With Stringent Oversight, Heritable Germline Editing Clinical Trials Could One Day Be Permitted for Serious Conditions; Non-Heritable Clinical Trials Should Be Limited to Treating or Preventing Disease or Disability at This Time

WASHINGTON – Clinical trials for genome editing of the human germline – adding, removing, or replacing DNA base pairs in gametes or early embryos – could be permitted in the future, but only for serious conditions under stringent oversight, says a new report from the National Academy of Sciences and the National Academy of Medicine.  The report outlines several criteria that should be met before allowing germline editing clinical trials to go forward.  Genome editing has already entered clinical trials for non-heritable applications, but should be allowed only for treating or preventing diseases or disabilities at this time.

Genome editing is not new.  But new powerful, precise, and less costly genome editing tools, such as CRISPR/Cas9, have led to an explosion of new research opportunities and potential clinical applications, both heritable and non-heritable, to address a wide range of human health issues.  Recognizing the promise and the concerns related to this technology, NAS and NAM appointed a study committee of international experts to examine the scientific, ethical, and governance issues surrounding human genome editing.

Human genome editing is already widely used in basic research and is in the early stages of development and trials for clinical applications that involve non-heritable (somatic) cells.  These therapies affect only the patient, not any offspring, and should continue for treatment and prevention of disease and disability, using the existing ethical norms and regulatory framework for development of gene therapy.  Oversight authorities should evaluate safety and efficacy of proposed somatic applications in the context of the risks and benefits of intended use.

However, there is significant public concern about the prospect of using these same techniques for so-called “enhancement” of human traits and capacities such as physical strength, or even for uses that are not possible, such as improving intelligence.  The report recommends that genome editing for enhancement should not be allowed at this time, and that broad public input and discussion should be solicited before allowing clinical trials for somatic genome editing for any purpose other than treating or preventing disease or disability.

“Human genome editing holds tremendous promise for understanding, treating, or preventing many devastating genetic diseases, and for improving treatment of many other illnesses,” said Alta Charo, co-chair of the study committee and Sheldon B. Lubar Distinguished Chair and Warren P. Knowles Professor of Law and Bioethics, University of Wisconsin-Madison.  “However, genome editing to enhance traits or abilities beyond ordinary health raises concerns about whether the benefits can outweigh the risks, and about fairness if available only to some people."

Germline genome editing, in contrast, is contentious because genetic changes would be inherited by the next generation.  Many view germline editing as crossing an “ethically inviolable” line, the report says.  Concerns raised include spiritual objections to interfering with human reproduction to speculation about effects on social attitudes toward people with disabilities to possible risks to the health and safety of future children.  But germline genome editing could provide some parents who are carriers of genetic diseases with their best or most acceptable option for having genetically related children who are born free of these diseases.

Heritable germline editing is not ready to be tried in humans.  Much more research is needed before it could meet the appropriate risk and benefit standards for clinical trials.  The technology is advancing very rapidly, though, making heritable genome editing of early embryos, eggs, sperm, or precursor cells in the foreseeable future “a realistic possibility that deserves serious consideration,” the report says.  Although heritable germline genome editing trials must be approached with caution, the committee said, caution does not mean prohibition.

At present, heritable germline editing is not permissible in the United States, due to an ongoing prohibition on the U.S. Food and Drug Administration's ability to use federal funds to review “research in which a human embryo is intentionally created or modified to include a heritable genetic modification.”  A number of other countries have signed an international convention that prohibits germline modification.

If current restrictions are removed, and for countries where germline editing would already be permitted, the committee recommended stringent criteria that would need to be met before going forward with clinical trials.  They include: (1) absence of reasonable alternatives; (2) restriction to editing genes that have been convincingly demonstrated to cause or strongly predispose to a serious disease or condition; (3) credible pre-clinical and/or clinical data on risks and potential health benefits; (4) ongoing, rigorous oversight during clinical trials; (5) comprehensive plans for long-term multigenerational follow-up; and (6) continued reassessment of both health and societal benefits and risks, with wide-ranging, ongoing input from the public.

Policymaking surrounding human genome editing applications should incorporate public participation, and funding of genome editing research should include support to study the socio-political, ethical, and legal aspects and evaluate efforts to build public communication and engagement on these issues.

The report recommends a set of overarching principles that should be used by any nation in governing human genome editing research or applications:

  • Promote well-being - providing benefit and preventing harm to those affected
  • Transparency - openness and sharing of information in ways that are accessible and understandable to patients, their families, and other stakeholders
  • Due care - proceeding only when supported by sufficient and robust evidence
  • Responsible science - adhering to the highest standards of research in accordance with international and professional norms
  • Respect for persons - recognizing the personal dignity of all individuals and with respect for their decisions
  • Fairness - treating all cases alike, with an equitable distribution of risks and benefits
  • Transnational cooperation - committing to collaborative approaches for research and governance while respecting different cultural contexts.

“Genome editing research is very much an international endeavor, and all nations should ensure that any potential clinical applications reflect societal values and be subject to appropriate oversight and regulation,” said committee co-chair Richard Hynes, Howard Hughes Medical Institute Investigator and Daniel K. Ludwig Professor for Cancer Research, Massachusetts Institute of Technology.  “These overarching principles and the responsibilities that flow from them should be reflected in each nation’s scientific community and regulatory processes.
Such international coordination would enhance consistency of regulation.”

Source: National Academy of Sciences


Gene Therapy & Blindness

Published results in the New England Journal of Medicine of two gene therapy trials (1 & 2) in Leber Congenital Amoarosis Type 2 ("LCA") showed a longer term decline in initially positive efficacy results. This was against the backdrop of ongoing maintained efficacy in a third trial in LCA by Spark Therapeutics.

This seemingly contradictory picture of the effectiveness of gene therapy in Leber's over the longer term has raised a number of clinically relevant questions, as to the methods needed to improve durable outcomes and whether combined therapeutic approaches will be needed.

Clearly gene therapy has proven to be a safe and an effective potential solution in certain identified genetic disease targets. However, there may be an optimization factor which may be required to ensure delivery and long term release of the supplementary gene, currently delivered by various designed viral vectors.

Photoreceptor decline in LCA may require cells transplants to support the existing retinal tissue from further loss, while replacing lost cells. Gene therapy may require additional neuroprotective support from cells to supplement the augmented genetic expression. A combined approach has been indicated in presentations and is potentially synergistic. Given the complex cascade of degenerative pathways in play with advanced blinding diseases leads one to believe that a more complete solution may be required, especially in diseases where there is a lead genetic cause.

An editorial of the reported NEJM data can be found here.

Further, the concept of actual gene editing versus supplementary gene insertion (which is the case in these studies using viral vectors) may be a more effective genetic treatment method should the initial pre-clinical work using this newer genetic technology becomes feasible to test in humans.

The below article by Ricki Lewis, a science writer with a PhD in genetics, summarizes the gene space activity as of writing, with specific reference to Eye programs in development (reposted here for educational purposes under Creative Commons authorization). In addition, Ms. Lewis reviews the LCA data referred to above here and here.


The current disease indications being addressed by gene therapy companies are:

• lipoprotein lipase deficiency (already available in Europe)
• childhood cerebral adrenoleukodystrophy (late clinical trials)
• SCID-X1 (better than allogeneic stem cell transplant; more boys got better and did so faster)
• Leber congenital amaurosis type 2 (RPE65 blindness mutation; late clinical trials, long-term effects published soon [data now published, as per above])

Next might be ADA deficiencyhemophilia B, and Wiskott-Aldrich syndrome, and just underway is giant axonal neuropathy. I’m sure I've missed a few.

Because thousands of single-gene disorders are theoretically candidate for gene therapy, yet only a few companies are shepherding treatments towards commercialization, I’m intrigued by how they choose their targets.

Applied Genetic Technologies Corp (AGTC) is one such company that has carved its niche in “orphan ophthalmology,” focusing on a trio of single-gene disorders in which the photoreceptors do not degenerate: X-linked retinoschisisachromatopsia, and X-linked retinitis pigmentosa. Five experts in the use of adeno-associated virus (AAV) to deliver genes founded the company.

AGTC’s vectors introduce functional versions of mutated genes, enabling the targeted cells to produce the crucial proteins whose production the mutation impairs. The company recently announced collaboration with 4D Molecular Therapeutics to develop new AAV vectors.

(A note concerning the recent flurry of reports on genome editing using CRISPR and other technologies: Gene therapy as envisioned since the first trial in 1990 delivers functional genes that supplement the actions or inactions of mutant genes. It doesn’t replace mutant genes as genome editing does. Some reports mix these up.)

I spoke recently with AGTC President and CEO Sue Washer.


Several reasons. These diseases are very well understood at the cellular and DNA levels, and we know how a missing protein affects vision. Robust animal models have the same genetic defect as human patients. Screening and testing efficacy is straightforward. Unlike other orphan drug spaces in which companies and researchers spend a lot of time figuring out clinically meaningful endpoints to negotiate with regulators and do tests reliably, with ophthalmology, you know the endpoints: visual acuity, visual field, and contrast sensitivity.

Cones appear red in these retinal layers. (Dr. Mark Pennesi)

Using OCT (optical coherence tomography) you can see the layers of specialized cells in the eye. In a patient with XLRS, the layers are pulled apart because a protein is not there to hold them together. Because the layers of the retina are not talking to teach other, electrical signals when photons hit can’t get to the back of the eye, even though the photoreceptors function.

XLRS affects 35,000 males in the US and Europe. All patients have a mutation in the RS1 gene that produces structural proteins in the extracellular matrix that form complexes that interact with cell surface molecules. The only treatment is off-label use of carbonic anhydrase inhibitors – glaucoma drops. These dehydrate the back of the eye so the retinal layers lay down on each other, but results are anecdotal and it doesn’t always help visual acuity.

By intravitreal injection of AAV with the correct copy of the gene, transduced cells in the macula and fovea (the area of densest photoreceptors) send the protein into the space and pull the layers of the retina back together. AAV supports secretion of the normal protein for the life of the cell because retinal cells don’t turn over. We expect human phase 1/2 clinical trial data by the end of the year. The first few cohorts will be over age 18, but once the maximum tolerated dose is determined, we’ll expand to age 6.


Oliver Sachs’ book “The Island of the Colorblind” made achromatopsia famous. (A typhoon in 1780 decimated the population of the Pingelapese people on an eastern Caroline island, and when the population grew anew from a few surviving individuals, up to 10% of them became blind in infancy. (It’s a classic population bottleneck.)

Achromatopsia is more than colorblindness. In typical X-linked colorblindness a man has normal visual acuity but can’t see red or green. In achromatopsia all 3 cone types have no function and the person only has rod vision, seeing in black and white and shades of grey. (It is autosomal recessive.) When the lights are on, the person is completely blind. A person with vision going to the bathroom in the middle of the night and turning on the light can see because the cones turn on. In achromatopsia, they don’t. People are severely photophobic, legally blind, and even in a normally lit office building wear heavily tinted glasses. Outside they wear goggles.

In the US and Europe 28,000 people have achromatopsia. Half have mutations in the CNGB3 gene (cyclic nucleotide-gated channel type B3) and another 25% in the CNGA3 gene. Both encode proteins that form channels in cones through which photons enter. In achromatopsia, photons won’t trigger the cascade, interrupting the visual pathway. We are developing gene therapy for each type. A proprietary engineered promoter only allows gene expression in the cell membrane of the photoreceptors.


RP is a disease class caused by at least 150 different gene mutations. X-linked RP accounts for 10% of cases, and about 90% of them, or 20,000 people, have the RPGR gene mutation. RPGR (retinitis pigmentosa GTPase regulator) is a protein that helps the phototransduction cascade from the inner to the outer segments of the photoreceptors.

The disease affects the rods initially, but the cones over time. It is progressive, starting with nightblindness and then constriction of the visual field until by the 50s or 60s there is only tunnel vision. Later in life people lose central vision as well. We’re working with a dog model to deliver AAV and improve visual function in the dog’s eyes and are beginning dosage studies in non-human primates in preparation for a toxicity study. We will file an investigational new drug application next year.


Lower mammals – mice, dogs, and pigs — have retinal cells that use the same phototransduction pathway as primates, but the structure of the eye is different. They have no macula or fovea or inner limiting membrane (which separates the retina from the vitreous body), as primate eyes do. Mice have tiny eyes, highly disorganized retinas, and cell types that eventually spread throughout the retina.

When we select the capsid (viral protein coat), promoters (genetic controls), and physical delivery methods for human clinical trials of a gene therapy, we need to screen in non-human primates. Capsid and promoters that work astoundingly well in mice, dogs and pigs don’t work well in primates. So we need 2 sets of data: the lower animal model to see if the protein goes to the right place and can have a clinical effect, and primate data to show that we can get the protein to the right place. Having these two sets of data significantly improves chances of success in human clinical trials.


With all of the pieces that must fit exactly right for delivery of a gene to have a therapeutic effect, it isn't surprising that gene therapy has taken a quarter of a century to get off the ground. In 2 weeks, DNA Science will revisit two incredible families about to embark on the gene therapy journey, if they can overcome potential problems posed by the immune system.

Eliza O'Neill has San Filippo syndrome type A.

Eliza O'Neill and her family have been in self-imposed quarantine in their home in South Carolina for nearly a year, to keep her virus-free so that she might be selected for a clinical trial of gene therapy to treat Sanfilippo syndrome A.

Hannah Sames has giant axonal neuropathy (Dr. Wendy Josephs)

Hannah Sames is not among the first children to participate in the clinical trial for giant axonal neuropathy that has just begun, and that her family largely funded, because she doesn’t make the missing protein. Her immune system might reject healing genes."

The above article (in-part) by Ricki Lewis was reposted here for community education purposes under authorized redistribution via CCBY Creative Commons Attribution License 4.0  Under a CCBY license, the original author keeps copyright but allows anyone to copy and distribute the work provided the individual blogger is given credit as the author. For more information:
PLOS BLOGS was the portal & Ricki's original article can be found here.


Germline Science & Embryo Use - The Law & Scope for Applied Research 

NIH statement on editing human embryo DNA
The recent reiteration by the Director of the NIH, Dr. Francis Collins, that the long held legal position of the US Federal Government is to not fund destructive embryo research, brings the US debate on germ line editing front & center in practical terms.

"Use" of human embryos, for their own benefit, is written into the established Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998 Recital(42) on the legal protection of biotechnological inventions in European states et al and is a foundational document addressing this area. The interpretation of this document has led to the European Patent Office guidelines and appeal rulings. 

However, apart from the embryo "use" issue, the Directive (Chapter 6.2.b) specifically states that "processes for modifying the germ line genetic identity of human beings" are prohibited from Patentability.
Also, the "Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine Oviedo,4.IV.1997" states "An intervention seeking to modify the human genome may only be undertaken for preventive, diagnostic or therapeutic purposes and only if its aim is not to introduce any modification in the genome of any descendants." This forms part of the overall European Convention on Human Rights, in all its parts "The Convention."

So in Europe the issue of Human Rights & Innovation Patentability are determined by guideline standards applied mainly throughout the membership via The Convention & the BioTech Directive, while Individual National Laws are deferred to, fundamentally by design, in determining the applicable interpretations & standards governing the specific ethical/moral & "ordre public" of that society in biomedical research.
In the US, it's also the actual "use" of embryos for research, including the derivation itself of ESCs, that is the Federal funding restriction. This is a result of, exclusively at the time of drafting, the destructive method employed to derive hESC lines. In addition research funding into destructive embryo studies in areas such as nuclear transfer & genetic modifications of the germ line were also restricted, as a result. The reiteration of this established position recently by the NIH reminds all of the reality of the current funding law governing destructive practices on "human embryos."
However, historically there has been somewhat of a mixed approach in practice applied to federally funded embryonic research in the US. The NIH has authorized funding for decades using donated IVF supernumerary embryonic stem cell lines for research. On the one hand the law states that no funding is allowed that destroys embryos (e.g. blastocyst ICM extraction of stem cells, or in this most recent case genetic editing on embryos that would result in their destruction). However, on the other hand, this law doesn't apply when work is done on Federal registry approved embryonic stem cell lines (see NIH guidelines). This reality is a middle way compromise to support the nascent field of advanced research into developmental biology and has resulted in significant progress in the understanding and therapeutic potential of pluripotent cell technologies.
Of note, more recent non-destructive methods, nor research using non-viable embryos, have yet to be written in. For example, non-embryo-destructive sourced Blastomere ESCs, nor non-viable SCNT-ESCs or Parthenogenetics-hpESCs, are notably excluded from federal support. So the actual working model isn't that current nor flexible to the evolving technology, which is reason to review the legislature as a result of the sector’s broadening scope.
The use of natural eggs in SCNT-ESCs/hpESCs was perhaps the concern and avowed aspect of these methods to the Federal Government - but has there been a recent review on this position given IVF has become a standard option in fertility treatment? Also the sector is moving fast and emerging reprogramming techniques look to create synthetic eggs, what then? Is this not a reasonable question to be asking now, given the discussion?     
This line can and may very well be taken further with technology to create synthetic sperm. Will the combination of synthetic eggs and sperm be the next ethical issue? I believe there needs to be a concerted effort to get ahead of the science & write updated Laws that apply new guidelines with scientifically prudent standards, while remaining open and flexible to potential benefit & future possibilities.

Further, the European Court of Justice has ruled recently that non-viability is a determining characteristic of the definition of a "human embryo," therefore non-viable zygotes & arrested/mutated pre-embryos that cannot develop do not fall within the restrictions of the Biotechnology Directive, as they have been ruled not to be considered by definition an "human embryo." However controversial this position may seem to some it is an accurate reflection and interpretation of the foundational biotechnology law in Europe, while deferring to national member states the issue of ethical/moral & "ordre public."

Fundamentally the underlying principles of the protection of life in the Chapter 1 Article 2 of The Convention doesn't state explicitly that germ line cells, nor for that matter an embryo or fetus, are to be given specific reserved consideration. This has been tested at the European Court of Human Rights. Should national laws allow in-vitro research on embryos The Convention states in Chapter 5 Article 18 that they should "ensure adequate protection of the embryo" and that "the creation of human embryos for research purposes is prohibited." This is the general positioning at the European Human Rights level, as a result of the union of culturally diverse member states. As previously indicated, individual countries apply local Laws to their societal ethical positions, which they all do in regard to embryos/ESCs, genetics, IVF & fetal development, considering The Convention. Generally the principle of human rights & dignity extends to all human beings and for that the definition of a "human being" is central to The Convention's interpretation. The UN's Universal Declaration of Human Rights is similarly worded and looks to respect individual human rights, while leaving the question of developing life to individual societies.

 With regard to cloning there was a specific Protocol added to The Convention in 1998, and enacted by other governing bodies internationally, as a result of the discussions surrounding animal cloning at the time. Specifically, The Convention states that "any intervention seeking to create a human being genetically identical to another human being, whether living or dead, is prohibited."

The objections to assisted reproduction by the Vatican or Christian Right may very well be subjectively valid, from their reasoned perspective, but that view, however correct or positioned to be morally sound, doesn't acknowledge nor properly address the very real practical issues inherent in today's advanced fertility, cell & genetic sciences. Many of the issues previously debated are being clinically applied with results. New ethical challenges and redefinitions are required by all as the science evolves, with appropriate regulatory & societal frameworks adapted, as necessary.
The fact that new technological advancements are being designed to address medical needs of those that suffer from, or may fall victim to, potentially treatable biological conditions warrants considered thought as to how best to unify behind the effort to achieve a host of goals in the process. Through public education and the application of successful next generation technology the substance and impact science can have on solving the very issues that divides opinion is possible.

The ethics of today will give way to the ethics of tomorrow, and so on - it's nature's way. Man plays his part in this cycle and uses what is available with intellect and inventiveness. Change is a process of adjustment and one could say that is the will of nature's law. The only unnatural aspect would be if man himself becomes defined as synthetic, which is, from this writer's perspective not the goal.

Germ line editing in clinical practice is indeed unnecessary at present until proven otherwise. However, basic research using gene editing technology of germ line cells is necessary, based on clearly defined updated ethical frameworks - with governmental support, if possible. The recent ISSCR Connect discussion on the issue was well presented and reasoned. More open dialogue is required and opinion sought from all stakeholders. There are too many questions yet unanswered to not search for the clues by all means so one day we may apply that knowledge to human frailty & suffering in developing or developed humans. That goal would be best served by furthering basic research efforts using genetics back to our original cells. iPS technology wouldn't have been invented had it not been for human embryonic research, which wouldn't have been possible without animal cloning studies…. the shoulders' metaphor applies.

From my perspective if gene editing research using germ line cells and pre-embryos is to be limited entirely to private companies then that would curtail potential scientific progress in research using non-viable donations or technology methods which cannot develop into a human by design.

Congress has the opportunity to get ahead of these issues and address squarely this area of leading biotechnology innovation in new legislation. This was shown to be important during the protracted court case against the Federal Govt.’s funding of scientific research using approved hESC lines. The high court ruled in favor of the Govt. but there was considerable discussion in legal circles of the need to update the law. The underlying legal basis being the Dickey Wicker amendment, which was written in 1995, and is considered by many to be too ambiguous and not a suitable legislative document for the sector moving forward. The need for a comprehensive bill is generally acknowledged. The use of Federal funds in developmental biology research should allow for opportunities to explore all non-destructive areas of the science to advance medical knowledge so that it does not impede the progress of scientific discovery for the benefit of all. Patients' interests must be considered paramount and consensus sought on majority based positioning. Public education can be an effective tool in defining such efforts.  
For example, currently there is an area of ambiguity with the written NIH hESC text on embryo donations, as a cell can be harvested from a pre-embryo and used for that embryo's own benefit, if not for all.

Ethical considerations are required to be taken into account, but not at the expense of an agreed roadmap to progress. If after broad inclusive deliberations legislative regulations & sector guidelines are updated, then that achieves the goal. However, I would add a caveat, it’s important to include into any new laws the non-viable/non-destructive aspects succinctly, as well as a considered inclusion of a benefit review for technologies applied to viable potential human embryos in-vitro & in-vivo.

However, "use" of embryos isn't the full picture. There remain issues of scope with respect to reprogramming technology, assisted reproduction techniques et al which should be clearly stated as part of new regulations & guidelines in the area.

Clarification is needed as to the somatic reprogramming limits that are acceptable and where there should be restrictions, if any, applied. Synthetic forms of human germ line cells and the creation of pure or part-synthetic embryos for cellular harvest cannot be overlooked and needs similarly considered language. Issues such as same sex couples wishing to use technology to assist having "natural" babies using reprogrammed cells back to the germline, artificial wombs and attempts at eugenics et al should be broadly covered in the legislative language.  

If there were clear legislature on the issues, after dialogue with all stakeholders, this would assist in eliminating the negative spin on today's advancing scientific discoveries that looks squarely to cure disease. Science would benefit from that clarity. The future possibilities would remain, however, guidelines would be established.

Consider if you will that if the science advances and we are able to achieve that long string of .999s on safety, what will be the benefit/risk scenario if implementation occurs some time in the future? Such science can be debated at that point and submitted for consideration, as long as there's a benefit window.
Generally in the future there may be a manner in which genetic technology proves its human potential for the application of germ line intervention. Leaving that door closed while holding a preexisting key isn't such an unethical position IMO - flexibility in today's fast paced scientific world is important.

The challenge in establishing regulations in this area will not be easy, but it isn't insurmountable. A flexible legal & regulatory basis for steps forward in the research is what is required IMO. Checkpoints along the way so that the whole map is not null if one road is opened up upon the presentation of correct documentation. A straightforward mechanism should be agreed for the review process that encompasses the appropriate nominated bodies. Congressional oversight may be appropriate but the nature of such a flexible system would be best served to have it's own adaptation authority once the law is written.

I have stated previously that the reduction in IVF supernumerary embryo creation should be a stated goal with new specific governance stipulations & authority guidelines over the fertility sector. This I believe is central to a consensus building working model.

The point is we as a society cannot any longer avoid the reality of the present and promise of the future by applying yesterday's fixed reasoning to bear. Without informed, concise & regularly updated language of the day the necessary support and freedom to research innovative solutions to pressing medical and biological issues will be unnecessarily limited.

Today the US is the leader in ethical biomedical technology but without Bold Action, Decisive New Legislature and Increased Government Support, across the board, the promise of tomorrow's technology with not meet the expectations of the people nor address the full potential for American solutions for the Common Good.


[Update: "US science academies take on human-genome editing. National Academy of Sciences and National Academy of Medicine to develop guidelines for rapidly advancing technology to modify human embryos and germ cells."]


Germline Editing using CRISPR-Cas9 - Totipotent Cell Research

Dr.Yorgos Nikas/SPL
Yesterday the first published paper was released detailing the preliminary scientific attempts at modifiying the germline of a human fertilized egg - a zygote.

What was striking here wasn't so much the attempt being officially published but the storm it has caused in the scientific community.

The science is far from effective and needs a great deal of work before it is even possible to consider using in a clinical setting. That much was shown. There are many steps before any such work should be even contemplated, as guided by the ISSCR in their call for a clinical moritorium on proceding with any human translational work. I personally believe that position will be respected given the laws in place that govern such human germline science. If there is a precedent the ban on attempts to pursue human cloning has shown to be effective.

What is curious here in respect to this work, undertaken in China, on germline editing is that it has quickly followed the cautionary notices by the scientific community leadership that the science was being practiced in human germline cells. This was and is a signal that there is much more going on behind the scenes than we know and that the nature of such developments isn't necessarily coordinated or managed in any practical manner. To some that is the issue perhaps...

The explosion of interest and experimental use of gene editing technology has opened up a proverbial Pandora's box of issues that have yet to be addressed collectively in a meaningful manner. But as these things go it's not always possible to steer scientific advances as the peer review process is built to open up the knowledge gates to replicability and improvement - hence the strength in it's design. Coordinated stakeholder dialogue is urgently needed and initiatives established.

Man's curiosity and pursuit of knowledge has driven momumental changes in our own lifetimes - that is accelerating and those that wish to somehow control the speed of which it is happening may find themselves catagorized as part of the old guard and not hip to the trending interwoven nature of the instant always on tech culture of today and tomorrow.

The ever expanding numbers of brains educated to think of new solutions to existing problems with ubiquitious tools made easy will allow discovery and experimentation to flourish. No one should be surprised when this momentum spawns innovation - especially in the new frontier of biological system design.

My comments on Paul Knoepfler's Blog about the natural reservations of the developments are below:

"Thx Paul for the viewpoint. 

I believe you´re correct to have reservations about the unknown steps on the discovery path to gene line editing. However, I do believe it's important to participate in order to have any chance to mold the outcome. As we have just learned the science is indeed moving ahead, like it or not. I don't believe debating the merits of the possibilities does justice to the technology - at least to me that doesn't seem productive at this stage. 

Some may not wish to go down this discovery path but as many have pointed out - it's not something anyone or even a group(s) can put a halt to, it seems. 

I would like to see the West actively engaged in an initiative to put a scientific team of institutional investigators together to spearhead a collaberative international effort to lead coordinated research into geneline editing - in all it's forms (there are many of course research methods to explore). This way the open nature of such an initiative would be beneficial to all stakeholders and those on the ground can draw down from this central resource.

Attention grabbing science papers as a methodology to present the public the work being done adhoc doesn't strike me as proactively getting ahead of the issues... 

Also, isn't it possible to establish a seperate arm's length oversight department, in an existing organizational structure? This would officially sanction & coordinate the independent local discovery groups to inform and assist the lab work & validate data collection for the entire space. Or are we looking at global independent action, reaction, applied science and IP castle building for human elitism?"

Belmonte paper ref

Further on the issue of gene editing, today Juan Carlos Izpisua Belmonte’s group published a paper in Cell that suggests a possible route to modify mutated mitochondrial for disease elimination using an alternative to the above "CRISPR-Cas9" technology but similar in puprose "TALEN" system.

The sum of these parts and the overall emerging landscape of profound medical advancements is a net positive IMO, while there remains a need to establish a collective approach to coordinating the possibilities for Common Good.



The Rise of Germline Science - Human DNA Modification

Genetic modification of human DNA to correct disease causing code has long been a stated goal of medical science. Ever since the discovery of the double helix has man dreamed of understanding the inner workings of its own self, at its very core. The successful mapping of our genome took us closer to that universally acknowledged ambition. Time has not stood still since then nor has science strayed yet from its intended course. The rapid expansion of practical applications for genetics addressed to medical needs is a testament to the pursuit of that knowledge for good. In time there will be more progress and deeper understanding of the impact changes to our code will have - in the meantime research must continue apace and the wings of discovery allowed to extend outwards.     

My perspective on extending genetic research to germ line DNA editing is in line with the recent guidance from the International Society for Stem Cell Research (ISSCR). 

Rather than positioning early, and perhaps prematurely, the ongoing conversation is best taken forward with open engagement and presentation of additional scientific data, as it becomes available. Without additional ethical germline research, supported by industry & regulators, the topic of whether there is reason for undue concern cannot be fully addressed scientifically, apart from debating the broader question of should we (which is conditional imo). To reach any natural conclusion will take time and further industry wide clinical application of non-germline editing technologies, acceptance of less invasive genetic modification technologies, such as mitochondrial transfer, and the implementation of other embryo technologies for human benefit. 

An observation that underlies the issue is perhaps the historical fear factor effect of the "dual-use dilemma." That is to say the mere fact that there exists a possibility of misuse of scientific discoveries has in the past created significant barriers to progress and inhibited otherwise important developments in the timely advancement of research efforts to eradicate human disease & suffering.  Human cloning wasn't on the agenda when Dolly was born, however the realization that SCNT technology had a possible "dual-use" potential has hobbled otherwise beneficial therapeutic sources for ES cells. The entire field of "embryo" science has itself been caught up in an unproductive polarization issue of creation, life & intervention for cell science application. Even today only a very small percentage of the public actually know science is able to establish ES cell lines across all "embryo" technologies in a non-destructive ethical manner for personal & universal cellular treatments. This generally needs to be factored in when discussing the topic as it's unethical in itself not to address the fundamental reasons for many objections to "embryo" science and how it has clouded the perspective of delivering solutions to those in need. Solutions need to be sought, compromise established & educational outreach in the mass media targeted to this very point to end the divisiveness. This germline debate presents an ideal opportunity for such rapprochement.

How is early genetic modification of DNA at the germ/embryo stage going to be any different than the hES cell source miscues of the past unless the rhetoric of the applied technological benefit conversations reflect the lessons learned? 

Getting ahead of the issue is important, as it is with all emerging technological innovations that involve health. However, ensuring the safe sector development of recombinant DNA isn't the same as the ethical impact of human cloning, creating tens of millions+ supernumerary IVF embryos, engineering synthetic eggs/sperm & embryos, conducting germ line editing for disease or introducing DNA species' enhancements et al. These topics aren't challenges for science to overcome alone, they are fundamentally moral & ethical questions of benefit and use. They require careful scientific study, presentation in an open forum (not pay walled), thoughtful inclusive dialogue, education and public outreach.

Perhaps Leadership should suggest specific beneficial goals and propose a working version of a current dual use limitation charter when addressing the issue in the public framework. This will enable the field and public to express themselves within a clearly defined yet productive manner - i.e. what is potentially acceptable to Leadership and what isn't at this stage. Otherwise I can see the conversation repeating itself along the same lines as the media spin of scientific hyper reporting for readership numbers & incorrect assumptions of SCNT=human cloning, which was & still is an acknowledged no-go area in embryonics. Remember this concern set the tone for almost 20 years now of fallout in the field, not as a result of any specific efforts to progress human cloning but for the open door it presented. This was irrespective of the inherent scientific value in autologous ES cells & the sound pursuit of careful research driven embryo based technologies.

History has presented a number of important dual use dilemmas over the course of human history, nuclear power may have been/is the most impactful to human life: energy versus war; restraint versus force; detente versus annihilation; rule of law versus rogue use... One can do the trade offs in perhaps more applicable sciences, for example: synthetic life forms; biological constructs; chemical engineering et al. We live in a never ending cauldron of possibilities where all outcomes increasingly exist as a result of human ingenuity. The rule of law and our moral codes are the only binding principles that the community can foster to fundamentally shape human will. If there is a need for new laws then do so with factual education, public debate and openness centered around a health priority of "for the people" being paramount. However, competitive currents in science run deep today and as such active participation with guidelines would seem the only logical course. 

If there were publicly exposed real life cases where germ line modification would alleviate suffering & disease in newborn children then I would recommend that be shared as widely as possible. Certain neurological diseases have been mentioned - if germline science is the only way forward in some of these cases it's important to publicly state that & make it clear why. These and other indications may very well be the first cases where there is a real need to use germline/embryo editing, however somatic cell gene therapy is without doubt the immediate and overwhelming priority. 

I sketch below a fictitious scenario whereby a family has no choice, unless assisted by science - would it be ethical and morally correct to deny them their human rights to bear healthy children, should a technology be available to solve their case?

What happens when a known gene mutation is detected in an IVF embryo to a family with a genetic mutation history? Choice & hope drove them to look to protect against the very real & terrible consequence of giving birth to a child that will only suffer and die. If they didn't choose IVF fertility they would have no ability to protect the health of their child. God to them doesn't mean accepting a cruel and unjust outcome that imposes suffering on an innocent if there is an alternative. Don't implant that embryo and select/create more embryos until there is one which doesn't have the mutation? Is that acceptable to those that oppose IVF supernumerary embryo creation? What happens when all the created IVF embryos have the mutations? Don't implant any and send the couple home without solving their problem at considerable cost and emotional stress? Is that ethical? 

What happens when the Docs find a potentially suitable IVF embryo but advise that there is a risk that the couple faces that the disease could manifest itself anyway without complete replacement of the relevant DNA strands? Implant without a DNA edit and hope for the best? Try to detect any malformation issues during fetal development? Then what? Fetal intervention? If that's not possible? Try to solve any postnatal genetic issues with best efforts? What if it's too late for any real chance to help and the child is effectively DOA or critical beyond hope and cannot be expected to regain near normal function even with the most advanced modern treatment at the cellular level? Don't risk it? 

This on the other hand is not fiction. My brother has a seemingly healthy young 7 yr old son but the child's siblings weren't so lucky. Both were taken to full term, delivered and died. My sister-in-law had excellent medical care and after the loss of the first child, within days of birth, was monitored constantly throughout the 2nd & 3rd pregnancies. Her second child was again naturally conceived and made it through the gauntlet. The 3rd child died weeks after being born "healthy" & welcomed home into the family. They have suffered immensely and you can sense their deep sadness but they have joy & love in their hearts with the one that survived. We pray that little chap makes it all the way but if there were a way to screen the germline of his parents they may not have needed to play Russian roulette. In hindsight and with use of today's technology who would in their right mind try to conceive naturally knowing there was a significant risk, especially after having a previous issue? If a fatal brain disorder could go undetected in today's system and manifest itself in 2 out of 3 full term pregnancies then there is a real need to improve the process. Genetics presents the best hope to protect against such outcomes and it must be taken forward for all families. Parents to be should seek basic genetic testing and those at most risk must be offered IVF & advanced screening as standard. Informed decisions can be made once the available options are presented by the medical experts. If at some point in the future the process includes safe interventional genetics to assist life in being born healthily then I favor presenting such a choice to would be parents, if science has made it possible.   

The parents of tomorrow are ultimately responsible for the next generations and therefore should be considered with weight, as with those that have direct experience in the diseases for which this germline technology would apply, if any. I don't believe shock is an emotion the youth of today exhibit when presented with the technology of tomorrow. Rather it would be a shock to all if the very real images of affected children were associated with political inaction to cure, if there was a chance to avoid such pain & suffering.

Having said that the entire field of somatic genetics and cellular therapeutics is just emerging and needs to be the focus to establish itself prior to more advanced possibilities taking over the headlines. The media feed off controversy so it's best to find a way to agree than to publicly disagree, for the sector.

Once the intervention technologies are sound the medical community has an obligation, if not a legal duty, to present the options. In time once the public are familiar with the detection technology their acceptance of the more complex interventional options will become less futuristic and ethically questioned, in those cases where the only guarantee is germ line modification. 

Genetics holds enormous promise, as do potent cellular therapeutics. The union of the two, and their by-products, will be a powerful force for good. Early detection, intervention and eventually genetic modifications will be the key to freeing humans from their own frailties, which if managed as a universal community goal will serve rather than enslave generations to come. This future must be controlled and accessible to all.

For the moment though I can't see any reason whatsoever to accept personalized genetic enhancements nor use germline technology, if proven safe, beyond the absolute required need. Intervention to eliminate any possibility of irreversible disease, when a couple has no opinion, is where science can help bear a healthy child free of fatal developmental mutations. 

Perhaps in time there will be safe cost effective universal "vaccine" like concepts that edit our DNA in order to eradicate disease, strengthen our physical constructs, enhance our immune systems and extend our cellular longevity. A legacy any generation would envy... That would be a world worth imagining into existence - along with some other wish list items! 

Advocacy for cures.



NIH Bioethics Resource


Human Genome Project

The four videos below were produced for Smithsonian Museum of Natural History in 2013. They were part of the “Genome: Unlocking Life’s Code” exhibit at the Museum in Washington, DC

Chapter 1

Chapter 2

Chapter 3

 Chapter 4

Source credit: Shraddha Chakradhar