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International Year of Chemistry

Medicine is made of molecules

Chemical components are behind diseases, diagnoses and treatments

CHRISTINE BALDERAS/GETTY IMAGESOn June 8th, those who attended the series of lectures celebrating the International Year of Chemistry saw medicine from a very different angle than usual. Instead of starting with the patient and their symptoms, medicinal chemistry focuses on the molecules behind the disease and the cure itself. The selection of a trio of speakers ensuring the presentation of a broad view of the subject was coordinated by chemist Heloisa Beraldo of the Federal University of Minas Gerais. Geneticist Silvia Rogatto, from the School of Medicine at Botucatu campus of the State University of São Paulo (UNESP), showed how genetics (and genes are molecules) is behind penile cancer and how it can contribute to diagnosing the disease. Chemists Luiz Carlos Dias, of the State University of Campinas (Unicamp), and Eliezer J. Barreiro, of Federal University of Rio de Janeiro (UFRJ), stressed the role that chemistry plays in the search for new drugs and the importance of research in Brazil to its development. An initiative of FAPESP and the Brazilian Society of Chemistry, the cycle of conferences continues until November, with a different theme each month that will be reported on in this space.

Starting the meeting with genetics was pertinent: according to Barriero (the father of medicinal chemistry in Brazil, according Heloisa), the structure of deoxyribonucleic acid (DNA) was the most brilliant discovery in the history of science. This landmark discovery, which won the Nobel Prize in 1962, by physicist Francis Crick, biologist James Watson and medical doctor Maurice Wilkins, is what allows Silvia Rogatto to better understand penile cancer today – a disease of poor countries, she said. This type of cancer is rare in rich countries and in Brazil, it is most common in the North and Northeast regions (where it affects 5.3% and 5.7% of the male population, respectively) than it is in the Southeast (1.2%). The geneticist detailed part of the explanation: human papillomavirus (HPV) is present in a substantial proportion of patients with penile cancer – of 36 patients from São Paulo that were evaluated in a study conducted by his lab, 42% were also infected with the virus. HPV is an important factor in the development of cancer of the cervix and oropharynx, and for a long time now, physicians have been discussing the importance of vaccinating men against the virus as well (see Pesquisa FAPESP nº 157) – the issue was advanced in May this year when the National Health Surveillance Agency (Anvisa) approved a vaccine for men.

The decision is quite welcome, as research has already demonstrated that the association between the virus and the vaccine is not accidental. Silvia showed that HPV interferes directly with the control of cell proliferation and causes cells to multiply uncontrollably when parts of the virus’s genetic material are inserted into the DNA of an infected person. Because HPV is sexually transmitted, the parts of the body that are most readily attacked are the penis, the female genitalia, and around the mouth and throat (or oropharynx), as a consequence of infection through oral sex, for example.

The studies conducted by Silvia’s research group have revealed that some changes in the human genome is a typical effect of tumors, suggesting that they play a critical role in the establishment of the cancer. More importantly, the geneticist showed that it is essential to determine the presence or absence of HPV in order to trace the course of treatment. Patients with penile cancer that are infected with HPV survive longer than those without the virus. In practice they are treated as if they were different diseases, and much less is known about the version of penile cancer that is not associated with virus. Furthermore, life expectancy declines with more changes in the DNA of a tumor. “A genomic profile gives us an idea about the evolution of a patient and can be used as a marker of the disease,” said the researcher, whose laboratory is cataloging these markers, some as potential therapeutic targets.

Rather than going through the list of genes one by one, the investigation of the group from Unesp and the AC Camargo Hospital focused on identifying gene networks – genes that influence each other and work in a coordinated way – related to the diseases being studied and the immunological and inflammatory responses. Together, the results make clear the importance of genetically characterizing the patient in order to treat them and predict the course of the disease. “The criteria for cancer patient treatments do not consider their genetic individuality.”

Silvia and her team continue to deepen their understanding of how the cancer, the virus, and the genome interact: they are trying to understand the role of micro-RNAs in the regulation of gene function and epigenetic effects, in which the genetic sequence is not altered, although chemical compounds bound to DNA do affect its activity in a process known as methylation, which involves the addition of a methyl group (CH3), one of the bases of DNA. “We found a metabolic pathway with almost all the genes altered by methylation. It’s amazing,” said the researcher.

Silvia’s concerns are not just limited to this type of cancer. “If the relationship with HPV is true for the penis, it should also be important for the oropharynx, and we need to alert and inform young people to prevent the disease.” The focus on young people is due to the increased risk of HPV transmission among people with more than one sexual partner. Prevention is essential, since the failure so far, according to the geneticist, has been in obtaining drugs that are effective against the disease.

New drugs
Finding the basis for new drugs is just what occupies Luiz Carlos Dias, from Unicamp. “Around 80% of all drugs have a synthetic origin,” he said. Aspirin, one of the most widely sold drugs in the world, is totally synthetic. Atorvastatin, a drug used to control cholesterol and the “the biggest blockbuster of the pharmaceutical industry”, is a synthetic substance developed from a naturally occurring molecule. The production of these drugs is the main responsibility of the powers that be in the pharmaceutical industry, but the researcher also highlighted the central position of scientific research: “It is the medicinal chemicals that provide the necessary information for the production of these molecules by means of organic synthesis .”

The idea is not just about finding new compounds to fight diseases that require treatment, but also to improve on what already exists: reduce solvent use, energy expenditure, and the production waste during the manufacturing process. One such example is migrastatina, a substance that was originally isolated from the bacterium Streptomyces platensis,which inhibits the process of metastasis. “The synthetic molecule that we developed in our laboratory is more potent than the naturally occurring molecule,” said Dias.

EDUARDO CESARSilvia Rogatto, Luiz Carlos Dias and Eliezer J. Barreiro FAPESPEDUARDO CESAR

He is seeking therapeutic substances against diseases that have been mostly neglected, such as Chagas disease. As part of the National Institute of Science and Technology of Drugs and Medications (INCT-Inofar), led by Eliezer J. Barreiro of UFRJ, Dias participates in projects that focus on producing the active ingredients of drugs whose patent is about to expire. An important recent success was the synthesizing of atorvastatin by means of an unprecedented route, different from what was already known – a feat of accomplishment that can be viewed as an improvement of the process used until now. “We need increasing interaction between government, industry and academia,” he pondered, citing India and China as examples of countries that have invested in becoming independent in their production of pharmaceuticals. “For Brazil, it’s still easier to buy from India and China, despite the low level of quality control in the production of these medications and the possibility of degradation during transport, requiring purification steps before some drugs can be packaged for distribution.”

Pharmaceuticals coming from India is also a concern for Barreiro. “We need to resolve this dependency on importing drugs, medications, and pharmaceutical adjuvants,” he said. And it is in this sense that the INCT-Inofar acts. “We have a responsibility to invent molecules that can be messengers of health.”

For this, he points out that the medicinal chemist, working with a myriad of elements, needs to master the interdisciplinary skills that characterize this area of scientific work. Just as it was in the discovering the structure of DNA, involving a physicist, a biologist and a medical doctor, the medicinal chemist from Rio de Janeiro stressed that the most important achievements in the history of science have come from the merging of disciplines. Even more than that, it must combine creativity and innovation . “Old methods may today allow you to discover six, instead of it being half a dozen,” he joked. The best environment for such creativity, in his view, is in the university, and not in large well-equipped pharmaceutical companies – which Barreiro observes as having passed through a creativity crisis, evident in the meager development of new compounds in recent years, despite having cutting edge technology at their immediate disposal. Gathering minds and technology together through the integration of professionals from different backgrounds and expertise is the great mission of Inofar.

In addition to being scientific, the issue is also political, as Silvia and Dias have already shown in their studies of diseases that affect mainly the least wealthy regions of the planet. “In a country like Brazil, the medicinal chemist must be very clear about its importance, the research has no ideology, but its social impact is important,” affirms Barreiro, far from considering the observation as a hitch. “The country’s scientific capabilities allow our sovereignty in the area of pharmaceuticals.”

With its increasing position in world rankings for scientific production, significant advances in the generation of knowledge, dissemination of science, technological innovation and growth in the business sector – all connected – , the coordinator of INCT-Inofar estimates that Brazil is on the right track. One more reason to celebrate the presence of young students at the Technical Institute of Barueri, a city on the outskirts of São Paulo, who filled the auditorium: the importance of training new professionals aware of the challenges was mentioned by all of the speakers. “The medicinal chemists deal with a multitude of parts, we must persist, pursue and achieve,” concluded Barreiro.