INSTITUTIONAL NEWS

Gabriel Rabinovich joined the European Molecular Biology Organization

With an outstanding career in the identification and study of key proteins in the regulation of the immune and vascular systems, the CONICET researcher went along the path from a scientific discovery to technology transfer.


Gabriel Rabinovich. Photo: CONICET Photography/ Verónica Tello.

The European Molecular Biology Organization (EMBO) incorporated CONICET researcher Gabriel Rabinovich, director of the Laboratory of Glycomedicine of the Institute of Biology and Experimental Medicine (IBYME, CONICET-F-IBYME). The membership of this organization, which includes more than 1,900 researchers –ninety Nobel Prize winners among them- seeks to honor distinguished scientists who have made outstanding contributions to the field of life sciences.

“I feel very honored and grateful for this appointment, since molecular biology has been and continues to be a key tool in our projects, allowing us to answer a large number of questions in the field of biomedicine. Just reading the name of the colleagues who are part of the institution makes me feel very proud. I hope this appointment will promote careers of young researchers from Argentina and the region,” says Rabinovich, who is also a full professor of Immunology at the Faculty of Exact and Natural Sciences of the University of Buenos Aires (FCEN, UBA).

 

First steps: identification of the role of Galectin-1 in the immune system

In the first half of the 1990s, after graduating as a biochemist, Rabinovich made a discovery that would later mark his scientific career: he identified the role of a protein now known as Galectin-1 (Gal-1) in the immune system.

It all started when he observed that an antibody that had been developed to detect lectins (a type of protein that binds to sugars) in the chicken retina recognized a protein in macrophages –cells of the innate immune system capable of activating or silencing T lymphocytes– in rat tissue.

“At that moment, we still did not fully understand what protein it was. We knew that it must from lectin, due to the type of antibody we had used, but in order to study it we need to purify it, characterize its properties and isolate it from the macrophage. On the other hand, given that it had been recognized, by cross reaction, in rats, by means of an antibody developed to be used in chickens, we knew that it must be a highly conserved structure throughout evolution. Something that was verified when we found the protein in other species, such as mice and humans,” says Rabinovich.

Once the protein was isolated, the scientist found that when this lectin was added to a culture of T cells, the cells disappeared from the plate only when activated. “This was quite strange because until then the lectins characterized were mitogenic. This means that they increase the number of activated lymphocytes, they did not decrease them,” the researcher indicates.

When sequencing it, we observed that it was a beta-galactoside sugar-binding protein, which was later called galectins.

“We were facing the identification in the immune system of Galectin-1 (Gal-1). My PhD thesis was the purification, molecular and functional characterization of a macrophage lectin that kills activated T cells. We have published several articles on this subject,” says the scientist.

Those first works included the participation of Clelia Riera,Rabinovich’s doctoral thesis, and Carlos Land, director of his undergraduate work and with whom he developed the antibodies that gave rise to the discovery, as well as other researchers from Córdoba who supported this finding in different phases such as Claudia Sotomayor and Silvia Correa.

After this first identification of the immunological functions of Gal-1, Rabinovich has spent almost three decades participating and directing several studies that have advanced in showing the key importance of this protein in the regulation of the immune system in cancer, autoimmune and metabolic diseases and infections, always with the objective in mind that study may one day reach patients with different pathologies.

 

First finding on the role of Galectin-1 in autoimmune diseases and cancer

In the mid-1990s, at an immunology congress held in Mar del Plata, Rabinovich heard a scientist who stated that to treat rheumatoid arthritis –an autoimmune disease that produces inflammation and pain in the joints– it was necessary to find some “missile” capable to control the function of activated T lymphocytes that damage the tissue.  Rabinovich approached him to tell him that he had purified a galectin that precisely had the property of killing active lymphocytes without affecting the rest. Shortly thereafter, he travelled to London to test the use of Gal-1 in mice that developed arthritis.

“In 1996 I went to England for three months and there I learnt molecular biology techniques, particularly gene therapy in arthritis. Then we introduced the gene that codes for Gal-1 into mouse fibroblasts and then administer these fibroblasts to mice with arthritis and we saw that mice that couldn’t walk started walking again. That was one of the most exciting moments of my career”, says Rabinovich. In 1991, he returned to London for another three months to complete the experiments, and in 1999 the study was published in Journal of Experimental Medicine and featured in an article in Nature.

In mid-1999, having already his doctorate in Chemical Sciences, Rabinovich moved to Buenos Aires to work –first as a postdoctoral fellow and then as a CONICET researcher– in the “Immunogenetics Division” of the Hospital de Clinicas led by Leonardo Fainbom.

“Back then it was already known that certain tumor cells had much higher amounts of Gal-1 than a normal cell. I thought that just as Gal-1 played a beneficial role in an autoimmune disease like rheumatoid arthritis, if we prevented T lymphocytes from attacking functional tissues, in cancer it must have a detrimental role as it killed the T cells that have to attack the tumor. So I started working on that hypothesis: first by in vitro tests and then also by in vivo experiments,” recalls Rabinovich.

It is worth mentioning that at the beginning of the 2000s, talking about immunotherapy against cancer was still very rare in the scientific community. Rabinovich recalls the hypothesis that a tumor could kill the lymphocytes that should attack it was still controversial.

This stage reached its culmination point with the publication of a work that was on the cover of the journal CancerCell, in which it was shown, based on the tests in cell cultures and in animal models and patient samples, that Gal-1 effectively helps to tumors to escape the immune response of T cells. “When we blocked Gal-1, we saw that a large number of T lymphocytes that killed the tumor appeared,” says the researcher. The article published in Cancer Cell already had Rabinovich as corresponding author and who was his first doctoral thesis student, Natalia Rubinstein,as first author.

Rabinovich recalls that back then several laboratories in the world began to study the role of Gal-1 in cancer and to confirm that this protein assisted tumors in escaping from the immune response. “In a time of crisis in the reproducibility of results, we were very happy with each publication confirming that Gal-1 regulated tumor escape mechanisms”, the scientist comments.

 

IBYME and Cell cover

In 2007, based on an offer from Eduardo Charreau –then president of CONICET– and the institution’s board of directors, Rabinovich and his fellows established their own laboratory where they would continue their work on the role of Gal-1 in tumors, autoimmunity, maternal-fetal intereface and chronic inflammation.

At IBYME, the scientist began a period of great activity, both at the level of publication of results and training of human resources and collaborations with institutes throughout the country and the world. Some of the most prominent journals in which he has published are: Cell, Nature, Nature Immunology, Nature Medicine, Immunity, Cancer Cell, The Journal of Experimental Medicine, PNAS and Sciences Advance. In this regard, several important studies demonstrated the impact of circuits activated by Gal-1 and glycans in key components of the immune response such as pathogenic T lymphocytes (Th1 and Th17), dendritic cells, regulatory T cells and myeloid cells. The protagonists of these investigations were Marta Toscano, Juan Ilarregui, Mariana Salatino, TomásDalottoMoreno, Santiago Méndez Huergo and Ada Blidner.

In February 2014, one of the most important moments in Rabinovich’s career came: a study conducted by his team was chosen as the cover of Cell, one of the most prestigious scientific journals.  The article showed that Gal-1, in addition to assisting tumor escape, modulates the formation of new blood vessels that favor the proliferation of tumor cells and the formation of metastases.

“This study was important because we discovered a new role for Gal-1 in cancer. In order to supply themselves with nutrients and oxygen, tumors create new blood vessels. This process is known as angiogenesis. To counteract this, antiangiogenic treatments have been developed that aim to stop the creation of new vessels. We saw that certain tumors resist this type of therapy from the production of Gal-1, which mimics the role of the vascular endothelial growth factor that antiangiogenic treatments block,” explains Rabinovich. The study had Rabinovich as corresponding author and Diego Croci as first author.

 

The homeostatic role of Gal-1

In an article published at the beginning of 2020 in the journal PNAS, Rabinovich and his team would finally reach the conclusion that Gal-1 is a hierarchical regulator of the immune system, which functions as an inhibitory checkpoint and prevents the spontaneous appearance of autoimmune diseases linked to age.

The researchers let mice deficient in Gal-1 age and observed that these animals spontaneously developed a phenotype similar to Sjögren’s syndrome, an autoimmune disease characterized by inflammation of the salivary glands.

“If the immune system of mice without Gal-1 had not become dysregulated as they aged, we would have had to consider that the immunosuppressive role of Gal-1 may be compensated by other mechanisms of the immune system. However, as this did not happen, we concluded that Gal-1 a hierarchical homeostatic role,” says Rabinovich. This study was co-directed by Marta Toscano and the first author was VerónicaAllo.

In recent studies the team demonstrated the importance of these interactions in the intestinal mucosa in both cancer and inflammation phenomena (models of Crohn’s disease and ulcerative colitis). These studies were also directed by Karina Mariño and led by Alejandro Cagnoni and Luciano Morosi.

 

Towards a transfer platform

Since the early 1990s when he began studying basic science, Rabinovich had the objective that one day his work could improve the lives of patients with different pathologies. In this sense, after having established that Gal-1 is a key immunomodulatory, which has a beneficial role in autoimmune diseases (such as rheumatoid arthritis, multiple sclerosis, uveitis and Sjögren’s syndrome), by preventing T cells from damaging functional tissues, and a detrimental one in cancer, by helping the tumor to escape from lymphocytes as well as to proliferate and metastasize by creating new blood vessels, Rabinovich and his team considered that they had to focus on the development of Gal-1 blocker and an agonist of the same protein.

“The drug that we developed to block Gal-1 is a monoclonal antibody with angioregulatory and immunomodulatory activity, which has the property of recognizing Gal-1 but not other members of the same protein family. We successfully tested it in vivo laboratory tests and published it in the journal Angiogenesis,” says Rabinovich. The leading authors of this study were Juan Manuel Pérez Saez and Pablo Hockl.

For Rabinovich, the development of Gal-1 agonist, that is, a drug that when administered exogenously can make up for the deficiency in this protein, is more complex because when injected directly Gal-1 is unstable, but the contribution of researchers, fellows, and technicians with experience in chemistry, molecular modeling, bioinformatics, and clinical research, such as Santiago Di Lella, Alejandro Cagnoni, Santiago Méndez Huergo, and Karina Mariño has helped to provide solutions to this problem.

“Twenty-nine years ago we managed to identify Gal-1 in the immune system, a path of almost three decades in which we managed to determine many of its functions in different pathological and physiological scenarios.  But we still have a long way to go until we reach its application in patients. I feel that we are getting closer every day and that is the biggest dream to fulfill”

 

About joining EMBO

This year, EMBO incorporated 67 new members from 22 different countries. The main goal of the organization is to support researchers at all stages of their careers, stimulate the exchange of scientific information and help build a research environment where scientists can do their best work.

Rabinovich is the fifth Argentinian to join EMBO, which already included four other CONICET members: Alfredo Cáceres (INIMEC, CONICET-UNC-IMMF); Alberto Kornblihtt (IFIBYNE, CONICET-UBA),Fernando Pitossi (IIBBA, CONICET-Fundación Instituto Leloir) y Fernanda Ceriani (IIBBA, CONICET-Fundación Instituto Leloir).

 

Other awards and recognitions

Throughout his professional career Rabinovich was distinguished with numerous awards. These are the most important ones: ‘Researcher of the Argentine Nation (2017); Houssay Award for Lifetime Achievement in Biochemistry and Molecular Biology (2017); Platinum Konex Award for Science and Technology in Biomedical Sciences (2013); Academy of Sciences Award for the Developing World (TWAS) in Medical Sciences (2010); Bunge & Born Stimulus Award in Biochemistry (2005).  Besides, he has been a Member of the National Academy of Sciences of the United States since 2016, of the Argentine National Academy of Sciences (2021) and of the Academy of Sciences (2011) and of the Academy of Exact and Natural Sciences (2021)’.

By Miguel Faigón