Álvaro Siza Vieira - Viana do Castelo Public Library

Master in Genetic Counselling to begin in Portugal

Plans are already advanced for a master course on genetic counselling to begin at the Univ. Porto (ICBAS), in 2009. Its main objective will be to train professional genetic counsellors, who will integrate multidisciplinary teams at genetic services and consultations. This profession is present for quite some time in a few countries, and is now being created is many others, but still did not exist in Portugal.

It will have theoretical courses and small group tutorials and discussions, but will be mainly practical. The main educational areas will be (1) principles and practice of genetic counselling; (2) human and medical genetics; (3) clinical psychology, mental health and communication skills; (4) public health, community genetics, organization of services, health policy and health economy; (5) quantitative and qualitative methodologies and research methods; and (6) bioethics and medical ethics. A range of (7) optional disciplines in these and other areas will offered, as well as (8) clinical rotations; and (9) a second (final) year in medical genetic services, with a final report.

(1) NEC Forum Work Group on databanks at the EC; (2) OECD expert group on biobanking

Portuguese Council for Bioethics (CNECV): 3rd mandate (2003-08) comes to an end

The Portuguese National Council of Ethics for the Life Sciences (CNECV) came this week to the end of its 3^rd mandate (2003-08).

During these years there were many important opinions regarding (or touching) the field of medical genetics, including on PGD (51/CNECV/2007), DNA profiling and genetic databases for forensic purposes (52/CNECV/2007), and direct marketing of genetic tests to the public (56/CNECV/2008; see also post of 13 July). Other opinions regarded medically assisted procreation (44/CNECV/2004), human cloning (48/CNECV/2006), and stem cell and human embryo research (47/CNECV/05 and 53/CNECV/2007).

Among other representations, CNECV was present at the Council of Europe for discussion of genetic testing and insurance, and will be represented tomorrow at the European Commission, DG-Research, for a new working group of the NEC Forum (Forum of the National Ethics Councils) on DNA databanks. The idea was introduced at the 10^th NEC Forum, which took place last year and was organized by CNECV, under the Portuguese presidency of the EU.

CNECV organzied various seminars and educational activities, including "From the Cell to the Embryo", "Teaching and Education in Bioethics", "Ethics and Research in the Life Sciences" and "Awake- nings for Bioethics". In just a few weeks, CNECV will be launching a book on Biomedical Research (Gradiva), which includes a chapter on genetic testing and translational research (see also post of 20 July).

At the last session, after a balance of the work done, Paula Martinho da Silva (President) evoked Falcão de Freitas, professor at Univ. Porto and member of CNECV, who died during this mandate. Daniel Serrão, a member since the first mandate, evoked also Maria de Lourdes Pintasilgo (1930-2004), first women PM in the country and former member of CNECV.

EHA and EHDN 2008 meetings

This past week, the 5^th Annual Plenary Meeting of European Huntington Disease Network (EHDN) was held in Lisbon, from September 5^th to September 6^th. It was the largest so far, with about 500 persons present, including researchers from all continents and patient association representatives.

A number of EHDN working groups reconvened at that time as well, including the one on genetitic testing and genetic counselling. The international guidelines for predictive testing were discussed and are being revisited.

The following weekend, took place the 12^th meeting of the European Huntington´s Disease Association (EHA), held September 6^th to September 8^th, 2008 (photos).

MJD Foundation launch in Groote, today

Today, the MJD Foundation was launched in Groote Eylandt, land of the Anindilyakwa people, in East Arnhem Land, Northern Territory. Machado-Joseph disease (MJD) was first reported here, in 1993 (see post of 10 August). MJD is a major local health problem in Groote, as in a few other parts of the world. People with MJD and other hereditary diseases have been neglected for a long time, here and in so many other countries and communities; neglected diseases in neglected persons, often in long neglected communities, can make the families and the community even more vulnerable, and thus need special attention.

Groote born Libby Morgan (chair) and her former teacher Gayangwa Lalara (vice-chair), are some of the major promoters of the foundation, which is deeply enrooted in the community and has already been instrumental in helping the affected persons and families to break their isolation. They came to know that MJD is not their exclusive problem, as it is all over the world and affects many other families of various ethnic backgrounds. Just as in other communities, people here became aware that MJD is a hereditary disease and that is helping to relieve feelings of guild and shame.

Groote Eylandt became well known to the MJD scientific and medical community, as well as to ataxia patient associations around the world. Though stigma is still a problem, this community grew proud of the work being done there, what was very evident today during the launch of their MJD Foundation today.

Timor-Leste (an image tale)

Graffiti (Douro valley)

Menzies and Menzies: Machado-Joseph disease, Groote Eylandt and manganese, or how the Chinese changed the world!

Sandra Martins et al. (2007) suggested an Asian origin for the worldwide-spread mutational event in Machado-Joseph disease (MJD). The only known affected population conspicuously absent from her worldwide study had been the Aborigines from Groote Eylandt and east Arnhem Land, northern Australia. Now, the Human Research Ethics Committee of NT Department of Health and Families and Menzies School of Health Research has just approved the study.

In 1980, LG Kiloh et al. reported 13 (possibly 16) cases of an endemic neurological disorder in tribal Australian aborigines, among 1100 tribal aborigines in Groote Eylandt and adjacent mainland. Curiously, they mention two distinct clinical pictures (one, in childhood, involved the motor system and very lax ligaments; the other, of later onset, comprised cerebellar, upper motor neurone and sometimes supranuclear ophthalmoplegic features), though both were probably varieties of a single condition, that might be genetically determined.

This has been attributed to manganese poisoning, mined there since the 1960s. From 1990, Tim Burt, from the Menzies School of Health Research (MSHR), studied this “Groote Eylandt syndrome”. Elevated blood levels of manganese were found, but both among those with or without the neurological signs. Of note also the familial clustering and, often, the absence of occupational exposure. The MSHR is a medical research institute focused primarily on Indigenous communities.

In 1993, Tim Burt and co-workers published on a dominant hereditary ataxia resembling Machado-Joseph disease in Arnhem Land, in four Aboriginal families who had many features in common with MJD: multiple system involvement, sparing of the inferior olives and cerebellar cortex. Portuguese ancestry was possible, but not proven. This work was presented at the 3rd Intern. Work. on MJD, São Miguel, Azores, 7-9 April 1994. But the gene and mutation had just been found so that, in 1996, with Garth Nicholson from Sidney, Tim Burt et al. published that the diagnosis of MJD was confirmed molecularly.

But this has not prevented Mark Purdey, an organic dairy farmer of Somerset, England, from suggesting, in 2004, in the J Am Coll Nutrition that the pathogenesis of MJD could be due to a high manganese/low magnesium initiated CAG expansion mutation in susceptible genotypes. Earlier on, he had stated that mad cow disease was related to manganese poisoning, as was Kuru, the Groote Eylandt syndrome, Parkinson and a variety of other neurological diseases. To him, the prevailing theory blamed the emergence on an inherited mutation introduced into the community 300 years ago, by Portuguese-Macassan sailors who interbred with Aboriginal women when harvesting the trepang in the island. But, he spoke to the Aboriginal elders who adamantly denied any such inter- relationships. So there you have it - manganese again.

MJD has been known in Japan and throughout Asia; more recently, China is emerging as a major foci of MJD. Gavin Menzies (apparently not related to Robert Menzies...), in How China Changed the World, cited Jerry Warsing from Crow, Virginia (USA), who believes MJD originated in the Yunnan province of southern China and was carried by Zheng He’s fleets to the Atlantic coast of N. America and then to the Azores. He was contacted by a local leader of the Melungeon people of West Virginia, who have a high incidence of MJD and this led him, in some sort, to the voyages of Zheng He. A squadron from Zheng He’s Fleet reached the Azores in 1422 (Columbus reported drowned Chinese at Flores and the statue of a horseman on the summit of Corvo). Menzies contends that there is corroborative evidence of ‘Chinese DNA’ in every country where MJD has been found, including Yemen, Brazil, the Malabar Coast of India, Japan, Darwin, California and New England.

With the right or wrong arguments, Gavin Menzies may just have hit the truth. The Menzies School, in Darwin, has now provided us a chance to prove it. All coincidences? ... Pero que las hay, las hay...!

Change, rather than Permanence: about Francisco M. Salzano’s 80th birthday

Francisco Mauro Salzano completed 80y last weekend, and is being honoured for his long and productive career, but certainly also for his charismatic personality and example of citizenship.

He has published over one thousand articles, including nearly two-hundred papers in international journals indexed in PubMed, authored/edited nine books and 29 chapters, and supervised 43 PhD theses concluded. He is Emeritus Professor atf the Genetics Depart., at the Federal Univ. of Rio Grande do Sul, in Porto Alegre, from where he graduated and where he began his career as instructor, later to become full professor and director of the Natural Sciences Institute. An honorary citizen of Porto Alegre, he received many prizes and honours, including membership of the Brazilian Academy of Sciences and the National Academy of Sciences of the US.

Salzano begun his genetics studies with Drosophila, in São Paulo (USP), where he concluded his PhD in 1955 (Dobzhansky was a member of his juri). The following year, Salzano began studying human populations with James Neel, at Ann Arbor, Univ. Michigan. With J. Neel, he worked out a population structure model where migration among indigenous groups explained the genetic variability found; he developed a new theory to explain colonization of the Americas. His genetic studies on the Xavantes Indians extend for over 50 years. He participated in the discovery of haemoglobin Porto Alegre, in 1963.

Salzano wrote, with Anna Magdalena Hurtado, Lost Paradises and the Ethics of Research and Publication, 2004) to defend, one by one, the accusations brought against Jim Neel in Darkness in El Dorado, as well his obituary in Genetics and Molecular Biology (James V. Neel and Latin America - or how scientific collaboration should be conducted).

In the interpretation of our existence two philosophies can be distinguished, one that places emphasis on stability, in the maintenance of the status quo, and another that emphasizes the importance of change. It is not unrealistic to relate these two positions to the biological constitution of the individuals who maintain them (Permanence or change? The meaning of genetic variation, PNAS 2000). And, Salzano has certainly been always among those favoring change.

He claims that some groups not only try to ignore science, but also are hostile to it, and those groups must be seriously opposed. Those are mainly the creationists, the anti-transgenic movement and the anti-stem cells groups.

But Salzano is also well known for his humour and good spirits, and for always being ready to show his amazing dancing skills.

Victor A. McKusick, M.D. (1921-2008)

This past Tuesday, 22 July, Victor A. McKusick died, at home. He would be 87 years, this 21^th October. The 49^th Annual Short Course on Medical and Experimental Mammalian Genetics, he founded in 1960, had just begun at The Jackson Laboratory, Bar Harbor, Maine, and was most probably the very first one he was missing. He also founded and directed, with Giovanni Romeo, the European School of Medical Genetics (at Sestri Levante, now in Bertinoro, Italy), a counterpart of the Short Course, without the mammalian component.

Dr. McKusick started, in 1966, the Catalog of Human Genes and Genetic Disorders - Mendelian Inheritance in Man (12 eds. up to 1998), and curated its online version OMIM, for over 40 years, to which he devoted ¾ of his work time. One of the most used resources in medical genetics practice and research, it has 18,853 entries, a Gene Map and a Morbid Map.

Father of Medical Genetics, Genetics pioneer, Genome Project pioneer and inspirer or key architect of the human Genome Project were some of the phrases used to describe him. "His tireless and creative contributions over more than half a century have provided a permanent foundation for a field that now occupies the center of modern medicine", said the NHGR director Francis S. Collins.

As soon as 1969, VAM urged establishing a map of the human genome; he officially launched the HGP in 1989, with J. Watson. The first draft was announced in Feb 2001; he was the president (since 1989) of what people then called Victor's HUGO. VAM served also on the NIH Human Genome Advisory Committee (1988-1992) and the joint NIH/Department of Energy Ethical, Legal, and Social Issues Working Group (1990-1995).

In 1957, Dr. McKusick established the Div. of Medical Genetics at Johns Hopkins, one of the first ever. It was located for a long time at the Moore Clinic, on Monu- ment St., predecessor of the McKusick-Nathans Institute of Genetic Medicine.

VAM described several “new” genetic disorders and contributed to map many human genes. Recently, he described his main research interests as the (1) comprehensive collation of information on human genes and genetic disorders, (2) genetic disorders in the Amish, and (3) history of Medical Genetics; his main clinical interests were the heritable disorders of connective tissue and the skeletal dysplasias. He was the editor of Medicine, and of Genomics (founded, in 1987, with Frank Rudle). His seminal contributions included a reference book on heart sounds, a classic textbook on the Heritable Disorders of Connective Tissue, a book about genetic diseases in the Amish, the one with Samia Temtamy about the congenital malformations of the hand, his early writings on Marfan, and many contributions to the study of various forms of dwarfism, among so many others.

Among many honors and prizes, VAM received 21 honorary degrees, the William A. Allan Award of the ASHG, the Benjamin Franklin Medal of the American Philosophical Society , the James Murray Luck Award of the National Academy of Science, the Kober Medal of the American Association of Physicians, the Lasker Award for Lifetime Achievement in Medical Research, the National Medal of Science by the US President, and, this year, the Japan Prize in Medical Genetics and Genomics.

Victor McKusick will be tremendously missed by so many of his students, residents, fellows and mentees, whom he inspired to follow his example of devotion to clinical medicine, medical genetics and genetics research, and to humankind. We will all miss his teachings, his acute intelligence and enormous clairvoyance, his humble wisdom and, above all, his great generosity and affectionate dedication to others. We will miss his gentle voice and his judicious words, his breath-taking pace, small change tingling in his pockets, an imaginative sense of humour, a nearly-comic uneasiness with (often even the commonest) foreign words, his kindness, the equanimity he worshiped and tried to convey to us, his humanity.

Victor, we will miss you immensely.

With Anne B. McKusick, in Bar Harbor, Maine (2001)

To read more about Victor A. McKusick:

• Johns Hopkins Medicine, Institute of Genetic Medicine: Victor A. McKusick, M.D.
• McKusick-Nathans Institute of Genetic Medicine: Victor A. McKusick, M.D. - 1921-2008 - Father of Medical Genetics
• National Human Genome Research Institute Pays Tribute to a Giant of Medical Genetics: Renowned Father of Medical Genetics, Victor Almon McKusick, 1921-2008
• The Ronzano Project - The European Genetics Foundation: Victor A. McKusick, University Professor, The Johns Hopkins University School of Medicine Baltimore, MD
• The Bologna Project: Giuseppe Levi and Victor A. McKusick Euro-Mediterranean Center for Genetics and Medicine
• Johns Hopkins Magazine (April 2000): The Man Who Put Genetics on the Map
• The Washington Post: Victor McKusick; Genetics Pioneer
• New York Times: Victor McKusick, 86, Dies; Medical Genetics Pioneer
• Los Angeles Times: Victor A. McKusick, 86; Johns Hopkins physician pioneered genetics research
• The Wall St Journal: Victor McKusick, Father of Medical Genetics
• Wikipedia: Victor Almon McKusick
• Obituary in the Baltimore Sun

Oil from a photo (with the first 8 eds. of MIM, the "Amish Madonna"
and the Heritable Disorders of Connective Tissue

To read by Victor A. McKusick:

• McKusick VA: Cardiovascular Sound in Health and Disease. Williams and Wilkins, Baltimore, 1958
• McKusick VA: Heritable Disorders of Connective Tissue (5th edition, 1993). CV Mosby, St. Louis, 1956
• McKusick VA (ed.): Medical Genetic Studies of the Amish.. Johns Hopkins University Press, Baltimore, 1978
• McKusick VA: Mendelian Inheritance in Man, (12th edition, 1998, in 3 volumes; online version OMIM). Johns Hopkins University Press, Baltimore, 1966
• Temtamy SA and McKusick VA: The Genetics of Hand Malformations. Alan R. Liss, New York, 1978
• McKusick VA: Presidential Address, 8^th Intern. Congress of Human Genetics. Human Genetics - the Last 35 Years, the Present, and the Future. Am J Hum Genet 50:663-70, 1992
• Peltonen L, McKusick VA: Dissecting Human Disease in the Post-Genomic Era. Science 29:1224-9, 2001

What is Translational Research?

To improve human health, scientific discoveries must be translated into practical applications (the NIH Roadmap for Medical Research). Typically, the process moves “from the bench”, with a molecular or cell study of disease, to the “bedside”, and is a two-way street. What might seem a natural, automatic process, in practice is a great barrier between basic and clinical research. In fact, the barrier is rising, with the ever-increasing amount of scientific knowledge available and the growing difficulties involved in clinical research, precisely at a time when this translational should be expanding. To reduce these barriers, the NIH launched the Clinical and Translational Science Awards (CTSA) Consortium, in October 2006.

The Howard Hughes Medical Institute (HHMI) had a similar initiative, back in 2002. Lee Nadler, of the Dana Farber Cancer Inst., Boston, challenged the HHMI definition of a translational researcher, who should be someone who takes something from basic research to a patient and measures an endpoint in a patient. He outlined the divide between translational researchers and biomedical scientists, during his Clinical Research Award Lecture, at the American Association of Cancer Research, San Francisco (8 Apr 2002), providing examples of what translational research is and is not. According to him, virtually nobody is concerned with creating the necessary middle infrastructure that takes work from the lab to the clinic.

A good definition is that of the Translational Research Working Group (TRWG) of the National Cancer Institute (at NIH): research that transforms scientific discoveries from lab, clinical, or population studies into clinical applications to reduce disease incidence, morbidity, and mortality. The TRWG performs early translation, in the definition of the President’s Cancer Panel (PCP), lead by the retired cycling-star Lance Armstrong. In the PCP 2004-2005 report, translational research is presented as a continuum from basic science discovery to dissemination and adoption of a clinical application, going through early and late translation.

NIH in its CTSA call, states that translational research includes two areas of translation: T1 is the process of applying discoveries from lab research or preclinical studies, to the development of trials in humans; T2 is aimed at enhancing the adoption of best practices in the community, and has been seen in the past as the domain of public health scientists. The Center for Clinical and Translational Sciences (CCTS) of the Univ. Texas, at Houston, considers its main goal is to replace T1 and T2, often seen as separate, with one smooth and rapid process of discovery, clinical application, and public knowledge, for which it has included public health, as well as lab and clinical scientists, to expedite the complete translation spectrum.

CNECV (the Portuguese Council of Bioethics) is just concluding a book on Biomedical Research, which will include a chapter on translational research in the area of pre-market validation of genetic tests.

Opinion of the Portuguese Bioethics Council (CNECV) about DTC genetic testing

This week, CNECV, the Portuguese Bioethics Council, approved recommendations on the commercial use of genetic tests and, in particular, on direct-to-public (DTC) genetic testing. The final recommendations (translated) and the background report (Portuguese only) are now publicly available.

In brief, CNECV was of the opinion that genetic tests for health- related purposes must not be offered directly to the public. Non-medical applications of genetic testing must follow the same requirements of quality assurance, transparency of claims and loyal advertising, if they are to be sold directly to consumers.

In general, any kind of genetic testing must follow the principles of transparency and rigorousness, in order to assure its quality and preserve the confidence of the public. Prior information about sensitivity, specificity and the predictive value of each test, and the evidence available for the specific population, as well as on the possible personal and family implications of its results, must be made available in a clear and easily accessible way, to enable informed decision-making. All genetic testing labs must have a quality system in place and assure privacy of their users and confidentiality of the information, and be subjected to appropriate licensing and certification, as well as to accreditation of the tests they offer.

It was felt that regulation is needed to address these quality requirements, including transparent reporting about the methods used and their limitations, the lab that has actually performed the test and its quality assurance status, as well as to promote and verify the practice of fair advertising. Given the difficulties of regulating transborder flow of samples and tests being offered over the web, it was considered that there is an important place for harmonization and international cooperation among regulating agencies, and that education of all the professionals involved and of the public at large will be of the utmost importance.

Specifically, any health-related genetic tests must not be made available without medical prescription and follow-up; and, in the particular case of predictive testing, pre and post-test genetic counselling must always be available.

It is hoped that this will now be followed by effective legislation and regulatory efforts from the competent authorities.

“A DNA bank in the net”? About risk profiling for breast cancer.

Yesterday, the front page of Expresso, a reference Portuguese weekly newspaper, stated that “there was an illegal DNA bank in the internet”. This was “according to the president of the Portuguese College of Medical Genetics”. The title (rather curious if taken literally) originated during a phone interview, when it was declared that companies like Sciona, who offers nutrigenomic and physical performance genetic profile testing directly to consumers on the internet, have been accused of storing the DNA samples they receive from their customers for further research, without proper consent.

But all this was brought about a rather different subject: the NEJM paper by Paul Pharoah and co-workers and the possibility of a new risk profiling test for breast cancer (non-BRCA1 or 2). This could result in a risk change to low, moderate or high. Thus, women at an increased risk would benefit from regular mammography at an age earlier that the usual 50 years (e.g., age 40 to 45), whereas those at a low risk could postpone it until age 55.

The Cambridge team estimated that the new 7 gene variants account for 1/3 of the genetic susceptibility for breast cancer. But this, of course, means that there must be another 14 genes or so, still unknown. Needless to say, risk for breast cancer is affected, in addition, by various non-genetic factors, reproductive history, breast feeding, and other lifestyle and environmental factors. For this reason, this important NEJM article raised some controversy in the UK and elsewhere.

Women (and men) with a strong family history of breast and ovarian cancer may benefit from genetic testing for BRCA1 and 2, or TP53 if indicated, after the right clinical criteria are met. For the general population or those with just sporadic cases in their families, any risk profile testing is most probably just too premature.

Still, the PGH foundation argues that “the results suggest that risk profiling based on genetic susceptibility is not clinically useful at an individual level, as it does not provide sufficient discrimination to warrant personalised prevention; however, it may be valuable for stratifying the population in order to target screening programmes more effectively”.

Winners of the ESHG DNA day assays announced this week

From the 118 assays by high-school students received, from 8 countries, the respective national societies of human genetics selected the best three. Then, the best assay in each country was chosen. A panel of members from Education Committee of the ESHG (one from Germany, Turkey, Sweden and Portugal, and 2 from the UK) classified the 8 finalists.

The winners were: 1^st Poland (Dorota Dziewońska); 2^nd Serbia (Dimitrije Cvetković); and 3^rd Italy (Giovanni Luca Maglione). The following places were Portugal, Greece, Slovenia, Belgium and Bosnia, in that order. These results will be posted at the ESHG website.

Of note were the facts that (1) some themes, as gene and cell therapy, were recurrent; (2) high-school students are, in general, very deterministic (perhaps a reflection of the teaching they have and the dominating tone in our society and media); (3) nevertheless, and in no apparent contradiction with the former (which is a matter for reflection), quite a few assays among the finalists showed important humanistic concerns (some included remarks about the need for ethical consideration of the recent advances in human genetics and/or the need for education in ethics of young students).

As an example, I will leave here an extract of the assay by the Portuguese finalist, Ricardo Carragosela, from Esc. Sec. Ferreira Dias, Cacém:

Medicine is going through the era of genetic manipulation, in which gene therapy may well come to be the great miracle. For the first time, devastating diseases, such as cancer and cardiac disease, among many others, might be completely cured. Gene therapy with its promises may come to be the greatest discovery medicine has ever seen. Society wants, however, in all its legitimacy, to make sure that science attains to ethical values. As someone once said, bioethics is “the bridge between science and humankind”; and that bridge must be preserved. Every health professional or scientist should assume the great complexity of the phenomenon of life, accept what we still don’t know and not run the risks of attempting against the dignity of human life, nor of violations to ethics in a plural society. Take for instance the following words: “it is being proclaimed with a tone of triumph that science begins to dominate life; may be one day we arrive at that, but it is certain that life, thus dominated, has no greater value, as it guarantees for the future much less life than that same life once did, dominated, not by science, but by instincts and a few great illusions”.

Having conducted a similar initiative among high-school students in Portugal, for the Programme Ciência Viva, 2000-2002, I cannot help noticing how the issues were now so remarkably similar to those raised then. It is expected that the ESHG and its Education Committee, as well as national human genetics societies and the educators in general, take a good note of that and act accordingly.