Falling in love with bacterial genetics

Marraffini was obsessed with space, astrophysics, and science fiction from a young age while growing up in Argentina. After reading about the advent and promise of recombinant DNA technology in a popular science magazine, his interest shifted toward biology. “During my undergraduate degree in biotechnology in Argentina, I did a lot of DNA manipulation and generated recombinant proteins. This experimental knowledge in molecular biology motivated me to follow a research path,” recollects Marraffini. Because the research opportunities were better in North America compared to Argentina, Marraffini uprooted his young family to pursue a PhD at the University of Chicago.

As part of the PhD curriculum, Marraffini recounts, “I took a class on bacterial pathogenesis and found molecular mechanisms by which bacteria cause diseases fascinating. I found bacteria a great experimental system because many tools were available to mutate and overexpress almost anything. There were also a lot of possibilities to purify proteins of interest using in vitro assays. This is why I fell in love with the bacterial experimental system and ended up joining the laboratory of the course teacher Olaf Schneewind for my PhD.” 

Dissecting CRISPR mechanisms in bacterial immunity

Bacteria are numerous but they are outnumbered by viruses that infect them. CRISPR-Cas is a major immune defense system that evolved in bacteria to fight viruses. Marraffini was interested in how bacteria employ CRISPR mechanisms to interact with and nullify infiltrating DNA and RNA. As a postdoc, Marraffini worked with Eric Sondheimer to experimentally demonstrate for the first time how CRISPR works against conjugative plasmids containing antibiotic resistance. “We showed that CRISPR can prevent the dissemination of antibiotic resistance among bacteria by directly targeting plasmid DNA,” explains Marraffini. This milestone in the CRISPR field was important later for gene editing technology development in mammalian cells. “I collaborated with Feng Zhang at the Massachusetts Institute of Technology. We transplanted a CRISPR-Cas9 system from Streptococcus pyogenes into human hepatocytes and showed that CRISPR cleaves DNA and can be repurposed for gene editing in cells,” shares Marraffini.

Over the years, Marraffini’s group gained mechanistic insights into how CRISPR systems contribute to bacterial immunity. When a phage or a plasmid invades bacteria, the CRISPR system captures a 30- to 40-nucleotides long sequence from the invader DNA called a spacer and incorporates it into the chromosome. This spacer DNA transcribed into the guide RNA gives Cas9—an enzyme that cuts DNA—the target specificity towards invading DNA. This is how bacteria acquire a memory of infection to then fight future infections.

Marraffini also discovered that phage DNA cleavage by Cas9 generates additional DNA fragments, resulting in the acquisition of new spacers for the CRISPR locus. More spacers and guide RNAs against the same-phage DNA are advantageous for bacteria as phages can escape Cas9 cleavage by mutating the target site, offering greater fitness to bacteria. According to Marraffini, “That’s one of our major contributions, showing how spacers acquisition determines infection memory. In addition, we also found that the CRISPR machinery uses free DNA ends, which is a way of diminishing autoimmunity since the bacterial chromosome is circular without a free end.”

Fostering curiosity and boldness

Joshua Modell, Assistant Professor of Molecular Biology and Genetics at Johns Hopkins University School of Medicine, describes his former postdoctoral mentor as “a rare scientist and an intellectual heavyweight who makes the laboratory a stimulating and fun place to do science.” Modell adds, “His ability to interact with and inspire scientists at any career stage, from the greenest summer intern to a long-tenured professor, is what makes him truly special. When I started my postdoc, he explained how much we still had to learn about CRISPR biology and how the work we do could end up in the textbooks. I still try to use that textbook standard with my trainees.”

“My mentors were extremely supportive of my interest in CRISPR despite CRISPR being unknown when I started my academic career,” says Marraffini. He champions the same generosity in his mentorship style, supporting projects his trainees want to pursue. 

“I wanted to investigate a new type of CRISPR that targeted RNA exclusively. No one understood how it worked. While everyone in the laboratory worked on Staphylococcus, I worked on a Listeria strain that naturally carried this RNA-targeting CRISPR system and developed it into a model system,” says Alex Meeske, Assistant Professor in the Department of Microbiology at the University of Washington, who did his postdoctoral training with Marraffini. “He encouraged me to be bold and try new methodologies, even if they were outside his expertise. He taught me to focus, keep my eyes on the prize, and investigate the most significant and testable questions.”

Join us in congratulating Luciano Marraffini, who received the Genetics Society of America Medal at The Allied Genetics Conference 2024 in Metro Washington, DC.

2024 GSA Awards Seminar Series

On September 9, at 1:00 p.m. EDT, Luciano Marraffini will join us to discuss CRISPR-CARF immunity and sacrificing the host for the benefit of the population. Save the date and register here!

Sejal Davla, PhD, is a neuroscientist, science writer, and data scientist with expertise in research in a variety of life sciences. She has more than a decade of experience studying the brain by using cutting-edge methodologies in microscopy, molecular biology, genetics, and biochemistry, and is a motivated storyteller and science communicator.

Joseph Uche Ogbede

Community and Membership Engagement

Harvard University/Boston Children’s Hospital

Research Interest

I am most interested in understanding molecular events and therefore discovering new treatment options for different human diseases. This interest has been inspired by several factors, but one of the most influential of these factors is to develop more effective medicines that can be made available to patients that appear to have lost hope. Despite advances in biomedical research, many human diseases are either difficult to treat or are untreatable with the options currently available and the pervasiveness of drug resistance continues to pose an additional significant challenge. These and other issues create serious obstacles to providing patients with the best quality of care possible. I aim to eliminate some of these obstacles with my overall research objective.

Throughout the course of my research career, I have used diverse model organisms to answer pertinent research questions, including rats, C. elegans, yeast, mice, and human cell lines. As a postdoctoral researcher at Harvard Medical School and Boston Children’s Hospital, one of my projects is focused on understanding the process of blood vessel formation and its involvement in eye diseases (retinal vascular disorders). Retinal vascular disorders including diabetic retinopathy, age related macular degeneration and retinal vein occlusion are leading causes of blindness globally. For people with any of these disorders, a primary cause is uncontrolled blood vessel formation (neovascularization) that results in leaky and bleeding blood vessels. Current treatment of these disorders has focused on agents that inhibit vascular endothelial growth factor (VEGF), which is elevated in people with retinal vascular disorders and plays a major role in angiogenesis and vascular permeability. Unfortunately, not all patients respond to anti-VEGF drugs. Recent studies have found a role of angiopoietin-1 receptor (TIE2), a tyrosine kinase that promotes vascular stability, in preventing retinal vascular disorders. My work seeks to develop a TIE2 agonist that could be used to improve current treatments. Consequently, I used a phage display library that contains approximately one billion unique peptides to identify a new cyclic peptide that binds strongly to TIE2 and stimulates its activity through phosphorylation. More in vitro, and then in vivo studies of this potential therapeutic agent are currently ongoing. Complementing this project is the mRNA-based gene therapy for multiple myeloma—a kind of blood cancer. This project seeks to help people with multiple myeloma overcome drug resistance and respond more effectively to treatment. Going forward, I want to continue to find solutions to ongoing problems in the world of biomedicine, so that my work can have a direct positive impact on the lives of many.

As a PhD-trained scientist, you have many career options. What interests you the most?

Before and during the early stage of my PhD program, I was more inclined to follow an academic career path. However, as I approached the last stage of acquiring my PhD, I started thinking about following a more industrial path instead. At present, I am most interested in continuing to develop research and leadership skills that will empower me to become an experienced research scientist, and I may be open to both academic and non-academic career tracks. My postdoctoral research fellowship would allow me to hone competitive skills that will suit either career path; however, I anticipate that by the time I am one or two years into my postdoc, I will be able to firmly decide on which path to take. My desire is to be in an environment where I can use my knowledge and skills to solve problems such as discovering more potent medicines, which I am currently doing as a postdoc researcher. Additionally, I am also interested in mentorship. I have mentored both undergraduate and graduate students; at least two of the undergraduate students whose thesis I supervised, have gotten into graduate schools. I have also reviewed several graduate school and scholarship essays, and most of these applications were successful. In addition, I am participating in the GSA mentorship program where an ECLP member is paired with a student for up to 12 months. I hope that my energy and passion continues to educate and inspire my mentees.

In addition to your research, how do you want to advance the scientific enterprise?

I will continue to advance science through volunteering and mentorship, as I have done for several years. However, in the future I also want to be involved in science communication. Being a good communicator is a strong asset for advancing science. There is currently  a huge gap between the scientific community and the public; many patients are not aware of the research efforts being made by scientists that are relevant to their treatment. And even when they are made aware, the specialized jargon in many published articles may be offputting or difficult for them to understand. I hope to bridge this gap in several ways, including engaging in events and programs where scientists can interact informally with people about their work. I am currently conceptualizing a platform that will improve how scientists communicate their work to the public, as well as to their fellow researchers and policymakers. When actualized, it would make the methods and results of research initiatives more accessible and understandable to both scientists and non-scientists alike. Nothing promotes science more than public engagement, so I hope to see a time when every scientific journal makes it compulsory for research papers to include a lay abstract that everyone can comfortably read. Doing so would allow non-experts (broadly defined) to be able to access and understand the trends in science that concern them.

As a leader within the Genetics Society of America, what do you hope to accomplish?

I want to accomplish two major things at GSA. First, I want to leave GSA better than how I found it by improving its programs and services. By doing so, I’ll continue to shape and enhance the experience of both graduate students and postdocs within GSA by working to improve existing initiatives of ECLP, such as workshops and seminars. As a member of the ECLP Community and Membership Engagement Subcommittee, I continue to be involved in the development of initiatives and content that will improve the welfare of early career scientists. And once my time with the ECLP comes to an end, I will have proposed and organized a networking event where graduate students and postdocs can join virtually to build connections. The goal would be to ensure that early career scientists have access to one another to share ideas, collaborate, or develop directions for future research and careers. 

Additionally, I hope to contribute to ensuring that GSA becomes more diverse and inclusive in its membership and programs. To achieve this, I proposed the Igbo Seminar Series as part of the GSA Multilingual Seminar Series, which was created to connect scientists so that they can talk about their work in a language other than English. The first edition of the Igbo seminar was successfully held on February 10, 2023, with five panel speakers, and more than 40 attendees. By organizing this seminar, I helped amplify GSA’s commitment to recognizing diverse languages and communities such as Igbo in science and communication.

Essentially, as a leader in GSA, I will continue to propose and support initiatives for early career scientists, while I also continue to work towards a more diverse and inclusive GSA. Both of these goals will help create an enabling and equal platform for early career scientists to thrive.

Previous leadership experience

I have assumed many leadership roles over the past years, allowing me to solve problems and acquire outstanding skills. 

Currently, I am the media chairperson of the Harvard Medical School (HMS) Black Postdoctoral Association, where I help to amplify the events and programs of black postdoc fellows within the HMS. Complementing this role is my membership of the mentorship subcommittee of the Boston Children’s Hospital (BCH) Postdoc Association, where I help in organizing events and programs that allow BCH postdoc fellows thrive in their current and prospective career endeavors.

As a co-chair of the Liu Institute Network for Africa at the University of British Columbia (UBC)—a network of stakeholders willing to address research and policy issues affecting Africa—I worked with fellow co-chairs in developing projects to meet our mission. This included organizing an inaugural symposium as well as webinars on the impacts of the COVID-19 pandemic on African economies, health systems and education, among others.

I was the student representative on the Steering Committee of the Genome Science and Technology (GSAT) graduate program at UBC. This position allowed me to review essential issues facing the GSAT program, as well as students and faculty, and then provided feedback and recommendations for an improved learning environment.

I was also the student council representative for the GSAT program (Graduate Students Society, UBC) and the Medical Genetics & Genomics program (​​Glasgow University Students’ Representative Council). These positions allowed me to learn how to play active roles in decision-making processes. I consulted with students, shared their views in meetings, and liaised with faculty, staff, and students alike to enhance students’ learning experiences. I have also played several other roles in supporting students and the scientific community; these include event manager at the Glasgow Explorathon 2016 (European Researchers’ Night Explorathon) and chairperson for the 2017 Medical Genetics & Genomics Symposium at the University of Glasgow.

Moreover, I have worked to create opportunities and have served as an agent of change. In October of 2016, a few months after starting my MSc study at the University of Glasgow, UK, I dedicated myself to devising an avenue to change by using campaigns and advocacy to solve social problems. I learned about Oxfam, a not-for-profit organization involved in the fight against poverty and inequality. Finding that the Students’ Oxfam Society on campus was defunct, I engaged in consultations, and through my strong interpersonal and networking abilities, I reached out to various students and re-instated the association. As the elected president, I worked with other executive members to sustain the society with exciting weekly activities: campaigns, fundraisers, social events, and discussions related to Oxfam’s mission. I succeeded in this role because of my initiative, commitment, and organizational skills. We raised several hundred pounds (donated to Oxfam Scotland to support humanitarian aid). By the time my term as president was complete, we had reached 55 members.

At the community level, I have served as the youth secretary (2019–2021) for the Nigeria-Canada Association of British Columbia (NCABC). This not-for-profit organization strives to support Nigerians in British Columbia, and to promote Nigerian culture. This position allowed me to interact with young people and deliver projects that met their needs. For instance, with five other persons, I organized and facilitated Vancouver’s #EndSARS in October 2020 with more than 800 attendees; #EndSARS was a global social movement where Nigerians protested against police brutality and social injustice in Nigeria. These experiences have shaped my values, molded my outlook, and improved my approach to tasks as both a scientist and a leader.