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Yvonne Primerano Mascarenhas

Yvonne Primerano Mascarenhas: The master of crystals

Physicist honored at the World Chemistry Congress began to study molecular structures using X-ray diffraction in the 1960s

Léo Ramos Chaves Physicist from the city of São Carlos identified the structures of the hormone oxytocin and of plant extracts with therapeutic potentialLéo Ramos Chaves

Yvonne Primerano Mascarenhas arrived in São Carlos in February 1956 with her first child on her lap and pregnant with her second. For the family from the big city of Rio de Janeiro, it was an adventure to reach the small town in the São Paulo countryside. Twenty-four hours were spent aboard two different trains—the paved road ended in the city of Rio Claro, 65 kilometers from São Carlos. Originally from the city of Pederneiras, São Paulo State, Mascarenhas had recently earned two degrees: one in chemistry and the other in physics, both from the University of Brazil, now known as the Federal University of Rio de Janeiro (UFRJ). She and her then husband, physicist Sérgio Mascarenhas de Oliveira, had been hired as professors for the new University of São Paulo (USP) campus in São Carlos, which at that time had only its School of Engineering.

Over the following decades, Mascarenhas and her husband played a crucial role in the creation of the USP São Carlos Institute of Physics (IFSC-USP) and in transforming the campus into one of the most important centers for research in Latin America. Combining her interests in chemistry and physics, she became the head of crystallography in the country, teaching generations of students to investigate the structure of a variety of molecules. Crystallography consists of the use of X-ray diffraction to determine both the molecular structure and the crystalline structure of a substance. These structures can be understood as the “packaging” of the molecules in crystalline solids, or crystals. In this technique, an X-ray beam strikes the crystal and generates other beams; the values ​​of the diffraction (or scattering) of these beams indicate the positions of the atoms in the molecule.

Now at 86, with four children, ten grandchildren, and seven great-grandchildren, Mascarenhas continues to publish scientific articles. One of her recent studies considers a substance extracted from the leaves of the jaborandi plant (Pilocarpus pennatifolius). This substance acts against the worm that causes schistosomiasis. Another study characterizes a protein isolated from the bacterium Bacillus thurigiensis that could be used as an insecticide.

In July, Mascarenhas was one of twelve scientists to receive the award offered by the International Union of Pure and Applied Chemistry (IUPAC) to women with achievements in chemistry or chemical engineering research. She hosted Pesquisa FAPESP in her laboratory at USP São Carlos a few days before traveling to the city of São Paulo to receive the award at the opening of the 46th IUPAC World Chemistry Congress.

What is the significance of your first international award?
It was interesting because, although I work in a physics institute, my work is interdisciplinary. I often work with chemistry; in fact, my first undergraduate degree was in chemistry. My relationship with chemistry began when I was fourteen or fifteen years old and I completed a classic program [a type of Brazilian secondary school offered at the time] at a very good private school called Mello e Souza in Rio de Janeiro. At that time, my great love was for languages. I was considering studying classics and planned to learn Greek as soon as I got to college. The students in my classic program were taking courses such as Latin, Brazilian and Portuguese literature, and French, but they also learned the basics of physics, chemistry, and mathematics. It was then that I took a chemistry course with a young teacher, a physician by training, named Albert Ebert [1916–2016]. It was he who piqued my interest, especially in organic chemistry.

What about chemistry interested you?
It was the possibility of studying the compounds that make up all substances, including living beings, and the very logical way Professor Ebert presented it all. He helped me see a universe of applications, that it was an extremely important science. As soon as I graduated, Professor Ebert helped me to get a job at the Franco-Brazilian Secondary School in Rio. Years later, he became dean of the School of Education of UFRJ.

When you were an undergraduate in 1953, the structure of the DNA molecule was uncovered and published based on the work on crystallography by a British chemist, Rosalind Franklin. How did this finding reach your team? Was it your inspiration to become a crystallographer?
My introduction to crystallography was much simpler. In my chemistry program, the course on crystallography was taught by natural history teachers, mineralogists who used only optical techniques with visible light to analyze and classify minerals. Fortunately, Elisiário Távora had started teaching at UFRJ the year before, after completing his doctorate at the Massachusetts Institute of Technology [MIT] with a well-known crystallographer, Martin Buerger. Távora arrived with fresh ideas on modern crystallography, and then I really saw the potential of the field, with the use of techniques such as X-ray diffraction. At first, I knew very little about biology and biochemistry; it was physical chemistry that impressed me, so much so that I went on to get a degree in physics because I thought I needed it to really involve myself in the field. At that time, it was very difficult to determine the structure of molecules using X-ray diffraction, but that possibility stayed with me as something worth trying. When Sérgio and I came to São Carlos in 1956, we were met with a good laboratory for teaching physics; it had German equipment and a medical X-ray machine in the basement. Sérgio was able to exchange it for another one that was more suited to our objectives, and we began to experiment to determine the orientation of single crystals. Then, in 1959, I went with Sérgio, who was already a full professor, to the University of Pittsburgh in the United States, and did a research internship in crystallography. It was there that I began to use analysis techniques using single crystals, and where I learned to interpret diffraction patterns and to use computers, which at the time were still enormous and very simple. We used punch cards to insert the experimental data and perform a part of the calculation with the programs available at that time, then another part with other cards, and so on. Each card had a hole in the last column to indicate that we needed to add the result to that of the next card.

Why are single crystals important?
To understand the structure of a molecule, we must obtain a single crystal from a solution. A good single crystal has a certain geometric shape according to its symmetry and is transparent, but it must be small. Smaller crystals, up to a hundredth of a millimeter, are becoming more and more viable as X-ray detectors and sources continue to improve.

The interpretation of crystallographic images seems to be intuitive or even artistic. Is that impression correct?
It is neither artistic nor intuitive. We obtain plenty of information from X-ray diffraction through the electrons in the material. Originally, structures were determined by trial and error; a model was proposed for the structure, and the intensities of the diffracted beams were calculated. If they agreed with the experimental data, the veracity of the model was established. Later, several methods were developed to treat experimental data. The first was a method using heavy atoms. A relatively heavier atom from a molecule will dominate the diffraction and show a peak on the electron density map, which is calculated using the intensities of the diffracted beams, and this information is a clue about the molecular structure. From there, you can calculate electron density maps and assign the peaks that are obtained to light atoms, such as oxygen and carbon. It is obvious that this process only began to work effectively with the help of computers; before that, all calculations were done by hand with calculators. Today, the biggest challenge is obtaining a good crystal. It’s important to remember the rule GI = GO, which means “garbage in, garbage out.” With good crystals and good programs to obtain the structure from experimental data produced by X-ray diffraction, it is increasingly easy to study small molecules—those with up to 200 atoms, not counting hydrogen atoms. For macromolecules like proteins, there are still the problems of how to purify them, how to obtain single crystals, and how to insert heavy atoms; we sometimes try this process for years, and it’s indispensable for determining molecular structure. Luckily, there is now automated equipment that really helps us to prepare solutions by simultaneously varying various parameters such as acidity, viscosity, and solvency.

Is a good crystal also aesthetically pleasing?
Definitely! I observe them under the microscope and consider them good when they have no defects. Sometimes, the crystal has a nice external shape but defects that complicate the analysis; in other cases, it’s twinned, which also hinders things. A desirable structure is one that appears when the distribution of unit cells [the crystallographic units with a defined shape and symmetry that make up the crystal] is as perfect as possible. Defects will always exist, but the final test of whether the crystal is good comes when we use the X-ray beam and we obtain data that allows us to determine, without a doubt, a unit cell with definite symmetry. There are quartz crystals and crystals made of other materials with many geminations in mesmerizing shapes, but they are not suitable for molecular structure analysis or for technological applications.

personal archive Mascarenhas (right) with physicist Herbert Hauptman and his wife, Edith Citrynell, on a visit to a farm in the city of Descalvado after a course in São Carlos in 1976personal archive

What are your most important studies?
The structures I studied were important to the chemists or physicists with whom I have always collaborated. I remember a collaboration with Otto Gottlieb [a Czech-Brazilian chemist, 1920–2011], who worked with compounds obtained from plants at the USP Institute of Chemistry and at UFRJ [see Pesquisa FAPESP, issue No. 43]. He studied substances from the plant Aniba gardineri and could not determine the mechanism of dimerization [the formation of a double structure through the union of two similar units] of one of its molecules, 5,6-dehydrokawain. I really enjoyed that work because Otto was happy when he saw the result. He was very interested in the plants of the family Lauraceae, which offer a wide variety of medicinal and industrial uses. The first study I did in the United States was to determine the molecular structure of a barbiturate: violuric acid. The results of its structure were unprecedented in the field of ​​hydrogen bonds because a molecule from water of crystallization was found to have a bifurcated bond—that is, one of its hydrogen atoms bonds to two different atoms of the violuric acid molecule. That’s why the published article was cited with certain frequency. In my opinion, it’s just another example of a scientific finding resulting from good luck! Another study that I consider important was when I determined the structure of oxytocin, a hormone of substantial biological importance, during a stay at the Crystallography Department of Birbeck College in London in collaboration with Sir Tom Blundell. I became interested in the characterization of semicrystalline materials after getting involved with the INCT [the Brazilian National Institute for Bio-Ethanol Science and Technology] in the study of conductive polymers, coordinated by Roberto Mendonça Faria, from our physics department. As part of my student Edgar Sanches’s doctoral program, we were able to clarify several details about polyaniline, both in its conductive form and its insulating form. My interest in natural products resurfaced when I coordinated the Advances, Benefits and Risks of Nanotechnology Applied to Health project within the scope of the NanoBiotec network for CAPES [Brazilian Commission for the Improvement of Higher Education Personnel], which partly addressed substances of natural origin with pharmacological properties. One of the plants studied was the jaborandi. One of the components extracted from its leaves is already used for medicinal purposes—to treat ophthalmological problems. However, the extraction residue, which contains other plant components diluted in organic solvents, should not simply be thrown into the environment. This led to the idea of ​​analyzing all of the compounds in the extract in search of other substances with properties of interest. This was the topic of study of a research group from the Delta do Parnaíba campus of the Federal University of Piauí, where we held one of our workshops. Incidentally, I noticed that the researchers in this group were giving samples of one of these components of the residue to Ana Maria da Costa Ferreira, a professor at the USP Institute of Chemistry, so I asked them, “Do you know about the structure of this molecule?” They said, “We’d love to know, but we do not have one of the single crystals in there.” Looking at the powder inside the glass, I saw some shiny particles, which meant that there were, in fact, crystals in there. They allowed me to take a sample of the substance to São Carlos. It acts on the worm Schistosoma mansoni, which causes schistosomiasis. Using the single crystals that were, in fact, in the powder, we were able to determine its structure. Because it is not ideal for administration as a drug in its natural form, and because it is insoluble in water, Ana Maria synthesized several derivatives of this substance, complexing it with zinc and copper, which make it more soluble in water. The molecular structures of these complexes were also determined in our group. Many students obtained their master’s and PhDs in the crystallography research group in our department, and these students, in turn, have advised their own students. There are now about one hundred researchers with a solid background in structural crystallography at various universities and research centers in Brazil.

Your prize at the IUPAC congress was centered around female scientists. How do you see the difficulties faced by women in research?
The most traditional universities in the world barred women from enrolling until the mid-twentieth century. In the National School of Philosophy at the former University of Brazil, now the UFRJ, this type of barrier did not exist, though there were few women in physical science programs, and there were more in the chemistry program than in the physics program. Even today, for what I consider historical and cultural reasons, men hold positions of leadership and decision making, and society is formed in such a way as to keep power in the hands of the dominant groups. A friend of mine was very upset when the members of a hiring committee asked her how she would handle the fact that her husband was already a professor in São Carlos. It’s the kind of thing no one would ask a male candidate. I always say that the struggle for women’s rights, in theory, has already been won. The issue is learning how to exercise those rights. In politics and government, most of our representatives are men. Who do women vote for? They generally vote for men, as election results clearly show.

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