“Globally, there is a huge disparity in access to scientific resources,” says Melissa Wu ’05, CEO of Seeding Labs. “About 80 percent of the world’s population lives in low- and middle-income countries, but 80 percent of research funding is directed to just 10 countries in the world.”
And that disparity, she explains, biases what gets studied, what societal challenges are addressed, and who is a part of the scientific workforce. Seeding Labs is an NGO focused on shifting that balance of resources. It empowers scientists to transform the world by providing the resources needed to fight global diseases, feed a growing population, and protect our planet.
After leaving MIT, where she was active in service to her community and discovered a passion for research, Wu intended to pursue a career as a research professor. While earning a PhD in cell and developmental biology at Harvard and getting involved in a student group that advocated for global research, she began to realize that she craved more immediate impact from her work.
“As students, we convened a panel to talk about the barriers that are unique to researchers in lower- and middle-income countries,” she says. “We saw an immediate solution to one of those challenges: access to laboratory equipment, which can be prohibitively expensive. I worked with other students to collect and ship surplus equipment to researchers in developing countries. Within a few months after receiving equipment, we heard back the impacts of our efforts―successful grant apps, staff hired, and graduate students recruited to their labs.”
“After a few years of doing this work as students, we realized that we’d found a solution to a challenge that nobody else seemed able to address,” Wu explained. She supported a Harvard classmate, Nina Dudnik, in forming Seeding Labs, a nonprofit that could grow and sustain their efforts. Wu joined the Boston-based company as a full-time staff member in 2014 after completing her PhD, holding several positions before becoming CEO in 2019.
Seeding Labs aims to unleash the power of the most talented scientists around the globe to do what they do best: research, innovate, and discover. Through its flagship program, Instrumental Access, the company provides high-quality laboratory equipment at huge discounts to universities and research institutes in developing countries. “Since 2003, we’ve supported nearly 100 universities in 36 countries around the world with equipment that would’ve cost an estimated $40 million to obtain otherwise.”
Wu says that the stories of success, and the gratitude, from the universities and research institutions are continually inspiring. “One of the researchers told us that it was his dream to start a lab. There is no better reward than to be told that you’re fulfilling someone’s dream.” And in the current pandemic, these established labs are helping to save lives. In southeastern Africa, the Malawi University of Science and Technology has been able to analyze thousands of Covid-19 test kits in its lab because of the specialized equipment received through a 2017 Instrumental Access award.
The impact of the new equipment has a ripple effect beyond the labs and their research projects. Seeding Labs recently supported the top school in Tanzania, the Dar es Salaam University College of Education, with a shipment of lab equipment to help train the next generation of chemistry teachers. The university reported NetBet live casinothat the student dropout rate fell by 50 percent after receipt of the lab equipment, Wu says.
Her commitment to service doesn’t stop at helping to fund the global science community through lab equipment—Wu has also devoted her time to mentoring, with a special interest in helping to foster more diversity and equity in the sciences. “You know the phrase when you ‘geek out’ about something? It’s like you have this overwhelming desire to share something that you’re really passionate about because it makes you happy and you want others to experience that too. That’s what my love of scientific research is like. Who wouldn’t be excited about the opportunity to understand and then literally transform the world we live in? I want to share that with others and hope that I can inspire them to chase their dreams.”
Eva Frederick | Whitehead Institute
January 11, 2022
Growing up is a complex process for multi-celled organisms — plants included. In the days or weeks it takes to go from a seed to a sprout to a full plant, plants express hundreds of genes in different places at different times.
In order to conduct this symphony of genes, plants rely in part on an elegant regulatory method called DNA methylation. By adding or removing small molecules called methyl groups to the DNA strand, the plant can silence or activate different regions of its genetic code without changing the underlying sequence.
In a new paper from the lab of Whitehead Institute Member Mary Gehring, researchers led by former Gehring lab postdoc Ben Williams (now an assistant professor at the University of California, Berkeley) tease apart the role of proteins governing this system of genetic control, and reveal how enzymes that regulate methylation can affect essential decisions for plants such as when to produce flowers. “We’re starting to see that there is actually a broader role for demethylation [in plant development] than we thought,” Gehring said.
In the model plant Arabidopsis thaliana, methylation is regulated in part by enzymes encoded by a family of four genes called the DEMETER genes. The protein products of these genes are in charge of demethylating, or removing those methyl groups from the DNA, allowing different parts of the strand to be expressed. “You have these enzymes that can come in and completely change the way the DNA is read in different cells, which I find super interesting,” Williams said.
But teasing apart the role of each DEMETER gene has proved difficult in the past, because one member of this gene family in particular, called DME, is essential for seed development. Knock out DME, and the seed is aborted. “We had to design a synthetic gene to get around that,” Williams said. “We had to create plants that would rescue the reproductive failure, but then still be mutated throughout the rest of the life cycle.”
The researchers accomplished this by putting the DME gene under the control of a genetic element called a promoter that allowed it to be expressed in a cell that only existed in the plant during seed development. Once the plant was past the critical point where DME was needed for development, the gene would no longer be expressed, allowing the plant to grow up as a dme knockout. “It was an exciting thing, finally being able to create this knockout,” Gehring said.
Now, for the first time, the researchers could create plants with any combination of the DEMETER family genes knocked out, and then compare them to try and understand what the enzymes produced by each of the four genes was doing.
As expected, plants missing any of the DEMETER demethylases ended up with areas of their genomes with too many methyl groups (this is called hypermethylation). These areas were often overlapping, suggesting that the four DEMETER genes shared responsibility for demethylating certain areas of the genome.
“When one of these enzymes is gone, the others are surprisingly good at knowing that they need to step forward and do the job instead,” Williams said. “So the system has flexibility built in, which makes sense if it’s going to be involved in making important decisions like when to make flowers. You’d want there to be multiple layers of responsibility, right? It’s like in an organization, you don’t want to load all responsibility on one person — you’d want a few people who can take on that responsibility.”
Williams hypothesizes that while the DEMETER enzymes could step in for each other when needed, each specialized in demethylating DNA in particular types of plant tissue. “If you look at the protein sequences,they are actually really similar,” he said. “What’s different about them is they’re expressed in different cell types.”
A crucial finding of the study came about when the researchers knocked out all four genes in the DEMETER family at the same time. “All flowering plants have this really important decision of when to make flowers,” Williams said. “For plants out in the wild, that decision is usually dependent on temperature and pollinators. What we found really strange is that these mutants just flowered straight away. It’s almost like they weren’t even putting any effort into the decision. They made a few leaves, then boom, flower.”
When the researchers dove deeper, they saw that one area of the genome in particular that controls flowering time is under very careful and continuous regulation by methylating and demethylating enzymes. “We don’t really know why they’re NetBet live casinodoing that,” he said. “But when you knock out the demethylases, that gene just becomes methylated, and it’s then switched off. And that just sends plants into an automatic flowering state.”
In the future, the researchers plan to investigate other outcomes associated with their quadruple knockout of the DEMETER genes. “When we knocked out all four of the enzymes, it led to a lot of interesting phenotypes and tons of stuff to study,” Williams said. “We’ve learned through doing this that with DEMETER, like many gene families, we had to knock out all the players to find out the importance of what they are doing.”
Gehring will continue the research at Whitehead Institute. Williams recently started his own lab at the University of California, Berkeley. “I feel very lucky because this project has given me two or three different avenues that I can pursue in my new lab,” Williams said. “It has opened a lot of doors, which is very rewarding.”
The clinically-trained cell biologist exploits the liver’s unique capacities in search of new medical applications.
Grace van Deelen | Department of Biology
December 15, 2021
Why is the liver the only human organ that can regenerate? How does it know when it’s been injured? What can our understanding of the liver contribute to regenerative medicine? These are just some of the questions that new assistant professor of biology Kristin Knouse and her lab members are asking in their research at the Koch Institute for Integrative Cancer Research. Knouse sat down to discuss why the liver is so unique, what lessons we might learn from the organ, and what its regeneration might teach us about cancer.
NetBet live casinoYour lab is interested in questions about how body tissues sense and respond to damage. What is it about the liver that makes it a good tool to model those questions?
A: I’ve always felt that we, as scientists, have so much to gain from treasuring nature’s exceptions, because those exceptions can shine light onto a completely unknown area of biology and provide building blocks to confer such novelty to other systems. When it comes to organ regeneration in mammals, the liver is that exception. It is the only solid organ that can completely regenerate itself. You can damage or remove over 75 percent of the liver and the organ will completely regenerate in a matter of weeks. The liver therefore contains the instructions for how to regenerate a solid organ; however, we have yet to access and interpret those instructions. If we could fully understand how the liver is able to regenerate itself, perhaps one day we could coax other solid organs to do the same.
There are some things we already know about liver regeneration, such as when it begins, what genes are expressed, and how long it takes. However, we still don’t understand why the liver can regenerate but other organs cannot. Why is it that these fully differentiated liver cells — cells that have already assumed specialized roles in the liver — can re-enter the cell cycle and regenerate the organ? We don’t have a molecular explanation for this. Our lab is working to answer this fundamental question of cell and organ biology and apply our discoveries to unlock new approaches for regenerative medicine. In this regard, I don’t necessarily consider myself exclusively a liver biologist, but rather someone who is leveraging the liver to address this much broader biological problem.
Q: As an MD/PhD student, you conducted your graduate research in the lab of the late Professor Angelika Amon here at MIT. How did your work in her lab lead to an interest in studying the liver’s regenerative capacities?
A: What was incredible about being in Angelika’s lab was that she had an interest in almost everything and gave me tremendous independence in what I pursued. I began my graduate research in her lab with an interest in cell division, and I was doing experiments to observe how cells from different mammalian tissues divide. I was isolating cells from different mouse tissues and then studying them in culture. In doing that, I found that when the cells were isolated and grown in a dish they could not segregate their chromosomes properly, suggesting that the tissue environment was essential for accurate cell division. In order to further study and compare these two different contexts — cells in a tissue versus cells in culture — I was keen to study a tissue in which I could observe a lot of cells undergoing cell division at the same time.
So I thought back to my time in medical school, and I remembered that the liver has the ability to completely regenerate itself. With a single surgery to remove part of the liver, I could stimulate millions of cells to divide. I therefore began exploiting liver regeneration as a means of studying chromosome segregation in tissue. But as I continued to perform surgeries on mice and watch the liver rapidly regenerate itself, I couldn’t help but become absolutely fascinated by this exceptional biological process. It was that fascination with this incredibly unique but poorly understood phenomenon — alongside the realization that there was a huge, unmet medical need in the area of regeneration — that convinced me to dedicate my career to studying this.
Q: What kinds of clinical applications might a better understanding of organ regeneration lead to, and what role do you see your lab playing in that research?
A: The most proximal medical application for our work is to confer regenerative capacity to organs that are currently non-regenerative. As we begin to achieve a molecular understanding of how and why the liver can regenerate, we put ourselves in a powerful position to identify and surmount the barriers to regeneration in non-regenerative tissues, such as the heart and nervous system. By answering these complementary questions, we bring ourselves closer to the possibility that, one day, if someone has a heart attack or a spinal cord injury, we could deliver a therapy that stimulates the tissue to regenerate itself. I realize that may sound like a moonshot now, but I don’t think any problem is insurmountable so long as it can be broken down into a series of tractable questions.
Beyond regenerative medicine, I believe our work studying liver regeneration also has implications for cancer. At first glance this may seem counterintuitive, as rapid regrowth is the exact opposite of what we want cancer cells to do. However, the reality is that the majority of cancer-related deaths are attributable not to the rapidly proliferating cells that constitute primary tumors, but rather to the cells that disperse from the primary tumor and lie dormant for years before manifesting as metastatic disease and creating another tumor. These dormant cells evade most of the cancer therapies designed to target rapidly proliferating cells. If you think about it, these dormant cells are not unlike the liver: they are quiet for months, maybe years, and then suddenly awaken. I hope that as we start to understand more about the liver, we might learn how to target these dormant cancer cells, prevent metastatic disease, and thereby offer lasting cancer cures.
December 14, 2021
December 5, 2021
After meeting at the University of Puerto Rico at Mayagüez, José McFaline-Figueroa and Nelly Cruz came to MIT to kick-start accomplished careers as biologists
Grace van Deelen
December 3, 2021
When biologists José McFaline-Figueroa PhD ’14 and Nelly Cruz PhD ’11 are sitting at the dinner table with their five-year-old daughter, they might be discussing which experiments may work in lab, how to improve each other’s protocols, or even what new model of microscope to buy. Although they work at separate institutions, they both study how cells respond to disease and disease therapy, which allows them to learn a lot from each other. “We’ve found that it works for us to be able to collaborate and work together,” McFaline-Figueroa says. “It maybe doesn’t make for the best dinner conversation for our daughter, though.”
Cruz and McFaline-Figueroa’s teamwork has helped them navigate the journey from undergrad at the University of Puerto Rico at Mayagüez (UPRM), where they met, to graduate school at MIT, and all the way to their current jobs. “There are always opportunities to learn from each other,” Cruz says.
As a senior research scientist at Sloan Kettering Institute (SKI) in New York City, Cruz studies melanoma, a type of skin cancer, using zebrafish. She and her colleagues at SKI are interested in developing new ways to model melanoma, as well as studying its disease progression and looking for possible new avenues to develop melanoma therapeutics. Meanwhile, as an assistant professor at Columbia University, McFaline-Figueroa’s biomedical engineering research focuses on defining how cancer cells respond to anti-cancer therapies, and how those responses relate to genetic differences among cancer cells. While McFaline-Figueroa brings a computational biology lens to Cruz’s work, Cruz helps him determine which model systems might be best for his research.
Set from the start
Cruz and McFaline-Figueroa both grew up in Puerto Rico: Cruz in San Sebastián and McFaline-Figueroa in San Germán and Sabana Grande. From an early age, they were both interested in science and math. Cruz had a penchant for animals in particular. Living in the northwest part of the island, she was surrounded by a rural, quiet environment where she had plenty of exposure to the natural world. There, she would read her grandfather’s encyclopedias, and was fascinated by the wildlife. The snow leopard was her favorite — mysterious and elusive, it inspired her to be curious about the biological phenomena around her.
In addition to his encyclopedias, her grandfather’s support and enthusiasm for learning was also key to Cruz’s upbringing. “He was basically the only one in his family to go to college, so he had this desire to learn,” Cruz says. His support, combined with her parents’ encouragement, gave Cruz the confidence to aspire to a career in science. “They always believed in me and always encouraged me to pursue whatever I wanted to pursue.”
When it came time to decide what path to follow in college at UPRM, it was clear to Cruz that the biological sciences were the way forward. From 2003 to 2005, Cruz became involved in a research training program called Maximizing Access to Research Careers (MARC), which was sponsored by the National Institutes of Health. Her mentors in the MARC program encouraged her to complete summer research at institutions in the U.S. According to Cruz, this early exposure to research helped her realize that being a scientist could be a viable career option. Through this program, she was able to visit MIT as an undergraduate and meet Professor of Biology Steve Bell and Director of Diversity and Outreach Mandana Sassanfar.
NetBet sport“It was a very positive interaction,” Cruz says. “The more I learned about the program at MIT, the more interested and excited I got about it.” The interactions she had at the Department of Biology really resonated with her, so she made the choice to come to MIT for her PhD.
Like Cruz, McFaline-Figueroa was also interested in math and science from a young age, and his parents and grandparents were also key to that early interest. “Every afternoon my grandmother was the one who would say, “Well, have you done your homework?”’ he says. “She was the person mostly in charge of that.”
Cruz and McFaline-Figueroa met through McFaline-Figueroa’s brother during their first year at UPRM, and McFaline-Figueroa attributes his eventual interest in biology to seeing his brother and Cruz succeed in their research pursuits. “The fact that Nelly and others around us were on that path fed me information indirectly,” McFaline-Figueroa says. “I started to realize, ‘Wow, that’s so cool. I should be doing it as well.’” Inspired, he joined the lab of UPRM biochemistry professor Joseph Bonaventura, who introduced him to biomedical research. His interest was piqued, and his path as a scientist began to take shape.
Exploring the reaches of biology
Cruz was accepted to the MIT Department of Biology directly after graduating from UPRM in 2005, and began working under Jaqueline Lees, the Virginia and D. K. Ludwig Professor for Cancer Research. There, Cruz used zebrafish to study how cells regulate different parts of their life cycles, with a particular focus on cell division.
During her time in the Lees lab, she remembers collaborating closely with other graduate students and postdocs, as well as with particularly influential mentors. Emblematic of her collaborative career, she says, was her thesis defense.
Cruz (left) graduated from MIT in 2011, followed by McFaline-Figueroa (right) in 2014.
“It was so emotional for me to be able to not only present my work, but also to acknowledge all the people who helped with my work,” she says. “It really marked an important time when I realized I was able to accomplish these goals in an environment that allowed me to grow professionally and also personally.” Lees’ mentorship was particularly influential, and helped Cruz build confidence and professional skills that she continues to carry with her today.
Meanwhile, McFaline-Figueroa was inspired by Nelly’s work, as well as the experiences of his brother, who had participated in the MIT Summer Research Program in Biology. McFaline-Figueroa had studied chemistry at UPRM, and needed to establish himself as a biologist before applying to PhD programs. So, in 2006, he landed a research technician position at MIT with Peter Dedon, the Underwood-Prescott Professor of Biological Engineering. There, McFaline-Figueroa used mass spectrometry to measure the genetic damage that exposure to cancer therapies did to cells — a research approach that was totally new to him.
While he was doing this research, he was able to work on some projects with an accomplished molecular biologist who would later become one of his PhD advisors: Leona Samson, who is currently a professor emerita in the departments of Biological Engineeering and Biology. McFaline-Figueroa says this less formal experience was a huge part of how he honed his research interests. “It gave me the opportunity to explore what it was that I wanted to study,” he says. “Then I was lucky enough, two years later, to be admitted to the PhD program in biology.”
As a PhD student, McFaline-Figueroa was jointly advised by Samson and Professor of Biological Engineering Forest White, and studied how an aggressive type of brain cancer responded to different therapies. He says it was exciting to navigate the questions at the intersection of the two very different labs. The supportive atmospheres of the Samson and White labs helped him develop his confidence and independence as a researcher. “My advisors were both very gracious and made sure that I was progressing while also giving me space, which worked well for me,” he says.
Full circle
In 2011, Cruz graduated from MIT with her PhD, then moved on to a postdoc position at the Schepens Eye Research Institute in Boston. There, she pivoted to the field of ophthalmology, and began studying murine models to understand how genes regulate disease progression in the retina. Then, in 2013, she took a job as a biology instructor at MIT, overseeing students in laboratory courses. Afterwards, she pivoted yet again to a position as a research scientist at the University of Washington, where she studied models of kidney disease using pluripotent stem cells.
Cruz feels that her work has now come full circle, and that, at SKI, she’s working on questions she was excited about during her time at MIT. However, now she has even more knowledge and skills to push those questions further — and more advanced tools to answer them.
“It’s really, really exciting to be able to use the novel technologies that have been developed since then, especially with the advancement of the genome editing tools we now have available,” she says. “I’m using all the different skills I have learned in my past research experiences, and I can see how it all comes together in my current projects.”
After McFaline-Figueroa completed his PhD in 2014, he made his own transition: from molecular cell biology to single cell genomics. Working as a postdoc at the University of Washington in Cole Trapnell’s lab, netbet sports bettingMcFaline-Figueroa decided to explore computational biology a bit more, after gaining confidence in his skills as a researcher from his time at MIT.
“There was a very broad view that I was able to get at MIT by learning so many different possible approaches to tackle one problem,” he says. “That really gave me the courage to explore this other field.” He says that, in his recent search for an assistant professorship before beginning at Columbia, he also prioritized finding a place where people take “varying approaches to tackle the questions they’re interested in.”
Today, McFaline-Figueroa is happy to be applying the skills and methods he learned at MIT to his own lab. “It’s very exciting when you start seeing your research become this comprehensive story,” he says. Over time, he says, he’s enjoyed seeing the full picture come together.
It helps, too, that Cruz has been there throughout the journey. “I’ve learned a ton from Nelly’s work over the years,” he says. Cruz feels the same. “I also learn a lot from José, he’s been super helpful.”
Whether their daughter is showing scientist tendencies, though, is to be determined. “We’ll let her make that choice,” McFaline-Figueroa says.
Posted: 12.2.21
Eva Frederick | Whitehead Institute
December 2, 2021
Humans need oxygen molecules for a process called cellular respiration, which takes place in our cells’ mitochondria. Through a series of reactions called the electron transport chain, electrons are passed along in a sort of cellular relay race, allowing the cell to create ATP, the molecule that gives our cells energy to complete their vital functions.
At the end of this chain, two electrons remain, which are typically passed off to oxygen, the “terminal electron acceptor.” This completes the reaction and allows the process to continue with more electrons entering the electron transport chain.
In the past, however, scientists have noticed that cells are able to maintain some functions of the electron transport chain, even in the absence of oxygen. “This indicated that mitochondria could actually have partial function, even when oxygen is not the electron acceptor,” said Whitehead Institute postdoctoral researcher Jessica Spinelli. “We wanted to understand, how does this work? How are mitochondria capable of maintaining these electron inputs when oxygen is not the terminal electron acceptor?”
In a paper published December 2 in the journal Science, Whitehead Institute scientists and collaborators led by Spinelli have found the answer to these questions. Their research shows that when cells are deprived of oxygen, another molecule called fumarate can step in and serve as a terminal electron acceptor to enable mitochondrial function in this environment. The research, which was completed in the laboratory of former Whitehead Member David Sabatini, answers a long-standing mystery in the field of cellular metabolism, and could potentially inform research into diseases that cause low oxygen levels in tissues, including ischemia, diabetes and cancer.
A new runner in the cellular relay
The researchers began their investigation into how cells can maintain mitochondrial function without oxygen by using mass spectrometry to measure the quantities of molecules called metabolites that are produced through cellular respiration in both normal and low-oxygen conditions. When cells were deprived of oxygen, researchers noticed a high level of a molecule called succinate.
When you add electrons to oxygen at the end of the electron transport chain, it picks up two protons and becomes water. When you add electrons to fumarate, it becomes succinate. “This led us to think that maybe this accumulation of succinate that’s occurring could actually be caused by fumarate being used as an electron acceptor, and that this reaction could explain the maintenance of mitochondrial functions in hypoxia,” Spinelli said.
Usually, the fumarate-succinate reaction runs the other direction in cells — a protein complex called the SDH complex takes away electrons from succinate, leaving fumarate. For the opposite to happen, the SDH complex would need to be running in reverse. “Although the SDH complex is known to catalyze some fumarate reduction, it was thought that it was thermodynamically impossible for this SDH complex to undergo a net reversal,” Spinelli said. “Fumarate is used as an electron acceptor in lower eukaryotes, but they use a totally different enzyme and electron carrier, and mammals are not known to possess either of these.”
Through a series of assays, however, the researchers were able to ascertain that this complex was indeed running in reverse in cultured cells, largely due to accumulation of a molecule called ubiquinol, which the researchers observed to build up under low-oxygen conditions.
With their hypothesis confirmed, “We wanted to get back to our initial question and ask, does that net reversal of the SDH complex maintain mitochondrial functions which are happening when cells are exposed to hypoxia?” said Spinelli. “So, we knocked out SDH complex and then we demonstrated through a number of means that loss of both oxygen and fumarate as an electron acceptors was sufficient to [bring the electron transport chain to a halt].”
All this work was done in cultured cells, so the next step for Spinelli and collaborators was to study whether fumarate could serve as a terminal electron acceptor in mouse models.
When they tried this, the team uncovered something NetBet live casinointeresting: some, but not all, of the mice’s tissues were able to successfully reverse the activity of the SDH complex and perform mitochondrial functions using fumarate as a terminal electron acceptor.
“What was really cool to see is that there were three tissues — the kidney, the liver, and the brain — which on a bulk tissue scale, are operating the SDH complex in a backwards direction, even at physiological oxygen levels,” said Spinelli. In other words, even in normal conditions, these tissues were reducing both fumarate and oxygen to maintain their functions, and when deprived of oxygen, fumarate could take over as a terminal electron acceptor.
In contrast, tissues such as the heart and the skeletal muscle are able to perform minimal fumarate reduction without reversing the SDH complex, but not to the extent that they could effectively retain mitochondrial function when deprived of oxygen.
“We think there’s a lot of exciting work downstream of this to figure out how exactly this process is regulated differently in different tissues — and understanding in disease settings whether the SDH complex is operating in the net reverse direction,” Spinelli said.
In particular, Spinelli is interested in studying the behavior of the SDH complex in cancer cells.
“Certain regions of solid tumors have very low levels of oxygen, and certain regions have high levels of oxygen,” Spinelli said. “It’s interesting to think about how those cells are surviving in that microenvironment — are they using fumarate as an electron acceptor to enable cell survival?”
