Growth factor makes a comeback in cystic fibrosis

Work in pigs points to culprit 

and potential treatment for growth retardation.

The stunted development common to cystic fibrosis begins at birth -- and could be a direct consequence of a growth-hormone deficiency caused by the disease.

In both people and pigs, newborns with cystic fibrosis tend to have abnormally low levels of a hormone called insulin-like growth factor 1 (IGF1), according to a study published this week in theProceedings of the National Academy of Sciences1. Unlike in healthy controls, in mutant pigs IGF1 levels do not increase over time. The blood concentration of IGF1 could one day be used as a marker to predict whether a patient with cystic fibrosis will have growth problems later in life, says David Stoltz, a physician in the Department of Internal Medicine at the University of Iowa, Iowa City, who led the study.

"We know there's variability -- some people progress quickly, some progress slowly. Some have a growth defect, some don't," says Stoltz. "There might be a sub-population of patients where IGF1 is really important."

Cystic fibrosis is a deadly genetic disease: many patients don't live past the age of 30. Scientists identified the culprit gene some two decades ago (see 'Human genetics: One gene, twenty years'). But the field is still struggling to understand how this glitch causes the disease's range of symptoms, which include scarring and mucus in the lungs and pancreas, diabetes, infertility, weak bones and impeded growth.

Revisiting the past

In the 1990s, researchers found that individuals with cystic fibrosis have low levels of IGF1 in their blood, driving speculation that this was at least partly responsible for their stunted growth. In 2001, researchers reported on a small trial that tested whether giving affected children aged 9-13 a synthetic version of the hormone would boost growth. It didn't, and most researchers lost interest in the connection.

"We were all discouraged by the results and moved on," says Robert Wilmott, a paediatrics expert at Saint Louis University in Missouri, who led that trial. But considering the new data, he says, "it's possible that we missed the boat by starting treatment at that age".

The prevailing wisdom is that the IGF1 deficiency and growth problems are not caused directly by the cystic fibrosis gene, but rather are by-products of malnutrition and lung inflammation. The new study challenges that idea by showing signatures of underdevelopment even at birth.

Stoltz and his collaborators took advantage of a pig model of cystic fibrosis that they debuted in 2008. The model has been the subject of much excitement among researchers because, unlike the mouse version, it develops symptoms similar to those seen in humans with the disease, such as infection and inflammation in the lungs.

Compared with controls, the team found that newborn mutant pigs had significantly less IGF1 in their blood at birth. Furthermore, in mutant newborns the humerus (shoulder to elbow) bones were 9% shorter.

The researchers then screened for IGF1 in samples of dried blood from 23 human newborns with cystic fibrosis. Like the pigs, the babies carried significantly less hormone than controls. "The data seem very robust," says David Dunger, a paediatric specialist at the University of Cambridge, UK. "They've done a lot of effort to repeat things in human subjects."

Brain drain

The cystic fibrosis gene -- CFTR -- codes for a protein called the cystic fibrosis transmembrane regulator, which helps to move chloride ions across cell membranes. Scientists don't know why damage to the gene leads to reduced IGF1 levels, but Stoltz and colleagues' study suggests that it is because of CFTR's action in the brain.

Normally, the brain's pituitary gland releases growth hormone, which travels to the liver and spurs the production and release of IGF1. The researchers found abnormally low levels of growth hormone in pituitary slices from the mutant pigs, which could explain the dearth of IGF1.

However, Dunger says that this hypothesis isn't very plausible because of human studies suggesting that IGF1 in fetuses is not affected by growth hormone. It's more likely, he says, that problems with insulin secretion associated with cystic fibrosis are responsible for the stalled IGF1 production in newborns -- insulin regulates the production of IGF1 in the liver in uteroand throughout life.

In any case, the findings point to IGF1 as a potential therapy for cystic fibrosis -- particularly because regulators in the United States and Europe have already approved synthetic IGF1 for the treatment of severely short stature.

Researchers at Stony Brook University Medical Center in New York are conducting a Phase I trial in which IGF1 is being administered to adults with cystic fibrosis. But before rushing to treat infants with the hormone, Stoltz says, it would be smart to try it in piglets.

Cellular 'alchemy' transforms skin into blood

Direct conversion of cell types could offer safer, simpler treatments than stem cells.

Human skin cells can be transformed into blood without first being sent through a primordial, stem-cell-like state, according to a ground-breaking study.

The breakthrough, published online today in Nature, follows work earlier this year showing that fibroblast cells from mouse skin, treated with the right cocktail of chemicals, can be transformed into neurons and heart muscle. However, it is the first study to accomplish this feat with human cells, and the first to create progenitor cells -- in this case for blood.

"It takes us a step along the line to believing that you can produce anything from almost anything," says Ian Wilmut, an embryologist and director of the MRC Centre for Regenerative Medicine in Edinburgh, UK. Such 'direct conversions' also offer a potentially safer, simpler tool for creating patient-specific cell therapies than is promised by adult cells reprogrammed to become stem cells (known as induced pluripotent stem cells, or iPS cells).

Mickie Bhatia, a stem-cell researcher at McMaster University in Hamilton, Canada, and his colleagues chose to make blood progenitors from skin cells because red blood cells created from stem cells do not make the adult form of haemoglobin. "Those cells, because they think they're embryonic, make embryonic and fetal blood," he says.

Creating a bloodline

To make blood progenitor cells, Bhatia and his team collected skin fibroblasts from several volunteers. They infected the cells with a virus that inserted the gene OCT4, and then grew them in a soup of immune-stimulating proteins called cytokines.

OCT4 is one of a handful of Yamanaka factors used to transform fibroblasts into iPS cells, but Bhatia's team found no evidence that the blood progenitor cells that they had made went through an embryonic state. The cells' gene-expression patterns never resembled those of embryonic stem cells, and the blood progenitor cells didn't cause mice to develop teratomas -- tumours that are characteristic of pluripotent cells.

"Everybody has their favourite cell type. There is a lot of this kind of alchemy going on."

The progenitors did, however, produce all three classes of blood cells -- white blood cells, red blood cells and platelets -- all of which seemed to function as they should, according to a battery of experiments. The red blood cells made adult haemoglobin, not the fetal form.

The ultimate test would be transplanting the cells into humans, says Bhatia, but that isn't on the cards -- at least not yet. "The clinical side is going to be a lot of work," he says. "At least from our estimation, this is the most encouraging result we've seen for using blood cells for cell-replacement therapy."

Sanguine about the possibilities

The potential for therapy is very much on the minds of Bhatia and other scientists who are converting cells directly. Because the progenitor cells bypass pluripotency, there is little risk of them forming tumours when implanted into patients, says Wilmut, who is working on creating other progenitor cells in his own lab.

Deepak Srivastava, a developmental biologist and director of the Gladstone Institute of Cardiovascular Disease in San Francisco, California, led the team responsible for making heart muscle from mouse fibroblasts3. He says that directly converted cells could also offer simpler treatments than iPS cells: the fibroblasts that surround the heart could be transformed into new heart muscle using a stent that delivers drugs to reprogram the cells.

Converted cells aren't without their drawbacks, though. Unlike iPS and embryonic stem cells, they cannot easily multiply in the lab, so producing the large quantities needed for applications such as screening drugs could prove tough, says Wilmut.

Despite lab experiments establishing that the converted blood cells are indistinguishable from adult blood cells, it is still too early to tell whether they will be as good as the real thing once they are inside patients, says George Daley, a stem-cell biologist at Children's Hospital Boston in Massachusetts.

In particular, epigenetic modifications -- changes that modify gene expression without altering the DNA sequence -- could differ between blood cells produced naturally and those created by direct conversion. "The journey from a zygote to a specialized blood cell is very long. The journey from a fibroblast to a blood cell in a petri dish may take a very different route," says Daley.

Even with these caveats, direct conversion is gaining in popularity. "Everybody has their favourite cell type," says Daley. "There is a lot of this kind of alchemy going on."

Maconha pode 'desativar' esperma

Estudo sugere que tanto a droga quanto uma substância produzida por nosso corpo podem atuar na diminuição temporária da fertilidade do homem

Estudo afirma que espermatozóides "perdem a força"
quando são ativados precocemente

Um estudo da Universidade da Califórnia acaba de mostrar os efeitos de um anticoncepcional inusitado: a maconha. Com um olhar mais a fundo sobre o funcionamento dos espermatozóides, os pesquisadores chegaram à conclusão de que a droga contêm um princípio ativo capaz de “gastar a bateria” dos espermatozóides antes da hora.

Os espermatozóides permanecem imóveis na maior parte do tempo em que estão no corpo dos homens. O movimento só começa quando ele está a caminho do corpo da mulher e sua “bateria” dura apenas o tempo suficiente para atingir o óvulo feminino.

Se os espermatozóides forem ativados em algum momento antes do necessário, eles não têm energia suficiente para chegar ao óvulo e perdem a chance de fecundação. E a maconha, assim como uma substância do canal reprodutor masculino e feminino, o encocabinóide, tem o poder de fazer essa ativação, de acordo com a pesquisa.

Um dos responsáveis pelo estudo, Yuriy Kirichok, compara os espermatozóides a balões cheios de ar. Assim como bexigas, os espermatozóides estão "inflados", com partículas com carga positiva - os prótons - em vez de ar. Quando liberamos todos estes prótons de uma vez, o espermatozóide se move. É como se estivéssemos abrindo um canal para que o ar escapasse do balão. Isso acontece porque, a carga do lado de fora de onde está o esperma é negativa e atraí os prótons que estão dentro dos espermatozóides, de carga positiva. “Nós identificamos a molécula que permite que isso aconteça", diz o pesquisador.

A maconha e os endocanabinóides, dizem os pesquisadores, abrem o caminho para essa reação ocorrer, e o "ar" sair do esperma. Com a ativação antes do tempo, quando chega a hora de correr para o corpo da mulher, já não há potência para alcançar o óvulo.

O estudo, por enquanto, trabalha em cima de hipóteses. Nenhum teste prático com consumidores de maconha foi feito para comprovar se o efeito, de fato, é significativo.

Maconha pode tornar fêmeas recém-nascidas mais masculinas

Cérebro e comportamento de ratas recém-nascidas ficaram mais masculinos depois de receberem compostos de canabis

Pesquisadores da Universidade de Maryland descobriram que as fêmeas do rato produzem mais células novas do que os machos em uma parte do cérebro chamada amígdala, que controla comportamento social e emocional. Eles também perceberam que as ratas têm um sistema endocanabinóide menor, que são os receptores cerebrais que reagem à canabis – princípio ativo da maconha.

Esta descoberta fez com que eles questionassem se, injetando substâncias que imitavam a canabis, iriam alterar a proliferação de células na amígdala. Para descobrir, a equipe injetou um componente que prolifera receptores canabinóides no cérebro dos ratos recém-nascidos. Eles também injetaram um produto químico que permitia ver a divisão celular no cérebro. Para descobrir também como essas mudanças alteravam o comportamento dos animais, eles estudaram as brincadeiras dos ratos durante quatro semanas. 

Sem o tratamento, as ratas produziram entre 30 a 50% mais células que os ratos, o que as ajudou a manter um equilíbrio e a proteger neurônios. Elas também brincaram de 30 a 40% menos do que os machos. No entanto, as fêmeas que receberam componentes canabinóides tiveram taxas de produção celular e comportamento igual ao dos machos. 

Os cientistas acreditam que as brincadeiras dos ratos sejam semelhantes à diferenciação sexual que acontece com os humanos. Resta saber se as bases neurológicas do comportamento estudado nos animais seria parecido com o dos seres humanos. 

Nenhum resultado conclusivo sobre os efeitos da canabis convencional em bebês humanos pode ser dado ainda, porque o processo foi avaliado somente em ratos. E o estudo não usou um derivado canabinóide de vegetais, ou doses maiores dele.

New Malaria Drug Could Save Tens of Thousands

Lifesaver. This Tanzanian child was one among more than 5000 enrolled in the study.

ATLANTA—It's not often that spontaneous applause erupts halfway through a scientific talk. But when malaria researcher Arjen Dondorp came to the crucial slide of his presentation here on Saturday, the audience at the American Society of Tropical Medicine and Hygiene's annual meeting couldn't contain itself. Dondorp's study showed that compared with an older drug called quinine, a new one called artesunate reduces the risk of death from severe malaria in African children by 23%—a finding that could save tens or even hundreds of thousands of lives annually.

The findings, which are published online today in The Lancet, "are very clear," says Melba Gomes, a scientist working on antimalarial policy at the World Health Organization (WHO) in Geneva, Switzerland. Given the results of this and previous studies, artesunate should replace quinine as soon as possible worldwide, she says.

Malaria kills up to a million people a year. Most are African children. In its early stages, the disease can be treated with pills, but in severe cases, when time is of the essence, drugs need to be given intravenously or via an intramuscular injection. The most widely used drug for this purpose until now was the centuries-old quinine, derived from the bark of a South American tree; no modern drug had worked better.

But in 2005, a large study in four Asian countries, led by Dondorp and Nicholas White, both employed by the University of Oxford in the United Kingdom but based at Mahidol University in Bangkok, showed that injections of artesunate reduced deaths from severe malaria by 35% over quinine. (Artesunate is part of a drug family derived from Artemisia annua, a plant that has long been used in Chinese medicine.) Since then, several Asian countries have started replacing quinine with artesunate for severe malaria. But it was unclear if the results would translate to Africa, where the population has a different genetic makeup and is generally more likely to be exposed to malaria. Moreover, only 202 of the 1603 subjects in the Asian study were children—not enough, most scientists felt, to warrant a major shift in drug policy.

For the new trial, Dondorp and White gathered a group of collaborators at 11 research centers in nine African countries. Together, they enrolled 5425 children under 15 years of age who had severe malaria. Of the children who received quinine, 10.9% died; in the artesunate group, 8.5% died. The difference may sound marginal, but it's a 22.5% reduction in mortality--reason to be "euphoric," says Dondorp. If all African children with severe malaria received artesunate in time, between 100,000 and 200,000 lives could be saved annually, he says.

The difference between the drugs might be that, as opposed to quinine, artesunate also kills very young malaria parasites, Dondorp says. As a result, fewer infected red blood cells might clog up the tiny blood vessels in patients' organs.

Artesunate, produced by a Chinese company called Guilin Pharmaceutical, is easier to give than quinine, which must be administered very slowly and carefully to avoid a dangerous drop in blood pressure. Artesunate is slightly more expensive, but its administration is cheaper, and an as-yet-unpublished cost-effectiveness study by Dondorp and colleagues shows that the average cost per life saved using the new drug is only $123. That's very low compared with many other interventions.

Changing national drug policies can take many years, however. As soon as possible, WHO should recommend artesunate for severely ill children, because that will stimulate African countries to switch policies, says Olugbenga Mokuolu, a clinical researcher at the University of Ilorin Teaching Hospital in Nigeria who collaborated on the study. Abul Faiz of the Sir Salimullah Medical College in Dhaka, who sits on the panel that makes WHO's malaria treatment recommendations, says the group will likely meet soon to discuss the new findings.