Progress and the Circle of Scientific Medical Innovation

Designing an adaptable system without the known variables is often an exercise in caution, unless of course you have been down a similar road before and can rely on established templates for creating repurposed guidelines. In some cases however old parameters simply don't fit any longer and the opportunity to engage in the development of more flexible rules with the benefit of hindsight becomes a net positive in the never ending cycle of innovation driven progress.

A series of high profile developments along this path have taken place of late on the topic of genetics and the advent of gene editing technologies that have the potential to alter the fate of human disease and the burden it represents to society. These policy reviews and the resulting position statements have been brought on by concerns that human gene editing presents a challenge to the perceived boundaries by which scientific discovery and possible therapeutic interventions are applied. 

However, as we have seen knowledge trumps and is critical to all human endeavors, given information is paramount to decision making. Accumulating scientific data in the unknown cause and effect realm of biological systems provides the fundamental opportunity to address the task of solving real world problems. This is the tenant by which translational science has always operated and without which we wouldn't have made profound human advances to our condition.     

Existing legislation in Western countries has provided a basis for clarification on the scope of scientific and translational activities, as reviewed here. Europe expressly prohibits at present germ line editing for reproduction. The UK has always had a pro-knowledge framework for discovery using early stage fertilized pre-embryos up to 14 days. The US presently restricts Federal Funding on embryo creation for research and when destructive practices are employed in the lab. 

What is apparent now is the scientific community's consensus on the inherent value of lab study of early embryonic state development using genetic tools to advance knowledge through research while adhering to the principals of caution in progressing any attempts to implement the alteration of the germ line for reproductive purposes. This was the Middle Way path.

The US National Academies summation of their International Summit on Gene Editing affirmed the above in early December last year and called for an ongoing forum to further the dialogue on the topic as the science develops with a view to establishing new recommended guidelines if and when appropriate. The fluid nature of the science requires such and was therefore prudent to set this investigative precedent for all respective regulatory bodies to consider, including the US. 

Previously the UK reaffirmed its position as a leading member of the international scientific community by being the first country to consider Mitochondrial DNA replacement therapy for families with genetic disorders wishing to have a baby free of the diseases associated with such inherited problems. Most recently the UK has agreed to allow genetic research on fertilized pre-embryos for infertility studies without intent to implant for reproductive purposes and always adhering to the prior 14 day limit on embryo development. A modification to the UK law was required for the Mitochondrial DNA therapy to proceed to review stage, while the research on early pre-embryos was already allowable under existing legislative framework which required prior approval and strict oversight.

Following on from the UK's position on Mitochondrial DNA therapy the US National Academies earlier this week announced its recommendation on this genetic intervention procedure for germ-line modification application. The result being an additional affirmation of the scientific potential to alleviate disease through continued research and potential use of the technology in the US. Notable was the necessary recommended investigational support for early pre-embryo studies. Current congressional restrictions inhibit actual Federal support for such studies on viable early stage pre-embryos. This may change in the fiscal year 2017 appropriations Bill as the restriction is not permanent. Support for non-viable pre-embryo research was expressly noted in the US National Academies recommendation paper.           

Both the ISSCR and CIRM have previously stated that they support research on early stage pre-embryos for scientific purposes and have reiterated that position also this week while calling for renewed study of the societal implication of gene therapy and germ line editing.

Commercially the recent change in the position of the European Patent Office on the acceptable use of non-viable pre-embryos methods via germ-line modification brings the alignment closer together and bodes well for the application of various stalled avenues of translational science for the benefit of patients in need. 

Coming around full circle, there would be little progress without the support for all forms of scientific innovation.

Advocacy for Cures.

Cheers

Refs:

1. International Summit on Human Gene Editing Washington DC - "On Human Gene Editing: International Summit Statement" (Dec. 3rd 2016)
2. UK "Scientists get 'gene editing' go-ahead" (BBC Feb. 1st 2016)
3. The National Academies "Clinical Investigations of Mitochondrial Replacement Techniques Are ‘Ethically Permissible’ If Significant Conditions Are Met, Says New Report" (Feb. 3rd 2016)
4. California Stem Cell Report items by David Jensen re: CIRM (1,2) & ISSCR (3) (Feb. 5th 2016)
5. Related blog posts: 1, 2, 3, 4

The Science and Ethics of Genetically Engineered Human DNA - Congressional Hearing

Backstory and current state-of-play review in a formal setting w/ Q&A - Via Paul Knoepfler's Blog post: "Doudna & Others Testify Before Congress on CRISPR, Human Germline Editing"

Cheers

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.

Cheers

References:

• Statement on NIH funding of research using gene-editing technologies in human embryos
• National Institutes of Health Guidelines on Human Stem Cell Research
• European Convention on Human Rights ("The Convention")
• Prohibition of Cloning Human Being
• Convention on HumanRights and Biomedicine, Oviedo, 4.IV.1997
• Dir 98/44/EC European Parliament/Council '98: Legal Protection Biotech Inventions
• European Court of Justice ruling on Parthenotes as not "human embryos"
• Council of Europe -Steering Committee on Bioethics: In Vitro Embryo Protection
• United Nations: The Universal Declaration of Human Rights
• European Court of Human Rights
• Dickey Wicker Amendment
• US Supreme Court ensures continued US funding of human embryonic-stem-cell research
• Genetic Modifications in Humans:The Scientific Methods, Medical Applications and Ethical Implications (ISSCR Connect Video On Demand: Dr. George Daley & Prof. Timothy Caulfield)
• European regulatory map on ES research via Eurostemcell.org

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.

Cheers

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.

Cheers


References:
MIT Gene Editing Article
PaulK Blog Interview with Dr. George Church
ARM Moratorium Request
ISSCR Guidance Statement
Genetic Scientists Policy Recommendations (pay walled)
Universal Declaration on the Human Genome & Human Rights - UNESCO
NIH Bioethics Resource