A GenÉtica precisa ter a ética em seu centro

Valores da sociedade

As informações geradas pelos avanços da genética podem abalar alguns dos valores mais importantes da sociedade.

Com isso, torna-se necessária a reflexão sobre dilemas e questionamentos éticos criados pelos avanços na área, como a possibilidade de análise do genoma humano a um custo cada vez mais acessível.

O alerta é da geneticista Mayana Zatz, da Universidade de São Paulo (USP).

Mayana levanta o tema em seu livro recém-lançado:GenÉtica: Escolhas que nossos avós não faziam.

O título do livro foi caprichosamente grafado, para mostrar que a genética deve ter a ética em seu centro.

Ética da genética

"Acredito que as questões éticas que descrevo no livro serão cada vez mais relevantes para toda a população", disse Mayana.

O livro, cuja ideia surgiu de um bate-papo entre ela e o médico Drauzio Varella, reúne alguns dos conflitos vivenciados pela cientista e que levantam percalços legais e éticos decorrentes da genética.

"Cada vez mais é possível descobrir algo com o DNA. E o que é feito a partir dessa informação pode, ou não, ser benéfico. Há um vazio legal em diversas questões da genética, cuja discussão é importante", ressaltou.

GenÉtica é voltado tanto para especialistas que atuam nas áreas de genética e bioética como ao público geral.

Terra sem lei

Cada capítulo descreve uma nova situação, que tem por objetivo levar o leitor a refletir sobre o uso da informação genética e seus limites.

Ao todo, são 13 capítulos que abordam temas com questões conceituais que dificultam a aplicação de normas, como os princípios da privacidade e da confidencialidade, a escolha seletiva de embriões, a clonagem humana e os testes de DNA.

"As pessoas têm a impressão de que, para estudar o DNA, é preciso coletar o sangue. Mas deixamos nosso DNA por todo lado, como, por exemplo, no copo e nos talheres que usamos. A questão é: a quem pertence esse DNA?", disse Zatz.

Direitos negligenciados

No livro, a cientista cita como exemplo o caso do menino conhecido como Pedrinho, sequestrado em Brasília na maternidade. Na mesma época em que o caso veio à tona, suspeitou-se que Roberta, sua suposta irmã, também pudesse ter sido sequestrada por Vilma, mãe adotiva do menino.

"Porém, ao prestar depoimento na polícia, Roberta - que não queria saber se Vilma era ou não sua mãe verdadeira - descartou restos de cigarro. A partir da análise daquele material foi possível fazer o exame de DNA e confirmar que ela também não era a filha biológica de Vilma."

"E o direito dela de não querer saber? Vários juristas dizem que isso é perfeitamente legal, que aquele DNA não lhe pertencia mais", ressaltou Zatz.

Debate ético

A geneticista também chama a atenção para o debate ético sobre a identificação precoce de genes que aumentam a predisposição para doenças - entre as quais certos tipos de câncer, hipertensão e males cardíacos - e os impactos da seleção do sexo em larga escala, como na China e na Índia, onde a proporção de homens é maior que a de mulheres.

"Hoje discutimos sobre isso. Mas, em um futuro próximo, os casais poderão escolher uma criança com olhos de determinada cor, habilidades para esportes ou mais inteligente", disse.

A obra conta também com uma seção bibliográfica, para quem desejar se aprofundar nos temas abordados, e outra com explicações sobre os termos técnicos citados nos textos.

"O livro é para as pessoas notarem o que está acontecendo. Essa provocação é importante para mostrar a realidade, pois o que se fala na teoria é muito bonito, mas na prática a teoria é outra", afirmou.

New Spin On Ibuprofen's Actions

ScienceDaily (Sep. 26, 2011) — Ibuprofen, naproxen, and related non-steroidal anti-inflammatory drugs (NSAIDs) -- the subjects of years of study -- still have some secrets to reveal about how they work. Vanderbilt University investigators have discovered surprising new insights into the actions of NSAIDs. Their findings, reported Sept. 25 in Nature Chemical Biology, raise the possibility of developing a new class of inflammation- and pain-fighting medicines.

Neurons (green) and glial cells from isolated dorsal root ganglia express COX-2 (red) after exposure to an inflammatory stimulus (cell nuclei are blue). Lawrence Marnett and colleagues have demonstrated that certain drugs selectively block COX-2 metabolism of endocannabinoids -- naturally occurring analgesic molecules -- in stimulated dorsal root ganglia. 

NSAIDs block the activity of the cyclooxygenase enzymes, COX-1 and COX-2.

"Until about three years ago, we thought we knew everything there was to know about these enzymes and these inhibitors, but we were unaware of some of the details of how they work," said Lawrence Marnett, Ph.D., director of the Vanderbilt Institute of Chemical Biology and professor of Biochemistry, Chemistry and Pharmacology.

COX-1 and COX-2 oxygenate (add oxygen to) the lipid arachidonic acid to generate biologically active prostaglandins. Marnett and his team discovered about 10 years ago that COX-2 (but not COX-1) also oxygenates endocannabinoids -- naturally occurring analgesic and anti-inflammatory agents that activate cannabinoid receptors (the same receptors that marijuana activates).

The investigators then made a puzzling observation. They found that ibuprofen was a more potent inhibitor of endocannabinoid metabolism compared to arachidonic acid metabolism.

"This was the same drug inhibiting two substrates of the same protein differently," Marnett said. "We didn't understand it."

In the current report, the researchers surveyed a series of different types of NSAIDs for inhibition of COX-2. They included the "mirror-image" versions of ibuprofen, naproxen and flurbiprofen (these drugs come in two different chemical configurations -- a "right hand" (R) version and a "left hand" (S) version -- over-the-counter ibuprofen is a mixture of both forms). It had previously been assumed that only the S-forms of these NSAIDs (S-profens) were able to inhibit COX-2.

Marnett and colleagues found that the R-profens inhibited endocannabinoid, but not arachidonic acid, oxygenation.

The researchers also determined that R-profens selectively block endocannabinoid metabolism in isolated dorsal root ganglia (neurons and glial cells from the spinal column). They found that treatment of these cultures with an inflammatory stimulus increased expression of COX-2 and stimulated release of arachidonic acid and endocannabinoids, which were oxidized by COX-2. The R-profens inhibited metabolism of the endocannabinoids (and increased their concentrations), but not arachidonic acid.

The findings offer a potential explanation for the reported observation that R-flurbiprofen is analgesic in people and that it inhibits neuropathic pain in a mouse model.

"We're proposing that R-flurbiprofen is effective in this neuropathic pain setting because it is preventing the metabolism of endocannabinoids by COX-2; so it's maintaining endocannabinoid tone and that's the basis for the analgesic activity," Marnett said.

"It's exciting because you will only see this effect at sites of inflammation where COX-2 might play a role in depleting endocannabinoids. Selective inhibitors like the R-profens could represent a new way to target analgesia without having the GI, and maybe cardiovascular, side effects of traditional NSAIDs."

Marnett and his team will pursue this idea by studying in vivo models of neuroinflammation to determine if these drugs -- and new compounds they are developing -- work to inhibit endocannabinoid oxidation and maintain endocannabinoid tone.

Kelsey Duggan, Ph.D., Daniel Hermanson, Joel Musee, Ph.D., Jeffery Prusakiewicz, Ph.D., Jami Scheib, Bruce Carter, Ph.D., Surajit Banerjee, Ph.D., and John Oates, M.D., contributed to the studies. The National Institutes of Health (National Institute of General Medical Sciences, National Cancer Institute, and National Institute of Neurological Disorders and Stroke) supported the research.

Marnett is University Professor of Biochemistry and Chemistry, Mary Geddes Stahlman Chair in Cancer Research, and director of the A.B. Hancock Jr. Memorial Laboratory for Cancer Research.

High Blood Pressure Is Linked to Increased Risk of Developing or Dying from Cancer

ScienceDaily (Sep. 26, 2011) — Raised blood pressure is linked to a higher risk of developing cancer or dying from the disease according to the findings of the largest study to date to investigate the association between the two conditions.

Dr Mieke Van Hemelrijck will tell the 2011 European Multidisciplinary Cancer Congress in Stockholm that there had been contradictory results from previous, smaller studies investigating the link between cancer and blood pressure. However, her study, which included 289,454 men and 288,345 women, showed that higher than normal blood pressure was statistically significantly associated with a 10-20% higher risk of developing cancer in men, and a higher risk of dying from the disease in both men and women.

Dr Van Hemelrijck, a research associate in the Cancer Epidemiology Group at King's College London (London, UK), and her colleagues analysed data on blood pressure and cancer incidence and death in a prospective study that included seven groups of participants in Norway, Austria and Sweden.

They used figures on mid-blood pressure for their calculations. Mid-blood pressure is defined as systolic blood pressure plus diastolic blood pressure, divided by two. The average mid-blood pressure in this study was 107 mmHg for men and 102 mmHG for women. The results were divided into five groups (or quintiles), so that people with the lowest mid-blood pressure were in the first, and those with the highest mid-blood pressure were in the fifth quintile.

After an average of 12 years of follow-up and excluding the first year, 22,184 men and 14,744 women had been diagnosed with cancer, and 8,724 men and 4,525 women died from the disease. The overall risk of developing any cancer increased by 29% between men in the lowest quintile and those in the highest. The researchers also found that, as blood pressure rose, the risk of oral, colorectal, lung, bladder, and kidney cancers, melanoma and non-melanoma skin cancers rose in men. In women, increased blood pressure was not statistically significantly associated with the overall risk of developing any cancer, but was associated with an increased risk of cancers of the liver, pancreas, cervix and endometrium and melanoma.

In both men and women, there was an increased risk of dying from cancer; men in the fifth quintile had a 49% increased risk of dying compared to those in the first quintile, and women in the fifth quintile had a 24% increased risk compared to those in the first.

Dr Van Hemelrijck explained: "This means that we found that men with mid-blood pressure in the highest fifth had an absolute risk of developing cancer of 16% compared to an absolute risk of 13% for those with mid-blood pressure in the lowest fifth. Men in the highest fifth had an absolute risk of dying from cancer of eight percent, compared to an absolute risk of five percent for those in the lowest; and for women, those in the highest fifth had an absolute risk of dying of five percent compared to an absolute risk of four percent in the lowest fifth.

"Our study shows that blood pressure is a risk factor for incident cancer in men and fatal cancer in men and women. Although the relative and absolute risk estimates were rather modest, these results are important from a public health perspective since a large proportion of the population in many western countries suffers from hypertension."

The researchers adjusted their results to take account of age, sex, body mass index, smoking and random errors in the exposure classification of blood pressure (errors that occur due to inaccuracy in blood pressure measurements or due to an individual patient's variations in blood pressure, which can be corrected by using data from several examinations).

Dr Van Hemelrijck warned that, as the study was observational, it could not show that blood pressure was the cause of the increased cancer risk. "We cannot claim that there is a causal link between high blood pressure and cancer risk, nor can we say that the cause of cancer is a factor related with high blood pressure," she said. "However a healthy lifestyle, including sufficient physical activity and a normal weight, has been shown to reduce the risk of several chronic diseases. For instance, high blood pressure is a known risk factor for cardiovascular disease, and our study now indicates that high blood pressure may also be a risk factor for cancer."

The researchers are unsure why men with high blood pressure appeared to have a higher cancer risk than women. "Our study, which to our knowledge is the largest and the first to take into account random error, showed that the association between hypertension and incident or fatal cancer is stronger for men than for women. In contrast, the second largest study previously found a higher cancer risk for women than for men. The differences in findings might be explained due to our larger sample size, slightly older population, adjustment for random error, or lack of information on anti-hypertensive treatment," she said.

The Metabolic syndrome and Cancer project (Me-Can) was set up in 2006 to investigate the relationship between various metabolic conditions and the risk of cancer using data from health examinations carried out on patients between 1972-2005. Two of its initiators, Dr Tanja Stocks and Professor Pär Stattin at Umeå University, Sweden, analysed these data on blood pressure and cancer together with Dr Van Hemelrijck.

ECCO spokesperson, Professor Jan Willem Coebergh, from the Eindhoven Cancer Registry (The Netherlands), said: "This extensive, population-based study of the role of concomitant hypertension shows that it has a modest effect on the risk of certain cancers, especially of the kidney and colorectum, but it is probably a smaller effect than that caused by diabetes and various vascular conditions."

ESMO spokesperson, Dr Franco Berrino, from the Istituto Nazionale Tumori in Milan, Italy, said: "There is increasing evidence that metabolic syndrome is associated with a higher risk of developing cancer as well as other chronic diseases. As an unhealthy lifestyle is a major determinant of hypertension, these results from the highly productive MeCan project add to the evidence that lifestyles affect both the risk and prognosis of cancer."

Researchers Uncover Gene Associated With Blood Cancers; New Genetic Insights Could Facilitate Screening for Mutation

ScienceDaily (Sep. 26, 2011) — A genomic study of chronic blood cancer -- a precursor to leukemia -- has discovered gene mutations that could enable diagnosis using only a blood test, avoiding the need for an invasive and painful bone marrow biopsy.

Researchers at the Wellcome Trust Sanger Institute identified the SF3B1 gene as being frequently mutated in myelodysplasia, one of the most common forms of blood cancer. Myelodysplasia is particularly prevalent among people over the age of 60, and often the only symptom is anemia, which makes it a challenge to give a positive diagnosis. Patients with mutations in the SF3B1 gene frequently had a specific abnormality of red blood cells in their bone marrow, called ring sideroblasts.

The findings have significant potential for clinical benefit, as the disease is often under-diagnosed. It is hoped that patients will soon be able to be screened for mutations in the SF3B1 gene through a single blood test.

"This discovery illustrates the promise of genome sequencing in cancer," says Dr Elli Papaemmanuil, lead author from the Sanger Institute. "We believe that by identifying SF3B1, and working to characterize the underlying biology of this disease, we will be able to build improved diagnosis and treatment protocols.

"Significantly, our analysis showed that patients with the SF3B1 mutation had a better overall chance of survival compared to those without the mutation. This suggests that the SF3B1 mutations drive a more benign form of myelodysplasia."

In order to piece together the genomic architecture of myelodysplasia, the team sequenced all genes in the genome of nine patients with the disease. To their surprise, six had mutations in the SF3B1 gene. To expand their analysis, the researchers sequenced the SF3B1 gene in 2,087 samples across many common cancers.

In myelodysplasia, SF3B1 mutations were found in 20.3 per cent of all patients, and in 65 per cent of those patients with ring sideroblasts, making it one of the most frequently mutated genes so far discovered in this disease. Researchers found mutations of the same gene in up to 5 per cent of a range of other common cancers, such as other leukemias, breast cancer and kidney cancer.

"Anemia affects 1 in 10 people over the age of 65, and we cannot easily find a cause for the anemia in a third of cases," says Peter Campbell, senior author, from the Sanger Institute and a practicing Haematologist at Addenbrooke's Hospital, Cambridge. "To diagnose myelodysplasia, we often have to resort to an invasive and painful bone marrow biopsy, but we hope this and future genetic insights will provide more straightforward diagnosis for patients through a simple blood test."

"Ever since I first saw these unusual and damaging blood cells -- ring sideroblasts -- down the microscope while training to become a haematologist, I have been fascinated by them and determined to find a cause. To discover a major genetic clue to their origins is very exciting, and I look forward to piecing together how the mutations cause these curious cells to develop and lead to this disease."

The SF3B1 gene encodes a core component of RNA splicing, an important editing mechanism that controls how the genome's message is delivered to the cell. The team discovered a strong association between the gene and the presence of ring sideroblasts, making it the first gene to be strongly associated with a specific feature of the disease. Ring sideroblasts are abnormal precursors to mature red blood cells with a partial or complete ring of iron-laden mitochondria (energy generators) surrounding the nucleus of the cell. Their presence is frequently associated with anemia.

"These genetic discoveries are very important and could potentially assist clinicians when diagnosing blood cancers in patients, avoiding the need for invasive bone marrow biopsies. Myelodysplasia is becoming increasingly prevalent in people over 60, and cases will continue to rise with our increasing aging population, particularly among those who suffer from anemia," says Dr David Grant, Scientific Director at Leukaemia & Lymphoma Research. "We are delighted to have supported research into the genomic architecture of myelodysplasia which will contribute towards making a difference for the diagnosis and treatment for patients."

The study was a project for the International Cancer Genome Consortium, a forum for collaborations among the world's leading cancer and genomic research.

Mice Stem Cells Guided Into Myelinating Cells by the Trillions

ScienceDaily (Sep. 26, 2011) — Scientists at Case Western Reserve University School of Medicine found a way to rapidly produce pure populations of cells that grow into the protective myelin coating on nerves in mice. Their process opens a door to research and potential treatments for multiple sclerosis, cerebral palsy and other demyelinating diseases afflicting millions of people worldwide.

The findings were published in the online issue of Nature Methods on Sept. 25.

"The mouse cells that we utilized, which are pluripotent epiblast stem cells, can make any cell type in body," Paul Tesar, an assistant professor of genetics at Case Western Reserve and senior author of the study, explained. "So our goal was to devise precise methods to specifically turn them into pure populations of myelinating cells, called oligodendrocyte progenitor cells, or OPCs."

Their success holds promise for basic research and beyond.

"The ability of these methods to produce functional cells that restore myelin in diseased mice provides a solid framework for the ability to produce analogous human cells for use in the clinic," said Robert H. Miller, vice dean for research at the school of medicine and an author of the paper.

Tesar worked with CWRU School of Medicine researchers Fadi J. Najm, Shreya Nayak, and Peter C. Scacheri, from the department of genetics; Anita Zaremba, Andrew V. Caprariello and Miller, from the department of neurosciences; and with Eric. C. Freundt, now at the University of Tampa.

Myelin protects nerve axons and provides insulation needed for signals to pass along nerves intact. Loss of the coating results in damage to nerves and diminished signal-carrying capacity, which can be expressed outwardly in symptoms such as loss of coordination and cognitive function.

Scientists believe that manipulating a patient's own OPCs or transplanting OPCs could be a way to restore myelin.

And, they have long known that pluripotent stem cells have the potential to differentiate into OPCs. But, efforts to push stem cells in that direction have resulted in a mix of cell types, unsuitable for studying the developmental process that produces myelin, or to be used in therapies.

Tesar and colleagues are now able to direct mouse stem cells into oligodendrocyte progenitor cells in just 10 days. The team's success relied upon guiding the cells through specific stages that match those that occur during normal embryonic development.

First, stem cells in a petri dish are treated with molecules to direct them to become the most primitive cells in the nervous system. These cells then organize into structures called neural rosettes reminiscent of the developing brain and spinal cord.

To produce OPCs, the neural rosettes are then treated with a defined set of signaling proteins previously known to be important for generation of OPCs in the developing spinal cord.

After this 10 day protocol, the researchers were able to maintain the OPCs in the lab for more than a month by growing them on a specific protein surface called laminin and adding growth factors associated with OPC development.

The OPCs were nearly homogenous and could be multiplied to obtain more than a trillion cells.

The OPCs were treated with thyroid hormone, which is key to regulating the transition of the OPCs to oligodendrocytes. The result was the OPCs stopped proliferating and turned into oligodendrocytes within four days.

Testing on nerves lacking myelin, both on the lab bench and in diseased mouse models, showed the OPCs derived from the process flourished into oligodendrocytes and restored normal myelin within days, demonstrating their potential use in therapeutic transplants.

Because they are able to produce considerable numbers of OPCs -- a capability that up until now has been lacking -- the researchers have created a platform for discovering modulators of oligodendrocyte differentiation and myelination. This may be useful for developing drugs to turn a patient's own cells into myelinating cells to counter disease.

The National Institutes of Health, CWRU School of Medicine, the New York Stem Cell Foundation, the Myelin Repair Foundation, the National Center for Regenerative Medicine, and the Case Comprehensive Cancer Center funded the research.