Tag Archives: Jennifer Doudna

CRISPR patent decision: Harvard’s and MIT’s Broad Institute victorious—for now

I have written about the CRISPR patent tussle (Harvard & MIT’s [Massachusetts Institute of Technology] Broad Institute vs the University of California at Berkeley) previously in a Jan. 6, 2015 posting and in a more detailed May 14, 2015 posting. I also mentioned (in a Jan. 17, 2017 posting) CRISPR and its patent issues in the context of a posting about a Slate.com series on Frankenstein and the novel’s applicability to our own time. This patent fight is being bitterly fought as fortunes are at stake.

It seems a decision has been made regarding the CRISPR patent claims. From a Feb. 17, 2017 article by Charmaine Distor for The Science Times,

After an intense court battle, the US Patent and Trademark Office (USPTO) released its ruling on February 15 [2017]. The rights for the CRISPR-Cas9 gene editing technology was handed over to the Broad Institute of Harvard University and the Massachusetts Institute of Technology (MIT).

According to an article in Nature, the said court battle was between the Broad Institute and the University of California. The two institutions are fighting over the intellectual property right for the CRISPR patent. The case between the two started when the patent was first awarded to the Broad Institute despite having the University of California apply first for the CRISPR patent.

Heidi Ledford’s Feb. 17, 2017 article for Nature provides more insight into the situation (Note: Links have been removed),

It [USPTO] ruled that the Broad Institute of Harvard and MIT in Cambridge could keep its patents on using CRISPR–Cas9 in eukaryotic cells. That was a blow to the University of California in Berkeley, which had filed its own patents and had hoped to have the Broad’s thrown out.

The fight goes back to 2012, when Jennifer Doudna at Berkeley, Emmanuelle Charpentier, then at the University of Vienna, and their colleagues outlined how CRISPR–Cas9 could be used to precisely cut isolated DNA1. In 2013, Feng Zhang at the Broad and his colleagues — and other teams — showed2 how it could be adapted to edit DNA in eukaryotic cells such as plants, livestock and humans.

Berkeley filed for a patent earlier, but the USPTO granted the Broad’s patents first — and this week upheld them. There are high stakes involved in the ruling. The holder of key patents could make millions of dollars from CRISPR–Cas9’s applications in industry: already, the technique has sped up genetic research, and scientists are using it to develop disease-resistant livestock and treatments for human diseases.

But the fight for patent rights to CRISPR technology is by no means over. Here are four reasons why.

1. Berkeley can appeal the ruling

2. European patents are still up for grabs

3. Other parties are also claiming patent rights on CRISPR–Cas9

4. CRISPR technology is moving beyond what the patents cover

As for Ledford’s 3rd point, there are an estimated 763 patent families (groups of related patents) claiming CAS9 leading to the distinct possibility that the Broad Institute will be fighting many patent claims in the future.

Once you’ve read Distor’s and Ledford’s articles, you may want to check out Adam Rogers’ and Eric Niiler’s Feb. 16, 2017 CRISPR patent article for Wired,

The fight over who owns the most promising technique for editing genes—cutting and pasting the stuff of life to cure disease and advance scientific knowledge—has been a rough one. A team on the West Coast, at UC Berkeley, filed patents on the method, Crispr-Cas9; a team on the East Coast, based at MIT and the Broad Institute, filed their own patents in 2014 after Berkeley’s, but got them granted first. The Berkeley group contended that this constituted “interference,” and that Berkeley deserved the patent.

At stake: millions, maybe billions of dollars in biotech money and licensing fees, the future of medicine, the future of bioscience. Not nothing. Who will benefit depends on who owns the patents.

On Wednesday [Feb. 15, 2017], the US Patent Trial and Appeal Board kind of, sort of, almost began to answer that question. Berkeley will get the patent for using the system called Crispr-Cas9 in any living cell, from bacteria to blue whales. Broad/MIT gets the patent in eukaryotic cells, which is to say, plants and animals.

It’s … confusing. “The patent that the Broad received is for the use of Crispr gene-editing technology in eukaryotic cells. The patent for the University of California is for all cells,” says Jennifer Doudna, the UC geneticist and co-founder of Caribou Biosciences who co-invented Crispr, on a conference call. Her metaphor: “They have a patent on green tennis balls; we have a patent for all tennis balls.”

Observers didn’t quite buy that topspin. If Caribou is playing tennis, it’s looking like Broad/MIT is Serena Williams.

“UC does not necessarily lose everything, but they’re no doubt spinning the story,” says Robert Cook-Deegan, an expert in genetic policy at Arizona State University’s School for the Future of Innovation in Society. “UC’s claims to eukaryotic uses of Crispr-Cas9 will not be granted in the form they sought. That’s a big deal, and UC was the big loser.”

UC officials said Wednesday [Feb. 15, 2017] that they are studying the 51-page decision and considering whether to appeal. That leaves members of the biotechnology sector wondering who they will have to pay to use Crispr as part of a business—and scientists hoping the outcome won’t somehow keep them from continuing their research.

….

Happy reading!

Essays on Frankenstein

Slate.com is dedicating a month (January 2017) to Frankenstein. This means there were will be one or more essays each week on one aspect or another of Frankenstein and science. These essays are one of a series of initiatives jointly supported by Slate, Arizona State University, and an organization known as New America. It gets confusing since these essays are listed as part of two initiatives:  Futurography and Future Tense.

The really odd part, as far as I’m concerned, is that there is no mention of Arizona State University’s (ASU) The Frankenstein Bicentennial Project (mentioned in my Oct. 26, 2016 posting). Perhaps they’re concerned that people will think ASU is advertising the project?

Introductions

Getting back to the essays, a Jan. 3, 2017 article by Jacob Brogan explains, by means of a ‘Question and Answer’ format article, why the book and the monster maintain popular interest after two centuries (Note: We never do find out who or how many people are supplying the answers),

OK, fine. I get that this book is important, but why are we talking about it in a series about emerging technology?

Though people still tend to weaponize it as a simple anti-scientific screed, Frankenstein, which was first published in 1818, is much richer when we read it as a complex dialogue about our relationship to innovation—both our desire for it and our fear of the changes it brings. Mary Shelley was just a teenager when she began to compose Frankenstein, but she was already grappling with our complex relationship to new forces. Almost two centuries on, the book is just as propulsive and compelling as it was when it was first published. That’s partly because it’s so thick with ambiguity—and so resistant to easy interpretation.

Is it really ambiguous? I mean, when someone calls something frankenfood, they aren’t calling it “ethically ambiguous food.”

It’s a fair point. For decades, Frankenstein has been central to discussions in and about bioethics. Perhaps most notably, it frequently crops up as a reference point in discussions of genetically modified organisms, where the prefix Franken- functions as a sort of convenient shorthand for human attempts to meddle with the natural order. Today, the most prominent flashpoint for those anxieties is probably the clustered regularly interspaced short palindromic repeats, or CRISPR, gene-editing technique [emphasis mine]. But it’s really oversimplifying to suggest Frankenstein is a cautionary tale about monkeying with life.

As we’ll see throughout this month on Futurography, it’s become a lens for looking at the unintended consequences of things like synthetic biology, animal experimentation, artificial intelligence, and maybe even social networking. Facebook, for example, has arguably taken on a life of its own, as its algorithms seem to influence the course of elections. Mark Zuckerberg, who’s sometimes been known to disavow the power of his own platform, might well be understood as a Frankensteinian figure, amplifying his creation’s monstrosity by neglecting its practical needs.

But this book is almost 200 years old! Surely the actual science in it is bad.

Shelley herself would probably be the first to admit that the science in the novel isn’t all that accurate. Early in the novel, Victor Frankenstein meets with a professor who castigates him for having read the wrong works of “natural philosophy.” Shelley’s protagonist has mostly been studying alchemical tomes and otherwise fantastical works, the sort of things that were recognized as pseudoscience, even by the standards of the day. Near the start of the novel, Frankenstein attends a lecture in which the professor declaims on the promise of modern science. He observes that where the old masters “promised impossibilities and performed nothing,” the new scientists achieve far more in part because they “promise very little; they know that metals cannot be transmuted and that the elixir of life is a chimera.”

Is it actually about bad science, though?

Not exactly, but it has been read as a story about bad scientists.

Ultimately, Frankenstein outstrips his own teachers, of course, and pulls off the very feats they derided as mere fantasy. But Shelley never seems to confuse fact and fiction, and, in fact, she largely elides any explanation of how Frankenstein pulls off the miraculous feat of animating dead tissue. We never actually get a scene of the doctor awakening his creature. The novel spends far more dwelling on the broader reverberations of that act, showing how his attempt to create one life destroys countless others. Read in this light, Frankenstein isn’t telling us that we shouldn’t try to accomplish new things, just that we should take care when we do.

This speaks to why the novel has stuck around for so long. It’s not about particular scientific accomplishments but the vagaries of scientific progress in general.

Does that make it into a warning against playing God?

It’s probably a mistake to suggest that the novel is just a critique of those who would usurp the divine mantle. Instead, you can read it as a warning about the ways that technologists fall short of their ambitions, even in their greatest moments of triumph.

Look at what happens in the novel: After bringing his creature to life, Frankenstein effectively abandons it. Later, when it entreats him to grant it the rights it thinks it deserves, he refuses. Only then—after he reneges on his responsibilities—does his creation really go bad. We all know that Frankenstein is the doctor and his creation is the monster, but to some extent it’s the doctor himself who’s made monstrous by his inability to take responsibility for what he’s wrought.

I encourage you to read Brogan’s piece in its entirety and perhaps supplement the reading. Mary Shelley has a pretty interesting history. She ran off with Percy Bysshe Shelley who was married to another woman, in 1814  at the age of seventeen years. Her parents were both well known and respected intellectuals and philosophers, William Godwin and Mary Wollstonecraft. By the time Mary Shelley wrote her book, her first baby had died and she had given birth to a second child, a boy.  Percy Shelley was to die a few years later as was her son and a third child she’d given birth to. (Her fourth child born in 1819 did survive.) I mention the births because one analysis I read suggests the novel is also a commentary on childbirth. In fact, the Frankenstein narrative has been examined from many perspectives (other than science) including feminism and LGBTQ studies.

Getting back to the science fiction end of things, the next part of the Futurography series is titled “A Cheat-Sheet Guide to Frankenstein” and that too is written by Jacob Brogan with a publication date of Jan. 3, 2017,

Key Players

Marilyn Butler: Butler, a literary critic and English professor at the University of Cambridge, authored the seminal essay “Frankenstein and Radical Science.”

Jennifer Doudna: A professor of chemistry and biology at the University of California, Berkeley, Doudna helped develop the CRISPR gene-editing technique [emphasis mine].

Stephen Jay Gould: Gould is an evolutionary biologist and has written in defense of Frankenstein’s scientific ambitions, arguing that hubris wasn’t the doctor’s true fault.

Seán Ó hÉigeartaigh: As executive director of the Center for Existential Risk at the University of Cambridge, hÉigeartaigh leads research into technologies that threaten the existience of our species.

Jim Hightower: This columnist and activist helped popularize the term frankenfood to describe genetically modified crops.

Mary Shelley: Shelley, the author of Frankenstein, helped create science fiction as we now know it.

J. Craig Venter: A leading genomic researcher, Venter has pursued a variety of human biotechnology projects.

Lingo

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Debates

Popular Culture

Further Reading

….

‘Franken’ and CRISPR

The first essay is in a Jan. 6, 2016 article by Kay Waldman focusing on the ‘franken’ prefix (Note: links have been removed),

In a letter to the New York Times on June 2, 1992, an English professor named Paul Lewis lopped off the top of Victor Frankenstein’s surname and sewed it onto a tomato. Railing against genetically modified crops, Lewis put a new generation of natural philosophers on notice: “If they want to sell us Frankenfood, perhaps it’s time to gather the villagers, light some torches and head to the castle,” he wrote.

William Safire, in a 2000 New York Times column, tracked the creation of the franken- prefix to this moment: an academic channeling popular distrust of science by invoking the man who tried to improve upon creation and ended up disfiguring it. “There’s no telling where or how it will end,” he wrote wryly, referring to the spread of the construction. “It has enhanced the sales of the metaphysical novel that Ms. Shelley’s husband, the poet Percy Bysshe Shelley, encouraged her to write, and has not harmed sales at ‘Frank’n’Stein,’ the fast-food chain whose hot dogs and beer I find delectably inorganic.” Safire went on to quote the American Dialect Society’s Laurence Horn, who lamented that despite the ’90s flowering of frankenfruits and frankenpigs, people hadn’t used Frankensense to describe “the opposite of common sense,” as in “politicians’ motivations for a creatively stupid piece of legislation.”

A year later, however, Safire returned to franken- in dead earnest. In an op-ed for the Times avowing the ethical value of embryonic stem cell research, the columnist suggested that a White House conference on bioethics would salve the fears of Americans concerned about “the real dangers of the slippery slope to Frankenscience.”

All of this is to say that franken-, the prefix we use to talk about human efforts to interfere with nature, flips between “funny” and “scary” with ease. Like Shelley’s monster himself, an ungainly patchwork of salvaged parts, it can seem goofy until it doesn’t—until it taps into an abiding anxiety that technology raises in us, a fear of overstepping.

Waldman’s piece hints at how language can shape discussions while retaining a rather playful quality.

This series looks to be a good introduction while being a bit problematic in spots, which roughly sums up my conclusion about their ‘nano’ series in my Oct. 7, 2016 posting titled: Futurography’s nanotechnology series: a digest.

By the way, I noted the mention of CRISPR as it brought up an issue that they don’t appear to be addressing in this series (perhaps they will do this elsewhere?): intellectual property.

There’s a patent dispute over CRISPR as noted in this American Chemical Society’s Chemistry and Engineering News Jan. 9, 2017 video,

Playing God

This series on Frankenstein is taking on other contentious issues. A perennial favourite is ‘playing God’ as noted in Bina Venkataraman’s Jan. 11, 2017 essay on the topic,

Since its publication nearly 200 years ago, Shelley’s gothic novel has been read as a cautionary tale of the dangers of creation and experimentation. James Whale’s 1931 film took the message further, assigning explicitly the hubris of playing God to the mad scientist. As his monster comes to life, Dr. Frankenstein, played by Colin Clive, triumphantly exclaims: “Now I know what it feels like to be God!”

The admonition against playing God has since been ceaselessly invoked as a rhetorical bogeyman. Secular and religious, critic and journalist alike have summoned the term to deride and outright dismiss entire areas of research and technology, including stem cells, genetically modified crops, recombinant DNA, geoengineering, and gene editing. As we near the two-century commemoration of Shelley’s captivating story, we would be wise to shed this shorthand lesson—and to put this part of the Frankenstein legacy to rest in its proverbial grave.

The trouble with the term arises first from its murkiness. What exactly does it mean to play God, and why should we find it objectionable on its face? All but zealots would likely agree that it’s fine to create new forms of life through selective breeding and grafting of fruit trees, or to use in-vitro fertilization to conceive life outside the womb to aid infertile couples. No one objects when people intervene in what some deem “acts of God,” such as earthquakes, to rescue victims and provide relief. People get fully behind treating patients dying of cancer with “unnatural” solutions like chemotherapy. Most people even find it morally justified for humans to mete out decisions as to who lives or dies in the form of organ transplant lists that prize certain people’s survival over others.

So what is it—if not the imitation of a deity or the creation of life—that inspires people to invoke the idea of “playing God” to warn against, or even stop, particular technologies? A presidential commission charged in the early 1980s with studying the ethics of genetic engineering of humans, in the wake of the recombinant DNA revolution, sheds some light on underlying motivations. The commission sought to understand the concerns expressed by leaders of three major religious groups in the United States—representing Protestants, Jews, and Catholics—who had used the phrase “playing God” in a 1980 letter to President Jimmy Carter urging government oversight. Scholars from the three faiths, the commission concluded, did not see a theological reason to flat-out prohibit genetic engineering. Their concerns, it turned out, weren’t exactly moral objections to scientists acting as God. Instead, they echoed those of the secular public; namely, they feared possible negative effects from creating new human traits or new species. In other words, the religious leaders who called recombinant DNA tools “playing God” wanted precautions taken against bad consequences but did not inherently oppose the use of the technology as an act of human hubris.

She presents an interesting argument and offers this as a solution,

The lesson for contemporary science, then, is not that we should cease creating and discovering at the boundaries of current human knowledge. It’s that scientists and technologists ought to steward their inventions into society, and to more rigorously participate in public debate about their work’s social and ethical consequences. Frankenstein’s proper legacy today would be to encourage researchers to address the unsavory implications of their technologies, whether it’s the cognitive and social effects of ubiquitous smartphone use or the long-term consequences of genetically engineered organisms on ecosystems and biodiversity.

Some will undoubtedly argue that this places an undue burden on innovators. Here, again, Shelley’s novel offers a lesson. Scientists who cloister themselves as Dr. Frankenstein did—those who do not fully contemplate the consequences of their work—risk later encounters with the horror of their own inventions.

At a guess, Venkataraman seems to be assuming that if scientists communicate and make their case that the public will cease to panic with reference moralistic and other concerns. My understanding is that social scientists have found this is not the case. Someone may understand the technology quite well and still oppose it.

Frankenstein and anti-vaxxers

The Jan. 16, 2017 essay by Charles Kenny is the weakest of the lot, so far (Note: Links have been removed),

In 1780, University of Bologna physician Luigi Galvani found something peculiar: When he applied an electric current to the legs of a dead frog, they twitched. Thirty-seven years later, Mary Shelley had Galvani’s experiments in mind as she wrote her fable of Faustian overreach, wherein Dr. Victor Frankenstein plays God by reanimating flesh.

And a little less than halfway between those two dates, English physician Edward Jenner demonstrated the efficacy of a vaccine against smallpox—one of the greatest killers of the age. Given the suspicion with which Romantic thinkers like Shelley regarded scientific progress, it is no surprise that many at the time damned the procedure as against the natural order. But what is surprising is how that suspicion continues to endure, even after two centuries of spectacular successes for vaccination. This anti-vaccination stance—which now infects even the White House—demonstrates the immense harm that can be done by excessive distrust of technological advance.

Kenny employs history as a framing device. Crudely, Galvani’s experiments led to Mary Shelley’s Frankenstein which is a fable about ‘playing God’. (Kenny seems unaware there are many other readings of and perspectives on the book.) As for his statement ” … the suspicion with which Romantic thinkers like Shelley regarded scientific progress … ,” I’m not sure how he arrived at his conclusion about Romantic thinkers. According to Richard Holmes (in his book, The Age of Wonder: How the Romantic Generation Discovered the Beauty and Terror of Science), their relationship to science was more complex. Percy Bysshe Shelley ran ballooning experiments and wrote poetry about science, which included footnotes for the literature and concepts he was referencing; John Keats was a medical student prior to his establishment as a poet; and Samuel Taylor Coleridge (The Rime of the Ancient Mariner, etc.) maintained a healthy correspondence with scientists of the day sometimes influencing their research. In fact, when you analyze the matter, you realize even scientists are, on occasion, suspicious of science.

As for the anti-vaccination wars, I wish this essay had been more thoughtful. Yes, Andrew Wakefield’s research showing a link between MMR (measles, mumps, and rubella) vaccinations and autism is a sham. However, having concerns and suspicions about technology does not render you a fool who hasn’t progressed from 18th/19th Century concerns and suspicions about science and technology. For example, vaccines are being touted for all kinds of things, the latest being a possible antidote to opiate addiction (see Susan Gados’ June 28, 2016 article for ScienceNews). Are we going to be vaccinated for everything? What happens when you keep piling vaccination on top of vaccination? Instead of a debate, the discussion has devolved to: “I’m right and you’re wrong.”

For the record, I’m grateful for the vaccinations I’ve had and the diminishment of diseases that were devastating and seem to be making a comeback with this current anti-vaccination fever. That said, I think there are some important questions about vaccines.

Kenny’s essay could have been a nuanced discussion of vaccines that have clearly raised the bar for public health and some of the concerns regarding the current pursuit of yet more vaccines. Instead, he’s been quite dismissive of anyone who questions vaccination orthodoxy.

The end of this piece

There will be more essays in Slate’s Frankenstein series but I don’t have time to digest and write commentary for all of them.

Please use this piece as a critical counterpoint to some of the series and, if I’ve done my job, you’ll critique this critique. Please do let me know if you find any errors or want to add an opinion or add your own critique in the Comments of this blog.

ETA Jan. 25, 2017: Here’s the Frankenstein webspace on Slate’s Futurography which lists all the essays in this series. It’s well worth looking at the list. There are several that were not covered here.

CRISPR genome editing tools and human genetic engineering issues

This post is going to feature a human genetic engineering roundup of sorts.

First, the field of human genetic engineering encompasses more than the human genome as this paper (open access until June 5, 2015) notes in the context of a discussion about a specific CRISPR gene editing tool,

CRISPR-Cas9 Based Genome Engineering: Opportunities in Agri-Food-Nutrition and Healthcare by Rajendran Subin Raj Cheri Kunnumal, Yau Yuan-Yeu, Pandey Dinesh, and Kumar Anil. OMICS: A Journal of Integrative Biology. May 2015, 19(5): 261-275. doi:10.1089/omi.2015.0023 Published Online Ahead of Print: April 14, 2015

Here’s more about the paper from a May 7, 2015 Mary Ann Liebert publisher news release on EurekAlert,

Researchers have customized and refined a technique derived from the immune system of bacteria to develop the CRISPR-Cas9 genome engineering system, which enables targeted modifications to the genes of virtually any organism. The discovery and development of CRISPR-Cas9 technology, its wide range of potential applications in the agriculture/food industry and in modern medicine, and emerging regulatory issues are explored in a Review article published in OMICS: A Journal of Integrative Biology, …

“CRISPR-Cas9 Based Genome Engineering: Opportunities in Agri-Food-Nutrition and Healthcare” provides a detailed description of the CRISPR system and its applications in post-genomics biology. Subin Raj, Cheri Kunnumal Rajendran, Dinish Pandey, and Anil Kumar, G.B. Pant University of Agriculture and Technology (Uttarakhand, India) and Yuan-Yeu Yau, Northeastern State University (Broken Arrow, OK) describe the advantages of the RNA-guided Cas9 endonuclease-based technology, including the activity, specificity, and target range of the enzyme. The authors discuss the rapidly expanding uses of the CRISPR system in both basic biological research and product development, such as for crop improvement and the discovery of novel therapeutic agents. The regulatory implications of applying CRISPR-based genome editing to agricultural products is an evolving issue awaiting guidance by international regulatory agencies.

“CRISPR-Cas9 technology has triggered a revolution in genome engineering within living systems,” says OMICS Editor-in-Chief Vural Özdemir, MD, PhD, DABCP. “This article explains the varied applications and potentials of this technology from agriculture to nutrition to medicine.

Intellectual property (patents)

The CRISPR technology has spawned a number of intellectual property (patent) issues as a Dec. 21,2014 post by Glyn Moody on Techdirt stated,

Although not many outside the world of the biological sciences have heard of it yet, the CRISPR gene editing technique may turn out to be one of the most important discoveries of recent years — if patent battles don’t ruin it. Technology Review describes it as:

… an invention that may be the most important new genetic engineering technique since the beginning of the biotechnology age in the 1970s. The CRISPR system, dubbed a “search and replace function” for DNA, lets scientists easily disable genes or change their function by replacing DNA letters. During the last few months, scientists have shown that it’s possible to use CRISPR to rid mice of muscular dystrophy, cure them of a rare liver disease, make human cells immune to HIV, and genetically modify monkeys.

Unfortunately, rivalry between scientists claiming the credit for key parts of CRISPR threatens to spill over into patent litigation:

[A researcher at the MIT-Harvard Broad Institute, Feng] Zhang cofounded Editas Medicine, and this week the startup announced that it had licensed his patent from the Broad Institute. But Editas doesn’t have CRISPR sewn up. That’s because [Jennifer] Doudna, a structural biologist at the University of California, Berkeley, was a cofounder of Editas, too. And since Zhang’s patent came out, she’s broken off with the company, and her intellectual property — in the form of her own pending patent — has been licensed to Intellia, a competing startup unveiled only last month. Making matters still more complicated, [another CRISPR researcher, Emmanuelle] Charpentier sold her own rights in the same patent application to CRISPR Therapeutics.

Things are moving quickly on the patent front, not least because the Broad Institute paid extra to speed up its application, conscious of the high stakes at play here:

Along with the patent came more than 1,000 pages of documents. According to Zhang, Doudna’s predictions in her own earlier patent application that her discovery would work in humans was “mere conjecture” and that, instead, he was the first to show it, in a separate and “surprising” act of invention.

The patent documents have caused consternation. The scientific literature shows that several scientists managed to get CRISPR to work in human cells. In fact, its easy reproducibility in different organisms is the technology’s most exciting hallmark. That would suggest that, in patent terms, it was “obvious” that CRISPR would work in human cells, and that Zhang’s invention might not be worthy of its own patent.

….

Ethical and moral issues

The CRISPR technology has reignited a discussion about ethical and moral issues of human genetic engineering some of which is reviewed in an April 7, 2015 posting about a moratorium by Sheila Jasanoff, J. Benjamin Hurlbut and Krishanu Saha for the Guardian science blogs (Note: A link has been removed),

On April 3, 2015, a group of prominent biologists and ethicists writing in Science called for a moratorium on germline gene engineering; modifications to the human genome that will be passed on to future generations. The moratorium would apply to a technology called CRISPR/Cas9, which enables the removal of undesirable genes, insertion of desirable ones, and the broad recoding of nearly any DNA sequence.

Such modifications could affect every cell in an adult human being, including germ cells, and therefore be passed down through the generations. Many organisms across the range of biological complexity have already been edited in this way to generate designer bacteria, plants and primates. There is little reason to believe the same could not be done with human eggs, sperm and embryos. Now that the technology to engineer human germlines is here, the advocates for a moratorium declared, it is time to chart a prudent path forward. They recommend four actions: a hold on clinical applications; creation of expert forums; transparent research; and a globally representative group to recommend policy approaches.

The authors go on to review precedents and reasons for the moratorium while suggesting we need better ways for citizens to engage with and debate these issues,

An effective moratorium must be grounded in the principle that the power to modify the human genome demands serious engagement not only from scientists and ethicists but from all citizens. We need a more complex architecture for public deliberation, built on the recognition that we, as citizens, have a duty to participate in shaping our biotechnological futures, just as governments have a duty to empower us to participate in that process. Decisions such as whether or not to edit human genes should not be left to elite and invisible experts, whether in universities, ad hoc commissions, or parliamentary advisory committees. Nor should public deliberation be temporally limited by the span of a moratorium or narrowed to topics that experts deem reasonable to debate.

I recommend reading the post in its entirety as there are nuances that are best appreciated in the entirety of the piece.

Shortly after this essay was published, Chinese scientists announced they had genetically modified (nonviable) human embryos. From an April 22, 2015 article by David Cyranoski and Sara Reardon in Nature where the research and some of the ethical issues discussed,

In a world first, Chinese scientists have reported editing the genomes of human embryos. The results are published1 in the online journal Protein & Cell and confirm widespread rumours that such experiments had been conducted — rumours that sparked a high-profile debate last month2, 3 about the ethical implications of such work.

In the paper, researchers led by Junjiu Huang, a gene-function researcher at Sun Yat-sen University in Guangzhou, tried to head off such concerns by using ‘non-viable’ embryos, which cannot result in a live birth, that were obtained from local fertility clinics. The team attempted to modify the gene responsible for β-thalassaemia, a potentially fatal blood disorder, using a gene-editing technique known as CRISPR/Cas9. The researchers say that their results reveal serious obstacles to using the method in medical applications.

“I believe this is the first report of CRISPR/Cas9 applied to human pre-implantation embryos and as such the study is a landmark, as well as a cautionary tale,” says George Daley, a stem-cell biologist at Harvard Medical School in Boston, Massachusetts. “Their study should be a stern warning to any practitioner who thinks the technology is ready for testing to eradicate disease genes.”

….

Huang says that the paper was rejected by Nature and Science, in part because of ethical objections; both journals declined to comment on the claim. (Nature’s news team is editorially independent of its research editorial team.)

He adds that critics of the paper have noted that the low efficiencies and high number of off-target mutations could be specific to the abnormal embryos used in the study. Huang acknowledges the critique, but because there are no examples of gene editing in normal embryos he says that there is no way to know if the technique operates differently in them.

Still, he maintains that the embryos allow for a more meaningful model — and one closer to a normal human embryo — than an animal model or one using adult human cells. “We wanted to show our data to the world so people know what really happened with this model, rather than just talking about what would happen without data,” he says.

This, too, is a good and thoughtful read.

There was an official response in the US to the publication of this research, from an April 29, 2015 post by David Bruggeman on his Pasco Phronesis blog (Note: Links have been removed),

In light of Chinese researchers reporting their efforts to edit the genes of ‘non-viable’ human embryos, the National Institutes of Health (NIH) Director Francis Collins issued a statement (H/T Carl Zimmer).

“NIH will not fund any use of gene-editing technologies in human embryos. The concept of altering the human germline in embryos for clinical purposes has been debated over many years from many different perspectives, and has been viewed almost universally as a line that should not be crossed. Advances in technology have given us an elegant new way of carrying out genome editing, but the strong arguments against engaging in this activity remain. These include the serious and unquantifiable safety issues, ethical issues presented by altering the germline in a way that affects the next generation without their consent, and a current lack of compelling medical applications justifying the use of CRISPR/Cas9 in embryos.” …

More than CRISPR

As well, following on the April 22, 2015 Nature article about the controversial research, the Guardian published an April 26, 2015 post by Filippa Lentzos, Koos van der Bruggen and Kathryn Nixdorff which makes the case that CRISPR techniques do not comprise the only worrisome genetic engineering technology,

The genome-editing technique CRISPR-Cas9 is the latest in a series of technologies to hit the headlines. This week Chinese scientists used the technology to genetically modify human embryos – the news coming less than a month after a prominent group of scientists had called for a moratorium on the technology. The use of ‘gene drives’ to alter the genetic composition of whole populations of insects and other life forms has also raised significant concern.

But the technology posing the greatest, most immediate threat to humanity comes from ‘gain-of-function’ (GOF) experiments. This technology adds new properties to biological agents such as viruses, allowing them to jump to new species or making them more transmissible. While these are not new concepts, there is grave concern about a subset of experiments on influenza and SARS viruses which could metamorphose them into pandemic pathogens with catastrophic potential.

In October 2014 the US government stepped in, imposing a federal funding pause on the most dangerous GOF experiments and announcing a year-long deliberative process. Yet, this process has not been without its teething-problems. Foremost is the de facto lack of transparency and open discussion. Genuine engagement is essential in the GOF debate where the stakes for public health and safety are unusually high, and the benefits seem marginal at best, or non-existent at worst. …

Particularly worrisome about the GOF process is that it is exceedingly US-centric and lacks engagement with the international community. Microbes know no borders. The rest of the world has a huge stake in the regulation and oversight of GOF experiments.

Canadian perspective?

I became somewhat curious about the Canadian perspective on all this genome engineering discussion and found a focus on agricultural issues in the single Canadian blog piece I found. It’s an April 30, 2015 posting by Lisa Willemse on Genome Alberta’s Livestock blog has a twist in the final paragraph,

The spectre of undesirable inherited traits as a result of DNA disruption via genome editing in human germline has placed the technique – and the ethical debate – on the front page of newspapers around the globe. Calls for a moratorium on further research until both the ethical implications can be worked out and the procedure better refined and understood, will undoubtedly temper research activities in many labs for months and years to come.

On the surface, it’s hard to see how any of this will advance similar research in livestock or crops – at least initially.

Groups already wary of so-called “frankenfoods” may step up efforts to prevent genome-edited food products from hitting supermarket shelves. In the EU, where a stringent ban on genetically-modified (GM) foods is already in place, there are concerns that genome-edited foods will be captured under this rubric, holding back many perceived benefits. This includes pork and beef from animals with disease resistance, lower methane emissions and improved feed-to-food ratios, milk from higher-yield or hornless cattle, as well as food and feed crops with better, higher quality yields or weed resistance.

Still, at the heart of the human germline editing is the notion of a permanent genetic change that can be passed on to offspring, leading to concerns of designer babies and other advantages afforded only to those who can pay. This is far less of a concern in genome-editing involving crops and livestock, where the overriding aim is to increase food supply for the world’s population at lower cost. Given this, and that research for human medical benefits has always relied on safety testing and data accumulation through experimentation in non-human animals, it’s more likely that any moratorium in human studies will place increased pressure to demonstrate long-term safety of such techniques on those who are conducting the work in other species.

Willemse’s last paragraph offers a strong contrast to the Guardian and Nature pieces.

Finally, there’s a May 8, 2015 posting (which seems to be an automat4d summary of an article in the New Scientist) on a blog maintained by the Canadian Raelian Movement. These are people who believe that alien scientists landed on earth and created all the forms of life on this planet. You can find  more on their About page. In case it needs to be said, I do not subscribe to this belief system but I do find it interesting in and of itself and because one of the few Canadian sites that I could find offering an opinion on the matter even if it is in the form of a borrowed piece from the New Scientist.

CRISPR gene editing technique and patents

I have two items about the CRISPR gene editing technique. The first concerns a new use for the CRISPR technique developed by researchers at Johns Hopkins University School of Medicine described in a Jan. 5, 2015 Johns Hopkins University news release on EurekAlert,

A powerful “genome editing” technology known as CRISPR has been used by researchers since 2012 to trim, disrupt, replace or add to sequences of an organism’s DNA. Now, scientists at Johns Hopkins Medicine have shown that the system also precisely and efficiently alters human stem cells.

“Stem cell technology is quickly advancing, and we think that the days when we can use iPSCs [human-induced pluripotent stem cells] for human therapy aren’t that far away,” says Zhaohui Ye, Ph.D., an instructor of medicine at the Johns Hopkins University School of Medicine. “This is one of the first studies to detail the use of CRISPR in human iPSCs, showcasing its potential in these cells.”

CRISPR originated from a microbial immune system that contains DNA segments known as clustered regularly interspaced short palindromic repeats. The engineered editing system makes use of an enzyme that nicks together DNA with a piece of small RNA that guides the tool to where researchers want to introduce cuts or other changes in the genome.

Previous research has shown that CRISPR can generate genomic changes or mutations through these interventions far more efficiently than other gene editing techniques, such as TALEN, short for transcription activator-like effector nuclease.

Despite CRISPR’s advantages, a recent study suggested that it might also produce a large number of “off-target” effects in human cancer cell lines, specifically modification of genes that researchers didn’t mean to change.

To see if this unwanted effect occurred in other human cell types, Ye; Linzhao Cheng, Ph.D., a professor of medicine and oncology in the Johns Hopkins University School of Medicine; and their colleagues pitted CRISPR against TALEN in human iPSCs, adult cells reprogrammed to act like embryonic stem cells. Human iPSCs have already shown enormous promise for treating and studying disease.

The researchers compared the ability of both genome editing systems to either cut out pieces of known genes in iPSCs or cut out a piece of these genes and replace it with another. As model genes, the researchers used JAK2, a gene that when mutated causes a bone marrow disorder known as polycythemia vera; SERPINA1, a gene that when mutated causes alpha1-antitrypsin deficiency, an inherited disorder that may cause lung and liver disease; and AAVS1, a gene that’s been recently discovered to be a “safe harbor” in the human genome for inserting foreign genes.

Their comparison found that when simply cutting out portions of genes, the CRISPR system was significantly more efficient than TALEN in all three gene systems, inducing up to 100 times more cuts. However, when using these genome editing tools for replacing portions of the genes, such as the disease-causing mutations in JAK2 and SERPINA1 genes, CRISPR and TALEN showed about the same efficiency in patient-derived iPSCs, the researchers report.

Contrary to results of the human cancer cell line study, both CRISPR and TALEN had the same targeting specificity in human iPSCs, hitting only the genes they were designed to affect, the team says. The researchers also found that the CRISPR system has an advantage over TALEN: It can be designed to target only the mutation-containing gene without affecting the healthy gene in patients, where only one copy of a gene is affected.

The findings, together with a related study that was published earlier in a leading journal of stem cell research (Cell Stem Cell), offer reassurance that CRISPR will be a useful tool for editing the genes of human iPSCs with little risk of off-target effects, say Ye and Cheng.

“CRISPR-mediated genome editing opens the door to many genetic applications in biologically relevant cells that can lead to better understanding of and potential cures for human diseases,” says Cheng.

Here’s a link to and citation for the paper by the Johns Hopkins researchers,

Efficient and Allele-Specific Genome Editing of Disease Loci in Human iPSCs by Cory Smith, Leire Abalde-Atristain, Chaoxia He, Brett R Brodsky, Evan M Braunstein, Pooja Chaudhari, Yoon-Young Jang, Linzhao Cheng and Zhaohui Ye. Molecular Therapy (24 November 2014) | doi:10.1038/mt.2014.226

This paper is behind a paywall.

Not mentioned in the Johns Hopkins Medicine news release is a brewing patent battle over the CRISPR technique. A Dec. 31, 2014 post by Glyn Moody for Techdirt lays out the situation (Note: Links have been removed),

Although not many outside the world of the biological sciences have heard of it yet, the CRISPR gene editing technique may turn out to be one of the most important discoveries of recent years — if patent battles don’t ruin it. Technology Review describes it as:

    an invention that may be the most important new genetic engineering technique since the beginning of the biotechnology age in the 1970s. The CRISPR system, dubbed a “search and replace function” for DNA, lets scientists easily disable genes or change their function by replacing DNA letters. During the last few months, scientists have shown that it’s possible to use CRISPR to rid mice of muscular dystrophy, cure them of a rare liver disease, make human cells immune to HIV, and genetically modify monkeys.

Unfortunately, rivalry between scientists claiming the credit for key parts of CRISPR threatens to spill over into patent litigation …

Moody describes three scientists vying for control via their patents,

[A researcher at the MIT-Harvard Broad Institute, Feng] Zhang cofounded Editas Medicine, and this week the startup announced that it had licensed his patent from the Broad Institute. But Editas doesn’t have CRISPR sewn up.

That’s because [Jennifer] Doudna, a structural biologist at the University of California, Berkeley, was a cofounder of Editas, too. And since Zhang’s patent came out, she’s broken off with the company, and her intellectual property — in the form of her own pending patent — has been licensed to Intellia, a competing startup unveiled only last month.

Making matters still more complicated, [another CRISPR researcher, Emmanuelle] Charpentier sold her own rights in the same patent application to CRISPR Therapeutics.

Moody notes,

Whether obvious or not, it looks like the patent granted may complicate turning the undoubtedly important CRISPR technique into products. That, in its turn, will mean delays for life-changing and even life-saving therapies: for example, CRISPR could potentially allow the defective gene that causes serious problems for those with cystic fibrosis to be edited to produce normal proteins, thus eliminating those problems.

It’s dispiriting to think that potentially valuable therapies could be lost to litigation battles particularly since the researchers are academics and their work was funded by taxpayers. In any event, I hope sanity reigns and they are able to avoid actions which will grind research down to a standstill.