How the FAPESP Genome Project advanced genomics and molecular biology

Researchers who participated in the groundbreaking initiative met at the Genome Workshop 20+2 to celebrate past achievements, analyze the current situation and assess future opportunities in the genomics of pathogens, cancer and agri-environmental management.

By Karina Toledo  |  Agência FAPESP – “It all began in 1997. I told Fernando Reinach that we needed to do something big in the area of biotechnology. On May 1, a national holiday for Labor Day, he came back with the idea of sequencing the genome of an agriculturally important microorganism. I was fascinated,” recalled José Fernando Perez, FAPESP’s Scientific Director when its Genome Project was launched and now the head of a biotech firm called Recepta Biopharma.

The project’s first feat was the whole-genome sequencing of Xylella fastidiosa, the bacterium that causes citrus variegated chlorosis (CVC), known to Brazilian orange growers as amarelinho because it causes yellowing of leaf tissue due to lack of chlorophyll. The disease was then ravaging orange groves in São Paulo state. This initiative resulted in a paper signed by 119 researchers based in São Paulo state. It featured on the cover of Nature (vol. 406, issue no. 6792) on July 13, 2000. “As the first public sequence of a free-living plant pathogen, the paper represents a significant scientific milestone,” the journal’s editors wrote.

It was a “bold initiative” that transformed the science done in São Paulo state, said Marco Antonio Zago, President of FAPESP, in his address to the Genome Workshop 20+2 held on November 21-22 as part of the commemorations of FAPESP’s sixtieth anniversary. The workshop celebrated the scientific leap that inaugurated research in genomics and molecular biology in Brazil 22 years ago.

The project was not so much about Xylella as about capacity building, Perez said in his presentation. It laid the physical and human foundations for similar projects to be undertaken in future, once this first challenge had been surmounted, such as the sequencing of several other organisms that were important to the health of people, animals and plants.

“Even before the X. fastidiosa genome was published, many groups had organized to investigate other animal and plant pathogens, and many of those people are here today,” said Zago, recalling that the first initiative was followed by the sequencing of sugarcane, of Xanthomonas citri (the bacterium that causes citrus canker), and of genes expressed in human tumors, among others.

Long-term vision

Twenty-two years later, the legacy of the FAPESP Genome Project can be seen in the progress of personalized medicine, gene therapy, vaccine development and research on the phylogenetic evolution of biodiversity, to take just a few examples. 

The knowledge acquired at that time, Zago stressed, proved essential during the COVID-19 pandemic, enabling Brazilian scientists to sequence SARS-CoV-2 in 48 hours, while other countries took two weeks on average. “The legacy of that period extends to all fields of research in the life sciences,” he said. “The second or third generation of scientists in this lineage are now manipulating the genome to help treat diseases and produce food.”

In 2010, ten years after publication of the paper describing the Xylella fastidiosa genome, another editorial in Nature had this to say: “Perhaps more than anything, Xylella demonstrates the benefits of aiming high.”

“Let me reinforce that,” Zago told the workshop. “If we only invest in regular, low-risk projects, the best result we’ll ever get is publication of an article. But if we aim high, we’ll have a chance to achieve real change, just as we did back then.”

Ambition and courage were needed to bring the plan to fruition. In 1997, as Perez recalled, the reaction of the academic community in São Paulo to the idea of sequencing the X. fastidiosa genome was mixed: part supported it enthusiastically, but many considered it pointless. “They asked me what I was going to do with the Xylella genome once we’d sequenced it. They were afraid I’d spend all of FAPESP’s money on the project. The older generation of researchers kept their distance,” he said.

The cost of the first sequencing of a plant pathogen in history – US$12 million for FAPESP and US$400,000 for Fundecitrus – was then the largest amount ever spent on a science project in Brazil. This was in fact a concern for Perez, who sought advice abroad, consulting Steve Oliver at Manchester University and John Sgouros at Imperial Cancer Research in the United Kingdom, as well as André Goffeau at Louvain Catholic University in Belgium. “They thought it was a great idea and I felt reassured,” Perez said.

A call for proposals was issued, and 35 laboratories in São Paulo state were selected to form a virtual network known as ONSA (Organization for Nucleotide Sequencing and Analysis), with more than 190 researchers.

The experience was “fantastic”, according to Reinach, who was also present at the Genome Workshop 20+2. At the time, he headed one of the labs selected in the call. “It was one of the best times of my life,” he said.

Holder of a PhD in cell biology from Cornell University (USA) and a former professorship at the University of São Paulo (USP), Reinach now runs Pitanga Fund and invests in innovative small firms. At the workshop he expressed the view that the Brazilian scientific community is no longer as prepared to take risks and conduct genuinely bold or challenging projects.

In a brief opening address to the workshop, Luiz Eugênio Mello, FAPESP’s current Scientific Director, compared the FAPESP Genome Project to “an epic saga”, with daring characters, heroic feats, and a plot full of successes, failures, great victories and long-lasting effects. 

“FAPESP invested in a long-term vision,” he said. “It set out not just to sequence one particular bacterium but also, and perhaps above all, to create a complex and powerful material and human infrastructure in the field of genomics. This endeavor would bear fruit in the ensuing decades.”

Mello congratulated the leaders of this groundbreaking scientific venture, praising their “refusal to knuckle under to short-termist worldviews”.

Biologist Ana Tereza Ribeiro de Vasconcelos, a researcher at the National Scientific Computing Laboratory (LNCC), noted in her presentation that the FAPESP Genome Project served as an inspiration for the Brazilian Genomics Network, created in 2000.

“We replicated the model established in São Paulo for the entire country,” she said. “We used the same methodology and spread the fantastic experience to 25 labs from north to south. We’re very grateful to FAPESP for conducting this project and to the then-leaders of the Ministry for Science [also known by the acronym MCTI, as the department also runs Technology and Innovation policies] and CNPq [the National Council for Scientific and Technological Development, MCTI’s research funding arm] for simply replicating this experience rather than creating something different. As a result, Brazil is now in a good position in genomics.”

She presented statistics showing that Brazil is the Latin American leader in publications and the only country in the region to rank among the top 30 worldwide in articles on genomics.

Thematic panels

The first panel in the workshop was on pathogen genomics and was chaired by Marie-Anne Van Sluys, a professor at USP and a member of FAPESP’s Adjunct Panel on Special Programs and Research Collaboration. The other speakers besides Perez were Alessandra Alves de Souza (IAC), Jorge Elias Kalil Filho (USP), João Marcelo Pereira Alves (USP), and Anna Childers (US Department of Agriculture, USDA).

Alves de Souza, who was still studying for a master’s degree when work began on the Xylella sequencing, said participating in the project helped shape her career. She too noted the role it played in making Brazil one of the world leaders in the field.

“CVC, the disease we call amarelinho, is no longer a problem for São Paulo’s citrus growers, but Xylella attacks several other crops [infecting 350 plant species all told]. It’s been a major problem for producers of olive oil in Puglia, southern Italy,” said Alves de Souza, who is participating in a project to solve the problem in partnership with Italian scientists.

Kalil Filho noted in his presentation how Brazil’s capacity to perform genomic monitoring of a pathogen evolved during the COVID-19 pandemic. “Initially the technology was here but there wasn’t the investment [needed to sequence a large number of genomes of SARS-CoV-2 quickly in order to detect the emergence of viral variants],” he said. “We didn’t have a chance to detect the gamma variant [which may have emerged in Manaus in late 2020]. It was detected in Japan.”

The leap forward in sequencing capacity began in May 2021, he continued, thanks to the structuring of Rede Corona-ômica by MCTI, support from Instituto Todos pela Saúde (led by Itaú, Brazil’s largest private bank) and partnerships with private laboratories. To date, Brazil has deposited some 183,000 whole genomes of the novel coronavirus with the international repository GISAID – a far larger number than for other pathogens important to public health in Brazil, such as dengue virus (281 genomes sequenced), yellow fever (195) or zika (76).

Pereira Alves spoke about his main research interest in connection with the genomics of bacteria and protozoans that cause neglected tropical diseases, such as trypanosomatids.

The second panel dealt with agri-environmental genomics and was chaired by Luis Eduardo Aranha Camargo, a professor at USP. One of the speakers was Paulo Arruda, a professor at the State University of Campinas (UNICAMP) and head of the Genomics for Climate Change Research Center (GCCRC), an Engineering Research Center (ERC) supported by FAPESP and Brazilian Agricultural Research Corporation (EMBRAPA). He described studies aimed at discovering genes that can make plants better able to withstand drought and other stress factors. These genes may be in the plant itself or in the adjacent microorganism community.

João Carlos Setubal, a professor at USP’s Chemistry Institute, presented studies he has led in the last eight years on the microbiota found in zoos. In a recent study, his group identified microorganisms that produce enzymes with significant potential to degrade lignin, an ingredient of plant rigidity, and of great interest in the field of biotechnology.

Claudia Vitorello, a professor at the Luiz de Queiroz College of Agriculture (ESALQ-USP), presented her studies on sugarcane pathogens, particularly Sporisorium scitamineum, a fungus that causes a disease known as sugarcane smut.

The last speaker on the first day of the workshop was Mark Blaxter, a researcher at Wellcome Sanger Institute in the UK. He is Program Lead for the Tree of Life, which aims to understand evolution by sequencing all known eukaryotic species.

“We’re experiencing a biological crisis, and wild species are at risk. One of the greatest challenges is climate change. If we fail to preserve the biodiversity that sustains us, we’ll fail to preserve ourselves, for our society relies on the ecosystem services provided by all the species with which we share the planet,” Blaxter said. “We hope to mitigate this crisis by means of genome sequencing, which can help us find ways to reverse species decline and provide data that feed into new bioindustries with less destructive effects on the planet.”

You can watch the full presentations of the event’s first day in the video below.