CRISPR babies

In November 2018, the world learned that a Chinese scientist, He Jiankui, had conducted an experiment that resulted in the birth of two gene-edited human babies.   Antonio Regalado broke the news on Nov. 25 in an article in MIT Technology Review.   Two days later, He gave a talk about this experiment at the Second International Summit on Human Genome Editing in Hong Kong.   His study was immediately, widely, and strongly criticized by the scientific community.    

There has been so much media reporting on this story that I have little to add, except a few links and personal comments.

STAT news has just published a great piece on He Jiankui's research timeline leading up to the story, mainly from the perspective of a few other researchers who had interactions with He during the period when he was planning, and carrying out, his human embryo work.   

At this time I remain opposed to gene-editing of human embryos with the intention of implanting the embryos to result in pregnancy.   This keeps in agreement with the ASHG statement on Human Germline Genome Editing.

He Jiankui's experiment was reckless for several reasons.  Here are three.

First, there has absolutely not yet been enough research to prove that gene-editing methods can be safely and effectively used in human embryos without unwanted side effects that could cause harm to the baby.    

Second, the particular gene (CCR5) and disease (HIV/AIDS) that were the targets of these experiments are very problematic.  Inactivating CCR5 may not always prevent HIV infection.  On the other hand, people who lack CCR5 have more severe symptoms if they are infected by West Nile Virus.   The embryos themselves were not infected with HIV, so the editing was intended to prevent a disease that the embryos did not carry, and is preventable in other, established ways.  This does not mean that HIV is not a serious problem, or that AIDS is not devastating.    It just means that the approach used here is very open to criticism from a scientific standpoint.

Third, it looks like the babies' parents did not have an ethically sound informed consent process.  The informed consent forms that the parents signed seem more designed to protect the legal exposure of the researchers than to inform the parents of the real risks and benefits of the experiment.

ASHG Position Statement on Human Germline Gene Editing.

An ASHG workgroup, of which I am privileged to be a part, has published a position statement in the American Journal of Human Genetics regarding our society's current views on human germline genome editing.   Here's a link to the ASHG press release.

Oregon researchers publish results on editing human embryos in Nature. Reduced mosaicism and insights into HDR in human zygotes.

Ma et al (PI: Shoukhrat Mitalipov) have published a highly anticipated paper in the Aug. 3 2017 issue of Nature:      Correction of a pathogenic gene mutation in human embryos.  

Release of the National Academies' Consensus Study on Human Genome Editing

The National Academies of Science, Medicine, and Engineering have jointly released their consensus study on Human Genome Editing: Science, Ethics and Governance.  The report was produced by a committee specifically created to consider this topic.   Here are links to either:

1. The report highlights, summarized in about 4 pages.  I recommend this!

2. The full report - it's over 200 pages.  You can download the full study from their website (you need to register to get the free PDF, but it's pretty painless) 

3. A one-page summary of the report.    

I can see that a "narrative" in the media coverage revolves around the report's cautious statement that human germline gene editing may be ethically OK, but: only in very specific disease-addressing situations; with appropriate oversight;  and some sort of public consensus/input.   In fact, this is probably the most contentious question the committee faced.   The committee clearly states that editing to produce enhancements, rather than to treat disease, is not recommended at this time.   On the other hand, somatic gene editing applications for treating diseases can be viewed essentially as technical improvements of "conventional" somatic gene therapies, for which the ethics and oversight issues have been dealt with for some years now.

There is abundant material in the full report and its summaries that calls for public input into the process of determining exactly what types of germline gene editing should be permitted.   For example, from the one-page report summary:  "Ongoing reassessment and public participation should precede any clinical trials of heritable germline editing".   This is a very clear call for public feedback. Nevertheless, at least some responses seem to argue that this sentiment was left out of the report.  I believe this to be purposefully misleading.  The report committee was co-chaired by a noted biomedical ethicist and regulatory expert.  Moreover, the committee has several additional bioethicists in its roster, who all are well acquainted with the need for communication between the public, scientists and policymakers in order for sensible policies to be created.    Furthermore - the report contains an entire chapter entitled "Public engagement".  !    

It is clear that the committee, and most scientists I know, feel strongly that any process of establishing policies, regulations or laws governing germline genome editing will absolutely require public engagement and feedback.

from Nature: CRISPR gene-editing tested in a person for the first time.

http://www.nature.com/news/crispr-gene-editing-tested-in-a-person-for-the-first-time-1.20988

Policy forum paper in Science on germline gene editing: "Editing policy to fit the genome?"

Back in late January, Rosari Isasi et al. published a policy forum paper in Science that discussed the issues surrounding genome editing policies around the world.  Key points discussed include the differences between "permissive" and "restrictive" viewpoints, whether restrictions on clinical applications also apply to research - and how vague legislative language sometimes makes this distinction unclear - and, how thresholds for acceptability have been applied in related contexts.

Nice maps are given that indicate the general level of regulation around the world for this issue and for related topics such as preimplantation diagnosis.    

Science. 2016 Jan 22;351(6271):337-9.  Isasi et al. GENETIC TECHNOLOGY REGULATION. Editing policy to fit the genome?

UK approves gene editing of human embryos for in vitro research purposes. (NOT for implantation/procreation).

The HFEA has approved an application from UK reserachers to perform specific gene editing experiments in human embryos for research purposes.  The embryos will not be cultured beyond the blastocyst stage (a small ball of ~250 cells).  The purpose of this research is to examine the development of cells that form the placenta and other tissues that support embryo growth.  This sort of research may lead to better understanding of why some miscarriages occur.

Reports from various news outlets:

BBC News

The Guardian

Washington Post

Statement released by the International Summit on Human Gene Editing, and related news links. #GeneEditing #CRISPR

Here is the link to the International Summit on Human Gene Editing Organizing Committee's statement on gene editing.

http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=12032015a

It's a fairly brief statement in comparison to the Hinxton report, but it makes its points.   Some may be surprised that an outright moratorium - or even more permanent restrictions - on germline gene editing were not called for specifically in the statement.   Instead the tone leaves the door open.  I think this is in keeping with the idea that it is conceptually possible that at some point in the future, germline modification might be safe and effective enough for preventing certain diseases that it would be ethically permissible - at least in come cases.

However, there are certainly strong notes of caution in the document - in particular, that germline gene editing to produce actual babies is clearly still too risky at this time.  At the same time, the statement leaves the door open for research in embryos that may shed light on these issues, while also possibly be very beneficial from a basic science perspective.

News reports:

The Guardian:  Summit rules out ban on gene editing embryos destined to become people.

LA Times: International gene editing conference declines to ban eventual use in humans.

Nature: Gene-editing summit supports some research in human embryos.

Reuters: Gene summit organizers urge caution on human gene editing.

Finally, here's a link to a good piece in STAT about the whole summit.

International summit on human gene editing is occurring now in DC. Live webcast. #geneediting #CRISPR

Link to webcast:

http://www.nationalacademies.org/gene-editing/Gene-Edit-Summit/index.htm

Commentary in Nature on genome editing ethics and #CRISPR by members of the Hinxton group.

This commentary provides a very good summary of key points discussed by the Hinxton group, during their process of creating their recent position statement on genome editing.

Debra J. H. Mathews, et al.  CRISPR: A path through the thicket.  Nature v.527:7577 pp.159-161.

New article in NY Times on #CRISPR ethics.

"The CRISPR Quandry" - Jennifer Kahn. NY times Nov. 9, 2015.

Somatic gene editing therapies hold great promise in treating disease.

...And because of this, it will be important that discussion of the ethics surrounding germline gene editing do not frame all gene editing applications in a dangerous light.    This post was stimulated by the news releases over the last day or so, concerning a young leukemia patient in the UK who apparently has responded extremely well to an infusion of gene-edited, cancer-fighting T-cells.  

e.g.

BBC :  "Dawn of gene-editing medicine?"

Nature:

http://www.nature.com/news/leukaemia-success-heralds-wave-of-gene-editing-therapies-1.18737

NBC news:

http://www.nbcnews.com/health/cancer/it-gone-gene-editing-technique-may-have-cured-babys-leukemia-n458786

In a nutshell, the team involved used heterologous T-cells that went through a few steps of editing before infusion into the patient.

Note this has not been peer-reviewed yet, and it's only one patient.  But hopefully it will be the first of many more similar good stories to come about gene editing.

Viewpoints on recent UK proposal for gene editing research in preimplantation embryos. #CRISPR

Dr. Kathy Niakan of the Francis Crick Institute has submitted a proposal to the UK's Human Fertilisation and Embryology Authority (HFEA) for permission to do basic research gene editing experiments on pre-implantation human embryos, as reported on in Nature and The Guardian.   Here are some recent perspectives on that development.

Is slippery slope argument against human embryo gene editing overblown? -  A
position posted by the Genetic Literacy Project that was adapted from the following article:

Scientists must be part of the ethical debate on human genetics - Phillip Ball, in The Guardian, 9/21/15.

Ball points out that despite the fact that this research proposal could be considered ethically acceptable, and be permitted and legal under current UK guidelines (pending HFEA's approval), this research would be a nonstarter in the USA largely due to laws prohibiting federal funding of such research.  

Taking a somewhat more critical stance comes a statement from the Center for Genetics and Society, a US nonprofit:  Center for Genetics and Society comments on First Application to Pursue Genome Editing Research in Human Embryos. 9/18/15.

First post: A timeline of selected articles, news, opinions, and statements about human germline gene editing during the period from March-September 2015.

You may be familiar with my CRISPR blog, which is focused on technical aspects of CRISPR/Cas9 methods - particularly for germline editing of mouse embryos.   However, the ethical implications of gene editing in human embryos has been a very hot topic lately.  

I've decided to start this blog to help me keep a record of links to various relevant articles, opinions, position statements, and the like.   Much of this was triggered by a paper earlier this year demonstrating CRISPR-mediated gene editing in human embryos.    I hope this blog will be useful, and hopefully, it will stimulate some discussion and thought among its readers.

CRISPR is so efficient and simple that it has brought urgency to the discussion of ethical issues surrounding gene editing in human somatic cells and embryos.  Actually, many of these issues have been explored by ethicists before, primarily during the early days of gene therapy, but the technical ability to precisely target and change existing genes in human embryos just didn't exist then.  CRISPR now allows the possibility to do this.  But should we?  And if so, under what circumstances should it be permissible?

As news items emerge on this topic I'll post links. In the meantime, I've got some catching up to do...Here is a timeline for various important items, starting in March of this year:


March 5, 2015:  “Engineering the perfect baby.” – an article in MIT Technology Review hints that researchers in China have already performed gene editing in human embryos, though it has not yet been published.

March 12, 2015: Edward Lanphier et al.’s letter published in Nature: “Don’t edit the human germ line.”   Lanphier is president and CEO of Sangamo Biosciences, which is developing an HIV resistance therapy based on gene editing in blood cells.

March 19, 2015: David Baltimore et al. publish astatement in Science calling for a moratorium on all human germline gene editing research.

April 17, 2015: “Germline editing: time for discussion.” Editorial in Nature Medicine.

April 18, 2015: Liang et al publish the first report of gene editing in human embryos in Protein Cell.   The embryos used were triploid embryos that were left over as a normal by-product of human IVF.  Triploid embryos cannot develop to term, so no human babies could have been generated from them.  Nevertheless, this paper generates some criticism.   

April 28, 2015: Protein Cell publishes an editorial defending their decision to publish the Liang et al paper while also adopting a cautionary stance.  “Urgency to Rein in the Gene Editing Technology”, Xiauxue Zhang.

April 29, 2015:  I published a blog post describing why Liang et al actually overstated the off-target effects in their human embryo experiments.

April 29, 2015:  NIH Director’s statement on NIH funding for human embryo gene editing research (spoiler alert: it’s not allowed).

May 12, 2015: “CRISPR germline engineering— the community speaks.”  Nature Biotechnology article in which numerous scientists were asked to comment on the issue.

May 18, 2015: U.S. National Academy of Science (NAS) and National Academy of Medicine (NAM) announce an initiative to develop guidelines for editing human genomes.

May 22, 2015: “Eugenics lurk in the shadow of CRISPR” - Robert Pollack, letter to Science.  

May 26, 2015: The USA White House announces support for moratorium.

June 19, 2015: “Germline gene therapy: We’re ready” - Henry I. Miller, letter to Science.

Sept. 5, 2015. “…Banning it is not the answer” – op-ed piece by Sarah Norcross in The Guardian.

Sept. 10, 2015. The Hinxton Group releases a detailed Statement on Genome Editing / Human Germline Modification.    The Hinxton Group is “An International Consortium on Stem Cells, Ethics and Law.” 

Sept. 12, 2015.  The UK MRC, Wellcome Trust and other groups announce a joint statement on genome editing.

Sept. 14, 2015: The Chinese Academy of Sciences (CAS) , Royal Society, U.S. NAS  and U.S. NAM announces plans to co-host an international summit on human gene editing in Washington, D. C. on Dec. 1-3, 2015.

Sept. 17, 2015: Scientists in the UK ask governmental permission to perform limited gene editing experiments on leftover embryos from IVF treatments.  The embryos in this research would not be kept more than 14 days nor would they be used to create pregnancies.

Sept. 18, 2015:  Interview with George Church in New Scientist, in defense of gene editing research and applications.