Category: Building 68

PNAS Profile: Catherine Drennan

Structural intuitions lead to structural insights

Jennifer Viegas | PNAS
November 8, 2024

HHMI Investigator and Professor of Biology and Chemistry Catherine Drennan has spent a distinguished career addressing challenging and wide-ranging structural biology problems.

Catherine Drennan, a Howard Hughes Medical Institute investigator and professor and a professor of biology and chemistry at the Massachusetts Institute of Technology (MIT), has spent a distinguished career addressing challenging and wide-ranging structural biology problems. These include her discovery, while she was a graduate student, of the structure of vitamin B12 bound to protein and her recent determination at atomic resolution of the structure of an active ribonucleotide reductase (RNR) with water molecules, findings reported in her Inaugural Article (IA) (1).

Drennan, who was elected to the National Academy of Sciences in 2023, has uncovered the form and function of metalloenzymes that use metal cofactors to catalyze chemical reactions involving free radicals. Metalloenzymes are of broad human health and environmental interest; some are promising antibiotic and cancer drug targets, whereas others hold the potential for bioremediation efforts, such as converting carbon dioxide into biofuels.

Family of Accomplished Scientists

Drennan was raised in New York City by her father, an obstetrician–gynecologist, and her mother, an anthropologist. Her father was born in Germany and attended medical school at the University of Hamburg. Harboring antifascist leanings, he fled Germany in 1933. He completed medical training in Geneva, Switzerland, before obtaining political asylum in 1940 in the United States, where he became one of the first doctors to practice the Lamaze Method of natural childbirth.
Drennan’s mother attended Antioch College, where she was a student of civil engineer Arthur Ernest Morgan, who was appointed in 1948 to India’s first University Education Commission. She accompanied Morgan to India and served as his administrative assistant before earning her doctorate in anthropology at Cornell University.

“Both my parents were endlessly curious,” says Drennan. “My father was fascinated by the molecular basis of medicine, and my mother was fascinated by people and instilled in me her love for storytelling, teaching, and mentoring.”

Diagnosed with Dyslexia

Although she was an attentive student, Drennan did not learn to read until her second time through sixth grade. “When I finally learned how to read, it was by memorizing the shapes of words,” says Drennan, who was diagnosed with dyslexia when she was in first grade. “Over time I became very good at shape recognition. I am not disabled; I am differently abled. The skill set that I developed to compensate for my dyslexia has made me a world-class structural biologist. We all have strengths and weaknesses, and my ‘weakness’ is also my superpower.”
She was accepted to Vassar College, where she earned a bachelor’s degree in chemistry in 1985. “Miriam Rossi was my undergraduate chemistry research advisor, and she believed in me before I believed in me,” Drennan says. Upon Rossi’s advice, Drennan pursued a doctorate, but not before teaching high-school science and drama at Scattergood Friends School in Iowa.
Following three years of high-school teaching, Drennan pursued graduate studies at the University of Michigan, Ann Arbor, where she earned a PhD in 1995, served as a research fellow from 1995 to 1996, and was mentored by biochemists Martha Ludwig and Rowena Matthews. “They treated me as a colleague, allowing me to see myself as a scientist of value,” Drennan says. “I learned so much from these two incredible scientists. They are, and always will be, my heroes.”

Structure of Vitamin B12 Bound to Protein

With Ludwig et al., Drennan determined the structure of cobalamin (vitamin B12) bound to protein (2). This crystal structure revealed how the protein modulates the reactivity of the B12 cofactor to enable its critical roles in metabolism.
From 1996 to 1999, Drennan did a postdoctoral stint at the California Institute of Technology, under the mentorship of structural biologist Douglas Rees. “Doug taught by example that one does not have to be cutthroat to succeed in the competitive area of structural biology,” she says. “He has continued to mentor me throughout my career, helping me through challenging times.”
Another important mentor was chemist JoAnne Stubbe, a leader in the study of RNRs who recruited Drennan to MIT in 1999 as an assistant professor of chemistry and has been her collaborator for the past 25 years. Drennan says, “Her passion for scientific discovery is unmatched and has inspired me to keep digging to try to understand, at the most fundamental level, how ribonucleotide reductase works.” Drennan advanced to an associate professorship at MIT in 2004 and a full professorship in 2006.

Revealing Metalloenzyme Form and Function

Drennan’s group continues to study B12 and has provided numerous snapshots of cobalamin-dependent proteins and protein complexes. The findings have changed what is known about B12 functions and mechanisms. Using X-ray crystallography, the researchers unveiled a protein complex capable of methyl transfer from folate to B12 (3). They obtained snapshots of the biological process involved in loading B12 into an enzyme (4) and provided structural data on how B12 can be repurposed from enzyme cofactor to light sensor (5).
Drennan has also worked on uncovering the structures of enzymes containing radical S-adenosylmethionine (SAM) cofactors. Drennan and colleagues revealed an X-ray structure of a radical SAM enzyme (6), helping to establish the “core” fold for an enzyme superfamily that has over 100,000 members. Her group further elucidated structures of SAM family members with functions including posttranslational modification (7), antibiotic and antiviral compound biosynthesis (8, 9), and vitamin biosynthesis (6, 10).
Mononuclear nonheme iron enzymes are also of interest to Drennan. The cofactor is simple, but the reactions catalyzed are complex. Her group reported the structure of a nonheme iron halogenase, showing that the halogen binds directly to the catalytic iron (11). Drennan says, “This was a complete surprise that required new mechanistic proposals to be written.”

“Oceanic Methane Paradox”

Early in her independent career, Drennan determined one of the first structures of a nickel-iron-sulfur-dependent carbon monoxide dehydrogenase (CODH), which plays an important role in the global carbon cycle (12). The structure, along with that of an associated enzyme complex (13), provided a series of snapshots of the multiple metal ion centers underlying the ability of certain microbes to live off hydrogen gas and carbon dioxide in a process known as acetogenesis. More recently, they investigated the molecular basis by which the activity of CODH enzymes can be restored after oxygen exposure (14), a discovery with implications for the industrial use of CODHs.
Drennan and her team have also studied the organic compound methylphosphonate that was proposed as a source of methane from the aerobic upper ocean; the biological source was long a mystery. When a methylphosphonate synthase was discovered by chemical biologist Wilfred van der Donk and coworkers, part of the mystery was solved but the gene for this enzyme did not appear to be widespread. When Drennan and colleagues solved the structure of a methylphosphonate synthase; however, they discovered a sequence motif showing that the gene was, in fact, abundant in microbes that inhabit the upper ocean (15). This seminal finding is credited with resolving the oceanic methane paradox.

Radical-Based Chemistry in Ribonucleotide Reductases

Human RNR is an established chemotherapeutic target, and bacterial RNRs hold promise as antibiotic targets. So Drennan and her team have a longstanding interest in uncovering the mechanisms of RNRs. In 2002, her lab determined the structure of a B12-dependent RNR, which showed how cobalamin could be used to initiate radical chemistry (16). Nearly a decade later, Drennan’s team revealed how high levels of the nucleotide deoxyadenosine triphosphate (dATP) down-regulate RNR activity (17, 18). They subsequently provided structures showing the molecular basis of allosteric specificity, which maintains the proper ratios of RNA to DNA building blocks (19), and demonstrated the importance of RNR activity regulation (20).
An atomic-resolution structure of any RNR in an active state had been elusive for many years. Drennan and her team achieved the feat in 2020 when they trapped the active state of Escherichia coli RNR and determined its structure by cryoelectron microscopy (21). However, the resolution of the structure was too low for the visualization of water molecules believed to be critical in the radical transfer pathway.
In her IA, Drennan (1) describes how her team resolved the problem, presenting the structure of an active RNR at atomic resolution allowing for the visualization of water molecules. She explains, “This time, instead of using unnatural amino acids to trap the structure, we used a mechanism-based inhibitor. It was a very long road to get to these data, but it was worth the wait.”

“Superheroes of the Cell”

For her achievements, Drennan has received MIT’s Everett Moore Baker Memorial Award for Excellence in Undergraduate Teaching (2005, 2024), the Dorothy Crowfoot Hodgkin Award from The Protein Society (2020), and the William C. Rose Award from the American Society for Biochemistry and Molecular Biology (2023), among other honors. She has mentored nearly 100 undergraduates and dozens of graduate students and postdoctoral associates, many of whom are from underrepresented minority groups or disadvantaged backgrounds. She considers her students extended family members and takes pride in their accomplishments.
She and her team continue to work on RNR using the tools of structural biology. She says, “We want to obtain a deeper level of understanding of the human RNR, which is a cancer drug target. We also want to identify differences between the human enzyme and bacterial RNRs, differences that could be exploited in the development of new antibiotics.”
Beyond these efforts, Drennan’s overall goal is to understand how enzymes control radical species to enable challenging chemical reactions without damaging themselves or their cellular environment. “Radical enzymes are like the Avengers, powerful but with a high potential for collateral damage,” she explains. “I am fascinated by how nature catalyzes the most challenging of chemical reactions. The enzymes that do this work are the superheroes of the cell and I want to know their secrets.”
1.
D. E. Westmoreland et al., 2.6-Å resolution cryo-EM structure of a class Ia ribonucleotide reductase trapped with mechanism-based inhibitor N3CDP. Proc. Natl. Acad. Sci. U.S.A. 121, e2417157121 (2024). Crossref. PubMed.
2.
C. L. Drennan et al., How a protein binds B12: A 3.0 Å X-ray structure of B12-binding domains of methionine synthase. Science 266, 1669–1674 (1994). Crossref. PubMed.
3.
Y. Kung et al., Visualizing molecular juggling within a B12-dependent methyltransferase complex. Nature 484, 265–269 (2012). Crossref. PubMed.
4.
F. A. Vaccaro, D. A. Born, C. L. Drennan, Structure of metallochaperone in complex with the cobalamin-binding domain of its target mutase provides insight into cofactor delivery. Proc. Natl. Acad. Sci. U.S.A. 120, e2214085120 (2023). Crossref. PubMed.
5.
M. Jost et al., Structural basis for gene regulation by a B12-dependent photoreceptor. Nature 526, 536–541 (2015). Crossref. PubMed.
6.
F. Berkovitch et al., Crystal structure of biotin synthase, an S-Adenosylmethionine-dependent radical enzyme. Science 303, 76–79 (2004). Crossref. PubMed.
7.
J. L. Vey et al., Structural basis for glycyl radical formation by pyruvate formate-lyase activating enzyme. Proc. Natl. Acad. Sci. U.S.A. 105, 16137–16141 (2008). Crossref. PubMed.
8.
J. Bridwell-Rabb et al., A B12-dependent radical SAM enzyme involved in oxetanocin A biosynthesis. Nature 544, 322–326 (2017). Crossref. PubMed.
9.
P. J. Goldman, T. L. Grove, S. J. Booker, C. L. Drennan, X-ray analysis of butirosin biosynthetic enzyme BtrN redefines structural motifs for AdoMet radical chemistry. Proc. Natl. Acad. Sci. U.S.A. 40, 15949–15954 (2013). Crossref.
10.
M. I. McLaughlin et al., Crystallographic snapshots of sulfur insertion by lipoyl synthase. Proc. Natl. Acad. Sci. U.S.A. 113, 9446–9450 (2016). Crossref. PubMed.
11.
L. C. Blasiak, F. H. Vaillancourt, C. T. Walsh, C. L. Drennan, Crystal structure of the non-haem iron halogenase SyrB2 in syringomycin biosynthesis. Nature 440, 368–371 (2006). Crossref. PubMed.
12.
C. L. Drennan et al., Life on carbon monoxide: X-ray structure of Rhodospirillum rubrum Ni-Fe-S carbon monoxide dehydrogenase. Proc. Natl. Acad. Sci. U.S.A. 98, 11973–11978 (2001). Crossref. PubMed.
13.
T. I. Doukov et al., A Ni-Fe-Cu center in a bifunctional carbon monoxide dehydrogenase/acetyl-CoA synthase. Science 298, 567–572 (2002). Crossref. PubMed.
14.
E. C. Wittenborn et al., Redox-dependent rearrangements of the NiFeS cluster of carbon monoxide dehydrogenase. Elife 7, e39451 (2018). Crossref. PubMed.
15.
D. A. Born et al., Structural basis for methylphosphonate biosynthesis. Science 358, 1336–1339 (2017). Crossref. PubMed.
16.
M. D. Sintchak et al., The crystal structure of class II ribonucleotide reductase reveals how an allosterically regulated monomer mimics a dimer. Nat. Struct. Mol. Biol. 9, 293–300 (2002). Crossref.
17.
N. Ando et al., Structural interconversions modulate activity of Escherichia coli ribonucleotide reductase. Proc. Natl. Acad. Sci. U.S.A. 108, 21046–21051 (2011). Crossref. PubMed.
18.
N. Ando et al., Allosteric inhibition of human ribonucleotide reductase by dATP entails the stabilization of a hexamer. Biochemistry 55, 373–381 (2016). Crossref. PubMed.
19.
C. M. Zimanyi et al., Molecular basis for allosteric specificity regulation in class Ia ribonucleotide reductase from Escherichia coli. Elife 5, e07141 (2016). Crossref. PubMed.
20.
P.Y.-T. Chen, M. A. Funk, E. J. Brignole, C. L. Drennan, Disruption of an oligomeric interface prevents allosteric inhibition of Escherichia coli class Ia ribonucleotide reductase. J. Biol. Chem. 293, 10404–10412 (2018). Crossref. PubMed.
21.
G. Kang, A. T. Taguchi, J. Stubbe, C. L. Drennan, Structure of a trapped radical transfer pathway within a ribonucleotide reductase holocomplex. Science 368, 424–427 (2020). Crossref. PubMed.
Sauer & Davis Lab News Brief: structures of molecular woodchippers reveal mechanism for versatility

Rest in pieces: deconstructing polypeptide degradation machinery

Lillian Eden | Department of Biology
November 12, 2024

Research from the Sauer and Davis Labs in the Department of Biology at MIT shows that conformational changes contribute to the specificity of “molecular woodchippers” 

Degradation is a crucial process for maintaining protein homeostasis by culling excess or damaged proteins whose components can then be recycled. It is also a highly regulated process—for good reason. A cell could potentially waste many resources if the degradation machinery destroys proteins it shouldn’t. 

One of the major pathways for protein degradation in bacteria and eukaryotic mitochondria involves a molecular machine called ClpXP. ClpXP is made up of two components: a star-shaped structure made up of six subunits called ClpX that engages and unfolds proteins tagged for degradation, and an associated barrel-shaped enzyme, called ClpP, that chemically breaks up proteins into small pieces called peptides. 

ClpXP is incredibly adaptable and is often compared to a woodchipper — able to take in materials and spit out their broken-down components. Thanks to biochemical experiments, this molecular degradation machine is known to be able to break down hundreds of different proteins in the cell regardless of physical or chemical properties such as size, shape, or charge. ClpX uses energy from ATP hydrolysis to unfold proteins before they are threaded through its central channel, referred to as the axial channel, and into the degradation chamber of ClpP.

In three papers, one in PNAS and two in Nature Communications, researchers from the Department of Biology at MIT have expanded our understanding of how this molecular machinery engages with, unfolds, and degrades proteins — and how that machinery refrains, by design, from unfolding proteins not tagged for degradation. 

Alireza Ghanbarpour, until recently a postdoc in the Sauer Lab and Davis Lab and first author on all three papers, began with a simple question: given the vast repertoire of potential substrates — that is, proteins to be degraded — how is ClpXP so specific?

Ghanbarpour — now an assistant professor in the Department of Biochemistry and Molecular Biology at Washington University School of Medicine in St. Louis — found that the answer to this question lies in conformational changes in the molecular machine as it engages with an ill-fated protein. 

Reverse Engineering using Structural Insights

Ghanbarpour approached the question of ClpXP’s versatility by characterizing conformational changes of the molecular machine using a technique called cryogenic electron microscopy. In cryo-EM, sample particles are frozen in solution, and images are collected; algorithms then create 3D renderings from the 2D images.

“It’s really useful to generate different structures in different conditions and then put them together until you know how a machine works,” he says. “I love structural biology, and these molecular machines make fascinating targets for structural work and biochemistry. Their structural plasticity and precise functions offer exciting opportunities to understand how nature leverages enzyme conformations to generate novel functions and tightly regulate protein degradation within the cell.”

Inside the cell, these proteases do not work alone but instead work together with “adaptor” proteins, which can promote — or inhibit — degradation by ClpXP. One of the adaptor proteins that promotes degradation by ClpXP is SspB. 

In E. coli and most other bacteria, ClpXP and SspB interact with a tag called ssrA that is added to incomplete proteins when their biosynthesis on ribosomes stalls. 

The tagging process frees up the ribosome to make more proteins, but creates a problem: incomplete proteins are prone to aggregation, which could be detrimental to cellular health and can lead to disease. By interacting with the degradation tag, ClpXP and SspB help to ensure the degradation of these incomplete proteins. Understanding this process and how it may go awry may open therapeutic avenues in the future.

“It wasn’t clear how certain adapters were interacting with the substrate and the molecular machines during substrate delivery,” Ghanbarpour notes. “My recent structure reveals that the adapter engages with the enzyme, reaching deep into the axial channel to deliver the substrate.” 

Ghanbarpour and colleagues showed that ClpX engages with both the SspB adaptor and the ssrA degradation tag of an ill-fated protein at the same time. Surprisingly, they also found that this interaction occurs while the upper part of the axial channel through ClpX is closed — in fact, the closed channel allows ClpX to contact both the tag and the adaptor simultaneously.

This result was surprising, according to senior author and Salvador E. Luria Professor of Biology Robert Sauer, whose lab has been working on understanding this molecular machine for more than two decades: it was unclear whether the channel through ClpX closes in response to a substrate interaction, or if the channel is always closed until it opens to pass an unfolded protein down to ClpP to be degraded.

Preventing Rogue Degradation

Throughout this project, Ghanbarpour was co-advised by structural biologist and Associate Professor of Biology Joey Davis and collaborated with members of the Davis Lab to better understand the conformational changes that allow these molecular machines to function. Using a cryo-EM analysis approach developed in the Davis lab called CryoDRGN, the researchers showed that there is an equilibrium between ClpXP in the open and closed states: it’s usually closed but is open in about 10% of the particles in their samples. 

The closed state is almost identical to the conformation ClpXP assumes when it is engaged with an ssrA-tagged substrate and the SspB adaptor. 

To better understand the biological significance of this equilibrium, Ghanbarpour created a mutant of ClpXP that is always in the open position. Compared to normal ClpXP, the mutant degraded some proteins lacking obvious degradation tags faster but degraded ssrA-tagged proteins more slowly. 

According to Ghanbarpour, these results indicate that the closed channel improves ClpXP’s ability to efficiently engage tagged proteins meant to be degraded, whereas the open channel allows more “promiscuous” degradation. 

Pausing the Process

The next question Ghanbarpour wanted to answer was what this molecular machine looks like while engaged with a protein it is attempting to unfold. To do that, he created a substrate with a highly stable protein attached to the degradation tag that is initially pulled into ClpX, but then dramatically slows protein unfolding and degradation.

In the structures where the degradation process stalls, Ghanbarpour found that the degradation tag was pulled far into the molecular machine—through ClpX and into ClpP—and the folded protein part of the substrate was pulled tightly against the axial channel of ClpX. 

The opening of the axial channel, called the axial pore, is made up of looping protein structures called RKH loops. These flexible loops were found to play roles both in recognizing the ssrA degradation tag and in how substrates or the SspB adaptor interact with or are pulled against the channel during degradation. 

The flexibility of these RKH loops allows ClpX to interact with a large number of different proteins and adapters, and these results clarify some previous biochemical and mutational studies of interactions between the substrate and ClpXP. 

Although Ghanbarpour’s recent work focused on just one adaptor and degradation tag, he noted there are many more targets — ClpXP is something akin to a Swiss army knife for breaking down polypeptide chains. 

The way those other substrates interact with ClpXP could differ from the structures solved with the SspB adaptor and ssrA tag. It also stands to reason that the way ClpXP reacts to each substrate may be unique. For example, given that ClpX is occasionally in an open state, some substrates may engage with ClpXP only while it’s in an open conformation. 

In his new position at Washington University, Ghanbarpour intends to continue exploring how ClpXP and other molecular machines locate their target substrates and interact with adaptors, shedding light on how cells regulate protein degradation and maintain protein homeostasis.

The structures Ghanbarpour solved involved free-floating protein degradation machinery, but membrane-bound degradation machinery also exists. The membrane-bound version’s structure and conformational adaptions potentially differ from the structures Ghanbarpour found in his previous three papers. Indeed, in a recent preprint, Ghanbarpour worked on the cryo-EM structure of a nautilus shell-shaped protein assembly that seems to control membrane-bound degradation machinery. This assembly plays a critical role in regulating protein degradation within the bacterial inner membrane.

“The function of these proteases goes beyond simply degrading damaged proteins. They also target transcription factors, regulatory proteins, and proteins that don’t exist in normal conditions,” he says. “My new lab is particularly interested in understanding how cells use these proteases and their accessory adaptors, both under normal and stress conditions, to reshape the proteome and support recovery from cellular distress.”

BSG-MSRP-Bio Student Profile: Adriana Camacho-Badillow, Calo Lab

Understanding the Role of PARPs and UBF1 in Building Ribosomes

Noah Daly | Department of Biology
September 25, 2024

While pursuing her passion for research, BSG-MSRP-Bio student Adriana Camacho-Badillo made major contributions to research in the Calo Lab in the Department of Biology at MIT.

Growing up in Puerto Rico, Adriana Camacho-Badillo had no explanation for her recurrent multiple fracture injuries. In her teens, she was finally able to see a geneticist who diagnosed her with a genetic syndrome that affects connective tissue throughout the body. 

This awakened an interest in genetics that led her to immerse herself in her genetic panel results, curious about the role of each gene that was tested. 

“I realized I wanted to find out how mutations affect gene expression that could possibly lead to a distinct phenotype or even a genetic syndrome,” she says. 

Within a few years of setting her sights on becoming a scientist, Camacho-Badillo began her first research experience working in the laboratory of Professors Hector Areizaga-Martínez and Elddie Román-Morales. Her work focused on experiments using enzymes to degrade Dichloro-diphenyl-trichloroethane, or DDT, a once-common pesticide known to be highly toxic to humans and other mammals that remains in the environment long after application to crops. 

As she became familiar with the day-to-day routines of designing and executing research experiments, she realized she was drawn to biochemistry and molecular biology. Camacho-Badillo soon applied to the molecular neuroscience lab of Professor Miguel Méndez at the University of Puerto Rico at Aguadilla and joined their team working on the effects of high glucose in the central nervous system of mice.

Expanding Experiences While Narrowing Focus

When Camacho-Badillo was sixteen, alongside Méndez and other students, she participated in the Quantitative Methods Workshop at MIT. The workshop allows undergraduate students from universities around the United States and the Caribbean to come together for a few days in January to learn how to apply computational tools that can help biological research. 

One of the sessions she attended was a talk about machine learning and studying the brain, presented by graduate student Taylor Baum. 

“I loved Taylor’s workshop,” Camacho-Badillo said, “When Taylor asked if anyone would be interested in volunteering to teach Spanish-speaking students in grade school science, I said yes without hesitation.” 

Baum, a neuroscientist and computer scientist working in the Munther Dahleh Research Group at MIT, is also the founder of Sprouting, Inc. The organization equips high-school students and undergraduates in Puerto Rico with STEM skills to help them pursue careers in science and technology.

After participating in QMW, it wasn’t long before Camacho-Badillo was back at MIT. She participated in the Bernard S. and Sophie G. Gould MIT Summer Research Program in Biology in 2023 and worked in the Yamashita Lab, studying two phenotypes of genetic mutations associated with cancer during cell division. 

The BSG-MSRP-Bio program offers lab experience and extracurricular activities such as journal clubs and dinners with professors. At one of these events, she met Associate Professor of Biology Eliezer Calo.

Camacho-Badillo and her mentor Eliezer Calo, Associate Professor of Biology. Photo Credit: Mandana Sassanfar.

“I loved meeting another scientist from Puerto Rico working on molecular biology, so I decided to look further into his research,” Camacho-Badillo recalls. 

In 2024, she was delighted to have the opportunity to return to the BSG-MSRP-Bio Program for a second time, and now to work in Calo’s Lab. 

The Unsolved Mysteries of UBF1

Although BSG-MSRP-Bio students are often mentored by graduate students or postdocs, Calo spent the summer mentoring Camacho-Badillo directly. As an alumnus of the MSRP-Bio program himself, Calo understands firsthand how much of an impact meaningful research can have for an undergraduate student spending a few months experiencing life in the lab at MIT. 

In the Calo Lab, Camacho-Badillo spent the early days of this summer poring over past research papers on genetic transcription, trying to answer a big question in molecular biology. Camacho-Badillo has been helping Calo understand how a particular protein affects the production of ribosomes in cells.

A ribosome is the molecular machinery that synthesizes proteins, and an average cell can produce around 10 million ribosomes to sustain its essential functions. Creating these protein engines requires the transcription of ribosomal DNA, or rDNA. 

In order to synthesize RNA, specific proteins called polymerases must bind to the DNA. Camacho-Badillo’s work focuses on one of those binding proteins called upstream binding factor, or UBF1. UBF1 is essential for the synthesis of the ribosomal RNA. The UBF1 transcription factor is responsible for recruiting the polymerase, RNA polymerase I, to transcribe the rDNA into rRNA.

Despite knowing the importance of UBF1 in ribosomal production, it’s unclear what its full purpose is in this process. Calo and Camacho-Badillo think that clarifying the role of UBF1 in ribosomal biogenesis will help scientists understand how certain neurological diseases occur. UBF1 is known to be associated with diseases such as acute myeloid leukemia and childhood-onset neurodegeneration with brain atrophy, but the mechanism is not yet understood.

UBF1 is a peculiar transcription factor. Before it can transcribe a gene, UBF1 must first dimerize, forming a bond with another UBF1 protein. After binding to the rDNA, UBF1 can recruit the remaining RNA transcription machinery. The dimer is crucial for transcription to occur, yet this protein can make further connections with other UBF1 monomers, a process called oligomerization. 

Nothing is concretely understood about how oligomers of UBF1 form: they could be critical for transcription, forming clusters that can no longer bind with rDNA or inhibit the recruitment of the remaining RNA transcription machinery. These clusters could also be directly contributing to a variety of neurological diseases.

“The genome contains multiple rDNA copies, but not all are utilized,” Calo explains. “UBF1 must precisely identify the correct copies to activate while avoiding the formation of aggregates that could impair its function.”

The regulation of these dimers is also a mystery. Early in the summer, Camacho-Badillo helped make an important connection: prior research from the Calo Lab showed that enzymes called poly ADP-ribose polymerases, or PARPs, play a role in maintaining chemical properties in the nucleolus, where ribosomes are produced and assembled. The main target of these proteins within the RNA transcriptional machinery before transcription is initiated is UBF1.  

Based on this initial result, Camacho-Badillo’s entire summer project shifted to further characterize PARPs in ribosome biogenesis.

“This observation about the role PARPs plays is a big deal for us,” Calo says. “We do many experiments in my lab, but Adriana’s work this summer has opened a key gateway to understanding the mysteries behind UBF1 regulation, leading to proper ribosome production and allowing the Calo lab to pursue this goal. She’s going to be a superstar.” 

Camacho-Badillo’s work hasn’t ended with the BSG-MSRP-Bio program, however. She’ll spend the fall semester at MIT, continuing to work on understanding how rDNA transcription is regulated as a visiting student in the Calo Lab. Although she still has a year and a half to go in her undergraduate degree, she’s already set her sights on graduate school. 

“This program has meant so much to me and brought so much into my life,” she says. “All I want to do right now is keep this research going.”

Want to know more about our BSG-MSRP-Bio Students? Read more testimonials and stories here.

BSG-MSRP-Bio student profile: Praise Lasekan, Vos Lab

A scientist’s toolkit: practice, patience, and plenty of questions

Noah Daly | Department of Biology
September 24, 2024

A childhood interest in the complex worlds within an organism that the naked eye cannot see ultimately led Praise Lasekan to the BSG-MSRP-Bio program at MIT working in the Vos Lab in the Department of Biology at MIT. 

Praise Lasekan talks about the fast protein liquid chromatography machines he used in the Vos Lab as though they were colleagues. 

“We have two of them,” he explains. “Sam and Frodo.” 

FPLC machines separate and analyze proteins based on their properties, such as size, charge, and binding affinity. When Lasekan first saw the FPLC machines, the tubing and valves, hooked up to a computer, reminded him of a fancy piece of plumbing. Much like an expert plumber, proficiency​​ with these machines required him to understand every valve and tube.

Although Lasekan is a Biology major with a Chemistry Minor at the University of Maryland, Baltimore County, Lasekan had the opportunity to spend his summer living in Boston and working on MIT’s campus as a Bernard S. and Sophie G. Gould MIT Summer Research Program in Biology student.

“I loved every part of this summer: Waking up in the morning, coming to the lab, setting up some stuff — whether it goes well or not,” Lasekan says. “Taking that experience and coming back the next day, you’re ready to keep going and improving.”

Lasekan spent his days in the lab of Seychelle Vos, Robert A. Swanson Career Development Professor of Life Sciences and HHMI Freeman Hrabowski Scholar. The Vos Lab examines how genetic information is stored so compactly yet is still accessible enough for genes to be expressed. All cells in an organism have the same DNA, but the organization of that DNA and how genes are expressed determine why one cell becomes part of the liver and another cell part of the brain. 

Lasekan worked with a highly conserved protein that plays a role in gene transcription called CCCTCF-binding factor, or CTCF. He worked to understand how adding a phosphate group, a process called phosphorylation, affects CTCF’s binding to DNA. Binding to DNA is the first step in the process of transcription, which creates proteins within a cell.

The Vos lab uses various tools and techniques that Vos learned during her training, often using simple systems with limited components to study phenomena such as molecular structures, the dynamics of proteins and nucleic acids, and how structural alterations affect the function of these molecules. The lab has also recently been delving into more systemic work, such as removing genes from cells to observe how that affects gene expression. 

“My lab is a little unconventional in some ways,” Vos says. “We use a lot of biochemistry and structural biology, but we want to use the tools of genetics and cell biology as well to understand how genome organization and genome expression are coupled.” 

BSG-MSRP-Bio Student Praise with Graduate Student and mentor, Bonnie Su, of the Vos Lab.

CTCF can play many roles during transcription, able to act as an activator or as a roadblock for transcription. Lasekan’s mentor, graduate student Bonnie Su, has been trying to figure out how cells control CTCF behavior.

“What if the cell needed something done ASAP, and CTCF was blocking its route to its destination on a DNA sequence?” Vos asks. “How does the cell regulate it?” 

Praise mutated different sites on CTCF that have been reported in previous research as possible points of phosphorylation of the CTCF protein. Several other amino acids can also be phosphorylated. Still, Su was particularly interested in the work other researchers have done on three specific sites along a segment called the zinc finger domain.  A zinc finger domain is a zinc ion that helps proteins stabilize their shape and the domain has a function in various cellular processes such as genetic transcription. The ion is regulated by amino acids to give it a finger-like structure that helps in binding the protein to DNA during transcription.

“Before we went on a wild goose chase,” Lasekan explains, “we needed to identify a specific area of the protein to concentrate on and examine the behavior of CTCF locally there.”

Off of the Drawing Board and Into the Laboratory

Lasekan was introduced to the microscopic world of the body — cells, organelles, molecules, and even atoms — in the pages of his secondary school science textbooks in Ondo, Nigeria. There began his curiosity about atomic structures, cells, and the complex worlds within an organism that the naked eye cannot see. He would spend much of his class time flipping through the pages of diagrams and ultimately decided to pursue science as his core focus during senior secondary school.

“It was there that I could take my first classes in chemistry, biology, and physics,” he says. “I realized I love all of the sciences, so my focus in school was science and technology.”

Initially drawn to engineering, Lasekan ended up dropping out of a technical drawing course.

“I loved the course,” Lasekan smiles, “but the course didn’t like me one bit.” 

Lasekan’s dreams shifted toward medicine and, with it, more science and math courses. 

When he graduated valedictorian from Staff Secondary School at the Federal University of Technology in Akure, his parents — both pharmacists — encouraged him to apply to university to become a medical doctor. However, getting into a good university is challenging in Nigeria. 

Praise opted instead to remain at home after graduating, building a successful business doing portrait photography. He also took chemistry, physics, and biology courses through Cambridge University International.

Despite making good money with photography, Praise was determined to go to university but wasn’t confident that he would get in. Nevertheless, an acquaintance encouraged him to apply to UMBC. 

“It was the only school I applied to, and I couldn’t believe that I got in,” says Lasekan. 

At UMBC, Lasekan discovered the pre-med track he’d signed up for was not a good fit for him either — many of the fundamental questions he was curious about were beyond the scope of his courses. A friend who was working in a research lab on campus suggested that Lasekan should try to find a lab to work in, too. 

“They told me I might like what they’re doing there because of the level of questions that I ask,” Lasekan says. “Sometimes people didn’t have answers for me, and maybe I could find some of those answers through research.” 

After he emailed PIs in biology and chemistry labs around campus, Lasekan was eventually accepted into the lab of Dr. Erin Green, Associate Professor of Biological Sciences at UMBC — his first experience doing research in the lab. 

Dr. Green focuses on trying to understand how post-translational modifications of proteins regulate functions, such as the establishment of proper states of gene expression and the ability of cells to respond to stress. 

“Dr. Green took a chance with me,” Lasekan says. “I am forever grateful to her for that.” 

MIT: A Destination for Scientific Discovery

When considering summer research programs, Praise applied to MIT, one institution he’d always remembered from his childhood textbooks as the birthplace of many great inventions and scientific discoveries. It’s also one of the few programs in the U.S. that accepts international students. 

“I’ve always had MIT at the back of my mind, but I didn’t think they’re looking for people like me,” Lasekan says. When he saw the notification for his acceptance to the program pop up on his smartwatch, he screamed, startling some students walking by him in the hallway.

“This is one of the best institutions in the world, and I just got an opportunity to go there for ten weeks, actually do a project of my own under the mentorship of my PI,” Lasekan recalls thinking. “This was a dream come true for me.”

In the Vos lab, Lasekan’s interest in the fundamental questions of biology was not only acceptable but encouraged, especially by his mentor, Su.

“Bonnie always had the patience to sit down with me, explain concepts to me, and write out the math with me if I need her to,” Lasekan says, “and sometimes I need it 25 times, but she’s there for me.” 

Now that the BSG-MSRP-Bio program has wrapped up, Praise has the confidence to set his sights higher than ever before — on the “big guys,” the universities and institutions doing the sort of cutting-edge research that first caught his eye in the textbooks back home. Praise is eagerly preparing his graduate school applications for fall 2025, including MIT.

“After being here, surrounded by people from everywhere driven by the same purpose, I know there’s an exciting future in science for me.” 

Want to know more about our BSG-MSRP-Bio Students? Read more testimonials and stories here.

MIT affiliates named 2024 HHMI Investigators

Four faculty members and four others with MIT ties are recognized for pushing the boundaries of science and for creating highly inclusive and collaborative research environments.

School of Science
July 23, 2024

The Howard Hughes Medical Institute (HHMI) today announced its 2024 investigators, four of whom hail from the School of Science at MIT: Steven Flavell, Mary Gehring, Mehrad Jazayeri, and Gene-Wei Li.

Four others with MIT ties were also honored: Jonathan Abraham, graduate of the Harvard/MIT MD-PhD Program; Dmitriy Aronov PhD ’10; Vijay Sankaran, graduate of the Harvard/MIT MD-PhD Program; and Steven McCarroll, institute member of the Broad Institute of MIT and Harvard.

Every three years, HHMI selects roughly two dozen new investigators who have significantly impacted their chosen disciplines to receive a substantial and completely discretionary grant. This funding can be reviewed and renewed indefinitely. The award, which totals roughly $11 million per investigator over the next seven years, enables scientists to continue working at their current institution, paying their full salary while providing financial support for researchers to be flexible enough to go wherever their scientific inquiries take them.

Of the almost 1,000 applicants this year, 26 investigators were selected for their ability to push the boundaries of science and for their efforts to create highly inclusive and collaborative research environments.

“When scientists create environments in which others can thrive, we all benefit,” says HHMI president Erin O’Shea. “These newest HHMI Investigators are extraordinary, not only because of their outstanding research endeavors but also because they mentor and empower the next generation of scientists to work alongside them at the cutting edge.”

Steven Flavell

Steven Flavell, associate professor of brain and cognitive sciences and investigator in the Picower Institute for Learning and Memory, seeks to uncover the neural mechanisms that generate the internal states of the brain, for example, different motivational and arousal states. Working in the model organism, the C. elegans worm, the lab has used genetic, systems, and computational approaches to relate neural activity across the brain to precise features of the animal’s behavior. In addition, they have mapped out the anatomical and functional organization of the serotonin system, mapping out how it modulates the internal state of C. elegans. As a newly named HHMI Investigator, Flavell will pursue research that he hopes will build a foundational understanding of how internal states arise and influence behavior in nervous systems in general. The work will employ brain-wide neural recordings, computational modeling, expansive research on neuromodulatory system organization, and studies of how the synaptic wiring of the nervous system constrains an animal’s ability to generate different internal states.

“I think that it should be possible to define the basis of internal states in C. elegans in concrete terms,” Flavell says. “If we can build a thread of understanding from the molecular architecture of neuromodulatory systems, to changes in brain-wide activity, to state-dependent changes in behavior, then I think we’ll be in a much better place as a field to think about the basis of brain states in more complex animals.”

Mary Gehring

Mary Gehring, professor of biology and core member and David Baltimore Chair in Biomedical Research at the Whitehead Institute for Biomedical Research, studies how plant epigenetics modulates plant growth and development, with a long-term goal of uncovering the essential genetic and epigenetic elements of plant seed biology. Ultimately, the Gehring Lab’s work provides the scientific foundations for engineering alternative modes of seed development and improving plant resiliency at a time when worldwide agriculture is in a uniquely precarious position due to climate changes.

The Gehring Lab uses genetic, genomic, computational, synthetic, and evolutionary approaches to explore heritable traits by investigating repetitive sequences, DNA methylation, and chromatin structure. The lab primarily uses the model plant A. thaliana, a member of the mustard family and the first plant to have its genome sequenced.

“I’m pleased that HHMI has been expanding its support for plant biology, and gratified that our lab will benefit from its generous support,” Gehring says. “The appointment gives us the freedom to step back, take a fresh look at the scientific opportunities before us, and pursue the ones that most interest us. And that’s a very exciting prospect.”

Mehrad Jazayeri

Mehrdad Jazayeri, a professor of brain and cognitive sciences and an investigator at the McGovern Institute for Brain Research, studies how physiological processes in the brain give rise to the abilities of the mind. Work in the Jazayeri Lab brings together ideas from cognitive science, neuroscience, and machine learning with experimental data in humans, animals, and computer models to develop a computational understanding of how the brain creates internal representations, or models, of the external world.

Before coming to MIT in 2013, Jazayeri received his BS in electrical engineering, majoring in telecommunications, from Sharif University of Technology in Tehran, Iran. He completed his MS in physiology at the University of Toronto and his PhD in neuroscience at New York University.

With his appointment to HHMI, Jazayeri plans to explore how the brain enables rapid learning and flexible behavior — central aspects of intelligence that have been difficult to study using traditional neuroscience approaches.

“This is a recognition of my lab’s past accomplishments and the promise of the exciting research we want to embark on,” he says. “I am looking forward to engaging with this wonderful community and making new friends and colleagues while we elevate our science to the next level.”

Gene-Wei Li,

Gene-Wei Li, associate professor of biology, has been working on quantifying the amount of proteins cells produce and how protein synthesis is orchestrated within the cell since opening his lab at MIT in 2015.

Li, whose background is in physics, credits the lab’s findings to the skills and communication among his research team, allowing them to explore the unexpected questions that arise in the lab.

For example, two of his graduate student researchers found that the coordination between transcription and translation fundamentally differs between the model organisms E. coli and B. subtilis. In B. subtilis, the ribosome lags far behind RNA polymerase, a process the lab termed “runaway transcription.” The discovery revealed that this kind of uncoupling between transcription and translation is widespread across many species of bacteria, a study that contradicted the long-standing dogma of molecular biology that the machinery of protein synthesis and RNA polymerase work side-by-side in all bacteria.

The support from HHMI enables Li and his team the flexibility to pursue the basic research that leads to discoveries at their discretion.

“Having this award allows us to be bold and to do things at a scale that wasn’t possible before,” Li says. “The discovery of runaway transcription is a great example. We didn’t have a traditional grant for that.”

Gene-Wei Li named 2024 HHMI Investigator

HHMI award will help Department of Biology faculty unravel the mysteries of precision gene expression across the proteome

Noah Daly | Department of Biology
July 23, 2024

To better understand how cells precisely control the levels of their proteins, Associate Professor Gene-Wei Li utilizes rigorous quantitative analysis to improve our molecular understandings of life. With the support he’ll receive as an HHMI Investigator, Li will explore how genomes are sculpted to allow lifeforms to survive in a competitive environment.

As versatile and durable as cells are, their every function depends on producing precise quantities of proteins. These proteins enable the cells to perform their functions, their organelles to work, and tell the cells when to grow or decompose. Without precise instructions for how much protein they need to generate, organisms would struggle to self-regulate efficiently, rendering them incapable of becoming competitive life forms. These “recipes” for protein production are written into the genetic code of all life. Recent advances in DNA sequencing have identified every protein an organism can produce–every “ingredient” in the genetic cookbook. Despite these significant advances, researchers still don’t know how to read the instructions. 

Since opening his lab at MIT in 2015, Associate Professor of Biology Gene-Wei Li has been working, among other things, on quantifying the amount of proteins cells produce and how that process is orchestrated within the cell. 

“The goal that we hope to achieve,” Li says, “is to read the genomic sequence and accurately tell you not just what types of proteins are made, but also how many of them will be made.” 

Li was recently named a 2024 Howard Hughes Medical Institute Investigator, one of 26 newly appointed Investigators hailing from 19 institutions. Each HHMI Investigator will receive roughly $11 million in support over a seven-year term, potentially renewable indefinitely. This support includes their full salary and benefits, a generous research budget, scientific equipment, and additional resources. 

“I feel grateful for the extremely supportive environment in my department,” Li says. “This award is also a recognition for the hard work and risk-taking by my lab’s current and past trainees.” 

Other MIT School of Science faculty joining the 2024 cohort include Mary Gehring, Professor of Biology and Core Member and David Baltimore Chair in Biomedical Research at the Whitehead Institute; Steven Flavell, Associate Professor of Brain and Cognitive Sciences and Investigator in the Picower Institute for Learning and Memory; and Mehrdad Jazayeri, Professor of Brain and Cognitive Sciences at the McGovern Institute.  

Of the nearly 1,000 researchers who applied to be HHMI investigators this year, successful applicants were selected for their singular accomplishments in scientific research. They receive extensive resources to continue their work at their home institution. HHMI enables scientists to pursue their work with extraordinary freedom, allowing them to expand their current efforts, pivot focus as needed, and execute original ideas. 

One of the hallmarks of Li’s lab is the devoted attention he gives to his students. Each member of the lab receives extensive guidance and mentorship, enabling them to pursue careers in science while sharing their ideas and concerns with fellow lab members and Li. For this inclusive culture, Li was honored by MIT as “Committed to Caring” for 2020-2021. 

“When scientists create environments in which others can thrive, we all benefit,” says HHMI President Erin O’Shea. “These newest HHMI Investigators are extraordinary, not only because of their outstanding research endeavors but also because they mentor and empower the next generation of scientists to work alongside them at the cutting edge.”  

In his lab, Li has emphasized the interweaving of individual achievement and the success of the group, creating a space for lab members to learn from one another, freely question their principal investigator, and ultimately make breakthroughs together. 

Discovery through Collaboration 

While Li’s lab was built around the question of quantifying a cell’s protein synthesis–that is, the amounts of all the proteins produced in a cell—his background is in physics. He approaches his work by making quantitative and systematic measurements (mainly with high-throughput DNA sequencing tools) and using that information to uncover fundamental molecular mechanisms in gene expression. 

The Li lab’s early work utilizing this methodology demonstrated that proteins that go on to form complexes are made in the correct ratios to immediately form complexes with few extra copies. 

Li’s team went on to discover that metabolic proteins are synthesized at precise ratios that are conserved across evolutionarily distant species, such as the two bacterial model organisms E. coli and B. subtilis. However, despite their shared output of protein production, the billions of years of evolution gave rise to two completely different ways to control protein quantity. 

In 2020, this line of research produced a study that contradicted the longstanding dogma of molecular biology that the machinery of protein synthesis and RNA polymerase work side by side in bacteria, which it does in E coli. 

According to Li, two of his graduate student researchers found that, in B. subtilis, the ribosome lags far behind RNA polymerase, a process the lab termed “runaway transcription.” They found that the coordination between transcription and translation is fundamentally different between E. coli and B. subtilis. They then identified bioinformatic signatures, revealing that this kind of uncoupling between transcription and translation is widespread across many species of bacteria. The students, Grace Johnson, a former graduate student in the Department of Biology, and Jean-Benoît Lalanne, a former graduate student in the Department of Physics, were the lead authors of the paper, which appeared in Nature. 

 “This is very exciting stuff, but all the credit goes to my grad students,” Li chuckles. 

Finding the Room to Be Bold 

The support from Howard Hughes Medical Institute enables Li and his team the flexibility to pursue the basic research that leads to discoveries. 

“Having this award really allows us to be bold and to do things at a scale that wasn’t possible before. The discovery of runaway transcription is a great example of this,” Li says.  

Li plans on using the funds made available from HHMI to help determine how functionally related genes differ in their expression and how signals are encoded in the genome at the DNA and RNA levels. According to Li, the collection of high-quality and system-wide data is essential to making discoveries in his field. 

“I’m incredibly grateful to HHMI for encouraging us to pursue this work and follow the science wherever it leads us,” he says. 

Li and his team are as eager as ever to understand life’s coded cookbook. 

“The work of science begins with great people,” Li says. “This award will help ensure our lab continues to be a place where incredible young scientists can work together to achieve miraculous things.” 

Sara Prescott named Pew Scholar in the Biomedical Sciences

Assistant Professor Sara Prescott and her lab plan to test whether and how neurons have a role in airway remodeling, which goes awry in many diseases.

David Orenstein | The Picower Institute for Learning and Memory
June 17, 2024
2024 Catalyst Symposium

Lowering ‘activation barriers’ for rising biology researchers

Lillian Eden | Department of Biology
May 16, 2024

The second annual Catalyst Symposium, sponsored by the Department of Biology and Picower Institute for Learning and Memory, invited postdocs from across the country to meet with faculty, present their work to the MIT community, and build relationships.

For science — and the scientists who practice it — to succeed, it must be shared. That’s why members of the MIT community recently gathered to learn about the research of eight postdocs from across the country for the second annual Catalyst Symposium, an event co-sponsored by the Department of Biology and The Picower Institute for Learning and Memory. 

The eight Catalyst Fellows came to campus as part of an effort to increase engagement between MIT scholars and postdocs excelling in their respective fields from traditionally underrepresented backgrounds in science. The three-day symposium included panel discussions with faculty and postdocs, one-on-one meetings, social events, and research talks from the Catalyst Fellows.

“I love the name of this symposium because we’re all, of course, eager to catalyze advancements in our professional lives, in science, and to move forward faster by lowering activation barriers,” says MIT Biology Department Head Amy Keating. “I feel we can’t afford to do science with only part of the talent pool, and I don’t think people can do their best work when they are worried about whether they belong.”  

The cohort of 2024 Catalyst Fellows included: Chloé Baron from Boston Children’s Hospital; Maria Cecília Canesso from The Rockefeller University; Kiara Eldred from the University of Washington School of Medicine; Caitlin Kowalski from the University of Oregon; Fabián Morales-Polanco from Stanford University; Kali Pruss from the Washington University School of Medicine in St. Louis; Rodrigo Romero from Memorial Sloan Kettering Cancer Center; and Zuri Sullivan from Harvard University. 

Romero, who received his PhD from MIT working in the Jacks Lab at the Koch Institute, said that it was “incredible to see so many familiar faces,” but he spent the Symposium lunch chatting with new students in his old lab. 

“Especially having been trained to think differently after MIT, I can now reach out to people that I didn’t as a graduate student, and make connections that I didn’t think about before,” Romero says. 

He presented his work on lineage plasticity in the tumor microenvironment. Lineage plasticity is a hallmark of tumor progression but also occurs during normal development, such as wound healing.

As for the general mission of the symposium, Romero agreed with Keating. 

“Trying to lower the boundary for other people to actually have a chance to do academic research in the future is important,” Romero says.

The Catalyst Symposium is aimed at early-career scientists who foresee a path in academia. Of the 2023 Catalyst Fellows, one has already secured a faculty position. Starting in September 2024, Shan Maltzer will be an assistant professor at Vanderbilt University in the Department of Pharmacology and the Vanderbilt Brain Institute studying mechanisms of somatosensory circuit assembly, development, and function. 

Another aim of the Catalyst Symposium is to facilitate collaborations and strengthen existing relationships. Sullivan, an immunologist and molecular neuroscientist who presented on the interactions between the immune system and the brain, is collaborating with Sebastian Lourido, an Associate Professor of Biology and Core Member of the Whitehead Institute. Lourido’s studies include pathogens such as Toxoplasma gondii, which is known to alter the behavior of infected rodents. In the long term, Sullivan hopes to bridge research in immunology and neuroscience — for instance by investigating how infection affects behavior. She has observed that two rodents experiencing illness will huddle together in a cage, whereas an unafflicted rodent and an ill one will generally avoid each other when sharing the same space. 

Pruss presented research on the interactions between the gut microbiome and the environment, and how they may affect physiology and fetal development. Kowalski discussed the relationship between fungi residing on our bodies and human health. Beyond the opportunity to deliver talks, both agreed that the small group settings of the three-day event were rewarding.

“The opportunity to meet with faculty throughout the symposium has been invaluable, both for finding familiar faces and for establishing friendly relationships,” Pruss says. “You don’t have to try to catch them when you’re running past them in the hallway.”

Eldred, who studies cell fate in the human retina, says she was excited about the faculty panels because they allowed her to ask faculty about fundamental aspects of recruiting for their labs, like bringing in graduate students. 

Kowalski also says she enjoyed interfacing with so many new ideas — the spread of scientific topics from among the cohort of speakers extended beyond those she usually interacts with.

Mike Laub, Professor of Biology and HHMI Investigator, and Yadira Soto-Feliciano, Assistant Professor of Biology and Intramural Faculty at the Koch Institute, were on the symposium’s planning committee, along with Diversity, Equity, and Inclusion Officer Hallie Dowling-Huppert. Laub hopes the symposium will continue to be offered annually; next year’s Catalyst Symposium is already scheduled to take place in early May.

“I thought this year’s Catalyst Symposium was another great success. The talks from the visiting Fellows featured some amazing science from a wide range of fields,” Laub says. “I also think it’s fair to say that their interactions with the faculty, postdocs, and students here generated a lot of excitement and energy in our community, which is exactly what we hoped to accomplish with this symposium.”

Staff Spotlight: John Fucillo, Building 68 Manager, EHS Coordinator; Chemical Hygiene Officer

Laying foundations for MIT Biology

Samantha Edelen | Department of Biology
May 2, 2024

Building 68 manager John Fucillo’s leadership, innovation, and laid-back attitude have built a community culture that will never be taken for granted. 

When entering the office of Building 68’s manager, you will likely be greeted first with an amiable nose boop and wagging tail from Shadow, a four-year-old black lab, followed by a warm welcome from the office’s other occupant, John Fucillo. Fucillo is an animal lover, and Shadow is the gentlest of roughly nine dogs and one Siamese cat he’s taken care of throughout his life. Fortunately for MIT Biology, Shadow is not the only lab Fucillo cares for. 

A Boston area local, Fucillo spent two years working at Revere Beach, then learned skills as an auto mechanic, and later completed an apprenticeship with the International Brotherhood of Electrical Workers. In 1989, Fucillo came to MIT Biology and says he couldn’t be happier.

As Building 68’s manager, Environment, Health & Safety coordinator, and Chemical Hygiene Officer, Fucillo’s goal is to make workflows “easier, less expensive, more desirable, and more comfortable.”

Fucillo was key for the Department’s successful move into its new home when Building 68 was completed in 1994, according to Mitchell Galanek, MIT Radiation Protection Officer and Fucillo’s colleague for over 30 years. 

Throughout his time as a building manager, Fucillo has decreased routine spending and increased sustainability. He lowered the cost of lab coats by a whopping 92%–from $2,600 to $200–with just one phone call to North Star, the building’s uniform/linens provider. Auditing the building’s plastic waste generation inspired the institute-wide MIT Lab Plastics Recycling Program, which now serves over 200 labs across campus. More than 50,000 lbs of plastic have been recycled in the last four years alone. 

“John is not a cog in the wheel, but an integral part of the whole system,” says Anthony Fuccione, Technical Instructor and Manager of the Biology Teaching lab.

Connecting and leading 

Fucillo says one of his favorite parts of the job is chatting with researchers and helping them achieve their goals. He reportedly clocks about 10,000 steps per day on campus, responding to requests from labs, collaborating with colleagues, and connecting Biology to the institute’s Environment, Health, & Safety office.

“John is called upon — literally and figuratively — morning, noon, and night,” says Whitehead Professor of Molecular Genetics Monty Krieger. “He has had to become an expert in so very many areas to support staff, faculty, and students. His enormous success is due in part to his technical talents, in part to his genuine care for the welfare of his colleagues, and in part to his very special and caring personality.” 

When MIT needed to comply with the EPA’s decree to improve safety standards across campus, Fucillo sat on the committees tasked with meeting those standards while avoiding undue burden on researchers, establishing the Environmental Health and Safety Management system in 2002.

“From a safety perspective, that was one of the most challenging things MIT had to go through–but it came out at the end a better, safer, place,” says John Collins, EHS Project Technician and friend and colleague to Fucillo for over 20 years.

Fucillo later co-led the initiative for a 2011 overhaul of MIT’s management of regulated medical waste (RMW), such as Petri dishes, blood, and needles. Fucillo volunteered to pilot a new approach in Building 68 — despite a lukewarm response to the proposal from other Biology EHS representatives, according to Galanek. This abundantly successful management system is now used by all MIT departments that generate RMW. It’s not only less expensive, but also does a better job at decontaminating waste than the previous management system.

“Anyone who has worked with John during his MIT career understands it is truly a privilege to partner with him,” Galanek says. “Not only does the work get done and done well, but you also gain a friend along the way.”

After consolidating a disparate group of individual lab assistants, Fucillo took on a supervisory role for the centralized staff tasked with cleaning glassware, preparing media, and ensuring consistency and sterility across Building 68 labs. 

According to maintenance mechanic James “Jimmy” Carr, “you can’t find a better boss.”

“He’s just an easy-going guy,” says Karen O’Leary, who has worked with Fucillo for over 30 years. “My voice matters–I feel heard and respected by him.” 

Looking forward

Although there are still many updates Fucillo hopes to see in Building 68, which will soon celebrate its 30th birthday, he is taking steps to cut back on his workload. 

He recently began passing on his knowledge to Facilities Manager and EHS Coordinator Cesar Duarte, who joined the department in 2023.

“It’s been a pleasure working alongside John and learning about the substantial role and responsibility he’s had in the Biology department for the last three decades,” Duarte says. “Not only is John’s knowledge of Building 68 and the department’s history unparalleled, but his dedication to MIT and continued care and commitment to the health and well-being of the Biology community throughout his career are truly remarkable.”

As he winds down his time at MIT, Fucillo hopes to spend more time on music, one of his earliest passions, which began when he picked up an accordion in first grade. He still plays guitar and bass nearly every day. When he rocks out at home more often, he’ll be leaving behind the foundations of innovation, leadership, and respect in Building 68.