English composition

This raises the question of whether stricter regulations could prevent rogue experiments or merely push them underground.

Human Germline Genome Editing 29

For some time after fertilization, the embryonic cells that may become a person’s body can become any type of body cell, but that changes quickly as the cells begin to specialize or to form pre- cursor cells that will form heart cells, brain cells, bone cells, and so forth. As early as the 12th to 14th day after fertilization, some of an embryo’s cells start to specialize to form a line of cells that will eventually produce, among other things, the germline and, ultimately, eggs and sperm. One might, in theory, intentionally do genome editing at, say, day 20, in such a way that only the cells that cannot become germ cells are edited— or so that only the cells that can become germ cells are edited. Or, if the earlier gene edit- ing produced a mosaic embryo, the same result could come about by accident. All (or some) of the cells that eventually became the germ cells might have, or not have, the edited CCR5 gene. So this embryo editing might, or might not, be germline editing.

Ultimately, this is why I write of germline editing rather than embryo editing. If you edit a zygote or edit all the cells of an early embryo, you are necessarily editing both somatic cells and germline cells (by editing cells that will eventually give rise to both of those categories). That is why zygote editing is necessar- ily, and early- stage embryo editing is usually, germline editing. In a later- stage embryo, though, one might edit only the cells that have already been differentiated along a path that means they could not become germline cells. That would be embryo editing, but not germline editing.

On the other hand, you don’t need to start at the embryo to edit human germline genomes. One might take egg and sperm samples from people and edit their CCR5 genes while the cells sit in a petri dish in the laboratory (in vitro, even though it is plastic, not glass). One could then use these edited gametes to create an embryo, rather than edit the embryo itself.7

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30 Chapter 2

One could also edit the germline by putting the editing mech- anism into living babies, adolescents, or adults (in vivo). If you edit the genome of the eggs of 20- year- old women or the sperm- forming cells of 20- year- old men, you edit their germline. 8 (At least one group has already suggested in vivo germline genome editing by doing “gene therapy” on sperm through an injection into a man’s testicles. 9 I’m not sure how many volunteers that would get.) This might be done on purpose, by injecting the editing agent into the ovaries or testes. But it might also hap- pen inadvertently, by providing gene therapy to a person with the goal of affecting a particular organ but unintentionally, and possibly unknowingly, also editing the person’s eggs and sperm.

Logically, these options are also human germline genome editing, whether intentional or accidental. But they are not what He Jiankui did or what people are currently worried about others repeating. It is worth remembering that it can happen, but in this book, when I talk of “human germline genome edit- ing,” I do not include intentional or accidental editing of eggs and sperm.

I use the term “genome” editing and not “gene” editing or “genetic” editing because such modifications may change more than one gene or change DNA that is not in what is usually con- sidered a “gene.” The “genome” is all of the DNA sequence in a person— the 6.4 billion base pairs (the adenines, cytosines, gua- nines, and thymines— As, Cs, Gs, and Ts) in the 46 chromosomes found in the cell’s nucleus as well as the 16,000 or so base pairs found in the DNA of the cells’ mitochondria. To be sure, the particular example of He’s experiment— editing CCR5— targeted one specific gene and could be considered “gene editing” or “genetic editing.” Many potential uses for germline editing— especially for enhancement, the most controversial use— will no

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Human Germline Genome Editing 31

doubt require changes to many pieces of DNA, some in genes and some not.

It is tempting just to call it “DNA editing”— after all, edit- ing DNA is fundamentally what it does. I prefer “genome edit- ing” because it reinforces the idea that this is not just editing a piece of DNA in a laboratory but editing the whole information- storing assembly that a person’s DNA makes up.

And, finally, I use “editing” instead of “modifying” or “chang- ing” or “mutating” (just a fancy Latinate word for changing) for two reasons. First, editing is a technique used to make a specific intentional change: for example, to change an A to a G, to delete a particular stretch of 32 bases, or to add an important 12- base sequence. Each of the other words accurately describes what is done, but they do not carry the same sense of intentionality. Note that this is intention, not necessarily result. He Jiankui intended to edit CCR5 genes by deleting a specific stretch of 32 base pairs. That he failed does not mean he did not do human germline genome editing, just that he did it without complete success.

Second, although this book’s title includes “CRISPR,” human germline genome editing need not be “CRISPRing.” Although He Jiankui says he used CRISPR, not all gene edits today must use CRISPR. Other, older methods, though more expensive, time- consuming, and difficult, can also be used to edit DNA. Transcription activator- like effector nucleases (TALENs) and zinc finger nucleases (ZnFs) are the two most significant. (Oddly enough, the first one is mainly known by its acronym while the second is often referred to by its full name, perhaps because the first name is hard to remember and the second is easy.) For the near future, CRISPR seems likely to be used much more often, but, also important, refinements upon CRISPR have already begun to

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32 Chapter 2

appear. Replacements for it are likely, with different sets of pluses and minuses. When referring to CRISPR as a specific technique, I may use “germline CRISPR” or even “CRISPR’d babies,” but the general topic is “genome editing,” not “CRISPR.”

That’s what I, and this book, mean by “human germline genome editing.” Lots of variations on “human germline genome editing” appear in scientific publications and the popu- lar press. Sometimes you will read about “human genome edit- ing” rather than “germline genome editing.” That is a fair use if the user intends to include somatic cell editing and germline editing, as in the report by the U.S. National Academies of Sci- ences and of Medicine, and in the Hong Kong Summit that led to the revelation of He’s experiment. You may read about human germline “gene editing,” human germline “genome editing,” or human germline “DNA editing”— and often this won’t include the important qualifiers “human” and “germline.” This is usu- ally just a shortcut that saves writers, especially headline writers, a few characters. And, finally, you may read of human germline genome (or gene or DNA) “CRISPRing” because that is the best technology at our disposal today. But not, perhaps, tomorrow. Usually, however, whatever words they use, articles about the He Jiankui experiment and its implications are talking about what I’ll call “human germline genome editing”: making intentional changes to the genomes of embryos that, it is hoped, will become people, people whose eggs or sperm will carry those changes.

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CRISPR People The Science and Ethics of Editing Humans

By: Henry T. Greely

Citation: CRISPR People: The Science and Ethics of Editing Humans By: DOI: ISBN (electronic): Publisher: Published:

Henry T. Greely

The MIT Press 2022

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© 2021 Massachusetts Institute of Technology

All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means (including photocopying, recording, or information storage and retrieval) without permission in writing from the publisher.

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Library of Congress Cataloging- in- Publication Data

Names: Greely, Henry T., author. Title: CRISPR people : the science and ethics of editing humans /

Henry T. Greely. Description: Cambridge, Massachusetts : The MIT Press, [2021] |

Includes bibliographical references and index. Identifiers: LCCN 2020012654 | ISBN 9780262044431 (hardcover) Subjects: MESH: Gene Editing | Genome, Human Classification: LCC QH447 | NLM QU 550.5.G47 | DDC 611/

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3 CRISPR— What Is It, Why Is It Important, and Who Will Benefit from It?

It is a tool, and one that leapt far beyond the existing tools— perhaps not as far as a chain saw leapt from a stone ax, but close. And we should all benefit from it, though which scientists, uni- versities, and companies will particularly benefit remains to be seen.

As noted earlier, CRISPR is also an acronym, standing for “clus- tered regularly interspaced short palindromic repeats.”1 This is a case where my distaste for COAs gives way. Not only is CRISPR a much shorter and easier to remember name for this tool but it makes a catchy word, one that can make a good sounding noun, but also a verb, and one that combines nicely with “- ed” and “- ing.” I love the name CRISPR, although, somewhat to my surprise, someone else has published an article on how and why he hates it (mainly because there is nothing crispy about it).2

And in another, earliest sense, CRISPR refers to molecular constructs that bacteria have used to defend themselves from viral invaders. In this sense, CRISPR goes back billions of years— perhaps three billion or more. The first time humans noticed them appears to have been in 1987, when a Japanese group pub- lished the sequence of one gene, along with some surrounding DNA sequences, of the ubiquitous gut (and laboratory) bacterium

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34 Chapter 3

E. coli. They found something never seen before— DNA that had a set of identical 29 base pair sequences, separated from each other by four sets of 32 base pairs, which they called spacers, each with a different sequence. They had no idea what this DNA did and wrote “the biological significance of these sequences is not known.” 3

In the early 1990s other scientists, most notably Spanish researcher Francisco Mojica at the University of Alicante, saw odd debris inside bacterial cells. In trying to understand them, he ran into this same kind of spacer arrangement. Mojica pushed to understand this phenomenon, publishing several articles on its mechanism as he understood more about it.

Naming of CRISPR

Others also were investigating the same repeating bits of DNA inside bacterial cells, but the phenomenon had no accepted name. In 2000, Mojica published an article on its biological sig- nificance, calling it “SRSR” for short regularly spaced repeats. 4 (Mojica has pointed out that this acronym nicely mirrored the way the clusters were organized: spacer/repeat/spacer/repeat.5) In 2002, Ruud Jansen in the Netherlands published an article on the same phenomenon, which he called “spacers interspersed direct repeats,” or SPIDR.6

Mojica says,

The potential naming conflict was solved after mutual agreement of the two research groups to use CRISPR (pronounced krisper) after “Clustered Regularly Interspaced Short Palindromic Repeats.” Jansen immediately accepted the new definition and acronym rather than the other, less descriptive or not so distinctive alternatives that were proposed.7

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CRISPR 35

The term seems to have been used first in print by Jansen, who wrote later in 2002:

To acknowledge the joining of this class of repeats as one family and to avoid confusing nomenclature, Mojica et al. and our research group have agreed to use in this report and future publication the acronym CRISPR, which reflects the characteristic features of this family of clustered regularly interspaced short palindromic repeats.8

(The article’s acknowledgments section states, “We enjoyed pleasant discussions with Francisco Mojica of the University of Alicante, Spain, about the renaming of CRISPRs.”)

Nailing down from publications the origin of the term CRISPR was satisfying, but it did not illuminate a question I really wanted answered: Were Mojica or Jansen influenced by the good sound of “CRISPR,” at least in English? So I emailed them. To my pleasant surprise both answered me. Mojica responded very quickly, in a very friendly and helpful email. 9 In his mem- ory, from 18 years ago, Jansen had proposed that, to avoid the confusion of two different terms, the two of them should rename these families of repeats to something they (and, he hoped, others) would use consistently. Jansen asked Mojica for suggestions.

Mojica had two goals for the name: he wanted the name to reflect the importantly distinctive feature of this family of repeats, and he wanted it to be easy to pronounce, especially in English. He also realized that they did not know enough about the function of CRISPR to give it a name that implied any func- tion. So he proposed “regularly spaced short repeats” (RISR), his own favorite, and CRISPR. Jansen also said he preferred CRISPR and noted that “Also not unimportant is the fact that in Med- Line CRISPR is a unique entry, which is not true of some of the other shorter acronyms.”10

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36 Chapter 3

As to the variations on CRISPR, Jansen told me, “At the time of the publication I could not imagine that there would ever be the verbs crispr, crisprs, crispring and crispred, but it sounds very well.” 11 Mojica said he had not thought about how well CRISPR could be used as a verb; it is ‘just a lucky coincidence.’” Mojica added

as it is also the fact that one of the meanings of the word Crisper, with identical pronunciation, is “a compartment for storing fruit and vegetables” and CRISPR is a segment of DNA for storing chunks of invading genetic elements: both are storing devices. [emphasis in original]12

Jansen also told me that the sound of CRISPR resembles the Dutch verb “knisperen.” This means to “crisp” as, Jansen said, “the freshly fallen autumn leaves or the crust of a freshly baked croissant. With these connotations, you can understand that CRISPR was the acronym of choice.” 13 Prompted by this email, Mojica pointed out that

In Spanish, the closest word to CRISPR is the verb crispar (to annoy in English), pronounced krees pahr. In consequence, many Span- ish people pronounce CRISPR that way, not at all appropriate in the context of the CRISPR field. Even worse, much more people say “krispies,” which really annoys me. Yet, I believe we made a great choice.14

Jansen summed up his experience by telling me,

At the time of publication I changed jobs and quit the work on the CRISPRS, because we could not get any funding for our following CRISPR project. I considered it very likely that the article would dis- appear in the pile of forgotten publications, although I hoped some- body would be able to solve the mystery of these abundantly present prokaryotic genetic units. The rest is history and I am happy to be part in the planting of this very vital seedling. 15

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CRISPR 37

As someone who has had some say in naming two children, the discussions between Mojica and Jansen, though very different in some details, have a very familiar feeling. And it is, indeed, quite a child they named.

Around 2005, Mojica and others realized that CRISPR was actually a form of an immune system for bacteria and archaea (another, nonbacterial, type of microbe16), and not just any immune system but one similar, in a key way, to the major human immune system, the adaptive immune system.17 This was an impressive discovery; no specifically bacterial (or archaeal) immune systems had been identified before. Humans and other animals use many different ways to defend themselves against microbial invaders, but one category of defense mechanism rec- ognizes specific invaders that it has seen before and attacks only them. This system is the basis for vaccination, as well as for your immunity to some infectious diseases, such as measles, if you have had them before. CRISPR does the same kind of thing with viruses, which don’t just plague us during cold and flu season, but also attack bacteria and archaea. (Viruses that attack these microbes are generally called “bacteriophages” or just “phages,” from the Greek word “to eat.”)

Microbes with a CRISPR system, if they successfully fight off a virus’s attack, will cut up the virus’s DNA (and also, it seems, the RNA in RNA- based viruses, but we’ll ignore these) and put bits of the virus’s sequence into their own DNA. It is these pieces of viral DNA incorporated into the microbe’s own DNA that are the “clustered regularly interspaced short palindromic repeats”— CRISPR. No need to worry about any of the specific words in that name; it’s sufficient to know that the DNA in a CRISPR region will be used as a template for RNA (which is most of what DNA does).

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38 Chapter 3

Basically, the CRISPR section of the microbe’s genome creates a homing mechanism. It serves as the template for the microbe to make an RNA molecule based on the CRISPR DNA template. The template is based on one of crucial aspects of the secret of life— how DNA, RNA, and proteins are related. The DNA bases, A, C, G, and T (adenine, cytosine, guanine, and thymine), bind to each other only in very specific ways. A binds with T, and T with A; C binds with G, and G with C.

With CRISPR, a bacterium will make an RNA molecule from the CRISPR template. The RNA molecule will have As where the DNA has Ts and Gs where it has Cs. In a complication unimport- ant for our purposes, RNA uses a U (for uracil) instead of a T. So, if a CRISPR section of the microbe’s DNA reads ATTTGGCAC (i.e., a sequence that it found in a past viral invader) the microbe will make an RNA that reads UAAACCGUG. This is called the “guide RNA.” The guide RNA (made from the template in the bacterium’s DNA) will diffuse through the bacterium’s cell.

Drifting along with, and attached to, the guide RNA is a microbial enzyme, a kind of protein. If, floating in the bacte- rium, there is viral DNA containing the complement of the guide RNA’s sequence, in this case ATTTGGCAC, the guide RNA will stick to it like glue, its bases holding on to their comple- ments in the viral DNA. (You have, I hope, noticed that this is the same sequence we started out with, the old virus’s DNA sequence found in the CRISPR region.) The attached protein, like a molecular scissors, cuts this viral DNA into pieces at the location the guide RNA has found. Unlike RNA, DNA comes in two connected strands of sequence, curling around each other in the famous “double helix.” (Think of a twisted ladder.) The asso- ciated protein cuts the viral DNA across both strands, “killing” the virus, making it unable to reproduce, and thus protecting

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CRISPR 39

the microbe.18 The first of these “scissors” proteins was given the poetic name “CAS,” for “CRISPR- associated” protein. It turned out to be one of a large family of CAS proteins and so had its name changed to Cas1. The great science writer Carl Zimmer summarized the whole process better than I can:

As the CRISPR region fills with virus DNA, it becomes a molecu- lar most- wanted gallery, representing the enemies the microbe has encountered. The microbe can then use this viral DNA to turn Cas enzymes into precision- guided weapons. The microbe copies the genetic material in each spacer into an RNA molecule. Cas enzymes then take up one of the RNA molecules and cradle it. Together, the viral RNA and the Cas enzymes drift through the cell. If they encoun- ter genetic material from a virus that matches the CRISPR RNA, the RNA latches on tightly. The Cas enzymes then chop the DNA in two, preventing the virus from replicating.19

It turns out that many different bacteria have CRISPR sys- tems, systems that use CRISPR in conjunction with many differ- ent “scissors” proteins, some in the Cas family and some with other obscure names, to do their work. (Cas9 has been particu- larly well explored.) Scientists have estimated that some kind of CRISPR system is found in 50 percent of bacterial species and 90 percent of species of archaea.20

During this century’s first decade, Mojica and others— including scientists working for Danisco, the company that makes Dannon yogurt— explored CRISPR as a fascinating piece of natural history, a cool and previously unknown trick of Mother Nature. It was not until 2012 that CRISPR, and especially CRISPR in combination with Cas9, began to be seen as a tool for humans. (People will often write about CRISPR along with the particular associated protein they have used, so you’ll see “CRISPR- Cas9,” “CRISPR- Cas13,” “CRISPR- cpf1,” and others. For this book I will usually talk about just “CRISPR,” but remember

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that it can only work in conjunction with one of these many associated proteins.)

It is CRISPR as a tool that is important for us, not CRISPR as an immune system. It makes it much easier, faster, and cheaper for humans to change the DNA of any living organism. This book is about the use of CRISPR to edit humans, specifically their germ- line genomes. But CRISPR will certainly be much more impor- tant as a tool we use to edit the rest of the biosphere; in fact, that is happening much faster with nonhumans than in humans, in large part due to our (appropriately) heightened safety concerns for editing in humans.21

The first publication of the idea of CRISPR as a tool came from Jennifer Doudna of the University of California, Berkeley, and Emmanuelle Charpentier, a researcher born in France who, from 2009 to 2014, was a faculty member of Umëa University in Sweden. In early June 2012, Doudna and Charpentier submit- ted an article to the journal Science on how humans could use CRISPR- Cas9 to reliably make double- stranded cuts in DNA in cells at very specific locations, determined by the guide RNA. 22 Science recognized the importance of the article and very quickly published it online on June 27. The last 12 words of the last sentence of the paper’s abstract explains why Science was so interested: “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 edit- ing” (emphasis added).23 The prospect of a new tool for program- mable genome editing was very exciting.

Often, when a scientific idea is ripe, several investigators will have similar ideas. Virginijus Šikšnys at Vilnius University in Lithuania and his group submitted an article with similar find- ings to the journal Proceedings of the National Academy of Sciences

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CRISPR 41

in May 2012, before Doudna and Charpentier.24 Proceedings of the National Academy of Sciences put the paper through a peer review process that resulted in questions to the authors and substantial back and forth. That paper was ultimately published in Septem- ber 2012.25

Science published some other important CRISPR articles in January 2013. Doudna and Charpentier had described how CRISPR with Cas9 could be a tool in bacterial (and presumably archaeal) cells. Feng Zhang and his group from the Broad Insti- tute (a collaboration between Harvard University and the Mas- sachusetts Institute of Technology, with the counterintuitive pronunciation of “Br ōd,” with a long “o”), showed that CRISPR could also work in cells from “eukaryotes,” the more compli- cated forms of life that include amoebas, fungi, plants, and ani- mals.26 In the same issue, though submitted a little later, Harvard Medical School’s George Church and his laboratory showed that CRISPR could be used to cut DNA in the cells of one eukaryote of particular interest to us— humans.27

The early uses of CRISPR- Cas9 (as the combination is called) were for cutting DNA, but scientists, those mentioned above and others, quickly began figuring out how to use CRISPR for many other purposes. This expansion of the uses of various constructs with CRISPR is still going on, with new methods, often for new purposes, announced regularly. One of the earliest, and most useful, of these extensions uses CRISPR constructs not just to cut out stretches of DNA but to replace them with other (human- chosen or human- engineered) stretches.

The irresistible (to me) analogy is to the cut- and- paste func- tions in word processors, particularly Microsoft Word and its “replace” function. With Word you can tell your computer to find any set of characters in a document (say “Greeley”),

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cut it out, and replace it with the correct version (in my case, “Greely”). In cells, the guide RNA in the CRISPR could be cho- sen to find a stretch of DNA that reads GTGCACCTGACTCCT- GTG. An associated protein would cut out these 24 bases, but the whole complex could include a different stretch of 24 bases, say GTGCACCTGACTCCTGAG, identical except for the next- to- last nucleotide base, which has changed from a “T” (thymine) to an “A” (adenine). Through one of several DNA repair processes, the cell will take the new DNA and put it in the place of the old DNA, thus permanently changing the cell’s DNA.

This isn’t a random example. That stretch of DNA is the first 24 bases of a version of the hemoglobin- beta gene found in mil- lions of people. This gene provides the instructions for making a part of the hemoglobin protein in some people. People with two copies of the first version of the gene will make only abnormal hemoglobin- beta protein, will have poorly functioning hemo- globin, and will develop sickle- cell disease. The edit, putting an A in the penultimate position in place of a T, turns that into the common version of the gene, found in people who do not, and cannot, have sickle- cell disease. So CRISPR might be used to change DNA of people with sickle- cell disease to a version that would give them normal hemoglobin and hence normal blood, blood that would not cause an always painful and often life- shortening condition. (And, in fact, people are trying to do just this, including my Stanford colleague Matt Porteus, of whom you will hear more.)

Overlapping inventions, with one scientist building on the work of other scientists— “standing on the shoulders of giants”28— is not unusual. It is often held up as the normal, and admirable, way in which science works. The issue of mul- tiple inventors, though, has taken on special significance here

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CRISPR 43

because CRISPR is so obviously important. Both fame (includ- ing prizes) and fortune (prize money but also patents and com- panies) are at stake. The history of, and credit for, CRISPR has become extremely controversial.

On the patent side, quite literally scores of millions of dol- lars have been spent on litigation over various CRISPR patents and patent applications, applications from the University of California system for Doudna and Charpentier’s work and from the Broad Institute for Zhang’s work. 29 The Broad filed its pat- ent later than UC, usually the kiss of death, but it used a special “short form” kind of application that gave it priority and it got the first U.S. patent, which has forced the UC system to paddle upstream, at least in the United States. Other people, including Šikšnys, also have patent claims that may turn out to be impor- tant— or not— but thus far Zhang/the Broad versus Doudna/UC has been the main event. As I write this, Zhang and the Broad Institute are (more or less) winning in the United States while Doudna, Charpentier, and the UC system are heavily winning in Europe and China, 30 but that could change in a week, let alone in the year before these words see the light of day.

I am not a patent lawyer and try to avoid playing one on television. Predicting the outcome of patent disputes is one of the darkest of all dark arts, and I leave it to the experts, such as my former Center for Law and the Biosciences fellow, Jacob Sherkow,31 and my colleague, the world’s leading academic pat- ent law expert, Mark Lemley. But I am willing to go out on a limb and say that the UC/Broad litigation is ridiculous. Truly, scores of millions, if not hundreds of millions, of dollars have been spent on this litigation. It has benefited the lawyers, many of them my former Stanford Law School students, but it is hard to see it benefiting others. Certainly, the world will little care— and little

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44 Chapter 3

benefit from— whichever of the two gets a de jure monopoly on the use of CRISPR- Cas9 for 20 years after the patent application was filed. From a social welfare perspective, except for those with the most blind attachment to the obscure and (largely) unpre- dictable rules that govern who gets patents (and what those pat- ents mean), this is just a question of who gets the rents from being able to charge higher prices for licensing CRISPR- Cas9 to firms.

Most likely, I think, is a result where whoever gets the dom- inant patent position will find it of little financial value. The key patents being fought over are about CRISPR- Cas9 (which is why I’m actually using “CRISPR- Cas9” here after earlier writing that I would generally avoid using it), but exciting publications have already seen the light of day about many other Cas pro- teins, as well as other “cutting” proteins that do not have the Cas name at all. Bacteria have been around for over 3 billion years and have evolved many immune systems with a CRISPR- like mechanism. If one institution has a patent on CRISPR- Cas9, that will only drive “invent arounds,” using noninfringing cut- ting enzymes, or possibly even noninfringing versions of or equivalents to CRISPR. The higher the royalty or other price charged for a license, the more likely an invent- around response becomes. And the more money the licensees spend on litigat- ing these patents, the more likely they are to need to charge high prices. It should be a classic death spiral. High prices lead customers to move to cheaper alternatives, which leads in turn to higher prices for the fewer remaining customers, which makes still more of them flee to alternatives. Madness lies along that path! (I am not an investment advisor, but I certainly wouldn’t invest in any of the firms paying for the CRISPR- Cas9 litigation— even if conflict of interest concerns didn’t keep me

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CRISPR 45

from investing in any bioscience firms.) This just seems irrational to me.

But perhaps there is some reason, albeit probably not a good one. A Nobel Prize has not yet been awarded for CRISPR (at least, as I write this— by the time you read it, that may have changed). Normally, this would not be a surprise for a relatively recent discovery. But CRISPR has been so universally adopted, and acclaimed, that people were predicting that some of its inventors would win the Nobel (either the prize in chemistry or the one in medicine or physiology) in 2017 or 2018. Some have speculated that the patent litigation has been pursued in part because Eric Lander, the director of the Broad Institute, is very eager to see his faculty member, Feng Zhang, win a part of this prize and that this may have influenced the course, and continuation, of the litigation. Lander is one of the most powerful people in genom- ics in the United States; the Broad Institute has long been one of the leading centers in the country for DNA sequencing. I am confident that Lander would have been a great appellate lawyer. (That’s a compliment coming from me. Mainly.)

In 2016, he published an article on the history of CRISPR in the journal Cell, which, in the biological sciences, is esteemed at about the same very high level as Science and Nature. The article, entitled “The Heroes of CRISPR,” 32 is an excellent review of the history of CRISPR, focusing heavily on the many people who worked on the bacterial uses of CRISPR. It has, however, been roundly criticized for lauding Zhang’s contributions and barely mentioning Doudna and Charpentier.33 The first sentence of the piece, published in 2016, reads, “Three years ago, scientists reported that CRISPR technology can enable precise and effi- cient genome editing in living eukaryotic cells.” That puts the key moment of CRISPR development in 2013, not in June 2012,

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46 Chapter 3

and with eukaryotic cells, Zhang’s work, not that of Doudna and Charpentier. The piece has many good points (including good writing— again, Lander would have been an excellent lawyer), but its treatment of Doudna and Charpentier compared with that of Zhang is, to my mind, at best, embarrassing and, at worst, shame- ful, particularly as the article, as published, made no mention of the conflict of interest that came from the author being Zhang’s boss. (Lander was not without defenders, including the excellent science journalist Sharon Begley in an article entitled “Why Eric Lander Morphed from Science God to Punching Bag.”34)

All that being said, as a lawyer myself (though largely recov- ered, having last practiced more than 35 years ago), I cannot fault Lander much. And I have no inside information on whether and to what extent the Broad/UC patent fights have been motivated by a desire to enhance, through patent priorities, Zhang’s posi- tion vis- à- vis Doudna and Charpentier. The Broad says that it has regularly offered to settle the dispute, through a patent pool or otherwise, but that the UC system has rebuffed its overtures.35 Having been a general civil litigator, I know that litigants can be irrational. Perhaps it is the (always strapped for cash) UC system or the firms to which they have licensed their intellectual prop- erty who are pushing the continued trench warfare over these patents. I find the speculation that the Broad is eager to enhance Zhang’s credit, fame, and chances for part of a Nobel Prize a fas- cinating possible explanation for the patent fight, but it is only speculation.

When will CRISPR Nobel Prizes be awarded? That is, of course, impossible to tell. The key discovery date is 2012. In recent decades, awards within five years of a discovery are uncommon but not unheard of; so are prizes 50 years after a discovery. The 2012 Nobel Prize in Medicine or Physiology provides a good

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CRISPR 47

example. Shinya Yamanaka won half the prize for his discov- ery of induced pluripotent stem cells, in mice in 2006 and in humans in 2007. He shared that prize with John Gurdon, whose work on reprogramming cells, through cloning frogs, started in the 1950s and arguably culminated in 1962. One waited six years; the other waited 50.

But there is another issue that may delay a CRISPR Nobel Prize: uncertainty about who should receive it. The science Nobel Prizes, by the organizers’ rules, cannot be awarded to more than three people in any one year. And yet every scien- tist knows, and every nondelusional scientist truly believes, that hundreds or thousands of researchers contributed to almost every significant advance. The history of the field— whether told by Doudna and Steinberg in A Crack in Creation, by Lander in “The Heroes of CRISPR,” or others— points out scores of people, in many countries, who contributed to the discovery. Yet only three can receive a Nobel Prize. And, as indicated in the discus- sion of the history of CRISPR, this raises a problem for which- ever Nobel Prize group considers CRISPR. Who invented it? And who should win the Nobel Prize for CRISPR when it is limited to three people?

Personally, I think Doudna and Charpentier should be shoo- ins, for their own insights and for the work of their labs, together and separately. That seems to leave one spot. None of the tal- ented scientists working under them in their labs are likely to win; their work will be subsumed into that of their superior’s lab. That leaves at least Mojica, Šikšnys, Zhang, and Church as plausible candidates— but only one spot seems open. We shall see— or, perhaps by the time you’ve seen this, we will have already seen in October 2020.36

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CRISPR People The Science and Ethics of Editing Humans

By: Henry T. Greely

Citation: CRISPR People: The Science and Ethics of Editing Humans By: DOI: ISBN (electronic): Publisher: Published:

Henry T. Greely

The MIT Press 2022

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© 2021 Massachusetts Institute of Technology

All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means (including photocopying, recording, or information storage and retrieval) without permission in writing from the publisher.

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Library of Congress Cataloging- in- Publication Data

Names: Greely, Henry T., author. Title: CRISPR people : the science and ethics of editing humans /

Henry T. Greely. Description: Cambridge, Massachusetts : The MIT Press, [2021] |

Includes bibliographical references and index. Identifiers: LCCN 2020012654 | ISBN 9780262044431 (hardcover) Subjects: MESH: Gene Editing | Genome, Human Classification: LCC QH447 | NLM QU 550.5.G47 | DDC 611/

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4 Ethics Discussions of CRISPR’d Babies before He

People have been talking about human germline genome modi- fication for decades, though without necessarily using those words. More than 15 years ago, I reviewed two books about changing a human’s DNA in ways that would get into the eggs or sperm and possibly be passed down to future generations,1 but even then, the debate had been raging for decades. This chapter looks at those discussions up to the disclosure of He’s experi- ment, in two parts: the early discussions of recombinant DNA technology, notably at the famous Asilomar Conference, and the more focused discussions after the development of CRISPR as a genome editing system. Along the way, it takes a look at some of the people, “CRISPR people,” although not “CRISPR’d people,” who were involved.

Asilomar and the Ethics of Recombinant DNA

Before the realization that DNA was the basis for human genetic inheritance and the knowledge, with Watson and Crick’s dis- covery of DNA’s structure, of the importance of DNA sequence, the discussion would not have been of “editing,” as the anal- ogy between the genome and a book (or a blueprint) did not

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50 Chapter 4

exist. But even after Watson and Crick, and after the working out during the 1960s of how DNA in the genome “coded for” the amino acids of proteins, the discussion remained abstract. No one knew how to edit the human germline genome— or any- thing’s genome for that matter.

That changed, a little, in 1971 with the invention of recom- binant DNA. Researchers learned how to move bits of DNA from one species into another using laboratory tools. The methods were crude. Stanford Medical School biochemistry professor Paul Berg used DNA from two different species of virus, the simian virus SV40 and a bacteriophage called lambda. These viruses kept their DNA in closed- loop structures. Berg’s team broke those loops in a particular location, using one of a then- recently discovered kind of enzyme called a restriction enzyme that cut DNA at specific sequences (rather like a single target version of CRISPR/CAS). Using techniques pioneered by other Stanford col- leagues, the ends of these linear fragments of DNA formed from the now- open loops were made “sticky” and able to attach to other bits of DNA. These linear pieces of DNA from the two dif- ferent species were mixed, and, sometimes, they combined so make a new closed loop with DNA from each species— Berg had “recombined” DNA from two different species into one piece.2

PAUL BERG

Berg was (and is) a biochemist’s biochemist. Born in June 1926 in Brooklyn, after military service in World War II, he ended up at Penn State as an undergraduate, finishing his bachelor’s degree in 1948. Largely by chance he ended up as a graduate student at Case Western Reserve University, where he got his Ph.D. in bio- chemistry in 1952. After postdoctoral and other fellowships in

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Ethics Discussions of CRISPR’d Babies 51

Copenhagen, at Washington University in St. Louis, and at Cam- bridge University, he started his first faculty position at Washing- ton University in 1955, working with Arthur Kornberg. In 1959 Kornberg, Berg, and several other Washington University faculty moved en masse to Stanford, where the university was moving its medical school from being mainly in San Francisco to being entirely on campus at Stanford and was opening a new biochem- istry department. Paul has been a leading light at Stanford Medi- cal School ever since.

I came to know Paul quite well starting in 1990. Stanford Uni- versity celebrated the centennial of its opening with three long symposia, one in fall, one in winter, and one in spring quarter. The winter quarter symposium was to be on the then- new Human Genome Project. The symposium planning committee was chaired by Berg, joined by David Botstein, then chair of Stanford genetics department, and Lucy Shapiro, the Founding Chair of Stanford’s then- new department of developmental biology. They wanted a law professor on the committee with them. One of my colleagues suggested me, probably, I’ve always joked, because I was the only Stanford law professor at the time who could spell DNA (let alone deoxyribonucleic acid).

I accepted and had a wonderful time on the committee. It was my first real close- up look at eminent scientists. These folks were not only brilliant, but enjoyable. I soaked up enormous amounts of information every time we met, I gained three friends who would patiently explain scientific issues to me, and I had great fun. I also ended up being chosen to give a talk at the sympo- sium, held January 11 through 13, 1991. I gave a talk on the likely effects of genetic information on the U.S. health care financing system, the first time I had given a talk about genetics. (It turned into my first publication on genetics, a book chapter.3) I met amazing people through the conference, people whose research I read about for years and people whose interactions with me would change my life. And it cemented my relationship with Paul Berg, a crucial mentor for me.

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52 Chapter 4

Berg did not immediately take the next step of then trying to move such recombinant DNA into a living organism. That was done first by two other Bay Area scientists, UC San Francisco (UCSF) professor Herb Boyer and Berg’s Stanford Medical School colleague Stan Cohen of the school’s genetics department. By spring 1973 they had moved an antibiotic resistance gene into E. coli bacteria. Soon they moved DNA from a staphylococcus bacteria into E. coli and eventually did the same with DNA from a frog species.4

There has long been some dispute over who deserves how much credit for the invention of recombinant DNA.5 As with CRISPR, many researchers contributed. Some have argued that others were as or even more deserving of a recognition for inventing recombinant DNA as Berg, notably Cohen and Boyer or Berg’s fellow Stanford biochemistry department researchers, Janet Mertz and Ron Davis. This debate has, over the years, had some special bite at Stanford Medical School. Berg was a member of the School’s biochemistry department, and Cohen, a profes- sor of the genetics department. Although it is fading with time, I remember hearing (mainly, but not entirely, good- natured) rib- bing between the departments over which should get credit.

As it happened, in October 1980 Berg won a share of the Nobel Prize for Chemistry for inventing recombinant DNA. Berg shared the prize with Frederick Sanger and Walter (Wally) Gilbert, who were awarded half the prize money for inventing techniques to determine the sequence of DNA. As with CRISPR today, the Nobel Committee allows no more than three people to be awarded a prize in most of its categories. Once the chem- istry committee decided to recognize Sanger and Gilbert for sequencing— each had made substantial progress in very differ- ent ways— that left only a slot for one inventor of recombinant

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Ethics Discussions of CRISPR’d Babies 53

DNA if that accomplishment were to be awarded the prize that year.

Ironically, exactly seven weeks later, the U.S. Patent and Trademark Office granted U.S. Patent No. 4,237,224, “Process for producing biologically functional molecular chimeras,” to two inventors, Cohen and Boyer. Their interests in the patent were assigned to Stanford and the UC system, respectively. Stan- ford managed the patent for the two universities. During its 17- year lifetime, it brought the two universities over $250 million. 6 (More than a quarter of Stanford’s royalties went to the genetics department with an equal amount to the medical school— none went directly to the biochemistry department.) Both Cohen and Boyer received some patent royalties through their universi- ties; Boyer cofounded Genentech in part based on a license of that patent.

You may well be wondering what this digression into the his- tory of recombinant DNA, patenting, and Nobel Prizes— as inter- esting as its parallels to CRISPR may be— has to do with ethics, the topic of this chapter. As far as Berg’s Nobel Prize goes, no one doubts that he and his lab made major contributions to the field and were driving forces in its advance, but Berg had another role that made him stand out from the rest of the recombinant DNA crowd. He was a leader, arguably the leader, in organizing a temporary moratorium on recombinant DNA research and in organizing and running the famous 1975 Asilomar Conference on recombinant DNA at which the moratorium was discussed. And the Asilomar Conference is an essential part of this story.

The Asilomar Conference, or, to give it its full name, the Asi- lomar Conference on Recombinant DNA Molecules, was held on February 24, 25, and 26, 1975, at the Asilomar State Beach and Conference Grounds, an unusual unit of the California State

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54 Chapter 4

Park system, located on the coast just south of Monterey, Cali- fornia (and one of the loveliest places in the world).7 It had been spawned in June 1973 at a Gordon Conference on the topic of nucleic acids.

Gordon Conferences are prestigious scientific meetings on frontier research in biology, chemistry, and the physical sciences. The first Gordon Conference was held in 1931, growing out of summer conferences held by the chemistry department at Johns Hopkins University in the 1920s. Initiated by Johns Hopkins pro- fessor Neil Gordon, the nonprofit organization that now runs them holds more than 300 conferences or seminars a year, usu- ally in scenic and isolated locations. 8 At these meetings, small invited groups of researchers come together “off the record” to discuss their field. (To my regret, I have never gone to one.)

From June 11 to 15, 1973, a Gordon Conference on Nucleic Acids was held in New Hampton, New Hampshire. Talk turned to concerns about the potential safety hazards of recombinant mole- cules. A majority of those attending the conference voted to send a letter expressing their concerns to both the president of the U.S. National Academy of Sciences and the president of the National Institute of Medicine (now the National Academy of Medicine), as well as to publicize their letter more widely. The letter was also published in the September 21, 1973, issue of Science.9 (No earlier online publication in those days.) The letter read, in part:

Certain such hybrid molecules may prove hazardous to laboratory workers and to the public. Although no hazard has yet been estab- lished, prudence suggests that the potential hazard be seriously considered. A majority of those attending the Conference voted to communicate their concern in this matter to you and to the Presi- dent of the Institute of Medicine (to whom this letter is also being sent). The conferees suggested that the Academies establish a study

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Ethics Discussions of CRISPR’d Babies 55

committee to consider this problem and to recommend specific actions or guidelines, should that seem appropriate.

The leadership of the National Academy of Sciences and the National Institute of Medicine took the letter seriously and appointed such a committee. That committee published its own letter in Science on July 26, 1974.10 This letter read, in relevant part:

The undersigned members of a committee, acting on behalf of and with the endorsement of the Assembly of Life Sciences of the National Research Council on this matter, propose the following recommendations.

First, and most important that until the potential hazards of such recombinant DNA molecule have been better evaluated or until adequate methods are developed for preventing their spread, scien- tists throughout the world join with the members of this committee in voluntarily deferring the following types of [recombinant DNA] experiments . . .

Additional recommendations advised caution with respect to some other types of recombinant experiments, asked the National Institutes of Health (NIH) to consider establishing an advisory committee on the topic, and said that “an international meeting of involved scientists from all over the world should be convened early in the coming year to review scientific progress in this area and to further discuss appropriate ways to deal with the potential biohazards of recombinant DNA molecules.” The letter was signed by the 11 members of the committee, with Paul Berg listed first, as chair. Among the others were Herb Boyer, Stan Cohen, and Ron Davis from the Bay Area’s recombinant DNA laboratories, as well as Jim Watson, codiscoverer of the structure of DNA, and a young biologist named David Baltimore, one of the discoverers of how some cells can turn RNA into DNA (for which he won a Nobel Prize).

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DAVID BALTIMORE

David Baltimore was born in March 1938 in New York City and raised in Queens until second grade, when his parents moved to the suburbs in search of better schools. He received his bachelor’s degree from Swarthmore College in 1960. He started his gradu- ate work at the Massachusetts Institute of Technology but moved to Rockefeller University, where he received his Ph.D. in 1964 for work with viruses. He went back to MIT for a postdoctoral fellowship, then got training at Albert Einstein College of Medi- cine before moving, in 1965, to a postdoc at the then- new Salk Institute in San Diego. By 1968 he was back at MIT, this time on the faculty, and there, in 1970, at the age of 32, he discovered reverse transcriptase. This enzyme disproves, or at least qualifies, the “Central Dogma” of molecular biology, announced by the venerable Francis Crick: DNA makes RNA makes protein. Instead, reverse transcriptase uses RNA to make DNA. For this discovery, Baltimore and Howard Temin (who had found the same thing independently) shared part of the Nobel Prize in Medicine or Physiology in 1975. Baltimore was 37.

Baltimore stayed at MIT until 1982 when he helped found the Whitehead Institute for Biomedical Research, an independent research center closely connected to MIT. He remained there, while being simultaneously a professor at MIT, until 1990, when he became president of the Rockefeller University in Manhattan, but only for 18 months. He resigned the presidency of Rockefeller in the wake of a research scandal involving a coauthor from MIT.11 He returned to MIT until 1997 when he was named president of the California Institute of Technology. He served until 2006, when he resigned as president in the wake of research fraud com- mitted by one of his postdocs. He has remained on the Caltech faculty since then. Over the years, Baltimore has taken part in various policy issues, from Asilomar to human germline genome editing, as well as cochairing the National Academies’ Committee on Science, Technology, and Law (CSTL).

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Ethics Discussions of CRISPR’d Babies 57

The National Academy of Sciences appointed a five person committee to organize this international meeting. Paul Berg was the chair, joined by David Baltimore, Sydney Brenner, Richard Roblin, and Maxine Singer, all eminent scientists. The result was the Asilomar Conference.

What was the Asilomar Conference? It was the best of things, and it was the worst of things. Almost from before it ended, it was lauded as a wonderful example of scientific responsibility and self- governance and denounced as a terrible example of sci- entific hubris and self- interest. It has been the subject of histo- ries, revisionist histories, and rerevisionist histories. It has been the model for other similar meetings, at Asilomar and elsewhere, though none of them achieved its fame— or infamy. It has, in short, been everything but forgotten.

But, to be concrete, it actually was a three- day conference with about 140 attendees from around the world. The attendees were mainly scientists doing, or planning, research in recombi- nant DNA but there were several government officials, 12 jour- nalists, and four lawyers.12

The meeting was held at the Asilomar Conference Grounds, located on nine acres of land at the westernmost tip of the Monterey Peninsula, between the town of Pacific Grove to the

Baltimore is a short man who, even in his early 80s, radiates power and energy. He is a force of nature, and, as I think I’ll put it, he is not afraid to lead. I first began to get to know him well in 2013 and 2014 through the CSTL. I must admit that I did not immediately take to him (when pushed, like a donkey, I tend to sit down), but with more experience with him I have seen and appreciated his less public and more contemplative side. And I have come to quite like and respect him.

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58 Chapter 4

north and what is now the Pebble Beach development to the south. The grounds were built starting in 1913 as a home for the annual conference of the Young Women’s Christian Association of the Pacific Coast and were designed by America’s first major female architect, Julia Hunt Morgan (later the main architect for William Randolph Hearst’s palatial estate, known as Hearst Castle, farther south along that coast).13 She designed 16 build- ings for the property, largely in the Arts and Crafts or California Craftsman style, 13 of which still stand. The property was never financially self- supporting for the YWCA, which, during the Depression, closed it and tried to sell it. It went through various empty periods, interspersed with different attempts to manage it profitably before, in 1956, it was purchased by the California State Park system. It was joined to state park– owned beach, tide pool, and dune property adjacent to it to become the Asilomar State Beach and Conference Grounds. The conference center was declared a National Historic Landmark in 1987 (although not for hosting the Asilomar Conference).14

For three days in February 1975 the scientists made presenta- tions on the science, its risks, their significance, and what could be done to limit them. On the second evening some of the law- yers made an eye- opening (to the scientists) presentation on the possible tort liability of the experimenters should things go wrong. That night, the organizing committee worked late writing up a document with recommendations for how to handle these experiments. Precautions were called for, and different levels of risk and types of experiments were identified, including some that the document said should not be done, at least at that time. The recommendations were debated and adopted by a majority vote of the attendees on the meeting’s last day. A more complete summary report of the conference and its recommendations was

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Ethics Discussions of CRISPR’d Babies 59

published in the Proceedings of the National Academy of Sciences four months later.15

But the news didn’t wait for that scientific publication. The 12 invited journalists had promised not to report until the con- ference ended, but then they reported a lot. Their publications, and others, carried stories about the conference, in publications as different as the New York Times, Wall Street Journal, Frankfurter Allgemeine Zeitung, Nature, and Rolling Stone.16 And the world was talking about recombinant DNA and about science’s effort to police itself.

Asilomar does have some ironies. First, it focused on the physical safety risks of recombinant DNA research, the chance that a life- form with recombinant DNA could harm lab work- ers, the public, or the environment. It did not discuss broader questions— of playing God, designer babies, hubris— that, then and now, would fascinate, and scare, the public.

Second, this exercise in scientific self- regulation actually became enforceable (in the United States) by a government action almost immediately after the conference ended. Its rec- ommendations were adopted by the NIH, acting through a Recombinant DNA Advisory Committee (RAC) that Donald Frederickson, then NIH director, had appointed shortly before the Conference. The RAC has had a long and shifting career, surviving, in spite of increasing government efforts to eliminate it over the last several decades, at least until 2019.17

And yet the idea that this was self- regulation by Science was not wrong. Asilomar helped lead to the rejection of legislative efforts to restrict or stop recombinant DNA research, in the Cam- bridge, Massachusetts, city council and in the U.S. Senate. Regula- tion was left to the NIH, an organization dominated by scientists who would at least understand the researchers’ perspectives.

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The CRISPR Discussions

Now we come to back to human germline genome editing. At 11:45 a.m. on October 2, 2014, I received an email from Jennifer Doudna. Doudna was already well on her way to being a very famous person. I had known her name since 2012 and had been following, to some extent, CRISPR’s progress, but I had never met or, as far as I know, been in the same room with her. She wrote, on behalf of an organizing group, as follows:

We (Mike Botchan, Jennifer Doudna, Jacob Corn, Ed Penhoet and Jonathan Weissman) are hosting a one- day workshop at the Carneros Inn in Napa Valley to discuss the bioethical issues raised by the explo- sion in new genomic editing methods. The purpose of this meeting is to ascertain which critical issues will warrant particular attention as the field expands into ethical territories and scientific fields that were first raised decades ago when the cloning revolution began. We would be delighted if you can join us for a day of lively discussion and brainstorming.

Twenty- three minutes later, I wrote back and said “yes” (with some questions about a scheduled flight back to the Bay Area and an upcoming, but then unscheduled, hip replacement sur- gery). I was enthusiastic: “Barring those two contingencies (as well as meteorites, World War III, the big earthquake, and all the other contingencies), yes.”

Why was I invited? I didn’t know Doudna or Botchan, Corn, or Weissman— I think I’d met Penhoet once or twice. Maybe they knew me by reputation, although I hadn’t written anything at that point about CRISPR or, in any detail, gene editing. But I did know one of her invitees, Paul Berg, I suspect he recom- mended me to Doudna, probably with support from my fellow law professor, Alta Charo.

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None of the bad contingencies came to pass, and so Janu- ary 24 found me, on a bright, clear, warm winter’s day, at a resort called the Carneros Inn in southern Napa Valley. Doudna had convened the event through the UC Berkeley Innovative Genomics Institute, which she directed (and directs). It was a meeting of a small working group. The 14 principals included mainly noted scientists, such as Nobel Prize winners Paul Berg and David Baltimore, and the soon- to- be- named dean of Har- vard Medical School, stem cell researcher George Daley. Other scientist- participants included Doudna’s fellow organizers, Botchan, Corn, Penhoet, and Weissman, and Betsy Nabel from Harvard, Jennifer Puck from UCSF, and Keith Yamamoto from UCSF, plus one video journalist, John Rubin from Tangled Bank Studios. (Kathy Hudson, Deputy Director for Science, Outreach and Policy at NIH, was supposed to attend but had to pull out at the last minute.) My friend Alta Charo of the University of Wis- consin and I were the only two lawyers/bioethicists at the meet- ing. Several students, postdocs, or staffers were also present and may have taken part in some of the substantive conversations.

The presence of Baltimore and Berg was powerfully evocative for me; they had been two of the five people on the organiz- ing committee for the Asilomar meeting. As I pointed out at the time, Asilomar had taken place in late February 1975, 40 years, less a single month, earlier.18

I took moderately detailed notes on my laptop, a habit of mine at meetings. These totaled about 900 words for the eight- hour meeting. I cannot, however, make maximal use of them here as the meeting was held under a version of Chatham House Rules— the substance of what was said can be discussed outside the group but statements cannot be attributed to individuals. I will abide by those rules (albeit with some regrets).

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The workshop started with a welcome from Doudna and introductions, then a workshop charge and goal from Doudna and Botchan. Paul Berg and David Baltimore led a spirited dis- cussion of the lessons of Asilomar (from the horses’ mouths, the agenda should have said). George Daley gave a wide- ranging talk on the future of somatic cell gene therapy, stem cell research and treatments, cloning, and in vitro gametogenesis, among other things. Then Alta Charo and I split up the legal aspects of genome engineering; she took the nonhuman aspects and I took the human ones. After a lunch break, Jacob Corn and Betsy Nabel led a discussion of emerging scenarios.

This description, which follows the premeeting agenda, makes the event sound like presentations in a lecture hall. But it wasn’t. The room was relatively small and held a long table just big enough for the 14 people at it, each of whom had things to say. These presentations were punctuated by frequent questions, pronouncements, and debate. Berg and Baltimore, in particu- lar, gave their opinions freely and often. In my notes, I called them the “old bulls,” but, as they were the two grand old men at the table— and both very smart and experienced— no one com- plained. By 3:00 the agenda called for the group to start to “draft a white paper position statement.”

Two and only two of the participants— whom I am not allowed to name— argued for at least some attention to the nonhuman uses of CRISPR, which they thought would, at least in the next few decades, likely be much more important than the human uses. The tide, however, ran strongly the other way, not just in favor of focusing on human uses but specifically on human germline uses. Some, whom I am also not able to name, expressed the view that, since Asilomar and the recombinant

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DNA debates, Science had promised that the human germline would not be manipulated and that this was a crucial issue to confront. And it is the case that, although they were not dis- cussed in any detail at the meeting, at least not openly, rumors abounded that Chinese scientists were about to announce that they used CRISPR to modify human embryos. Those rumors, whatever we thought of them, added a certain urgency to the meeting.

The group reached consensus surprisingly quickly, dividing its attention into three main areas: in vitro research, somatic cell therapy, and germline genome editing. We all agreed that CRISPR had an important and immediate role to play with regard to in vitro research in humans, had great promise for use to edit the genes of people born with genetic diseases, but should not be used— at least for the time being— for germline editing. We broke up just about on time— maybe early though my notes don’t give the time— with the goal that some of the participants would turn that consensus into a paper. Then we all, the participants and in some cases their partners or guests (my wife came), had a delightful dinner in downtown Napa, with the participants, I believe, all feeling we had put in a good day’s work. (I certainly did.) We went back to the Inn, slept at the resort, and dispersed the next day.

JENNIFER DOUDNA

That was the first time I met Jennifer Doudna,19 whom I have been fortunate to interact with another dozen or so times since then. Jennifer was born in Washington, DC, in 1964, but from the age of seven, she grew up in Hilo, on the northeast (rainy)

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corner of the Big Island of Hawai’i where her father was a profes- sor of American literature at the University of Hawai’i, Hilo. She graduated with a bachelor’s degree in biochemistry from Pomona College (home of the Sagehens) in 1985. (Like Baltimore, she is a graduate of a liberal arts college and not a research university.) She received her Ph.D. in biological chemistry and molecular pharmacology in 1989 from Harvard Medical School, writing a dissertation on RNA under the supervision of Jack Szostak, who won a Nobel Prize in 2009. After two years of postdocs in Boston, she spent four years, until 1994, as a postdoc at the University of Colorado, working with Thomas Cech, who had already won a Nobel Prize in 1989. Her first appointment as a professor was at Yale, but she moved to UC Berkeley in 2002.

Doudna did basic science research on RNA, not a sexy sub- ject. Her fame dates from her June 2012 paper on CRISPR with Emmanuelle Charpentier, but she had already been recognized as an eminent scientist. She was elected to the National Academy of Sciences in 2002, at age 38, to the American Academy of Arts and Sciences in 2003, and to the Institute of Medicine (now the National Academy of Medicine) in 2010, all before her pathbreak- ing work on CRISPR.

Doudna is a tall woman with light colored hair. She has no bluster; she speaks quietly and calmly but commands respect with what she says and how she says it. She is thoughtful and smiles a lot. I liked her immediately and, after all our interac- tions since January 2015, have only come to like her more. She seems totally unspoiled by fame. (I’ve also admired how she has become an excellent public speaker and “science explainer” with those several years of practice.) It is probably worth noting, though, that between prizes for CRISPR, interests in companies working on CRISPR, speaking fees, potential royalties from the UC system for CRISPR patents, and other income— including the royalties on her coauthored book, A Crack in Creation— she has undoubtedly made a lot of money as a result of CRISPR, with interests in the technology that are likely to continue to pay off.

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Over the next several weeks, the Napa meeting participants would get regular updates, with new drafts of a publication to comment upon. I was not one of the drafters but, along with many of the participants, offered substantive and stylistic advice to those preparing the publication. And, remarkably, in fewer than eight weeks after the Napa meeting, those drafts, with the addition of a few more authors, became an article published online in Science on March 19, 2015. 20 (The authors were listed in alphabetical order, but it did feel right to me that the alphabet made the citation start with the two Asilomar veterans, David Baltimore and Paul Berg.)

That article made four recommendations: Strongly discourage, even in those countries with lax jurisdictions

where it might be permitted, any attempts at germline genome modification for clinical application in humans, while societal, environmental, and ethical implications of such activity are dis- cussed among scientific and governmental organizations . . .

Create forums in which experts from the scientific and bioethics communities can provide information and education about this new era of human biology, the issues accompanying the risks and rewards of using such powerful technology for a wide vari- ety of applications including the potential to treat or cure human genetic disease, and the attendant ethical, social, and legal impli- cations of genome modification.

Encourage and support transparent research to evaluate the efficacy and specificity of CRISPR- Cas9 genome engineering technology in human and nonhuman model systems relevant to its potential applications for germline gene therapy . . .

Convene a globally representative group of developers and users of genome engineering technology and experts in genetics, law, and bioethics, as well as members of the scientific community, the public, and relevant government agencies and interest groups, to further consider these important issues, and where appropriate, recommend policies.

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In the meantime, another article on the use of CRISPR in humans had appeared online the week before in Nature, calling for an absolute ban on germline modifications in humans, in part expressly to prevent germline genome editing from sour- ing the public on the good uses of CRISPR in somatic cell gene therapy.21 And, on April 18, the shoe dropped with the publica- tion of an article by Chinese scientists, discussed in chapter 1, reporting that they had, with some limited success, used CRISPR to edit (nonviable) human embryos.22

This narrative should sound familiar from the discussion of Asilomar. A small group of leading researchers meets at a work- shop and worries about the ethical issues raised by a new technol- ogy. They publish their concerns and call for, among other things, more discussion. And the next step unfolded in the same general way as the Asilomar Conference process: the U.S. National Acad- emy of Sciences and National Academy of Medicine got involved. On May 18, 2015, the presidents of the two academies announced the creation of a Human Genome Editing Initiative along with a conference to be held at a yet to be determined date and place.23 (At least one newspaper article says, without a stated source, that Doudna wanted the conference to be organized by the Howard Hughes Medical Institute, a large science philanthropy, but Bal- timore had pushed for National Academies.24) On June 15, the Academies announced the membership of a 14- person advisory group for this initiative. It included Baltimore, Berg, Charo, Doudna, Penhoet, and Yamamoto from the Napa meeting.25

The details of the initiative’s conference were announced on September 14— an International Summit on Human Gene Editing, to be held in Washington, DC, from December 1 to 3, 2015.26 This was jointly sponsored by the National Academy of Sciences, the National Academy of Medicine, the Royal Society

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of the United Kingdom, and the Chinese Academy of Sciences. The organizing committee, announced the same day, included David Baltimore as chair, along with Napa meeting alumni Paul Berg, George Daley, and Jennifer Doudna. Other notable additions included Eric Lander from the Broad Institute, Cana- dian bioethicist Françoise Baylis, and British researcher Robin Lovell- Badge.

This highly publicized two- and- a- half- day event was held in the main auditorium of the Academies’ impressive 1924 build- ing, lodged between the National Mall to its south and the State Department to its north. It included scores of speakers and pan- elists and even more journalists. (Information about this first summit, including the agenda and links to video recordings of the entire event, can be found on the initiative’s website, 27 and the Academies’ summary of the summit, prepared by science journalist Steve Olson, is also available.28)

My own role (other than engaged listening) was limited to moderating the very last panel of the event, on governance, regulation, and control. That panel was followed by lunch and “closing thoughts” from organizing committee chair David Bal- timore. Baltimore’s closing thoughts included a statement from its organizing committee, prepared, no doubt, over the previ- ous day and night. 29 This statement was not an official position of the National Academy of Sciences, the National Academy of Medicine, or other sponsors, as those entities were quick to stress, but was the organizing committee speaking for itself. The statement’s recommendations were quite similar to those of the March 2015 Science article— perhaps not surprisingly, since David Baltimore chaired the organizing committee.

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The short statement, under 1,000 words, encouraged basic and clinical research as well as somatic cell clinical uses. As to germline uses, the committee concluded,

It would be irresponsible to proceed with any clinical use of germ- line editing unless and until (i) the relevant safety and efficacy issues have been resolved, based on appropriate understanding and bal- ancing of risks, potential benefits, and alternatives, and (ii) there is broad societal consensus about the appropriateness of the proposed application. Moreover, any clinical use should proceed only under appropriate regulatory oversight. At present, these criteria have not been met for any proposed clinical use: the safety issues have not yet been adequately explored; the cases of most compelling benefit are limited; and many nations have legislative or regulatory bans on germline modification. However, as scientific knowledge advances and societal views evolve, the clinical use of germline editing should be revisited on a regular basis.

It then pointed out the international importance of the question:

While each nation ultimately has the authority to regulate activi- ties under its jurisdiction, the human genome is shared among all nations. The international community should strive to establish norms concerning acceptable uses of human germline editing and to harmonize regulations, in order to discourage unacceptable activities while advancing human health and welfare.

And it called for an ongoing international forum to continue discussing these issues, with a “wide range of perspectives and expertise— including from biomedical scientists, social scientists, ethicists, health care providers, patients and their families, peo- ple with disabilities, policymakers, regulators, research funders, faith leaders, public interest advocates, industry representatives, and members of the general public.”

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Ethics Discussions of CRISPR’d Babies 69

ALTA CHARO

I can’t quite figure out how long I’ve known R. Alta Charo (don’t ask about the “R”; she doesn’t use it); it has been at least since 2003 but probably earlier. Charo is a law (and bioethics) professor at the University of Wisconsin at Madison. She grew up in New York City and graduated from Harvard in 1979 with a biology degree, then got her JD from Columbia in 1982. At some point during those years, she spent at least some time doing labora- tory work looking at chromosome numbers in embryos. This was an omen of a career spent in bioethics and particularly on repro- ductive and stem cell issues. After law school she worked, among other places, in the Biological Applications Program of the late (as of 1995) and lamented (still today, by some of us) Congressional Office of Technology Assessment. She joined the Wisconsin fac- ulty in 1989, and, with the exception of various visits and leaves, she has been there ever since.

In spite of her Madison, Wisconsin, address, much of Charo’s work has been conducted in Washington, DC. She served on an NIH Human Embryo Research Panel in the early 1990s and on Pres- ident Clinton’s National Bioethics Advisory Commission. She has served on innumerable National Academy of Sciences or Medicine committees and boards; she was elected a member of the National Academy of Medicine in 2006. She worked on President Obama’s transition team for the U.S. Department of Health and Human Ser- vices (HHS) and stayed in Washington until 2011, serving as a senior policy advisor on emerging technology issues at the U.S. Food and Drug Administration (FDA) before returning to Wisconsin.

Charo is regularly asked to do these things mainly because she is smart and hardworking, with good writing and political skills, but I suspect also because she is fun to have around. She is verbally quick, with a flashing sense of humor, sometimes self- deprecating (as in the jokes about how short she is). She loves various itera- tions of Star Trek and composing satirical lyrics to show tunes. (I live in fear that she has one with my name in it.)

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The National Academy of Sciences and the National Academy of Medicine followed up the summit with a February 14, 2017, consensus report, written by a 22- person committee, which Alta Charo cochaired with MIT scientist Richard Hynes.

This Valentine’s Day report, like most Academies reports, was the result of many public and private meetings and a long engagement with many peer reviews.30 The report, as do all such National Academies’ reports, states the “official position” of the Academies. The report had chapters on basic research, somatic genome editing, heritable (germline) genome editing, enhance- ment, and public engagement. It offered clear, and strong, conclusions on germline genome editing: “In particular, clini- cal trials using heritable germline editing should be permitted only if done within a regulatory framework that includes the following [10] criteria and structures. . . .” These criteria deal at some length with the conditions to be addressed by the editing and the mechanisms by which it should be considered and car- ried out:

1. absence of reasonable alternatives; 2. restriction to preventing a serious disease or condition; 3. restriction to editing genes that have been convincingly dem-

onstrated to cause or to strongly predispose to the disease or condition;

4. restriction to converting such genes to versions that are prevalent in the population and are known to be associated with ordinary health with little or no evidence of adverse effects;

5. availability of credible preclinical and/or clinical data on risks and potential health benefits of the procedures;

6. ongoing, rigorous oversight during clinical trials of the effects of the procedure on the health and safety of the research participants;

7. comprehensive plans for long- term, multigenerational follow- up while still respecting personal autonomy;

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8. maximum transparency consistent with patient privacy; 9. continued reassessment of both health and societal benefits

and risks, with broad ongoing participation and input by the pub- lic; and

10. reliable oversight mechanisms to prevent extension to uses other than preventing a serious disease or condition.31

The report noted the difficulties of defining “enhancement”:

For example, using genome editing to lower the cholesterol level of someone with abnormally high cholesterol might be considered pre- vention of heart disease, but using it to lower cholesterol that is in the desirable range is less easily characterized, and would either inter- vention differ from the current use of statins?32

That chapter concluded that “genome editing for purposes other than treatment or prevention of disease and disability should not proceed at this time, and that it is essential for these public discussions to precede any decisions about whether, or how, to pursue clinical trials of such applications.” 33

The authors pushed strongly for public engagement in deci- sions about genome editing, specifically recommending that, “[w]ith respect to heritable germline editing, broad participa- tion and input by the public and ongoing reassessment of both health and societal benefits and risks are particularly critical con- ditions for approval of clinical trials.”

Some commentaries on the National Academy of Sciences/ National Academy of Medicine report saw it as opposing heri- table genome editing; others saw it as permissive.34 Meanwhile, in the United Kingdom, the Nuffield Council, an independent nonprofit bioethics advisory group, issued two relevant reports. In 2016, it issued a general report entitled Genome Editing: An Ethical Review.35 And then, in July 2018, it issued Genome Editing and Human Reproduction, saying, “We conclude that the potential

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use of heritable genome editing interventions to influence the characteristics of future generations could be ethically accept- able.”36 Their eight requirements and recommendations overlap some with those of the Valentine’s Day report but, interestingly, include more explicit discussion of social issues and of specific regulatory recommendations (albeit for the United Kingdom only). It wrote,

We conclude that the potential use of heritable genome editing inter- ventions to influence the characteristics of future generations could be ethically acceptable in some circumstances, so long as:

• it is intended to secure, and is consistent with, the welfare of a person who may be born as a consequence of interventions using genome edited cells; and

• it is consistent with social justice and solidarity, i.e. it should not be expected to increase disadvantage, discrimination, or division in society.

• We recommend that research should be carried out on the safety and feasibility of heritable genome editing interventions to estab- lish standards for clinical use.

• We recommend that social research should be carried out to develop greater understanding of the implications of genome editing for the welfare of the future person.

• We recommend that before any move is made to amend UK leg- islation to permit heritable genome editing interventions, there should be sufficient opportunity for broad and inclusive societal debate.

• We recommend the establishment of an independent UK body to promote public debate on the use of genomic and related tech- nologies to respond to societal challenges; to help to identify and understand the public interests at stake; and to monitor social, cultural, legal, and health impacts.

• We recommend that governments in the UK and elsewhere should work with international human rights institutions, such

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