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  1. Planning for translational research in genomics | Genome Medicine | Full Text
  2. Comparing the human and chimpanzee genomes: Searching for needles in a haystack
  3. Academics Like None Other

Cloning may help overcome present hazards of graft procedures. Embryonic cells could be taken from cloned embryos prior to implantation into the uterus and cultured to form tissues of pancreatic cells to treat diabetes, or brain nerve cells, that could be genetically engineered to treat Parkinson's or other neuro degenerative diseases". A similar view was expressed to a conference in Adelaide in South Australia in November by Professor R V Short who wrote: "Human cloning could usher in a therapeutic revolution if it was used to generate in vitro cultures of pluri potent embryonic stem cells, which after differentiation into haemopoetic or neural tissue for example could then be used for re-implantation back into the nuclear donor for cellular or tissue repair.

Thomson et al in Wisconsin, USA, have recently published in Science the successful long-term culture of human embryonic stem cells. Fourteen human eggs fertilised in vitro were donated by the parents and for five of them, the inner cell masses were successfully harvested to produce embryonic stem cell cultures. When these cell lines were injected into mice, they differentiated into skin, bone, nerve, muscle and gut but not normal placental tissue , thus proving their pluripotency.

This exciting break-through, particularly if it could be coupled with nuclear fusion cloning, could hold as much promise for the future as did the discovery of antibiotics half a century ago". Professor Short points out that the growing of human embryo stem cells in culture in this way would be illegal in a number of the States of Australia and, doubtless, in many legal jurisdictions around the world.

Many ordinary citizens would have a reaction of rejection, possibly even horror, at the notion of human cells being injected into the living cells of mice. Certainly, if such experiments were directed towards the banal object of producing a kind of genetic immortality in the subject, they might involve nothing more than a misguided "ego trip" of little scientific or social justification.

But much more contentious is the suggestion that international principle and domestic legislation should intervene to prevent therapeutic experiments in the nature of cloning of human material. If experiments of that kind represent the next natural step in scientific discovery, should we permit intuitive reactions and feelings of revulsion on the part of communities and individuals to stand in the way?

The challenge for the preservation of scientific freedom and the freedoms of the human species that protect its integrity, dignity and basic rights, is to permit and even encourage potentially beneficial science, whilst ensuring that this occurs in a context of expert ethical reflection and general public knowledge. For my own part, I do not read Article 11 of the UNESCO Declaration as being addressed to therapeutic cloning of human material as distinct from reproductive cloning of an entire human being.

But even the latter may need in due course to be reconsidered as we have more time to explore the constant interaction of scientific freedom and human freedom. Twenty-five years ago, when I was first involved in bioethical controversies in the Australian Law Reform Commission, there was an energetic debate about the ethical and legal acceptability of AIH Artificial Insemination Husband. Within Australia, legislation was enacted in the State of Victoria where considerable progress had been made in the scientific work on in vitro fertilisation. The result was that the scientists and technologists packed their bags and moved to mainland Asia.

The scientific work went on; but not in Australia. Cloning is now, potentially, upon us. Many of the debates and controversies of the earlier time are being repeated. The lesson seems to be that notions of human dignity and of what is acceptable, or not, change in time. In part, the changes come about with increasing public familiarity with the scientific and technological developments, a perception of the benefits which they can bring in identified cases and a realisation that the dangers to human dignity and freedom may be less than at first feared.

So can we defend human freedom in the age of the Human Genome Project? That is the fundamental question. I suggest that we can. But to do so we need to observe certain "rules". I am so bold as to call these rules The Ten Rules of Valencia. They concern an approach to the issues to be discussed here, such as genomics in the workplace; genetic data and the availability of insurance; genetic testing and therapy and medical practice; and the protection of individual rights to privacy and confidentiality.

But the Ten Rules of Valencia also provide a framework for our approach to other topics; indeed all issues which now, or in the future, are presented as apparent challenges to human freedoms in consequence of the Human Genome Project. All laws, policies and strategies to deal with a new and puzzling challenge having a scientific dimension must be based on good science.

Not ignorance, prejudice, unquestioned dogma or even instinctive reaction. Ethical judgments which cannot claim a thorough understanding of the applicable science rest on the shifting sands of ignorance. Alarmism, extravagance and pandering to fear of the new should have no place in the building of legal and ethical principles to respond to the developments of genomic science. Justice Stephen Breyer, of the Supreme Court of the United States, made this point in an address to the annual meeting of the American Association for the Advancement of Science reproduced in Science : "I believe that in this age of science we must build legal foundations that are sound in science as well as in law.

Scientists have offered their help. We in the legal community should accept that offer The result, in my view, will further not only the interests of truth but also those of justice. The law will work better to resolve many of the most important human problems of our time". Only by knowing the true dimensions of the scientific issue will laws and policies be well targeted. Involve multi-disciplinary dialogue: In furtherance of this idea, it is essential to encourage multi-disciplinary and multi-cultural dialogue. Multi-disciplinary, so that lawyers, ethicists and social policy makers can get their minds around the latest scientific developments and understand what they do, and do not, mean for present and future medical therapies and experimental endeavours.

Multi-disciplinary because this will help representatives of the scientific community to perceive and perhaps understand the anxieties of lawyers, ethicists and others. The latter will tend to reflect the concerns of the general community. As past experience demonstrates, when science rushes ahead of community consensus alarm and political sensitivity can sometimes, at least in democratic societies, result in administrative policies which obstruct scientific work or even in laws that restrict it.

Such was the agitation about the unknown dimensions of in vitro fertilisation, that laws were passed in several jurisdictions which had the effect of inhibiting activities of some scientists. The Director of the WHO Programme on Research in Human Reproduction has complained that widespread political opposition to cloning has resulted in rational debate on the topic falling victim to emotion and politics.

The establishment, as the UNESCO Universal Declaration urges, of national bioethics committees is one way of ensuring an institutional structure for the orderly exchange of information and the promotion of true public debate. The desirability of multicultural dialogue was instanced at the Summit of Bioethical Commissions held in Tokyo in November A handful of countries are at the cutting edge of genomic science.

Most countries are potential clients of the pharmaceuticals and therapies which will result. They are venues for the experiments that will take place.

Planning for translational research in genomics | Genome Medicine | Full Text

Unless there is global dialogue and exchanges of knowledge and understanding, local pressure may build up to demand moratoriums and prohibitions which impede legitimate scientific experimentation. Think positively: It is natural to observers of the scene presented by the Human Genome Project to despair of the capacity of lawyers, ethicists and other social scientists to provide useful input to the regimes by which scientists actually work. In the face of the Internet, it may seem impossible, or at least virtually so, to devise an effective international regime that will safeguard agreed basic standards in information flows.

Similarly, with the Human Genome Project. The interests, attitudes, religious beliefs and ethical perceptions are likely to be quite different from one country to another and certainly as between continents.

It is true that the achievement of effective global regulation of a pervasive scientific development is extremely difficult to attain. Quite apart from the different interests of different societies, there are often different starting points for the very idea of regulation. In some societies, the view is adopted that science carries risks and should not be permitted unless scientists can demonstrate affirmatively that there is no risk, or that the risks are negligible. In other societies, there is a presumption that science should be free to advance and will ultimately benefit humanity, as it has generally done in the past.

Sometimes different approaches of this kind coincide with the differing investments which countries have in the products of scientific endeavour. Yet, despite the differences, regimes of general principle can still be established. The very achievement of the Universal Declaration of Human Rights in , covering so many controversial issues, indicates that basic rules can sometimes be agreed globally. We have seen this happen in the development of the Nuclear Non-Proliferation Treaty which seeks to control the spread of nuclear weapons.

Comparing the human and chimpanzee genomes: Searching for needles in a haystack

Twenty years ago I worked on a committee of the OECD in Paris devising principles to govern the protection of privacy in the context of trans-border data flows. Those principles have profoundly affected the development of national law on privacy protection in the context of informatics. It promotes a small number of basic norms addressed to the rights of individuals and, the obligations of States and of the international community.

In this way "core norms" can be laid down to promote local lawmaking and policy development.

Academics Like None Other

The very presentation and statement of international principles can help avoid unnecessary disparities of approach and inconsistency of laws. Choose manageable issues: In dealing with the social consequences of the Human Genome Project, wisdom suggests that particular issues should be selected for early treatment. Some issues are more readily managed than others. Take for example the adoption of laws and policies to govern genetic testing. When it may be done? With whose consent? Where the data will go in identifiable form?

Issues of this kind are susceptible to regulation by protocols adopted by the medical profession supplemented, if necessary, by law. Similarly, with insurance. Whether insurers may demand, before accepting a proposal for life or health insurance, the provision of a report on genetic tests of a particular, limited or general character? Such issues may be decided at least in the first instance by a voluntary moratorium accepted by insurers, banning the demand for the disclosure of genetic test results in the case of a policy of a certain size; or excluding new genetic tests but requiring the disclosure of those already known to the proponent for insurance.

In the long run, the rights of insurers and the obligations of the insured, to genetic data may be governed by law. So far as the results of tests already known are concerned, the universal principle that insurance is a contract of uberrimae fides may already require disclosure to the insurer of such information, if known by the insured. Much more difficult of management by law or effective voluntary regulation are the deeper questions. Whether genetic data is relevant to the criminal responsibility of an accused convicted of a crime of violence allegedly attributable to genetic predisposition?

Whether the protections of intellectual property law are apt to the patenting of mere fragments of human genes, such as those known as expressed sequence tags. Or whether laws can and should ban both therapeutic and reproductive experiments with cloning involving human biomaterial? In the first instance, at least, ethics committees and lawmakers will do well to concentrate on manageable, achievable tasks. The larger, more fundamental issues may require time until "the dust has settled and the emotions have been vented". Affirmative approach: Whilst it is proper for ethicists, public policy makers and lawyers to be vigilant about the implications of genomic science, an attitude of suspicion, or even of antagonism, is unwarranted.

Overwhelmingly, the Human Genome Project will be for the benefit of humanity. Needlessly living with a preventable serious genetic disorder is not ethical. Seeing children and other loved ones suffer debilitating and fatal illnesses beckons us to the promises which the ultimate development of gene therapy may hold out. Already, there have been significant achievements, despite the still primitive tools available to medical science: "Because of the methods by which deleterious mutations are identified, many of the new pathological conditions that have been associated with unusual alleles have been attributed to Ashkenazi Jews?.

The number of diseases now being described might suggest that Jews from Eastern Europe are the carriers of rather a large number of genetic disorders. That this is an artefact of the methodology may often be forgotten. Once identified, people who carry this mutation can use regular colon examinations to detect cancer growth early, when it is most easily treated'.

There is no beauty in needless death and painful suffering. Attitudes to such problems tend to vary sharply in accordance with one's proximity to their urgent demands. Although undoubted dilemmas are presented by genomic science, it is important to remind ourselves that the beginning of therapy is knowledge and that, already, simple genetic screening is providing to some patients the possibility of therapy which, until recently, did not exist.

Be realistic: Another requirement is to be realistic in appreciating the proper limits of legal administrative or other controls upon scientific endeavour. Rules of professional conduct or legal regulation may simply chase a scientist from one legal jurisdiction to another, when there is no relevant inhibition on the research in the latter. In times of economic uncertainty, different countries vie with each other to attract investment, particularly in potentially lucrative and futuristic activities such as are involved in gene therapy.

In the past, there have always been tax havens. In the future, it seems likely that there may be regulation-free zones for that genetic research which promises large investments and speedy economic rewards. The attraction of agreeing to his bid is not only the suggested market for reproductive cloning as a solution to infertility where IVF, say, has failed. It is also the other suspected benefits of cloning as a means, ultimately, for producing compatible organs and tissues for transplantation.

Professor Michel Revel observes: "Today's organ traffic could appear to many a more dangerous peril than producing one's own cloned embryo for autograft" 7. Engage the public: One of the problems of late twentieth century science is that it has gone beyond the ready understanding of even an informed layman. How many well educated people understand Einstein's relativity theory?

The notion of the atom? Thornock also conducts research on the ethical, religious, and social implications of next generation genetic technologies—including rapid whole genome sequencing and CRISPR. He has published and presented on the organizational ethics of genomic medicine and is currently writing a series of papers integrating principles and strategies from business ethics and behavioral economics to genomic research and medicine.

In his spare time, Dr. Thornock enjoys painting and drawing, as well as playing racquetball and hiking. Louis University — Graduate Assistant St. Louis University Adjunct Instructor St. Louis University Full Scholarship St. Ann Public Health Reports , 1 1 Rare variants in one population may be common or absent in other populations. By capitalizing on population and disease genetic architecture, we can better elucidate the relationship of specific variants and genes with disease.

Integrating Genomic Variant Discovery with Function As discussed in the NHGRI Strategic Plan , continued acquisition of knowledge on genome function is valuable for understanding the biology of genomes and the genomic basis of disease. One challenge is that regulatory elements can act over long distances, implying that regulatory variants do not necessarily target the nearest gene. There is an opportunity to characterize long-range chromatin interactions and regulation at scale, to learn the connectivity between genes and their regulatory elements.

A recent paper on the molecular basis for blond hair color Guenther, et al. Nature Genetics. Goals, opportunities and recommendations from the talk, break-out group and discussions included: Define the molecular, cellular, organ and organismal functions of coding and non-coding genome sequences as foundational for biology and interpretation of genomes.

Prioritization should be given to both coding and non-coding regions. This information will provide foundational resources that integrate functional information with disease- and health- related variants. We need to evaluate how different molecular, biochemical, and cellular assays capture organismal and clinical outcomes.

Assays that do not correlate with the organismal or clinical outcomes may result in incorrect assessments of putative function and can mislead scientists utilizing functional resources. Jay Shendure's challenge talk is a hybrid approach, and David Haussler's a variant-first approach. Computational methods should be developed to predict accurately the molecular functions of variation in non-coding and coding sequences, along with models that reflect cellular responses to perturbations.

Develop and make widely available tools to manipulate genomic sequences at scale and experimentally characterize their impact, with the goal of developing generalizable methods for large-scale functional characterization of sequence variants in faithful models. No matter how large the sample sizes become in clinical databases and disease discovery cohorts, causal variants cannot be definitively identified solely on the basis of statistical associations. Supporting data will be needed to prioritize associations for further experimental testing to determine causality.

NHGRI has the opportunity to lead the field in developing new ways to measure function and use the resulting information to inform disease discovery, perhaps resulting in better identification of clinically actionable variants. NHGRI should raise the technical challenge on how to scale up the most important functional assays i. Large-scale assays should be benchmarked against deep and detailed functional studies in specific diseases or domains.

NHGRI could facilitate this work by partnering with domain experts who understand the complexities and subtleties of these "gold standard" assays and diseases. Initial development of large-scale assays and tools will likely focus on the molecular level, but should also consider how to scale to organ, organismal and clinical levels. This will be facilitated by the development of faithful models and assays that correlate with organismal and clinical outcomes in the relevant tissues and individuals. Some assays will provide more provisional information, and balanced expectations are needed when considering what specific assays can and cannot tell us about function at different levels.

The field currently has an unsophisticated view of how proteins interact with our genome and should work to improve our knowledge base in this area. NHGRI could help foster cellular assays and other models that allow us to test how drugs and other environmental agents interact with our genome. Personal genomics can be expanded to include personal functional genomics, where the functions of variants are directly measured in clinical settings. Systematically catalog molecular components and their interactions, across cell fates and cell states.

Functional genomics is valuable beyond simple characterization of variants. High-throughput sequencing can be used to characterize cell types N. The catalog of regulatory elements is not complete. Additional profiling of regulatory data needs to be done in key tissues and cell types, with a focus on cellular contexts most relevant to human diseases. Function should also be considered at the pathway and systems biology level. This requires incorporating concepts of pleiotropy and epistasis, as well as interactions of variants and genes, rather than focusing solely on the impact of individual variants in a single disease.

In addition, the group recognized that genomic assays are informative for genetic, environmental, gene by environment, and microbiome studies; however, they decided the NHGRI remit was probably limited to consideration of genetic effects, and did not further consider the other topics. Clinical Genome Sequencing at Scale As noted in the NHGRI Strategic Plan, "Genomic discoveries will increasingly advance the science of medicine in the coming decades, as important advances are made in developing improved diagnostics, more effective therapeutic strategies, an evidence-based approach for demonstrating clinical efficacy, and better decision-making tools for patients and providers.

These efforts have different focuses discovery and clinical , methodological approaches and patient populations. Common issues include integrating genomics into clinical practice and the electronic medical record EMR , return of results, defining actionability for targeted and incidental findings, best practices for data sharing, and understanding longitudinal impacts on patients and research. A paradox of precision medicine is that sequencing data needs to be generated in large numbers of subjects to interpret what is seen in individual patients.

The 6 th Genomic Medicine meeting in January demonstrated the value of international collaboration. It is imperative for NHGRI to take coordinated action in this area to maximize the benefits and minimize the risks associated with clinical sequencing. Goals, opportunities and recommendations from the talks, break-out groups and discussions included: Define clinical contexts in which genome sequencing improves patient outcomes, including clinical validity and utility, value and cost effectiveness.

The general consensus was that NHGRI grants should not be paying for clinical services in the provision of routine care. Instead the Institute should support catalytic research that advances the translation of genetic and genomic findings into clinical settings, again providing a model to be built on by other groups. Action in this area is needed to reach the goal of improving human health. NHGRI should support research that demonstrates whether, and in what situations, genome-scale testing improves health.

Widely employed tests should have a rational basis, and additional knowledge, data and experience is needed to inform decisions made by funders and regulators. An evidence-based paradigm is needed to demonstrate clinical utility, cost-effectiveness, and the overall value of implementing genomic sequencing in clinical settings. Work in this area will require partnering with disease experts. It will also require different types of studies and study designs, including randomized trials, implemented in a variety of clinical settings and across diverse populations.

NHGRI should complement work in diagnostic clinical sequencing with research that addresses the role of sequencing for prevention, screening and other public health applications. Improve technical platforms to enable rapid, robust detection of all clinically relevant variation in a single test. Clinical sequencing will benefit from improvements in accuracy, expansion of mutation types detected, and decreases in cost and turn-around time. The private sector is also driving innovation in this area.

The spectrum of tissues undergoing clinical sequencing should be increased, including circulating cell-free DNA, single cells and samples that will help improve our understanding of non-cancer somatic variation. Leverage clinical sequencing data for research use, leading to a learning system that improves our understanding of variant and gene disease relationships. NHGRI needs to position itself to positively influence the large amount of sequencing that occurs, and is increasingly going to occur, outside of NHGRI's purview in both the public and private sectors.

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NHGRI can make targeted contributions by improving data sharing, developing and cataloging tools, and modeling "exemplar" studies focused on clinical utility and implementation. NHGRI should foster the "virtuous cycle" between sequencing in clinical practice and in discovery research. Research drives discovery and creates tools that improve diagnosis and translation. Complementary to this, clinical sequencing and clinical data can be harnessed to drive novel discovery and knowledge integration.

Flow between the two areas is needed to maximize both translation and discovery.

NHGRI should help develop a multi-use longitudinal cohort of all patients undergoing clinical genome-scale sequencing. Ideally this resource will allow targeted re-phenotyping of individuals based on their sequence results. Distributed platforms need to be developed that make data sharing as easy as possible for busy laboratories and doctors. NHGRI should also consider other approaches, including sequencing in populations with EMR records to collect targeted and genome-wide sequence data in well-phentoyped individuals.

Data and knowledge aggregation, which is crucial for variant interpretation, will be facilitated by improving sharing of clinical data, but must be balanced with patient and privacy concerns. Physicians, patients and families should be engaged in all aspects of clinical genomics and genomic medicine. This will require improved education of the public on the value of genomics and health. COG is an NCI-sponsored clinical trials cooperative group, comprising over institutions with multidisciplinary teams, that conducts a spectrum of clinical research and translational research.

Define robust approaches to determine the pathogenicity of genomic variants using genetic, functional, and computational data in a statistically valid framework. If clinical sequencing is implemented at scale, we cannot continue to rely on manual curation.

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NIH should facilitate the development of standards for clinical genomic sequencing, variant annotation, interpretation and clinical delivery. Identify effective and efficient methods for implementing sequencing into routine medical practice, and further refine an NHGRI agenda for implementation research in genomic medicine. NHGRI should help develop novel clinical decision support tools for ordering and applying genomic information N.

When possible, these tools should incorporate point-of-care education for physicians. To broaden the population impact, sequencing that is shown to have clinical utility should be incorporated into a wider set of clinical and socioeconomic settings. NHGRI should connect with professional societies to provide appropriate expertise, guidance and data at the early stages of consensus development for guidelines. Breakout chairs Andrew Clark and Evan Eichler highlighted significance and accomplishments in this area: Evolution and population genetics can provide an unbiased framework for the discovery and prioritization of genomic regions for genotype-phenotype correlations.