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Intense doubt

Nobody knows if it really is adult stem cells that work in related cases of success

VINICIUS BASSANEZE/USPMetamorphosis continues: Stem cells of adult adiposis tissue, treated so that they will differentiate into fatty cells (magnification 200 times)VINICIUS BASSANEZE/USP

At the beginning of May, Sátiro da Costa, from the state of Ceará, told the national TV news that he was feeling better after having received a dose of stem cells at a hospital in Rio de Janeiro. Faced with the remote possibility of a heart transplant, the application of these cells, which form a whitish liquid, was an alternative to re-establish the vigor of the cardiac muscle weakened through Chagas’ disease. In the city of Ribeirão Preto, in the  interior of the state of São Paulo, a week after having received stem cells extracted from her own bone marrow, the housewife Martinha da Cunha verified that she had begun to re-conquer her freedom of movement lost through multiple sclerosis, which had paralyzed the right side of her body. In the entire world at least 65 tests with adult stem cells are going on, with the proposal of combating tumors, heart problems, Parkinson’s disease, lesions in the spinal cord, autoimmune illnesses and anemia. But up until now neither researchers nor doctors are sure that the apparent benefits are really due to adult stem cells.

Capable of turning themselves into other types of cells, in accordance with the organ or the tissue into which they are installed, adult stem cells are manufactured – and removed – along with other types of cells, mainly in the bone marrow, the reddish mass that fills the large bones of the body. “All the world would like to use the label ‘stem cell therapy’, but even here in the United States the majority of the researchers don’t even purify the cells before applying them”, explains Alysson Muotri, a Brazilian geneticist who works at the Salk Institute of the United States.

But how to explain the results? Ricardo Ribeiro dos Santos, the coordinator at the Millennium Institute of Tissue Bio-Engineering, who for four years has been studying this form of therapy in order to reduce the impact of Chagas’ disease, believes that the stem cells can release hormones and action cells that re-establish the activity of the damaged tissue. This would be a form of understanding the recovery of the general health picture exhibited for about a year by 50 patients who have already received stem cell applications at the Oswaldo Cruz Foundation (Fiocruz) unit in Salvador, where Santos is working: 20 suffering from serious liver problems and are far from receiving a transplant and a further 30 who are burdened with Chagas’ disease. “As we inject a mixture of the cell populations”, comments Santos, “it’s still not possible to say which one or which group is or are working”.

Tarcísio Barros Filho, from the Hospital das Clinicas of the University of São Paulo (USP), also cannot prove if the stem cells that he and his team have used to treat chronic lesions on the spinal medulla differentiate into neurons or only cling onto others and in this way assist in recovering the transmission capacity of the nerve impulses. No nerve stimulant had passed from the spinal medulla in the 30 patients who has lost the movement of their legs and had participated in an experimental study at the HC. Two years later, none returned to walking, but in 60% of this study’s cases a recovery in the passage of the sensitive electrical impulses of the legs in the direction of the brain has been verified. “This is an animating result”, advised Dr. Barros Filho, “but it’s a long way from being the cure”.

Just one block from there, in another HC unit, at the Heart Institute (InCor), 35 heart patients submitted themselves to the implant of a vein in their heart in order to restore the irrigation of the heart muscle and, at the same time, they received doses of stem cells directly into the heart. Two years afterwards, they have recovered more quickly than the other 30 who received only the blood vessel. José Eduardo Krieger, one of this study’s coordinators, would really like to know how these patients have managed to recover.

Up until now one of the few proven results in which stem cells could function both in laboratory animals and in human beings – putting aside the secondary effects caused by other types of bone marrow cells – was obtained by Irving Weissman, from Stanford University, and has lit up the prospect of new treatments against leukemia and some forms of cancer in blood cells. “The transplant of hematopoietic stem cells (that originate from blood cells) is the only form of therapy with stem cells in safe medical use today”, assures Marco Antonio Zago, an USP professor at Ribeirão Preto. This type of transplant, normally made with cells from the patient himself who is to be treated, is a way of replacing the already mature blood cells that were destroyed through the treatment of the cancer – this is a technique that has been adopted with regularity for more or less ten years, indeed, long before this form of cellular therapy had gained visibility.

eduardo cesarStem cells that will grow in a hot room (above) at 37o Celsiuseduardo cesar

Jefferson Luis Braga da Silva, from the Catholic Pontificate University (PUC) of Rio Grande do Sul, recognizes that “these stem cell tests gave lots of false hope”. He himself felt the weight of anguish of who suffers from a chronic illness after the national TV news of April 17th presented the results of his studies for treating nerve lesions. In less than a month he had received more than 1,000 e-mail messages from people who insisted in being volunteers for his next tests. Only five, however, had suffered ruptures in the peripheral nerves less than a year before and still had some chance of recovery. Silva made use of silicon tubes filled with stem cells to treat lesions of up to 3 centimeters in the nerves of the forearm of 20 patients, who, according to him, recovered their movements and sensibility in up to one year, while another 22 patients, treated only with the silicon tubing, took up to three years. “The improvements are clear”, he says. “I just don’t know how to confirm if it really was the stem cells that worked, because I didn’t mark them.”

Bianca Gutfilen and Lea Mirian have solved this problem at the Federal University of Rio de Janeiro (UFRJ) by marking the stem cells with technium 99-m, an isotope of a radioactive element widely used in nuclear medicine. It was this radioactive element that was used in the stem cells of patient Satiro, the Cearense who participated in one of the tests to evaluate stem cells ongoing at the UFRJ. “Now we know exactly where the stem cells are going to stop”, explains Bianca. According to her, only the damaged area from the Chagas’ illness in the regions of the cardiac muscle that received stem cells recovered, but the challenge of demonstrating that these cells are the ones responsible for these benefits persists.

“Many people are jumping steps and wanting to put the cart before the horse”, observes Sílvio Duailibi, a researcher at the Federal University of São Paulo (UNIFESP), who defends more basic research and pre-clinical trials before use on human beings, so that what is happening can be clearly understood. “Before application in humans, we need more basic research and pre-clinical trials, in order to understand with clarity what could be happening”, says Krieger, from InCor, who alerted: studies such as those done up until now with dozens of people, even if they bring positive results, must be seen with caution. They do not represent the population of potential users nor exhibit sufficient scientific arguments, in accordance with the international medical research models, in order to give the final words about the limits of the efficiency of this form of cellular therapy.

More consistent conclusions will only come with clinical tests made upon hundreds of patients at the same time and by more than one research institution. With support from the Ministry, Antonio Carlos Campos de Carvalho, a professor at UFRJ, is coordinating one of these studies, called multi-centric. Four teams – in Rio, Salvador, Sao Paulo and Porto Alegre – began at the start of this year to treat 1,200 patients with Chagas’ disease, with their hearts dilated by another type of illness or with lesions caused by a heart attack. This is the type of study known as double blind: until the end of the work neither the patients will know who received stem cells or a placebo nor will the doctors who will apply them (the syringe will be covered so as not to show what it contains). “We have to present the results in the maximum time of two years”, a concerned Ricardo Santos said, who will follow up the treatment of the Chagas’ disease patients.

Until they have checked the decisive demonstrations, stem cells should follow a course similar to that of genetic therapy, seen with great hope some ten years ago, but still distant from application. Notoriety should follow disillusion, “when it’s verified that a large part of the current promises of its medical applications can’t be reached in the short period or are non-existent”, comments Zago in an article published in the magazine Hipertensão [Hypertension]. The setbacks should not take away the value of the advances, part of them dealt with in the book entitled, Células-tronco – A nova fronteira da medicina [Stem cells – the new frontier of medicine], organized by Zago and Dimas Tadeu Covas, also from USP at Ribeirao Preto. As professor Barros Filho says: “We’ve got hold of only the first pieces of this enormous jig-saw puzzle, but we still have a lot to learn”.