Cynata & The Rubik of Cell Science

As with the sun rising in the East so have the first two pioneering programs using Induced Pluripotent Stem Cell (iPSC) technology for human clinical study. Independently initiated, but now strategic brethren, the Japanese and Australian efforts to provide a next gen proof-of-concept foundation have all the makings of a new dawn in Stem Cell Science, one that many hope will deliver on unfulfilled expectations for the field.

Methods and mechanics, protocols and parameters - these are but a few of the myriad of defining characteristics that a commercial cell product needs to elucidate in the highly complex rubik of molecular innovation and translational steps. Barcodes if you will of cell product definitions underlying the very nature of scientific clarity and positioning that will pave the road moving forward and deliver safely on The N Factor of human trials with data.

To highlight movement in this direction I’ve addressed a few questions to Dr. Ross MacDonald, CEO of the Australian stem cell company Cynata Therapeutics, on recent progress with their iPSC programs and business plan for this update review piece on the previous conversation I posted last year.

Q&A:

M - Cynata is poised to begin an important sector accomplishment with a first-in-man clinical trial involving a therapeutic product derived from Allogeneic Induced Pluripotent Stem Cells (iPSCs). Can you kindly provide a brief refresh for us on the cell type/technology being used, the target indication and the clinical trial sites prep/patient application/data timelines?

R - We are using a clinical grade, human iPSC as the starting material.  The iPSC cells were obtained from Cellular Dynamics International (CDI).  From these cells we manufacture our finished product, a therapeutic mesenchymal stem cell (MSC) preparation, using our proprietary Cymerus™ manufacturing process.  The target indication is steroid-resistant acute Graft versus Host Disease (GvHD) and the Phase 1 clinical trial is entitled: “An Open-Label Phase 1 Study to Investigate the Safety and Efficacy of CYP-001 for the Treatment of Adults With Steroid-Resistant Acute Graft Versus Host Disease”.  The trial will aim to recruit approximately 16 participants who have undergone a bone marrow transplant or similar procedure, and were subsequently diagnosed with steroid-resistant Grade II-IV acute GvHD.  The study centers are located in the United Kingdom and in Australia and we expect the study should conclude by the end of 2017. GvHD is a potentially fatal disease that often follows a bone marrow transplant procedure and occurs when the immune cells in the donor material (the graft) attack the recipient’s tissues (the host) as “foreign”. 

M - Your recent validating announcement that Cynata has signed a definitive License Option and Equity Investment Agreement with FujiFilm reiterates your strategy to develop and partner development programs with leading sector players. Could you review for us this strategy, the determining factors involved in the decision to sign a partner to your lead program at this stage and the synergy with FujiFilm’s Regenerative Medicine divisions moving forward.

R - Cynata’s Cymerus technology enables the economic manufacture of a consistent and robust therapeutic MSC product.  Given the very many potential therapeutic applications for MSCs (noting the >600 clinical trials underway using MSCs) it would not be possible for Cynata on its own to adequately exploit even a small fraction of the potential commercial opportunities.  Moreover, the Australian environment for biotech companies is challenging for those seeking to become a fully integrated, sales and marketing enterprise.  Accordingly, we believe the best path to ensure shareholders derive stellar returns is to partner our technology with those companies that have the resources, expertise, enthusiasm and global exposure to drive commercialisation of our products.  Clearly Fujifilm is a very active participant in the regenerative medicine sector and has shown a willingness to invest very heavily to maximise the chances of success.  They are an ideal partner for Cynata.  We have however left open the opportunity to work with other companies as well.

M - In your press release on the deal with FujiFilm you mentioned that the arrangement included “certain rights to other Cynata technology.” Are you at liberty to detail somewhat the nature of the technology and the rights granted.

R -  No.

M - Currently Cynata has targeted UK/Europe and Australia as its initial trial territories and has received favorable green light feedback from the respective regulators. Could you comment on the developing regulatory framework to commence these types of pioneering iPSC studies in the US and Cynata’s plans for clinical work in the US market.

R - We have already had very positive initial dialogue with the US FDA. We plan to progress these interactions this year, and we will certainly seek to include US centres in our clinical trials as we move forward. The Regenerative Advanced Therapy Designation process, which the FDA has recently introduced, is of great interest to us and potentially has numerous advantages, including accelerated approval, greater interaction with the FDA, assistance with study design, smaller trials, and ability to rely on real world evidence rather than solely data from formal clinical trials.

M - As Cynata is a leader in the development of Pluripotent derived Allogeneic iPSC treatment technology is there a perspective you could share that puts into context the application specific potential for programs that seek personalized treatment options with Autologous iPSC technologies versus Allogeneic iPSC approaches. Is there a case for both, putting aside the cost issues for a moment, with regard to targeted therapeutic potential, safety and immunogenicity?   

R - I do think there is a case for both, but as always it will come down to (i) the weight of clinical evidence and (ii) cost. Autologous iPSCs may have a greater role to play in tissue engineering applications, where the aim is directly replace or repair damaged tissue at a site of injury or disease.  With our Cymerus technology we have sought to provide a solution to the practical shortcomings associated with manufacturing an “off-the-shelf” allogeneic MSC product.  We firmly believe that our approach, ie using iPSCs, will yield a huge cost and regulatory advantage, at least insofar as MSC therapeutics are concerned.  The broader applications of iPSC-derived cell therapy products is being hotly debated and much research capital is being expended on developing the “super haplobanks” to make allogeneic products more practical. 

M - As previously reviewed, the IP surrounding your technology was invented by scientists at the University of Wisconsin and exclusively licensed to Cynata by the University’s IP management arm, WARF. You note that that these foundational patents are being expanded upon by the filing of additional Cynata patent applications related to progressive discoveries to the underlying technology. Could you provide some specifics at this stage as to the substance of the novel and unique aspects of the invention mentioned, given, I believe, these innovations are as yet unpublished.

R - Indeed we are seeking to build the IP platform with additional patents around new inventions in our Cymerus technology.  As these applications are in the early stages of prosecution we are unable to provide details at this stage.

M - In respect to your other program assets, could you highlight recent developments that pertain to Cynata’s pipeline and any news on initiated research into new indications, such as the positive impact Cymerus™ mesenchymal stem cells (MSCs) could have for Asthma suffers.

R - The data we reported late last year in the well-established chronic allergic airways disease model was certainly very exciting and accordingly we have been encouraged to further study the effects of our Cymerus MSCs in related models and potentially into the clinical setting.  We also have active programs underway in cancer (through Harvard/MGH) and in cardiovascular disease (with Westmead Hospital/University of Sydney).  With the success of our recent capital raising the company is now very well positioned to accelerate these ongoing programs as well as to consider other areas where we might be able to quickly build value.

M - Finally, at present Cynata is a publicly traded entity on the Australian securities exchange (ASX). Do you have any plans in the near term to reach out to more investors through a UK or US listing?

R - This is a question that stimulates much discussion around the boardroom tables of Australian biotech companies.  Certainly US and European investors have a very high level of understanding of the potential risks and rewards of biotech and the availability and quantum of capital is typically higher than in Australia.  However, an offshore listing is not for the faint hearted and some recent spectacular fails have made Aussie’s very circumspect. We have an open mind, but would prefer to really build a solid and supportive shareholder base in Australia first and thus have a solid foundation beneath us before we would contemplate a foreign exchange.

M - Thank you Ross for your time and all the best for the upcoming trial. Cheers

UPDATE: See latest Cynata program news at "Cynata's iMSCs" blog tab.

The N Factor

The mere mention of a possible stop-gap option to the grave medical realities of those that suffer, let alone a lifeline to a solution, is enough to get most patients and their families/friends talking. Clinical trials however are relatively few and far between for specific diseases and those that are available are currently akin to drawing the lottery where circumstances such as referral, timing, scale, proximity and onerous inclusion criteria set a very high bar to entry.

The vast majority of patients don’t have any options.

I’ll relay a representative case in point - a friend of mine was diagnosed recently with Stage 4 Melanoma, an advanced skin Cancer which is all but fatal in relatively short order. His doctors gave him the ticking clock and little hope. However, given his wish to live and determination to see his young son grow up he studied, turned over every rock and reached out. He landed a very rare spot as a tag along to a new immunotherapy trial. He was lucky, most are not, given he didn’t meet the strict criteria for official entry. The trial treatment saved his life.

T-Cells in Action

Hope is a cruel bedfellow with its constant draw of energy and resources from the very reservoir it seeks to fill. Yet without that flicker of a flame gasping for oxygen the very medical system built upon empirical data derived from clinical trials designed to advance knowledge wouldn’t exist.

The system needs patients and patients need the system - both rely on the other and as such require inclusive practices to further the agenda of progress towards real solutions.

Emily Whitehead

N is a strong and decisive letter in our everyday language but in investigative medicine it’s a defining research statement which confers status and validity where quantitative analysis imbues significance and wields judgement on meaningfulness. For those not on the in, the N is translational science parlance for the number of patients treated and their data sets. The lower the N the more likely there will be variability in the eventual safety and benefit outcomes when applied to the patient population at large. While the larger the N the more significant the potential correlation in delivering a safe option and potentially treating the targeted disease indication. 

As fundamental as the N is to applying the scientific method to proving the safety and potential for wide scale application, it cannot be suggested to be devoid of meaning at any level, especially considering the human impact and nascent development of promising new therapeutic modalities for treating previously unmet medical needs.

The mere fact that we will all suffer in one form or another from the debilitating conditions of age is enough to warrant more attention to the secondary benefits in N data given the lack of achieved endpoints of trialed drug interventions to-date. Combine the natural degenerative conditions of the aged with a population rife with chronic and acute medical issues that continue to overburden the system, leaving a significant population of those in need without a solution, and you have the argument for considered change.

Breakthroughs in medical science indeed offer a real opportunity to effect change and the more that can be done to allow for inclusion and support for that transformative process to occur the more representative the N will be that correlates to real tangible wellbeing data logged for the betterment of the science as well as the patient. 

Cheers

Ref: Related Cancer Blog on Emily Whitehead

Balancing Paradigms with Mesenchymal Stromal Cells

Steve Gschmeissner/Science Photo Library

Innovation isn't uniquely devoid of commonality of adoption by discipline. Rather the likelihood of acceptance generally tracks evenly to historical norms in parallel with society's openness to progress and the search for solutions. However, the impact of technological change is variable and dependent on societal factors related to income and health. One could argue the greatest benefit comes when change drives both economic prosperity and improved health standards.   

While the average pace of technological innovation slowed some decades ago the recent rapid rise of medical science has taken on the mantle of sustainability for growth. The dramatic impact potential of fundamentally transformative practices in healthcare is being fueled by access to new knowledge and a greater sharing of insight. 

Today, due to the convergence of various technology led disciplines, there are many important catalysts for paradigm shifting change. A key criteria common to all are the Drivers - fundamental products or processes that opens up the gates to new realms of understanding and acceptance. At each juncture a bridge must span the divide and a stake ground into new terrain. 

Are MSCs a Driver that can forge a paradigm shift in stem cell healthcare & how did we get here?
         

The investigation of bone marrow (“BM”) stem cells led to the establishment and widespread clinical practice using cells of the mesodermal blood lineage via bone marrow transplantation – known as hematopoietic cells (“HSCs”).

The first use of these BM  stem cells as therapy was pioneered over 50 years ago when transplants were first introduced experimentally to treat leukemia. However, as with most donor tissue the understanding of immune rejection of foreign non-self cells was and still is of major concern for the successful treatment of disease using allogeneic (donor) tissue. This is even the case when immuno-histocompatibility is done via matching of the cells to the host. This complication has stymied the field of cellular therapeutics due to the severe adverse events that can result from the administration of donor derived cellular treatments. In the case of BM transplantation they routinely cause Graft versus Host Disease (“GvHD”) as a result of the treatment, with approximately 50% of all such patients reporting complications. The percentage of mortality as a result of this last resort treatment intervention even today is staggering with up to 17% of all severe liver/gut GvHD cases resulting in death(1).

NIH.gov

As a field the discovery and isolation of Mesenchymal Stromal Cells (“MSCs”), a small subset of BM niches representing less than 0.01% of all HSCs, was a watershed moment. It was a true breakthrough as these cells were found to be able to replicate as multipotent precursors and can be differentiated into fat, bone and cartilage. The isolation and clonal nature of these MSCs opened up a whole new avenue for cellular investigation. Further sources of MSCs were discovered in a range of bodily tissues, including fat, perinatal tissue and dental pulp. The technology for human application of these adult cells gave rise to the stem cell industry we know today. Upwards of 500+ clinical trials using MSCs are registered currently in the US central database clincaltrial.gov for a variety of unmet disease indications (2).

In addition, there is a large growing trend of undocumented cases using MSC products in private medical offices as marketed treatments via autologous (self-to-self) therapies (3). These unlicensed medical practitioners using MSCs products are the subject of considerable debate as to where the line should be drawn between required regulatory oversight and freedom of medical use in private clinics for autologous treatments. The US FDA is currently reviewing draft guidelines (4,5,6,7) for treatment products using MSCs. They are preparing to define what constitutes more than minimal manipulation and cell use parameters. This is with a view to determining clinical trial requirements for MSC biologics, in keeping with current drug development procedures already in place.

Safe and Effective?   

The prospect of MSC utility for therapeutics has been due in large part to the evident immunological privileged nature of MSCs and their potential for universal application without immunosuppressive drugs – unlike HSCs themselves. Although MSCs have an antigen profile they lack major class antigens which makes them relatively immune-privileged to the host system thereby allowing for donor derived cell treatments without treatment rejection in low dose regimes.      

The Scientist - Keith Kasnot

The properties of MSC have been appropriately described as “ambulatory” and “paramedic” – i.e. they’re built to respond to injury in the body and assist in its repair. How they detect, migrate and signal, in addition to what biological manner they act, and what way in different circumstances, is a source of considerable study. It seems clear though now that their “method of action” (“MOA”) is modulatory in nature via complex regulatory mechanisms (8). One such mechanistic attribute is via the excretion of bioactive factors (vesicles, exosomes et al) and work to facilitate cell to cell communication networks (9).

Much has been written about the potential of tissue derived MSCs as a treatment option for a host of acute, immune and degenerative conditions. However, the field is still developing and protocols are being tested and adjusted to maximize possible outcomes. I’ve added an overview video below on the challenges and issues faced by MSCs product developers’ to-date by a leading expert in the field Dr. Jacques Galipeau of Emory University. The presentation highlights a number of findings on research and data in this sector and is well worth watching

Dr. Jacques Galipeau of Emory University

As mentioned, and referred to in the video, numerous clinical studies are underway on the use of MSCs and case reports have been published on both the potential benefits and in certain cases a lack of statistical benefit in patients receiving these cells from a variety of tissue sources.

With regard to the clinical trial results there is clear validation of MSCs safety profile, which is fundamental to their successful translation. Potential treatment efficacy of MSCs is suggestive to-date of positive activity on various outcome measures in a number of reported studies. These positive results are counter-balanced with questions on method of action (“MOA”) and some failed studies. This somewhat mixed picture generally points to issues relating to the development of medicinal products and cellular biologics should be viewed as no different.

A few of the better known company examples of MSC sector developments in the sector are briefly summarized below with links to the company for further details on the data.

• TiGenix (adipose/fat) – has moved on from the 1st EU approved and marketed autologous (“auto”) MSC cell therapy called ChrondroCelect for cartilage repair to an allogeneic (“allo”) product strategy with solid Phase III results in hand for Cx601 in Crohn’s Disease. This will mark their first allo indication nearing approval with other adipose stem cell products in the pipeline. 

• Mesoblast (BM) – bought the first approved western auto cell therapy Prochymal for GvHD from Osiris which had mixed results and was never released. They are developing a full in-house line-up of allo product candidates with good support data and are partnered with a Teva Pharma. Notable pipeline news include marketing approval of TemCell in Japan for GvHD with local partner JCR Pharma (repackaged Osiris product) and solid data in late stage trials (MSC-100-IV for GvHD also, MPC-150-IM for heart and MPC-06-ID for back pain, amongst others).

• Athersys (BM) – lost Pfizer as a program partner for MultiStem after releasing mediocre data in ulcerative colitis. A second Phase II read-out, this time in stroke, also failed to meet endpoints. However, newly released interim data in its ongoing stroke study is now suggestive of positive results from the homing-in strategy on potential earlier treatment window benefit. Also of note are the additional clinical programs in development for cardiovascular and inflammatory/immune indications. In addition there’s a solid validation deal with Healios of Japan for MultiStem in that market and use of the product for Healios’ ongoing development programs.

• Pluristem (placenta) – “PLX” product line for vascular, muscular and immune indications in early stage clinical trials (PI & PII) with solid data in muscle and critical limb ischemia. Promising preclinical results for bone marrow repair with government sponsorship for rapid route to market in acute radiation syndrome.

• 
  Vericel (BM for heart program) – previously known as Aastrom with a long history of development of auto MSCs for heart and CLI indications with poor accumulated data continues to develop the heart product in clinical studies with recent positive data after previous endpoint failure, indicative of statistical benefit. In 2014 they secured additional auto cell therapy products from Sanofi (Carticel & MACI – cartilage and Epicel – skin) which had previously received certain market authorizations and are generating revenue with patient benefit.

Indicative data sets for comparative analysis and ratio breakout are yet to be tabulated with regard to which conditions and methodologies the cells work well for and in which cases they don’t help all that much or at all. However, one must be cautious when assessing the efficacy value of cellular products as they are biologics and there are many issues relating to their degree of effectiveness, such as: their source; derivation method; inherent donor variability; passage potency; culture conditions & scale-up manufacturing; cold chain methodology; target indication; patient population; disease states and application methods, amongst others. As a result not all cellular products will perform well in human studies. These issues play a significant role in whether they achieve benefit in tests on patients, and to what extent in relation to standard of care. Although the jury is still out there is a general agreement based on empirical data that these cells are on the whole safe, when developed and used appropriately. Where they have been shown to have positive outcome and biological activity there is acknowledged room for improvement with regard to enhancing efficiency, potency and cell mechanistic action, which is encouraging.

One aspect of the development of industrial scale cellular therapies speaks to the need for increased replicative capacity, lower passaged products and standardization via use of optimization technologies and shifting to pluripotent cell sources instead of donor derived batch processing of multipotent cells.

Octane Bioreactors

As a result of this progressive development culture method adjustments gleaned from the early pioneering work of MSC development are giving rise to efficiencies of process and improved manufacturing protocols for next generation methods in both multipotent and pluripotent products. The above mentioned early leaders in MSC product offerings are beginning to line up their treatments for entry to the market, while the sector looks to prepare and trial the more advanced cell factories of the future.

UC Davis MSC Investigators

This momentum is also being driven by the rise of synthetic constructs using MSCs - the personalized tailoring of targeted medicines for improved performance. MSCs possess inherent homing and immunomodulatory properties and therefore are ideal for use in combination with gene and nano technologies. In addition, the extraction of the inherent cell properties of MSCs for standalone biologic products adds to the overall picture and excitement in the field.

MSC products are representative of the wider cell therapeutic field and are the standard bearers in the effort to bridge the shifting paradigms of new treatment modalities for patients in need.

Cheers

Ref: Sector Update on Asian Market for MSCs > "Cell Therapy in Asia Erupts with Partnerships and Joint Ventures"

ISSCR 2015 Annual Meeting Coverage

I recently attended the annual meeting of the International Society for Stem Cell Research and have been writing up the coverage in dedicated articles which you will find the links to below and also to the right.

The interview with Dr. Sally Temple entitled "Cells, Leadership & Audacious Innovation" can be found here.

I wish to thank the ISSCR for the opportunity and to Michelle Quivey, Snr Comms Mgr, for her professional handling of the media scheduling.

Cheers


ISSCR 2015 Introduction

Stem Cells & The Aging Brain - Karolinska Symposium



Biotech Spin-Outs: Discovery > Company



Media Hype | ESi Bio | CIRM's Chairman



Masayo Takahashi - "Hope - Yes" & "Patients First"



GDF11 | Adult MSCs > MS | NYSCF Mito/NT



The Pluripotency Trilogy



Jeanne Loring - Parkinson's, Mice, DNA, hPSCs & Rhinos



Utility by Design - Bio-Engineered MedTech Devices

Congressional Debate Heats Up on Germ Line Editing

Recently a story by Sara Reardon for Nature broke that the US House of Representatives had introduced as part of the 2016 spending package a Bill that would seek to add restrictions on top of already existing regulatory provisions and guidelines in respect to human genetic editing of embryos, sperm or eggs (germ line cells).

The idea would be to restrict access to federal funds to evaluate or permit proposed research applications in this area. This would in effect stall any positive progress in the US in respect to basic biology questions in regard to potential solutions for inherited genetic disorders. Mitochondrial technologies that are being considered would for example be effected by this ban.

In addition, the language in the House Appropriations Committee's Bill would look to establish an “an independent panel of experts, including those from faith-based institutions with expertise on bioethics and faith-based medical associations” to review recommendations from federal advisory institutions, such as the US Institute of Medicine (IOM), with regard to such technologies and their use.

Non-viable embryos would be notably allowable under these new proposed rules for research purposes.

The US National Academy of Sciences (NAS) who oversees the IOM are due to conduct a review of the human gene editing area later this fall, as noted in the video below and detailed in the NAS/NAM press release here.

As a few have pointed out the involvement of "faith-based institutions" doesn't seem to warrant concern as the topic is for the entire community to discuss and participation from all members is recommended. Consensus can only be legitimate if all voices have had equal representation in the discussions.

However, this I believe is more to the point. Where does it state that democracy first establishes law then allows inclusive debate? This initiative seems on the surface to be more of the same rather than a genuine effort to collaborate on an effective and universally applicable set of guidelines for legislative consideration in all international jurisdictions. 

Cheers

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