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Immunology

The art of working together

European groups work together to integrate research and save time in the search for new cancer and Aids treatments

GORDON MACPHERSON AND JON AUSTYN/UNIVERSITY OF OXFORDIn action: dendritic cells (with veil-like ramifications) activating lymphocytes (smaller round cells)GORDON MACPHERSON AND JON AUSTYN/UNIVERSITY OF OXFORD

Five teams from hospitals in Germany, Belgium, Hungary and France plan to start implementing a different strategy, starting this year, for evaluating the efficiency of a type of defense cell among people suffering from skin tumors or Aids: they will  now adopt standardized work methods in order to be able to compare their results later on. This was virtually impossible to achieve previously, because each researcher used his own procedures. Meanwhile, a team in Paris is studying how these cells react when they find tumors or infectious agents such as viruses and bacteria. In Milan, Italy, another group identifies the genes that control the functioning of the so-called dendritic cells, currently regarded as a promising therapeutic possibility to fight a number of diseases, as these cells control the production of antibodies and of other defense cells. The leaders of each group know that they can ask for help from the other teams in order to complement results. They can also expand the debate to other participants, since they are part of the European DC-Thera network, one of the rare global initiatives for integrating basic and applied research, comprising 26 research groups, 39 associated laboratories and six small and medium-sized firms.

Implemented almost three years ago, DC-Thera, short for Dendritic Cells for Novel Immunotherapies, brings together renowned European dendritic cell experts from the fields of genomics, proteomics, molecular and cellular biology and experimentation in animal models and in humans, with the aim of finding an alternative to the current treatments, especially where cancer is concerned. “A knowledge of genomics can be used to design these human tests, which are often very empirical”, says Jonathan Austyn, an immunobiology professor from the University of Oxford, who created the network. “We want to complete the course from the microcosm to the macrocosm”.

Research in this field was stepped up in the last few years in the USA and in Brazil as well, thanks to the encouraging results of preliminary clinical tests and of low toxicity. The side effects tend to be minimal because each person receives cells from his own body, once they have been laboratory selected, cultivated and strengthened.

“In ten years we will possibly manage to stimulate dendritic cells within the patients’ bodies”, says Roger Chammas, who studies  mechanisms for differentiating dendritic cells at the University of São Paulo (USP) Medical School, together with Lewis Joel Greene’s team, from the Ribeirão Preto Cellular Therapy Center.

Working within a network may be a way of reaching more consistent results sooner, but it is not easy. Even within just one country it would be difficult to motivate physicians and biologists to embrace a converging thought process and language. Austyn tempted fate by bringing together 61 groups from 18 countries across Europe, each one with its own cultural barriers, which are particularly marked in a continent historically torn by wars. Under his coordination, English, Italian, German, Portuguese, Swiss, French, Croatian and Spanish businessmen, physicians and biologists congregate around the same table every three months to discuss scientific results or work strategies.

It is not always easy to negotiate with scientists, especially those, such as Austyn, who prefer to respect the priorities and work styles of each group rather than to impose a standardized behavior. In order to articulate knowledge and overcome the specialization that limits the capacity for  reflection , he also has to forecast and manage the conflicts ensuing from different views of the world. An awareness of the limits of one’s own knowledge often causes some to gain and others to lose authority.

However, the dialogue frequently wins over and strengthens the bonds of trust. In June, for instance, at a meeting organized by Gerold Schuler, from the University of Erlangen, in Bamberg, a medieval German town, the network’s members agreed to test the dendritic cells using the same preparation, quality control and application methods.

Lack of standardization is one of the chief problems that make it difficult to analyze and compare the approximately one hundred clinical tests with dendritic cells already carried out around the world. Carl Figdor, a researcher from the University of Nijmegen in The Netherlands and a member of DC-Thera, together with other experts, voiced a warning in 2004 in Nature Medicine about the need to plan, prepare and evaluate clinical testing more strictly.

Austyn and the project manager, Brazilian biologist Miriam Mendes, discovered little by little how to make teams that previously barely saw each other start to share equipment, doubts, hopes and findings. One of the strategies is to recognize the value of tacit knowledge – details of work techniques that do not appear in the studies published in scientific journals, but that save time and avoid mistakes. The researchers learnt that it was better to learn a technique in one week from another laboratory than to take months developing it on their own.

Austyn and Miriam invest in a lot of talk, as money is short. Financed by the European Community, the network has a – 7.6 million budget distributed over five years – or – 1.5 million (about R$ 4.5 million) a year. Each group is given only enough to cover travel expenses and part of the reagents used in their experiments.

“We don’t provide research funds, but we try to cut research costs by bringing the groups together and making information flow more easily”, says Miriam. A graduate of USP, she previously worked on the Human Genome Project in England and headed a survey about the reasons underlying success or failure in the transfer of technology between universities and American and British pharmaceutical companies. She then reached the conclusion that often it is lack of communication, rather than a shortage of money, that proves to be the greatest scientific production bottleneck.

Tim Evans, the World Health Organization’s assistant director-general for information, evidence and research, agrees. According to him, there is enough information already available to face infectious diseases in developing countries. “People are drowning in data.” In his mind, illnesses spread, among other reasons, because information rises to the highest hierarchical levels, but rarely trickles down to the formulators of public policy and common citizens.
“If each group’s questions were more complementary, perhaps the efficiency of networks would be greater, as  results would be achieved faster”, says Lyris Godoy, a Brazilian biologist who did her doctorate at the Ribeirão Preto Cellular Therapy Center and who has been studying proteins at the Max Planck Institute of Biochemistry in Martinsried, Germany, since July 2005.

In July 2006, Lyris went to St. Moritz, a Swiss ski resort, to ski and to discuss her work with more experienced researchers, who gave her and other post-graduate students suggestions on how to advance faster. This was the second annual gathering of the Graduate School, a sort of winter course created by Mark Suter, a researcher from the University of Zurich and a DC-Thera member. “It’s very useful”, evaluated Lyris, who left St. Moritz with a plan for an experiment to be carried out with colleagues from England. “The personal bonds that strengthen the network are more consistent when they spring from real problems, from the bottom up”, observed Miriam.

Another way to bring groups together involves four technological platforms: teams or facilities that can help other groups by providing them with services, tips or courses about genomics, cell images, information technology and cell production for testing in humans. At one of these platforms, at the Curie Institute in Paris, Argentine biologist Sebastian Amigorena recorded the movements of dendritic cells in mouse tissues, live and in real time, through nuclear magnetic resonance and microscopy.

Seeing how cells move through the body helps to interpret the results of experiments on animals, especially when the results can be added together: one of the Italian groups, for instance, is expected to list by the end of the year the thousands of genes associated with the differentiation and regulation of dendritic cells. “We can now work on associating the genes with cell responses”, says Austyn. Out of these studies  strategies for action also emerge, in order, for instance, to block a gene whose action hampers the working of dendritic cells.

Found in almost all tissues, dendritic cells act as antigen presenters. They find and digest parts of tumors, small microorganisms, such as viruses and bacteria, and larger microorganisms, such as worms. Afterwards, some proteins that remain stuck to the surface of the dendritic cells can activate other defense cells, such as T and B lymphocytes. Tumors block this communication, inhibiting the maturing of dendritic cells. And not only tumors. The protozoan that causes malaria also blocks their development, according to a study conducted by Austyn and other researchers from the University of Oxford and published in 1999 in Nature.

Work in hospitals tries, precisely, to avoid this loss of cells that are essential for the body’s defense. A piece of equipment similar to the one that filters the blood of people with kidney failure removes blood cells called monocytes from people with cancer or infections diseases such as Aids. In a solution with proteins and growth stimulators, the monocytes originate  the dendritic cells. Five or six days later, this solution receives tumor parts, also extracted from the people who are undergoing treatment, as well as other agents that cause the dendritic cells to mature and became effective in terms of stimulating the immune system. Finally, once they have become mature and capable of recognizing the tumors, the dendritic cells are put back into the patients” body to coordinate the fight against the cancer or the infectious diseases.

Though labor intensive, this is a promising strategy. Frank Nestlé, a researcher from the University of Zurich and an associate member of DC-Thera, announced in 1998, in Nature Medicine, the results of a pilot study conducted on 16 patients with advanced skin cancer; five had their metastases regress after being given injections of dendritic cells from their own blood. Other studies did not reach such positive results, but this technique, called autologous vaccine, because it is prepared from the blood of the patient under treatment him (her) self, became acknowledged as a promising and safe line of research in 1999. This was when Schuler’s group, which currently coordinates the clinical tests, published more encouraging results, also in connection with skin cancer.

Uncertainties
This may become an alternative for treating other types of cancer, autoimmune diseases, allergies or transplant rejection, but many challenges lie ahead. “As there is a shortage of standardized work procedures”, stated Chammas, “we are still unable to make an independent evaluation of its efficiency”. Austyn encourages the groups to use the same criteria in all human tests not only to ensure the comparability of results from different countries, but also to enable Emea, the organization that approves new treatments in Europe, to issue a  license valid across all European countries faster.

Another problem is that because it is individualized, this treatment is still expensive. Nonetheless, it is cheaper than chemotherapy and hospitalization in intensive care units, stated physician José Alexandre Barbuto, a researcher from the USP Biomedical Sciences Institute.

Heading one of the few centers of basic and clinical research into dendritic cells in Brazil (there are others in the states of São Paulo, Rio de Janeiro and Rio Grande do Sul), Barbuto was one of the coordinators of one of the few clinical studies involving dendritic cells in this country. According to its results, published in 2004 in Cancer Immunology and Immunotherapy, the tumors stopped growing in 71% of the 35 people treated (who suffered from advanced kidney cancer or skin cancer). “We are on  a  par with other countries”, he said.

Here there is also a lack of standardized work methods, while uncertainties abound regarding the mechanisms for obtaining government approval. There is no lack of daring, however. In the tests that led to the 2004 article, Barbuto disregarded certain immunology norms and merged dendritic cells removed from healthy donors with tumor cells taken from the patients under treatment. Normally, both the cells and the tumors are taken from the same person. Eventual rejection, he imagined, might stimulate other defense cells even more strongly. The results encouraged him to initiate, as soon as possible, testing  more people and  more diseases. For the time being, optimism reigns.

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