbes and organisms. But bio-terrorists
might use it to turn common microbes into a pathogenic weapon. The US
military started a program called Safe Genes to gene modify organisms to
be used in battle and anti-Crispr tools to disable bio-weapons. “Mail-Order
Crispr Kits Allow Absolutely Anyone to Hack DNA,” declared the headline
of a November 2017 article in Scientific American. The iconoclast scientist
Josiah Zayner has used Crispr to hack into his own genes.
Most controversially, Crispr is being used to modify human genes as a
logical extension of what is called gene therapy, a decades-old strategy to
slip a supplementary copy of a gene into a human cell by packaging it into a
virus. Viruses can be engineered to work as tiny crafts to pilot bits of
restorative gene code into our cells. Some of these viruses, such as adeno-
associated virus, slip into our cells but don’t integrate into a chromosome as
a permanent fixture, while other viruses, such as gammaretrovirus and
lentivirus, do install in a chromosome. In many ways, modern gene therapy
is coming of age, effectively being used to modify the genes in the cells of
living humans to treat eye diseases, which can cause blindness, such as
Leber congenital amaurosis; promote the growth of healthy skin to treat the
rare skin-blistering disease epidermolysis bullosa; or add supplementary
copies of working genes that fix rare blood or immune system disorders,
such as Severe Combined Immunodeficiency Disorder.
 In the process of using viruses to randomly insert new genes into our
cells or chromosomes, those same viruses can randomly disrupt the function
of existing genes in the process. Gene modification tools such as Crispr
enable researchers to package a pair of GPS-guided molecular scissors into
a virus so that the craft travels to, and makes a break at, a specific genetic
address in a sea of six billion nucleotide bases that assemble into our 23
pairs of chromosomes. In theory, this makes gene therapy far safer and also
allows us to alter our existing genes. The first applications of Crispr in
humans will be used to alter somatic cells, adult cells in our bodies with
genetic code that is not passed to our children, cells in our existing organs,
or blood, or immune cells. By contrast, if we use the technology to alter
sperm, eggs, or embryos, it will change the heritable, or germline, code that
gets passed forth in future generations, ushering us into a futuristic age of
“transhumanism.”
In humans, Crispr will be most applicable for so-called Mendelian
disorders, meaning those that are caused by variations in a single gene; or
by altering our immune system cells to improve their ability to seek and
destroy cancer. In truth, it’s unlikely we will be using genetics to predict
intelligence, eliminate mental illness, or engineer “superhumans,” which
are far better than us. In fact, thousands of genetic variations can influence
complex traits, psychiatric risk, personality traits, and capacities such as
human intelligence. Genes interact in complex relationships which we call
epistatic. In fact, each of the variants in our genes can have enhancing or
diminishing effects on other genes depending on the context in which they
are inherited. These relationships are often indecipherable: the
combinatorial interactions of a three billion nucleotide human genome are
staggering. The relationships are also kaleidoscopic, meaning the context of
genes and environment are ever-shifting. As the plant ecologist Frank Egler
once quipped, “ecosystems are not just more complex than we think,
they’re more complex than we can think.”
Consider that computational scientists who want to understand how
genes interact in systems to create the most optimal networks come up
against some hard limitations as suggested by the “traveling salesperson
problem.” The problem is to find the most optimal way to wire a network
given some input. In the words of theoretical biologist Stuart Kauffman:
“The task is to begin at one of N cities, travel in turn to each city, and return
to the initial city by the shortest route available. This problem, so
remarkably simple to state, is extremely difficult.” Evolution figures it out,
locking in some models of what works early on, and hammering out
incrementally optimal solutions over millennia. But the best that computer
junkies can do to draw up an optimal biological network is to create
heuristics, which are shorthand solutions. Even if technologists had the
computer power to design biology from the ground up, it’s unlikely they
could re-engineer man into far superior forms.
In “The Origins of Order,” Kauffman introduced the concept of
“complexity catastrophe,” a situation in complex organisms where genetic
mutations are optimized to interact so tightly together that the role of
natural selection becomes diminished in selecting molecular traits which
produce organisms which can claim a step-up in fitness. In short, it has
tinkered and fashioned its way into a shape that it cannot easily hammer on
even further to improve. If so, most of what we think is our superiority may
just be another subtle variation on complex systems such as intelligence and
language which may be close to optimal.1 The greatest obstacle to
evolutionary progress may be our complexity.
 And, by deduction, statistics often fail because they can’t capture the
nuance of a situation. In the biological sciences, the contribution of any
single genetic variant to its associated effect is context-dependent, while
each of us has a unique genome and lives in a variable environment. In
social terms, data-science may function as a salve for social problems and
the struggles of existence as decisions are increasingly thought to be “in the
data” and evaluated by metrics and their consequences. Many scientists
aspire to the biotech startup culture as a means to strike it rich, although
biotech objectives are not the same as public health objectives. Mounting
scientific evidence shows that chronic stress and poverty contribute to
alterations in brain circuitry and blood pressure, dramatically influencing
health and mortality.2 Nevertheless, gene modification is having immediate
value to treating genetic disorders that are traced to single genes, and it is
being used to alter our own immune cells to seek and destroy cancers. But
technologies, which alter or enhance our genomes, have the potential to
engender qualities of “otherness,” initiate new forms of techno-scientific
racism, and could introduce new inequalities if not everyone can afford the
same access to expensive gene-modification tricks that provide health
advantages or the next generation of cancer drugs.
Biology does not work as simple computer circuits, but the
Frankensteinian idea that we can control fate through reductionist
mechanics is an idea that is very much alive. In 1747, French enlightenment
thinker Julien Offray de La Mettrie published “L’homme Machine,” or
“Man, a Machine.” The philosopher Karl Popper noted later that the
“theory of evolution gave the problem an even sharper edge.” Meanwhile,
adherents to the view of biology as mere clockwork grew. The “doctrine
that man is a machine has perhaps more defenders than before among
physicists, biologists and philosophers,” Popper observed, “especially in
the form of the thesis that man is a computer.” Today, the analogies of man
and machine are constant, thanks in part to computational biology and
Silicon Valley which seek to solve or cure human problems by fixing the
“bugs” at the genetic level. A panel at the Vanity Fair New Establishment
Summit was titled “Hacking Cancer,” and after philanthropist Ted Stanley
gave $650 million to the Broad Institute to investigate the underpinnings of
neuropsychiatric disorders, Broad director Eric Lander’s team created
“Opening Schizophrenia’s Black Box,” a video that suggests we are on our
way to “hacking” into the genetics of mental diseases. Lander has referred
to “a revolution in psychiatric disease,” and NIH chief Francis Collins said
psychiatric genomics stands “poised for rapid advances.” Whether I agree
with them (I don’t) should be separated from the ambition to “industrialize
the human genome” – and start a conversion on how the alteration of our
biology can exemplify hubris.
Take any given genetic variant. None has more than a fraction of a
single percentage point of an effect on the risk for a psychiatric disorder or
condition. None may be purely deleterious or advantageous, but may have
pleiotropic effects, meaning enhancing or attenuating effects on other
genetic variants which it is inherited along with. Genetic variants may be
deleterious in some cell types, such as neurons, but advantageous in other
cell types, such as immune cells. Biological features can discover new
meanings and uses in different contexts. In more general terms, not every
social problem in life is a science problem or is solvable with an
engineering solution, but a situation of local adaptation. Certainly, gene
modification will not solve our psychiatric problems; focusing our financial
resources on identifying a “neuro-signature” depletes resources for social
services, social and economic mobility and psychotherapy.3 Wealth
inequality contributes to the chronic stress that we all live with, and that
stress imprints itself in the epigenetic code of our genes (dampening the
expression of genes key to learning and development such as GRIN1,
NR3C1, BDNF).
In fact, genetic variants that contribute to psychiatric risk with small
effect sizes may even provide evolutionary advantages when inherited in
the right genetic background, or at certain developmental stages, or in
specific environmental niches. In the 19th century, French physiologist
Claude Bernard and Belgian scientist Adolphe Quetelet applied statistics to
establish “norms” in the population that could be used in theory to present
any metric, height, body mass index, weight, blood pressure, into
bellcurves. In 1943, French philosopher Georges Canguilhem challenged
the status quo of normalcy, noting it failed to capture what evolutionary
biology says about human nature. For Canguilhem, no matter how deviant
or rare a genetic variant or trait is, it could still be considered “normal” if it
contributes to survival in a given niche. A reason that scientists will not
eliminate conditions such as psychiatric disorders or conditions such as
autism is that some of the risk for these disorders almost certainly comes in
trade for small competitive advantages, such as heightened sensitivity,
concentration, or openness to experience.
“In ‘Enormous Success’ Scientists Tie 52 Genes to Human
Intelligence,” screamed a headline from The New York Times in May 2017,
which went on to say that no single genetic variant contributed more than a
tiny fraction of a single percentage point to intelligence. Danielle Posthuma,
a senior author of the study, noted “It means there is a long way to go.”
(But to what ends? So that we can use these small effect-size variants to
better subdivide our children into tracks earlier in school, or to bring us one
small step closer to the thinking of Oxford ethicist Julian Savulescu, who
has argued that if we have a drug to cognitively enhance ourselves, we may
have a moral obligation to buy it?) I don’t believe that we will use data-
science or biochemical transformations to engineer our way out of the
entanglement of psychological pain, or the stressful situation of being alive.
But data will be used to support an illusion of superiority, or to sell one.
In fact, much of science is sales-pitched based on a utopian view of
human nature. The tragic version of human nature, otherwise known as the
“constrained view,” is a concept that can be traced to economist Thomas
Sowell and suggests that people are guided by innate self-interests, and
limitations into what we can know and do, and thus society requires checks
and balances. It is contrasted with an unconstrained or neolibertarian
worldview which suggests that people are essentially good, even
perfectible, and that “self-anointed” leaders including those in biotech
should further be free of regulation and moral checks because they are
leading us to a world that is more just, disease-free, equitable for everyone.
Under this utopian vision, biotech leaders are moving us into a brighter
future, and human life will come closer to utopia through technology. The
$1.8 billion Cancer Moonshot promises to “end cancer as we know it”; the
Sean Parker Cancer Institute has similar ambitions, but claims proceeds on
patents that turn into blockbuster drugs; the $1.4 billion Broad Institute has
been in an elbow-throwing battle for rights to Crispr, in which it granted
exclusive rights for medical applications to one of its own spin-off
companies, Editas Medicine; the $3 billion Zuckerberg Chan Initiative
promises to “advance human potential” and “cure all diseases,” while
maintaining exclusive rights to commercial patents. While the utopian
vision is sold, the dystopian reality is evident in the financial structure of
these institutions, which create salaries for management that can reach $1
million per year and engage in fights for exclusive patents. Layers of
financial deals are resulting in a new class of biologic medicines so
expensive some insurance companies may not pay for it.
Importantly, gene- and cell-based therapies have emerged at a time in
science when research is becoming highly contractual, highly structured
around large scientific hubs. A seismic shift is occurring in science whereby
tax-exempt research institutes established under an emerging model of
“free-market philanthropy” or “philanthrocapitalism” can amass money to
protect and defend commercial interests. The Broad Institute, the Parker
Institute for Cancer Immunotherapy and the Chan Zuckerberg Biohub are
tax-free shelters which retain the exclusive right to commercialize
inventions and prosecute patents. Scientific research is becoming more
organizational, investment-driven, perhaps even more authoritarian, as
control over basic research is exerted hierarchically from the top of the
organization. Science, once considered a public trust, is increasingly
defined by an ownership culture bent on monetization.
Scientists can appeal to a mythos of bringing us closer to reality, as if
peering into neuroimagery or analyzing the genome gives us information
that is more true than life as we experience it. To some extent we learn bits
and pieces of what makes us who we are. But, ironically, science can
weaken our sense of reality due to the obsession with statistical signals,
which are often taken out of context and put our problems into simplistic
reductionistic terms. As Sowell put it, “The march of science and
technology does not imply growing intellectual complexity in the lives of
most people. It often means the opposite.” If there is a coming backlash
against science, it is due to an ongoing struggle for freedom in a scientific
age, due in part to the perception or subliminal wish for scientists to explain
who we are and regulate our lives. To the extent that science seeks to
remove “the self,” this process can lend itself to repression, even
devaluation.
In 2008, the President’s Council on Bioethics released a 555-page
report, titled Human Dignity and Bioethics, which fielded essays by a wide
array of thinkers including Dennett and conservatives such as Leon Kass.
As Dennett put the problem, “When we start treating living bodies as
motherboards on which to assemble cyborgs, or as spare parts collections to
be sold to the highest bidder, where will it all end?” The solution of
rescuing the human spirit from the commercial forces of science, Dennett
noted, cannot involve resorting to “traditional myths” because this “will
backfire,” but instead concepts of human dignity should be based on our
sovereign right to “belief in the belief that something matters.”
Dennett argues that belief is important in an everyday sense, such as
most people have belief in democracy even as “we are often conflicted,
eager to point to flaws that ought to be repaired, while just as eager to
reassure people that the flaws are not that bad, that democracy can police
itself, so their faith in it is not misplaced.” The point is also true about
science, “since the belief in the integrity of scientific procedures is almost
as important as the actual integrity.” In fact, we engage in a sort of “belief
maintenance” insofar that “this idea that there are myths we live by, myths
that must not be disturbed at any cost, is always in conflict with our ideal of
truth-seeking” and even as we commit to ideas in public or just in our
hearts, “a strange dynamic process is brought into being, in which the
original commitment gets buried” in layers of internal dialog and
counterargument. “Personal rules are a recursive mechanism; they
continually take their own pulse, and if they feel it falter, that very fact will
cause further faltering,” the psychiatrist George Ainslie wrote in the
Breakdown of Will. If science can challenge beliefs, dignity is more primal
– it is the right to hold beliefs, make use of science, and exercise belief
maintenance.
The question of dignity is thornier than we might imagine, as science
tends to challenge the belief in abstract or enduring concepts of value. How
to uphold beliefs or a sense of dignity seems ever confusing and appears to
throw us up against an age of radical nihilism as scientists today are using
the gene-editing tool Crispr to do things such as tinker with the color of
butterfly wings, and genetically alter pigs and humans. Indeed, dignity may
be tricky to defend against the explication and engineering of human life by
means of chemical processes, and it is complicated by the reality that many
people increasingly look to science to shape their world view and moral
direction, as we are living through a new age of resurgent scientism – an
assumption that science encodes social values. A century ago, scientism
appeared to be all but dead. The modernist break caused rupture between
the moral and cultural commitments and sheer existence – hence it led to
existentialism and the struggle over defining our commitments. Whatever it
meant to live a good life, it couldn’t be predefined by culture or science. In
Anton Chekhov’s 1889 short story, “A Boring Story,” Nikolai Stepanovich,
an internationally recognized scientist and professor of medicine, slips into
melancholy near the end of his life. Despite his incredible success, his life
seems ever more ambiguous, as the modernist movement comes to displace
his authority. Katja, a young girl, and a representative of the new
generation, comes to him asking for advice and guidance, but Nikolai