Compromisso com o cidadão - SIDNEY BERALDO

Vamos introduzir no Estado de São Paulo a remuneração por desempenho e a gestão por resultados, começando pela educação

EM QUE pesem as críticas recorrentes sobre a qualidade e os custos do Estado brasileiro, a sociedade expressa, ao mesmo tempo, seu desejo de contar com bons serviços públicos e a regulação competente de atividades econômicas e sociais, prestados de forma eficiente.
Há muitas razões pelas quais os serviços públicos são considerados ineficazes e ineficientes pelos cidadãos.
Freqüentemente o Estado demora para captar as novas necessidades da sociedade ou para se reestruturar, de modo a atender satisfatoriamente a novas expectativas.
Com efeito, a globalização, a intensa urbanização, as novas condições ambientais, o envelhecimento da população e a sociedade do conhecimento têm gerado intensos e novos desafios, aos quais os Estados não conseguem prontamente responder.
É possível afirmar que esse sentimento de insatisfação é bastante generalizado no mundo. Por essa razão, especialmente os países de tradição anglo-saxã -Nova Zelândia, Austrália, Reino Unido, Canadá, Estados Unidos- promoveram reformas de Estado a partir da década de 80.
Coincidentemente ou não, foram esses os países -entre os mais desenvolvidos- que mais cresceram a partir daquele período. Em larga medida, modificaram os contornos, as funções e os modos de operação de suas administrações públicas.
As experiências de quase três décadas produziram importantes resultados em seus serviços públicos. Seus Estados deixam cada vez mais de intervir e executar para regular. Suas organizações públicas empreendem a gestão do desempenho e fortalecem a capacidade administrativa, induzem o controle social e a competição entre prestadores de serviços públicos.
Afortunadamente para nós, o pioneirismo desses países nos permite aprender de sua experiência, adequando-a à nossa realidade.
O Brasil, em seus três níveis de governo, já iniciou sua reforma da gestão pública, substituindo progressivamente o Estado burocrático a partir de 1995.
No Estado de São Paulo, procuramos nos aproximar do cidadão por meio do Poupatempo, dos postos do Acessa São Paulo, da rede de ouvidorias, dos centros integrados de cidadania, do uso do governo eletrônico. Modificamos o modo de operação de áreas como a saúde e a cultura por meio das organizações sociais, que têm se provado mais ágeis e eficientes que os modelos tradicionais. Aperfeiçoamos os mecanismos de compras estatais, trazendo significativos ganhos, entre outras inovações.
Mas é necessário ampliar a abrangência das ações, fazendo-as alcançar ainda mais a prestação de serviços, os servidores e os níveis gerenciais.
É com esse sentido que estamos procurando criar novos incentivos, como a remuneração por desempenho. Evocando mais uma vez a experiência internacional, os países da OCDE (Organização para a Cooperação e o Desenvolvimento Econômico) confirmam que a remuneração por desempenho constitui uma forma importante de mobilização e motivação nas organizações públicas.
Porém, ela é insuficiente: precisa estar associada à gestão por resultados. Tal método demonstra que a definição de metas motiva, ajuda a comunicar os objetivos a serem perseguidos pela organização e leva a importantes percepções sobre causas de acertos e/ou fracassos nas estratégias de gestão. A divulgação de metas e resultados atingidos fortalece a democracia, na medida em que dá mais transparência à ação governamental, permite o controle social, com reflexos positivos para a gestão pública.
Com o estabelecimento das metas de melhora do serviço público e a divulgação dos resultados alcançados, a população passa a se apropriar de informações e a desempenhar um papel fiscalizador em relação aos administradores públicos.
Por determinação do governador José Serra, em São Paulo, vamos introduzir a remuneração por desempenho e a gestão por resultados, iniciando pela educação. Iremos premiar as organizações que conseguirem atingir metas que apresentam melhoria em relação a seu próprio desempenho em anos anteriores.
As avaliações serão feitas por escolas, e não por indivíduos, estimulando o espírito de equipe, e o pagamento do bônus aos servidores se dará em torno do alcance de resultados.
Com essa iniciativa, acreditamos que daremos mais um importante passo em direção a uma educação de qualidade.

The Geneticist's Best Friend

Dogs are helping to hunt down more than foxes and lions: Researchers are increasingly relying on them to track down genes and pathways involved in canine and human diseases

Talk about blind faith. Twenty years ago, Gustavo Aguirre and his colleague Gregory Acland were struggling to understand a common cause of inherited blindness in dogs. They had bred affected and unaffected individuals and traced the inheritance patterns in the offspring, but "there was no hope of finding the gene," recalls Aguirre, a veterinarian at the University of Pennsylvania's School of Veterinary Medicine in Philadelphia. At the time, researchers hadn't even assigned numbers to the canine chromosomes, let alone begun to map the locations of genes. Nonetheless, "I decided that in the future, someone somewhere would come up with [a way] to come up with the gene," he says. So they banked blood from their dogs and waited.

Their patience paid off. A decade later, their freezers provided the raw material for a linkage map of the dog genome and, eventually, the discovery of the long-sought gene for progressive rod-cone degeneration. With that map as a starting point, researchers have built a community that has proven the value of dog genetics not just for veterinarians and dog breeders but also for human geneticists.

Dogs are a geneticist's dream. Pure breeds, as the name implies, are often highly inbred for specific traits. They have large families and well-documented genealogies, all of which greatly simplifies the task of tracking down mutations that cause disease or genes that underlie traits such as size, coat color, or even behavior. And the link to humans can be direct: The top 10 diseases in dogs include cancer, epilepsy, allergy, and heart disease--disorders that affect many millions of people. Also, because dogs live in the same environment as people, they share some of the same environmental risk factors. As a result, more and more researchers, including a consortium about to be announced in Europe (see p. 1670), are turning to the dog for clues to human genetics. "All of a sudden, people from a wide range of disciplines can see the value, power, and practicality of genetic studies in dogs to shed light on issues of concern to them," says Acland, a geneticist now at Cornell University.

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Lessons from a Genomewide Association Study of Rheumatoid Arthritis

Rheumatoid arthritis is a chronic inflammatory disorder in which the articular joints are gradually destroyed. Occasionally there is systemic involvement, which can include vasculitis in various organs and pulmonary fibrosis. The disease has multifactorial causes to which genetic and environmental factors are thought to contribute. The presence of autoantibodies to cyclic citrullinated peptide (CCP) is specific to rheumatoid arthritis; although the mechanistic significance of these autoantibodies is obscure, their detection contributes both to the differential diagnosis and to a prediction of the severity of joint destruction. Rheumatoid arthritis causes substantial morbidity and mortality and is sometimes accompanied by severe infection or accelerated atherosclerosis.

During the past couple of decades, therapy for rheumatoid arthritis has been improved through the introduction of new antirheumatic drugs, such as the antimetabolite and antifolate drug methotrexate, and biologic therapeutics, such as antagonists to tumor necrosis factor (TNF). However, these treatments can have adverse effects,¹ and responsiveness to these treatments varies considerably. Perhaps "personalized medicine" may one day address such variation. An improved understanding of the genetic causes of the disease represents a step toward this goal and the development of other therapeutic approaches.

The article by Plenge et al.² in this issue of the Journal is therefore welcome. The authors report the results of a genomewide association study of an anti–CCP-positive subclass of rheumatoid arthritis. It is reassuring that the authors observed associations between rheumatoid arthritis and loci in and around HLA-DRB1 and PTPN22; these loci have been repeatedly implicated as genetic risk factors in persons of European descent.

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Emphysematous Cholecystitis

A 70-year-old man with a history of heart disease, hyperlipidemia, and diabetes mellitus presented at the hospital with a 4-day history of increasing abdominal pain, nausea, and vomiting. The temperature was 38°C, and examination of the abdomen showed mild tenderness in the right upper quadrant. The white-cell count, including the differential count, showed leukocytosis associated with a left shift. Computed tomography of the abdomen showed multiple small gallstones, pericholecystic fat stranding, an air–liquid level within the gallbladder lumen, and gas dissecting along the entirety of the gallbladder wall — findings consistent with emphysematous cholecystitis. The patient underwent an emergency laparotomy with cholecystectomy. The gallbladder was gangrenous and emphysematous. The patient was treated with broad-spectrum antimicrobial agents and had an uneventful recovery. The culture of a gallbladder-tissue specimen showed Clostridium perfringens, which is known to be a gas-forming organism. Patients with diabetes mellitus may present with advanced infection and a paucity of symptoms.

Herpetic Glossitis

A 75-year-old woman with more than a 10-year history of hypertension and diabetes mellitus reported a 3-day history of throat discomfort and white eruptions on the tongue. On examination, multiple well-defined, white papules, 2 to 3 mm in diameter with a central punctum, were found on the surface of her tongue (Panel A). She reported only minimal oral pain. A shave biopsy revealed histologic findings typical of herpetic infection, including perinuclear halo, margination of chromatin, and multinucleated cells (Panel B, arrows). Culture of the lesions showed herpes simplex virus type 1 (HSV-1). Differing from herpetic vesicles on the skin, round, discrete areas of ulceration are the typical presentation of herpetic glossitis. Oral HSV-1 reactivation typically affects the keratinized surfaces of the mouth, whereas primary HSV-1 infection usually involves other mucosal surfaces as well. The typical clinical appearance of this condition differentiates it from oral candidiasis and aphthous ulcers. The lesions had healed completely, without any treatment, at the 2-week follow-up visit.

Ageing: From stem to stern

Immortality is the stuff of myth and legend, but lifespan extension is the subject of serious scientific inquiry. Exploring the causes and effects of ageing in stem cells should aid this quest.

The explosion of research on stem cells has given the promise of treatments for degenerative diseases of ageing, enhancement of the repair of damaged tissues and possibly even slowing of decline-in-function that occurs with advancing age. But how stem cells are affected by the ageing process, and whether such changes are a cause or a consequence of organismal ageing, remain unclear¹. Three research teams^{2, 3, 4} have recently reported their findings on how age-related accumulation of DNA damage and changes in global patterns of gene expression might lead to the decline of stem-cell function.

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Biotechs go generic: The same but different

Heidi Ledford¹

As several lucrative protein-based drugs are poised to go off patent, makers of biopharmaceuticals argue that their products are too complex to be reproduced as generics. Heidi Ledford investigates how close 'biosimilar' drugs can get to the original.

In 2006, Craig Wheeler, then president of Chiron BioPharmaceuticals in Emeryville, California, received a call from across the country that would challenge his perspective on the biotechnology industry. Momenta Pharmaceuticals, a small firm in Cambridge, Massachusetts, was looking for a new chief executive. The company planned to develop new drugs, in part relying on its ability to detect and manipulate the carbohydrate molecules that decorate proteins. But Momenta also intended to create generic versions of therapeutic proteins, something that Wheeler says he thought was impossible.

Unlike the straightforward industrial chemistry techniques used to make small-molecule drugs, the methods of producing and isolating 'biologics' — complex drugs, vaccines or antitoxins made by or from living cells — can be complex and fickle. "The process is the product" was the mantra of the biopharmaceutical world, says Wheeler. Even those who developed drugs in the first place were loath to play around with their methods. "We were deathly afraid of changing anything because we couldn't tell where it would lead," he says.

Debate has flared over whether proteins are too complex to be copied. Even nomenclature for the replicants has changed as a result. Many have discarded the term 'biogenerics' in favour of 'biosimilars', saying that the word 'generic' unfairly implies a perfect replication. And companies and lobbyists on both sides are battling over whether biosimilars should be allowed to follow the fast track to approval available for small-molecule generics, or whether they should undergo expensive clinical trials beforehand. Pending US legislation on the matter could result in billions of dollars being won or lost by companies such as Momenta and the larger biotechnology and pharmaceutical companies that own the ageing patent rights to biologic drugs.

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Gene therapy might not have caused patient's death

Case was complicated by immunosuppressant drug regime.

A patient with arthritis who died in July during a gene-therapy trial may have succumbed to an infection she had before the viral vector was administered, experts said on Monday at a meeting of an advisory panel in Bethesda, Maryland, investigating the incident.

Little of the evidence presented to the panel seemed to indicate that the injected viral vector had a key role in 36-year-old Jolee Mohr's demise. Although DNA sequences from the vector were found in her liver and spleen, "the detection of the sample is very low and below the limit of quantification in these assays", said Jeffrey Bartlett, a member of the National Institutes of Health (NIH) Recombinant DNA Advisory Committee (RAC). "It really indicates the absence of ongoing replication of the vector in these tissues."

The panel is still awaiting the results of tests on Mohr's tissue samples, expected by December, and the results of blood studies looking for the vector and protein produced by the transgene. It will then reach a firmer conclusion about whether the gene therapy she received three weeks before her death was in any way responsible for it. But even with all the information in hand, "there will I think still be some uncertainty", said RAC chair Howard Federoff.

Mohr died on 24 July, 22 days after her right knee was injected with an adeno-associated virus (AAV) vector made by Targeted Genetics, a Seattle company. This vector was engineered to contain a gene for an anti-inflammatory protein, TNFR:Fc, which inhibits tumour-necrosis factor- (TNF-). TNF- causes inflammation in rheumatoid arthritis.

Autopsy results and the clinical history of the patient presented at the 17 September meeting indicated that the immediate cause of her death was massive bleeding of unknown origin in the tissue space behind the kidneys. This displaced her abdominal organs and ultimately compressed her lungs, making them unable to function. She was also overwhelmingly infected with histoplasmosis, an environmental fungus that can cause serious infections in immunocompromised individuals. She began to feel ill with fatigue and a low-grade fever three days before the gene therapy was administered, the panel heard.

TNFR:Fc suppresses the immune system, and so it is possible that the gene therapy caused the infection. However, the design of the trial, in which some patients were also taking similarly acting immunosuppressant drugs, means that it will be difficult to ascertain what caused the infection to take hold. Mohr was also taking a TNF--inhibitor drug for the arthritis, which suppresses the immune system. Carol Kauffman, an infectious-disease specialist at the University of Michigan, Ann Arbor, told the panel that overwhelming histoplasmosis infection had killed several patients taking such TNF-inhibitory drugs.

Of the 871 gene-therapy trials registered with the NIH, 4% have used AAV. Officials at the NIH and the US Food and Drug Administration reported at the meeting that they had reviewed all the AAV trials to date and found no pattern of adverse events associated with AAV, or any increased incidence of adverse events compared with trials using other gene-therapy vectors. The trial Mohr took part in was unusual in that it involved repeated injections. It was halted after her death.

Malaria research should go 'back to basics'

Too many ineffectual vaccines threaten vital work.

Efforts to wipe out malaria must stop squandering resources on trials of ineffectual vaccines and focus instead on generating better candidates, according to a report released on 17 September by the George Institute for International Health in Sydney, Australia.

The report looked at the status and future prospects of 47 vaccines and 21 drugs in various stages of development. The vaccine furthest along is one developed by GlaxoSmithKline (GSK). It should enter large-scale, phase III trials in 2008, with licensing pegged for 2012. The vaccine nearly halved severe malaria in a 2005 trial in 2,000 children younger than 5 years in Mozambique (P. L. Alonso et al. Lancet 366, 2012–2018; 2005). But the report comes down hard on the other vaccines. Far too many have been tested in clinical trials, in which most are certain to fail, eating up resources, says lead author Mary Moran, director of health policy at the George Institute. "You can't have all this stuff going to the field, you have to start weeding them out," she says.

But GSK's vice-president of clinical development, Ripley Ballou, argues that clinical tests are the only way to determine whether a vaccine works or not, and says that the trials can be done relatively cheaply. "For a couple of million dollars you can do a clinical study and kill a product if it doesn't work," he says.

Moran's team is calling for more basic research into malaria and the Plasmodium parasites that cause the disease. "There's not much new science coming into the field," agrees Stephen Matlin of the Geneva-based Global Forum for Health Research. Researchers barely know how humans fend off malaria, he points out, an insight that would help vaccine-makers to focus their efforts.

But Pedro Alonso, a researcher at the University of Barcelona in Spain who led trials of the GSK vaccine, says that the world shouldn't wait for science to catch up before going forward with malaria vaccines. "I worry that other vaccines aren't doing as well," he says. But they shouldn't be abandoned. "It is not healthy to rely on just one candidate. Things can go wrong."

Despite large donors such as the US National Institutes of Health and the Gates Foundation infusing the field with cash, much more money is needed, the report claims. At least $560 million will be required over the next five years to see current vaccines and drugs through development and clinical trials, Moran's team says. The report also calls for more cooperation between people who talk regularly but don't often work together. Such coordination would make more efficient use of the 23 clinical test sites for malaria vaccines in Africa. With so many vaccines moving forward, researchers could end up fighting for access to patients.

Dengue pode estar mais agressiva em PE

Estudo da Fiocruz em Recife mostra que a versão hemorrágica da doença está ocorrendo já na primeira infecção

Metade dos pacientes com sintomas mais graves não havia sido infectada antes; vírus pode estar mais virulento, dizem cientistas

GIOVANA GIRARDI
COLABORAÇÃO PARA A FOLHA

A idéia de que a dengue é uma doença preocupante apenas a partir da segunda infecção pode cair por terra. Pesquisadores de Recife descobriram que metade dos pacientes que apresentaram dengue hemorrágica entre 2004 e 2005 adquiriram a variante mais grave da moléstia já na primeira infecção. O estudo lança a suspeita de que o vírus da doença possa estar se tornando mais virulento.
Médicos e epidemiologistas normalmente trabalham com a idéia de que a dengue hemorrágica só tem chance de aparecer após a segunda infecção, porque os anticorpos que lutaram contra a doença da primeira vez acabam potencializando a ação do vírus na segunda.
Os sintomas mais graves, que podem inclusive levar à morte, até podem ocorrer na primeira infecção, mas só em pacientes com condições genéticas raras ou se, por algum motivo, a pessoa infectada está com o sistema imunológico debilitado. Mesmo assim, são poucos os casos. Mais de 90%, de acordo com a literatura científica, ocorre após a segunda infecção.
O estudo feito no Recife considerou uma amostragem de 211 pacientes -recrutados em três hospitais da cidade- que tiveram dengue entre 2004 a 2005. Destes, 30 apresentaram dengue hemorrágica, sendo 16 em primeira infecção. Ou seja, 53% dos casos. A partir desse recorte, a equipe estimou os resultados para toda a população da cidade. Os dados estarão no "American Journal of Tropical Medicine and Hygiene".
"É possível que a explicação para isso seja uma maior patogenicidade do vírus, mas pode ser também que a população daqui tenha alguma característica genética que possibilite isso. De qualquer modo, precisamos de mais estudos não só aqui como em outras regiões do país", afirma Carlos Brito, pesquisador do Departamento de Virologia da unidade da Fiocruz no Recife que liderou a pesquisa.
Brito lembra que um outro levantamento feito no Rio, em 2002, já mostrou resultados semelhantes. Realizado com pessoas que morreram por dengue hemorrágica, o estudo indicou que 52% delas tinham apresentado a variante durante a primeira infecção.

Mudança de parâmetros
Para o médico, se a suspeita gerada por seu estudo for confirmada, ela pode mudar toda a forma de lidar com a doença. "Hoje raciocinamos a dengue por conta da resposta imune que ela causa na segunda infecção. Se o vírus realmente estiver causando sintomas mais severos logo na primeira infecção, teremos de reavaliar os mecanismos dos vírus", diz.
Isso aumenta, inclusive, a necessidade de identificar mais rapidamente que o paciente pode ter a dengue hemorrágica. Nos primeiros dias de infecção, os sintomas das duas variantes da dengue são bastante similares. Quando eles se diferenciam, lá pelo quinto dia, o paciente já está debilitado, e aumenta o risco de morte.
O virologista Paulo Zanotto, da Rede de Diversidade Genética de Vírus, também concorda que existe a possibilidade de o patógeno da dengue estar se tornando mais agressivo.
Ele não participou do estudo da Fiocruz, mas vem avaliando há evolução da dengue há alguns anos. "Ao pensarmos em um cenário em que há uma competição entre as linhagens do vírus, como é o que vemos hoje, é plausível, sim, que eles se tornem mais virulentos. Os dados de Recife pedem atenção", afirma Zanotto.
Mas ele pondera que para confirmar é preciso analisar a evolução do vírus, de modo a mapear a expansão da doença e identificar exatamente quem está por trás disso.
A equipe de Zanotto desenvolveu uma tecnologia que poderia ajudar a responder essa pergunta. A metodologia, em fase piloto, está sendo testada em São José do Rio Preto, interior de São Paulo, e promete o monitoramento da epidemia em tempo real.

Invasão e inclusão

JOSÉ ARISTODEMO PINOTTI

Os problemas na área de ensino superior estavam encobertos e intocados. Diagnosticados, podem ser resolvidos com baixo custo

SOU TOTALMENTE contrário a esse modismo agressivo, entrópico e tolo de invasão de universidades. Mas a questão de mérito levantada pelos manifestantes que ocuparam as arcadas há quase um mês por algumas horas é real, grave, intocada e não deve ser menosprezada.
A partir do quinto ano do ensino fundamental, os alunos das escolas públicas (nitidamente os mais pobres) vão se evadindo celeremente, a ponto de se tornarem invisíveis no ensino superior.
Dos 400 mil jovens que terminam o ensino médio público em São Paulo, apenas 4.000 (1%) conseguem entrar nas três universidades públicas estaduais. A inadimplência nas universidades privadas chega a 30%, e a evasão, ao absurdo de 25% ao ano. Esse é o retrato acabado da exclusão.
A falta de uma política educacional construída de acordo com os interesses da nação faz a tragédia ir além. Dos 6 milhões de crianças que entram no primeiro ano do ensino primário, apenas 600 mil se formam nas universidades, nas quais temos somente 11% de jovens entre 18 e 25 anos -a Coréia tem 60%, a Espanha, 50%, e a Argentina, 35%. Sem um mínimo de 35% não há desenvolvimento. Vivemos em plena sociedade do conhecimento e desperdiçamos 90% da maior riqueza do país!
As três universidades públicas de São Paulo, nos últimos anos, vêm combatendo com ações afirmativas a iniqüidade do vestibular, que exclui os alunos mais carentes provenientes do ensino médio público.
A Unicamp (Universidade Estadual de Campinas) mostrou que a bonificação oferecida aos alunos do ensino público aumentou o número deles nos diferentes cursos, e aqueles que entraram, acompanhados durante três anos, tiveram, em 31 dos 55 cursos, uma performance melhor do que a dos demais.
O número absoluto é irrisório, mas a experiência desmistificou o vestibular e mostrou que, quando se dá oportunidade, há notória capacidade de recuperação e que não se pode sequer pensar em uma educação superior pobre para os pobres como solução para a exclusão, mas sim em oportunidades iguais.
Recentemente, o governo do Estado, por meio da Secretaria de Ensino Superior, apostou nos cursinhos gratuitos pré-vestibular para alunos do ensino médio público e, em convênio com a Unesp (Universidade Estadual Paulista), passamos a oferecer 3.500 vagas em 21 municípios, dando um segundo passo para colocar mais jovens egressos do ensino público nas universidades estaduais.
No próximo ano, a secretaria está preparada para chegar a 7.000 alunos nesses mesmos campi e iniciar o projeto na região metropolitana de São Paulo, com um número significativo de vagas. Como benefício colateral, remunera-se os alunos universitários, professores dos cursinhos, contribuindo para sua permanência nas universidades.
Entretanto, isso é ainda muito pouco para resolver o problema da exclusão social e menos ainda o da preparação de cidadãos qualificados e em quantidade para alavancar o desenvolvimento. Por essas razões, já havíamos planejado, com o atual secretário Carlos Vogt, o terceiro passo, que é um sistema estadual público, gratuito e de qualidade de ensino universitário à distância, que poderá aumentar -aí, sim, significativamente- o número de vagas e abrigar jovens que precisam compatibilizar estudo com trabalho.
Esse projeto, no qual estamos atrasados há décadas, torna-se obrigatório diante da tecnologia à disposição.
Esse conjunto de programas objetiva combater também o desemprego (falta mão-de-obra qualificada) e a violência, pois jovens ocupados não são presa fácil de atividade ilícita.
Por tudo isso, se pode perceber como os problemas na área de ensino superior estavam encobertos e intocados e, uma vez diagnosticados, podem ser resolvidos -com baixo custo.
O programa dos cursinhos custou aos cofres públicos apenas R$ 1,5 milhão e mostra que a questão da educação não é predominantemente de dinheiro -até porque a vinculação orçamentária a favorece (felizmente)-, mas de reconstruí-la pedagógica e socialmente em todos os níveis, visando um desenvolvimento humano e sustentado do país.

Trashing the brain

Biologists are learning how prions kill brain cells

SEEMINGLY different diseases can sometimes share a common cause. Tumours of all sorts, for example, are clusters of cells run out of control, dividing incessantly. Over the past decade, another unifying medical principle has emerged. It holds that many diseases of the central nervous system—including Alzheimer's, Huntington's and Parkinson's diseases—also share a mechanism. Instead of non-stop proliferation, the theme in this case is rubbish-disposal gone wrong.

The garbage in question is abnormally folded proteins. These are usually collected by dustmen (molecules called “ubiquitins” that pick up proteinaceous litter) before being taken to the cell's waste-processing centre (a structure known to biologists as the “proteasome”). Healthy cells create plenty of junk that keeps the system busy. The hundreds of steps of folding that create a complex protein can take a cell many minutes to complete. And with so many steps, mistakes often occur, or toxins push a perfectly configured protein out of place. Such wrongly wrought proteins need to be binned before they cause substantial damage.

In the current issue of the New England Journal of Medicine, Alfred Goldberg of Harvard Medical School, who helped discover the proteasome 20 years ago, discusses what happens to this waste-disposal system when the brain is infected by a particularly nasty protein called a prion. Prions cause Creutzfeldt-Jakob disease (or “mad cow disease” in cattle) by rearranging the structure of normal proteins in their own image. Recently scientists have started to think that prions might also disrupt the rubbish-disposal system, and that such interference might explain how they destroy nerve cells in the brain. Dr Goldberg proposes that globules of prions plug the waste-processing proteasome. That would cause all cellular garbage disposal to cease. Trash would thus remain in the brain until the accumulating filth killed the nerve cells.
Deadly origami

Sarah Tabrizi of University College London, and her colleagues, have also examined the question of how prions kill nerve cells, transforming the brain into a spongy organ riddled with holes. They used a Petri dish of mouse nerve cells and a fluorescent lamp. The cells they studied had been modified to produce a waste protein that glows green under fluorescent light.

First Dr Tabrizi infected the nerve cells with disease-causing prions. Doing so made them grow more luminous as their waste proteins accumulated. Then she added an antibody that cleared the cells of prions but left the ubiquitins, the proteasome and the waste proteins in place. As expected, this made the nerve cells dim because they had regained the ability to dispose of their fluorescent rubbish.

A similar experiment using living mice gave corresponding results. When the mice were infected with prions, ubiquitins collected in their brains. Those ubiquitins were pinned to proteins destined for destruction but, after prions had entered the brains, the junk somehow survived.

Although these tests show that prions can force the waste disposal system to malfunction, they did not identify which part of the process went wrong. So, to work out whether the dustmen were on strike or whether the rubbish-crunching centre had been closed down, Dr Tabrizi purified some proteasomes and took a closer look. By carefully measuring the rate at which proteasomes laboured, she found a clear correlation: as the clumps of prions in the sample got bigger, the proteasomes slowed down. Thus it is the rubbish dump that ceases to work rather than the dustmen neglecting their duties.

That infectious prions cause rubbish to accumulate in brain cells may not be the only way in which they cause damage. Alex Greenwood of the Technical University of Munich, in Germany, and his colleagues, have another idea. They believe that infectious prions might wake viruses that lie dormant in the DNA of an uninfected cell.

Dr Greenwood also works with cells taken from mice. These cells contain disabled viruses because murine ancestors, just like human ones, accumulated them in their genomes whenever infections entered their sex cells. Those historical viruses have been largely disabled by evolution over many millions of years, but they remain, they are numerous, and their genomes constitute about 10% of the DNA of most mammals.

Like Dr Tabrizi, Dr Greenwood infected several types of mouse nerve cells with prions. Next, he examined those cells to see whether they started making the previously disabled viruses. He found some in which this was happening. When he added an anti-prion drug to the mix, though, the virus production halted. The research is reported in Biochemical and Biophysical Research Communications.

Dr Greenwood's data support the theory that prions stimulate brain cells to make viruses that natural selection long put to bed. He thinks that these viruses might even transport prions between nerve cells, spreading the infection to other parts of the brain. If that idea proves correct, prions would be more than flying pickets that closed municipal dumps. They would be muck-spreaders too.