DNA de 'rato pelado' traz pistas para estudos antivelhice

Será que o segredo da juventude eterna se esconde no DNA de um rato pelado? Colocada nesses termos, a possibilidade parece absurda, mas o genoma do roedor desnudo em questão --o rato-toupeira-pelado, ou Heterocephalus glaber, como preferem os cientistas-- talvez traga pistas importantes sobre como mamíferos como eles e nós envelhecemos e lidamos com o câncer.

Isso porque essa criatura sui generis, cujo DNA decifrado está sendo apresentado na edição de hoje da revista científica "Nature", é o Matusalém dos roedores.

Arte 

Enquanto ratos mais vagabundos, como os que povoam esgotos e biotérios de universidades, têm expectativa de vida de uns dois anos, o H. glaber, nativo da savana da África Oriental, pode até chegar à casa dos 30.

À PROVA DE CÂNCER

O bicho aparentemente consegue isso sendo extremamente refratário a tumores, por exemplo. Em laboratório, os pesquisadores têm até dificuldade de induzir a formação de cânceres na espécie.

Também é quase imperceptível o processo de envelhecimento das criaturas. A mortalidade não aumenta com a idade (menos quando se chega perto da longevidade natural do bicho, claro), e a fecundidade também é alta durante a vida toda.

Alta, quer dizer, para os poucos ratos-toupeiras-pelados que conseguem se reproduzir.

Ocorre que o bicho é o paralelo mais próximo com os insetos sociais (como abelhas e formigas) no mundo dos mamíferos. Isso significa que, como as abelhas, os ratos têm "rainhas" --e elas são as únicas fêmeas do grupo que se tornam mães.

Grandalhonas --de novo, assim como ocorre com as abelhas-rainhas--, as fêmeas reprodutoras têm características hormonais especiais, suprimindo o desenvolvimento das companheiras.

A rainha se une a um pequeno número de machos, enquanto o resto da colônia é estéril, adotando funções de operários (abrindo os túneis onde os bichos vivem) ou soldados (defendendo o grupo de invasores).

SEGREDO NAS PONTAS

Essa lista de características únicas pode ser vista por um novo prisma graças ao genoma recém-soletrado, trabalho que foi coordenado por Vadim Gladyshev, da Escola Médica de Harvard (EUA).

Para começar, os pesquisadores verificaram que, entre os genes do bicho que os diferenciam dos demais mamíferos, estão os que coordenam a estrutura dos telômeros --as pontinhas dos cromossomos, os quais abrigam o material genético. Os telômeros estão justamente ligados à divisão e ao envelhecimento das células.

A tendência é que, conforme as células se dividem e envelhecem, os telômeros encurtem --e isso leva a uma série de problemas bioquímicos. Os bichos, pelo jeito, acharam um modo de contornar esse fenômeno comum.

Os dados de DNA também indicam que a criatura é mais eficiente na hora de fazer uma faxina nas proteínas do organismo que sofreram danos. E também mantém em funcionamento pleno as mitocôndrias, usinas de energia das células, durante todo o seu período de vida.

Finalmente, os pesquisadores liderados por Gladyshev também acharam genes que ajudam o bicho a sobreviver em condições de baixo teor de oxigênio. Agora, o desafio é aplicar os dados em estudos sobre doenças que afetam seres humanos.

TEÓRICO PREVIU BICHO

Quem diz que a teoria da evolução é incapaz de fazer previsões sobre uma forma de vida que ainda está para ser descoberta deveria ser apresentado aos ratos-toupeiras-pelados.

Isso porque, nos anos 1970, o zoólogo americano Richard Alexander sugeriu que hábitos sociais como os de abelhas e formigas poderiam muito bem evoluir entre mamíferos, se as condições fossem adequadas.

Para que isso ocorresse, ele afirmou que a espécie em questão teria de ser um roedor, vivendo debaixo da terra nos trópicos africanos, em ninhos facilmente defensáveis e com fonte de comida abundante na forma de grandes tubérculos.

Na época, os ratos eram conhecidos, mas nada se sabia sobre seus hábitos. Alexander estava certo.

Vitamina D ativa resposta do sistema imunológico à tuberculose

A vitamina D é necessária para ativar a resposta do sistema imunológico à tuberculose, aponta um estudo americano divulgado na quarta-feira (12). A descoberta pode levar a novos tratamentos contra a doença, que mata 1,8 milhão de pessoas por ano.

Casos de tuberculose no mundo caem pela primeira vez, diz OMS

Pesquisadores já sabiam que a vitamina D desempenha um papel na resposta do organismo à tuberculose, mas o estudo, publicado na "Science Translational Medicine", mostra que ela deve estar presente em níveis adequados para que a resposta imunológica seja ativada.

A descoberta pode ser crucial para os esforços para tratar a doença em lugares como a África, uma vez que pessoas de pele negra são mais suscetíveis à tuberculose e à carência de vitamina D.

Embora se possa obter a vitamina por meio da exposição solar, a pele negra tem mais melanina, que protege o corpo dos raios ultravioleta e reduz a produção de vitamina D.

"Ao longo dos séculos, a vitamina D vem sendo usada intrinsicamente para tratar a tuberculose", lembrou Mario Fabri, que fez a pesquisa para o estudo na Universidade da Califórnia em Los Angeles e trabalha para o Departamento de Dermatologia da Universidade de Colônia, Alemanha.

"Os sanatórios dedicados a pacientes com tuberculose situavam-se, por tradição, em locais ensolarados, o que parecia ajudar no tratamento, mas ninguém sabia por que isso funcionava", comentou Fabri. "Nossa descoberta sugere que aumentar os níveis de vitamina D por meio de suplementos pode ampliar a resposta imunológica a infecções como a tuberculose."

Estudos anteriores feitos pela mesma equipe de pesquisadores determinaram que a vitamina D tinha um papel-chave na produção da molécula catelicidina, que ajuda o sistema imunológico a matar a bactéria da tuberculose. A descoberta atual mostra que a vitamina é necessária para as células T, que respondem a ameaças produzindo a proteína interferon, que direciona células para atacar as bactérias.

"No momento em que formas resistentes de tuberculose estão surgindo, entender como aumentar a imunidade por meio da vitamina D pode ser muito útil", indicou o coautor do estudo Barry Bloom.

A Organização Mundial de Saúde anunciou esta semana que 8,8 milhões de pessoas tiveram tuberculose no ano passado, sendo que um quarto dos casos foram registrados na África, e 40%, na Índia e China.

Descoberto novo alvo de medicamentos para Alzheimer e AVC

Aprendizado e memória

Um grupo de cientistas norte-americanos identificou um novo receptor no cérebro que pode ser usado como alvo para novos medicamentos contra doenças neurodegenerativas.

O que mais surpreendeu na pesquisa é que o receptor NMDA (N-metil-D-aspartato) é crítico para o aprendizado e para a memória, com um comportamento exatamente oposto à que se atribuía a ele até agora.

Os cientistas da Universidade de Buffalo afirmam que a descoberta abre caminho para o desenvolvimento de medicamentos contra uma série de doenças, do AVC aoAlzheimer.

O receptor NMDA é crítico para o aprendizado e para a memória, com um comportamento exatamente oposto à que se atribuía a ele até agora.

Alvo para medicamentos

A descoberta de um "alvo" é sempre o primeiro passo no desenvolvimento de tratamentos para doenças porque permite que os cientistas projetem racionalmente moléculas que possam até lá e ativar ou desativar o receptor, dependendo do caso.

Sem conhecer o receptor com precisão, a única forma de projetar um medicamento é na base da tentativa e erro, testando centenas ou até milhares de moléculas candidatas a fármaco.

A caracterização do receptor e o projeto da molécula-fármaco também diminui os riscos de efeitos colaterais.

Receptor cerebral

"É a primeira vez que essa região do cérebro se mostrou útil como um alvo de drogas. Se pudermos encontrar um composto químico que se ligue nessa região e prenda as subunidades dos receptores NMDA, o resultado será muito importante na busca de alternativas de tratamentos para danos provocados por acidentes vasculares cerebrais (AVC), Alzheimer e outras doenças neurodegenerativas", disse Gabriela Popescu, principal autora do estudo.

A pesquisa foi focada nos receptores cerebrais para o neurotransmissor glutamato, que está envolvido com tais doenças bem como outras condições, como o glaucoma.

Os dois principais receptores no cérebro para o glutamato são o NMDA e o AMPA, ambos compostos de quatro subunidades organizadas em pares.

Como os dois receptores têm estruturas semelhantes, os cientistas estimavam que eles funcionassem de modo parecido.

"Mas quando alteramos a interface de seus pares - o local em que as duas subunidades se agrupam com cada par -, verificamos que o NMDA funciona de maneira oposta ao AMPA", contou Popescu.

Papel do cálcio

Além de sua identificação, os cientistas conseguiram induzir uma redução na atividade do NMDA.

Essa redução gerou uma diminuição significativa na quantidade de cálcio que entra os neurônios em resposta ao glutamato.

É o excesso de cálcio que eventualmente termina por matar os neurônios, levando aos sintomas comuns que ocorrem após um AVC ou outras doenças neurodegenerativas.

Inhibiting Allergic Reactions Without Side Effects

ScienceDaily (Oct. 13, 2011) — Researchers from the University of Notre Dame have announced a breakthrough approach to allergy treatment that inhibits food allergies, drug allergies, and asthmatic reactions without suppressing a sufferer's entire immunological system.

Backbone alignment of IgG, IgE, and IgM antibody crystal structure, including residues of the conserved nucleotide binding pocket.

The therapy centers on a special molecule the researchers designed, a heterobivalent ligand (HBL), which when introduced into a person's bloodstream can, in essence, out-compete allergens like egg or peanut proteins in their race to attach to mast cells, a type of white blood cell that is the source of type-I hypersensitivity (that is, allergy).

"Unlike most current treatments, this approach prevents allergic reactions from occurring in the first place" says Basar Bilgicer, assistant professor of Chemical and Biomolecular Engineering and Chemistry and Biochemistry and principal investigator in Notre Dame's Advanced Diagnostics & Therapeutics initiative.

Michael Handlogten, lead scientist on the paper and a graduate student in Dr. Bilgicer's group, explained that among the various chemical functionalities he analyzed to be used as the scaffold HBL synthesis, ethylene glycol, an FDA-approved molecule, proved to be the most promising.

Mast cells are part the human body's defense against parasites (such as tapeworms), and when working normally they are attracted to, attach to, and annihilate these pathogens. But type-I hypersensitivity occurs when the cells react to non-threatening substances. More common allergies are due to ambient stimulants, and an allergic response may range from a mild itch to life-threatening anaphylactic shock.

Tanyel Kiziltepe, a research professor in Advanced Diagnostics & Therapeutics, adds that "anaphylaxis can be caused by certain food allergens, insect stings, antibiotics, and some medicines, and we believe HBL has a very high potential to be developed as a preventative medication."

While many medicines treat allergies by weakening a person's entire immune system, this approach only disrupts the process whereby white blood cells bond with allergens in the first place.

"It also does not leave patients open to an increased risk for infections or the development of cancers," explains Bilgicer. "HBLs may be most useful in situations where it's not possible to speak to or gauge someone's sensitivity."

"For example, in an emergency, on a battlefield, or in a remote location, doctors may not be able to ask a patient about an allergy before administering penicillin. An engineered HBL could be given along with the medicine and perhaps prevent a deadly reaction from occurring."

In a normal allergic reaction, allergens bind to a white blood cell, or "mast" cell, and cause the release of inflammatory molecules. Researchers at Notre Dame have shown how non-allergenic molecules, known as heterobivalent ligands, can be designed to attach to mast cells first, preventing the allergic reaction in the first place.

Clean Correction of a Patient's Genetic Mutation: New Gene Therapy Methods Accurately Correct Mutation in Patient's Stem Cells

Immunofluorescence showing the absence of polymeric A1AT protein in hepatocyte-like cells generated from correctediPSCs. All forms of A1AT (left panels) and misfolded polymeric A1AT (middlepanels) are shown.

ScienceDaily (Oct. 13, 2011) — For the first time, scientists have cleanly corrected a human gene mutation in a patient's stem cells. The result, reported Oct. 12 in the journal Nature, brings the possibility of patient-specific therapies closer to becoming a reality.

The team, led by researchers from the Wellcome Trust Sanger Institute and the University of Cambridge, targeted a gene mutation responsible for both cirrhotic liver disease and lung emphysema. Using cutting-edge methods, they were able to correct the sequence of a patient's genome, remove all exogenous DNA and show that the corrected gene worked normally.

The researchers used human induced pluripotent stem cells (hIPSCs) for their research because, once reprogrammed in the Petri dish, these cells can be converted into a wide range of tissues. If stem cells from a patient with a gene defect can be corrected, scientists believe that when reintroduced into the patient they could treat the effects of the mutation causing the disease. To make such a hope reality, efficient methods of introducing DNA, repairing the gene, removing all foreign DNA and verifying the changes are needed.

For this research, the team looked at a deficiency caused by a mutation in alpha1-antitrypsin, a gene that is active in the liver where it is responsible for making a protein that protects against excessive inflammation. People with mutant alpha1-antitrypsin cannot release the protein properly from the liver, where it becomes trapped, eventually leading to liver cirrhosis and lung emphysema as a consequence. This is the commonest known inherited disorder of the liver and lung, occurring in about one in 2000 people of North European origin.

Building on previous work from Cambridge which showed that it was possible to transform skin cells into liver cells by reprogramming stem cells, the team successfully and accurately corrected an alpha1-antitrypsin gene in an established cell line containing the mutation. Using 'molecular scissors' to snip the genome at precisely the right place, they then inserted a correct version of the gene using a DNA transporter called piggyBac. The piggyBac sequences were subsequently removed from the cells, allowing them to be converted into liver cells without any trace of residual DNA damage at the site of correction.

The scientists then proved that the accurate copy of the gene was now active in the liver cells they had produced by demonstrating the presence of normal alpha1-antitrypsin protein in both test tube and mouse experiments.

"We have developed new systems to target genes and integrated all the components to correct, efficiently, defects in patient cells," says Professor Allan Bradley, Director Emeritus of the Wellcome Trust Sanger Institute. "Our systems leave behind no trace of the genetic manipulation, save for the gene correction.

"These are early steps but, if this technology can be taken into treatment, it will offer great possible benefits for patients."

"This study represents a first step toward personalised cell therapy for genetic disorders of the liver," explains Dr Ludovic Vallier, Medical Research Council (MRC) senior Fellow and Principal Investigator at the University of Cambridge's MRC Centre for Stem Cell Biology and Regenerative Medicine and Department of Surgery, who studies human pluripotent stem cell biology. "We still have major challenges to overcome before any clinical applications but we have now the tools necessary to advance toward this essential objective."

In their analysis of the stem cells, the research team showed that genomes of stem cells commonly contain mutations, whose cause remains unclear. However, the researchers were able to use the latest sequencing techniques to find cells with minimum numbers of mutations whose genetic consequences they could examine. They make clear that careful screening of stem cells will be needed to contribute to safe adoption of the technology.

In the final step of the project, they took cells directly from a patient with alpha1-antitrypsin deficiency and corrected the mutation exactly as they had with the established cell line. The corrected cells produced normal alpha1-antitrypsin protein.

"As there is currently no cure for this disease other than liver transplantation, and given the increasing strains being placed on the national liver transplant programme as a result of the sharp increase in the frequency of liver disease, alternative therapies for genetic and other liver diseases are urgently being sought," says Professor David Lomas, Professor of Respiratory Biology at the University of Cambridge and Consultant Physician at Addenbrooke's and Papworth Hospitals (who has worked on the mechanism of alpha1-antitrypsin deficiency for 20 years and looks after patients with this condition). "Our research is a critical step to developing enhancing or life-saving treatments these individuals.

"It is a quite remarkable series of results, founded on strong research and the generous participation of our patients. One of the next steps will be exploring the use of this technique in human trials."

This work was supported by the Wellcome Trust, the Medical Research Council, the Cambridge Hospitals National Institute for Health Research Biomedical Research Center, the Papworth NHS Trust, Bill and Melinda Gates Foundation, Inserm and Institut Pasteur, as well as individual fellowships from Japan Society for the Promotion of Science, Wellcome Trust Clinical Training Fellowships and the International Human Frontiers Science Program Organization.

Researchers Correct Sickle Cell Disease in Adult Mice: Protein Could Be a Target for Treating People Who Have the Blood Disorder

ScienceDaily (Oct. 13, 2011) — National Institutes of Health-funded scientists have corrected sickle cell disease in adult laboratory mice by activating production of a special blood component normally produced before, but not after, birth.

Laboratory mouse.

"This discovery provides an important new target for future therapies in people with sickle cell disease," said Susan B. Shurin, M.D., acting director of the NIH's National Heart, Lung, and Blood Institute, which co-funded the study. "More work is needed before it will be possible to test such therapies in people, but this study demonstrates that the approach works in principle."

Researchers at Harvard Medical School in Boston and the University of Texas at Austin corrected sickle cell disease in mice that had been bred to have the inherited blood disorder. The National Heart, Lung, and Blood Institute, the National Cancer Institute, and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) -- all part of the NIH -- funded the research. The results of the study will appear online Oct. 13 in the journal Science.

Sickle cell disease results from an abnormality in hemoglobin, the protein found in red blood cells that is responsible for transporting oxygen throughout the body. People living with sickle cell disease have two copies of an altered gene that produces sickle hemoglobin instead of normal adult hemoglobin. Sickle hemoglobin changes shape after releasing its oxygen, causing the red blood cell to become stiff, misshapen and sticky, and slowing blood flow to tissues. This process damages organs and causes pain.

The study tested a new approach to increasing the production of a third form of hemoglobin -- fetal hemoglobin. Production of fetal hemoglobin predominates before birth, but turns off thereafter as adult hemoglobin production takes over. People with sickle cell disease are unable to make normal adult hemoglobin, and instead make sickle hemoglobin starting in infancy.

An elevated level of fetal hemoglobin within the red blood cell reduces the tendency of sickle hemoglobin to change the shape of red blood cells. Considerable NIH- supported research has shown that the drug hydroxyurea increases production of fetal hemoglobin and reduces the number of pain crises and other complications of sickle cell disease in adults and children. However, not all patients respond well to hydroxyurea, and adverse side effects are a concern.

The current study explores a more targeted approach to increasing fetal hemoglobin production. It builds upon earlier studies by Stuart Orkin, M.D., and his team at Harvard Medical School, Children's Hospital of Boston, and the Howard Hughes Medical Institute, Boston, which discovered that a protein called BCL11A normally suppresses the production of fetal hemoglobin soon after birth. The researchers viewed the BCL11A protein as a target for therapy and decided to see what would happen if they blocked production of the protein.

"This important advance in the battle against sickle cell disease is another outstanding example of how great things can happen when work proceeds from bench to bedside, and back to the bench," said Griffin P. Rodgers, M.D., M.A.C.P., director of NIDDK. "We hope that one day, this discovery and any that build upon it will translate into a viable treatment option for those suffering from this devastating illness."

The current paper details how the research team silenced the mouse gene that produces the BCL11A protein in mice with sickle cell disease. Silencing the gene turned off production of the BCL11A protein and allowed the adult mice to continue to produce fetal hemoglobin. It appears to have eliminated disease symptoms without affecting other aspects of blood production.

Approximately 100,000 Americans live with sickle cell disease. It is most prevalent in people of African, Hispanic, Mediterranean, and Middle Eastern descent. There is no widely available cure for sickle cell disease. Bone marrow transplants have cured some patients, but the treatment is not without risk and most patients do not have relatives who can donate compatible and healthy bone marrow to them.

Stem Cells from Cord Blood Could Help Repair Damaged Heart Muscle

ScienceDaily (Oct. 13, 2011) — New research has found that stem cells derived from human cord blood could be an effective alternative in repairing heart attacks.

At least 20 million people survive heart attacks and strokes every year, according to World Health Organisation estimates, but many have poor life expectancy and require continual costly clinical care. The use of patient's own stem cells may repair heart attacks, although their benefit may be limited due to scarce availability and aging. The researchers have found heart muscle-like cells grown using stem cells from human umbilical cord blood could help repair heart muscle cells damaged by a heart attack.

The study, led by Professor Raimondo Ascione, Chair of Cardiac Surgery & Translational Research in the School of Clinical Sciences at the University of Bristol, is published online in Stem Cell Reviews & Reports.

The study, funded by the British Heart Foundation (BHF) and the National Institute for Health Research (NIHR), found that it is possible to expand up to seven-fold, in vitro, rare stem cells (called CD133+) from human cord blood and then grow them into cardiac muscle cells.

The findings could have major implications on future treatment following a heart attack given that cells obtained from adults following a heart attack may be less functional due to aging and risk factors.

Professor Ascione said: "We believe our study represents a significant advancement and overcomes the technical hurdle of deriving cardiac muscle-type cells from human cord blood. The method we have found has the attributes of simplicity and consistency. This will permit more robust manipulation of these cells towards better cell homing and cardiac repair in patients with myocardial infarction.

"Our research suggests that in the future stem cells derived from cord blood bank facilities might be used for repair after a heart attack."

The study focused on a rare type of stem cells, called CD133+, which is also present in adult bone marrow. There is also strong experimental evidence these cells derived from bone marrow may help with the regeneration of damaged heart muscle.

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, said: "Regenerative medicine research in the lab, alongside studies of patients, is absolutely crucial. Right now, the damage to the heart caused by heart attack cannot be reversed. Through research like this across the UK, we hope to bring our vision of mending broken hearts to reality.

"There has been interest for some time in the potential use of blood from the umbilical cord as a source of stem cells for therapy in a variety of diseases. This study has shown for the first time that it's possible to turn cord blood stem cells into cells that look like heart muscle, in the lab. The results are encouraging, but there are still lots of questions to answer before we'll know whether these cells can be used successfully for heart repair in patients."

In 2007, the British Heart Foundation (BHF) awarded Professor Ascione, over £200,000 for the world's first clinical trial, TransACT, to test whether bone marrow derived CD133+ stem cells can repair heart muscle cells damaged by a heart attack. Recently, funding for the trial has been extended to 2013.

The double blind placebo-controlled trial has successfully recruited 50 per cent of its patients with no safety concerns. Under Professor Ascione's leadership, 31 out of 60 patients, who have suffered a major heart attack, have been injected to date at the Bristol Heart Institute with stem cells from their own bone marrow or a placebo into their damaged hearts during routine coronary bypass surgery.