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Gene-editing technique could speed up study of cancer mutations

With the new method, scientists can explore many cancer mutations whose roles are unknown, helping them develop new drugs that target those mutations.

Anne Trafton | MIT News Office
May 11, 2023

Genomic studies of cancer patients have revealed thousands of mutations linked to tumor development. However, for the vast majority of those mutations, researchers are unsure of how they contribute to cancer because there’s no easy way to study them in animal models.

In an advance that could help scientists make a dent in that long list of unexplored mutations, MIT researchers have developed a way to easily engineer specific cancer-linked mutations into mouse models.

Using this technique, which is based on CRISPR genome-editing technology, the researchers have created models of several different mutations of the cancer-causing gene Kras, in different organs. They believe this technique could also be used for nearly any other type of cancer mutation that has been identified.

Such models could help researchers identify and test new drugs that target these mutations.

“This is a remarkably powerful tool for examining the effects of essentially any mutation of interest in an intact animal, and in a fraction of the time required for earlier methods,” says Tyler Jacks, the David H. Koch Professor of Biology, a member of the Koch Institute for Integrative Cancer Research at MIT, and one of the senior authors of the new study.

Francisco Sánchez-Rivera, an assistant professor of biology at MIT and member of the Koch Institute, and David Liu, a professor in the Harvard University Department of Chemistry and Chemical Biology and a core institute member of the Broad Institute, are also senior authors of the study, which appears today in Nature Biotechnology.

Zack Ely PhD ’22, a former MIT graduate student who is now a visiting scientist at MIT, and MIT graduate student Nicolas Mathey-Andrews are the lead authors of the paper.

Faster editing

Testing cancer drugs in mouse models is an important step in determining whether they are safe and effective enough to go into human clinical trials. Over the past 20 years, researchers have used genetic engineering to create mouse models by deleting tumor suppressor genes or activating cancer-promoting genes. However, this approach is labor-intensive and requires several months or even years to produce and analyze mice with a single cancer-linked mutation.

“A graduate student can build a whole PhD around building a model for one mutation,” Ely says. “With traditional models, it would take the field decades to catch up to all of the mutations we’ve discovered with the Cancer Genome Atlas.”

In the mid-2010s, researchers began exploring the possibility of using the CRISPR genome-editing system to make cancerous mutations more easily. Some of this work occurred in Jacks’ lab, where Sánchez-Rivera (then an MIT graduate student) and his colleagues showed that they could use CRISPR to quickly and easily knock out genes that are often lost in tumors. However, while this approach makes it easy to knock out genes, it doesn’t lend itself to inserting new mutations into a gene because it relies on the cell’s DNA repair mechanisms, which tend to introduce errors.

Inspired by research from Liu’s lab at the Broad Institute, the MIT team wanted to come up with a way to perform more precise gene-editing that would allow them to make very targeted mutations to either oncogenes (genes that drive cancer) or tumor suppressors.

In 2019, Liu and colleagues reported a new version of CRISPR genome-editing called prime editing. Unlike the original version of CRISPR, which uses an enzyme called Cas9 to create double-stranded breaks in DNA, prime editing uses a modified enzyme called Cas9 nickase, which is fused to another enzyme called reverse transcriptase. This fusion enzyme cuts only one strand of the DNA helix, which avoids introducing double-stranded DNA breaks that can lead to errors when the cell repairs the DNA.

The MIT researchers designed their new mouse models by engineering the gene for the prime editor enzyme into the germline cells of the mice, which means that it will be present in every cell of the organism. The encoded prime editor enzyme allows cells to copy an RNA sequence into DNA that is incorporated into the genome. However, the prime editor gene remains silent until activated by the delivery of a specific protein called Cre recombinase.

Since the prime editing system is installed in the mouse genome, researchers can initiate tumor growth by injecting Cre recombinase into the tissue where they want a cancer mutation to be expressed, along with a guide RNA that directs Cas9 nickase to make a specific edit in the cells’ genome. The RNA guide can be designed to induce single DNA base substitutions, deletions, or additions in a specified gene, allowing the researchers to create any cancer mutation they wish.

Modeling mutations

To demonstrate the potential of this technique, the researchers engineered several different mutations into the Kras gene, which drives about 30 percent of all human cancers, including nearly all pancreatic adenocarcinomas. However, not all Kras mutations are identical. Many Kras mutations occur at a location known as G12, where the amino acid glycine is found, and depending on the mutation, this glycine can be converted into one of several different amino acids.

The researchers developed models of four different types of Kras mutations found in lung cancer: G12C, G12D, G12R, and G12A. To their surprise, they found that the tumors generated in each of these models had very different traits. For example, G12R mutations produced large, aggressive lung tumors, while G12A tumors were smaller and progressed more slowly.

Learning more about how these mutations affect tumor development differently could help researchers develop drugs that target each of the different mutations. Currently, there are only two FDA-approved drugs that target Kras mutations, and they are both specific to the G12C mutation, which accounts for about 30 percent of the Kras mutations seen in lung cancer.

The researchers also used their technique to create pancreatic organoids with several different types of mutations in the tumor suppressor gene p53, and they are now developing mouse models of these mutations. They are also working on generating models of additional Kras mutations, along with other mutations that help to confer resistance to Kras inhibitors.

“One thing that we’re excited about is looking at combinations of mutations including Kras mutations that drives tumorigenesis, along with resistance associated mutations,” Mathey-Andrews says. “We hope that will give us a handle on not just whether the mutation causes resistance, but what does a resistant tumor look like?”

The researchers have made mice with the prime editing system engineered into their genome available through a repository at the Jackson Laboratory, and they hope that other labs will begin to use this technique for their own studies of cancer mutations.

The research was funded by the Ludwig Center at MIT, the National Cancer Institute, a Howard Hughes Medical Institute Hanna Grey Fellowship, the V Foundation for Cancer Research, a Koch Institute Frontier Award, the MIT Research Support Committee, a Helen Hay Whitney Postdoctoral Fellowship, the David H. Koch Graduate Fellowship Fund, the National Institutes of Health, and the Lustgarten Foundation for Pancreatic Cancer Research.

Other authors of the paper include Santiago Naranjo, Samuel Gould, Kim Mercer, Gregory Newby, Christina Cabana, William Rideout, Grissel Cervantes Jaramillo, Jennifer Khirallah, Katie Holland, Peyton Randolph, William Freed-Pastor, Jessie Davis, Zachary Kulstad, Peter Westcott, Lin Lin, Andrew Anzalone, Brendan Horton, Nimisha Pattada, Sean-Luc Shanahan, Zhongfeng Ye, Stefani Spranger, and Qiaobing Xu.

Inaugural J-WAFS Grand Challenge aims to develop enhanced crop variants and move them from lab to land

Matt Shoulders will lead an interdisciplinary team to improve RuBisCO — the photosynthesis enzyme thought to be the holy grail for improving agricultural yield.

Carolyn Blais | Abdul Latif Jameel Water and Food Systems Lab
May 10, 2023

According to MIT’s charter, established in 1861, part of the Institute’s mission is to advance the “development and practical application of science in connection with arts, agriculture, manufactures, and commerce.” Today, the Abdul Latif Jameel Water and Food Systems Lab (J-WAFS) is one of the driving forces behind water and food-related research on campus, much of which relates to agriculture. In 2022, J-WAFS established the Water and Food Grand Challenge Grant to inspire MIT researchers to work toward a water-secure and food-secure future for our changing planet. Not unlike MIT’s Climate Grand Challenges, the J-WAFS Grand Challenge seeks to leverage multiple areas of expertise, programs, and Institute resources. The initial call for statements of interests returned 23 letters from MIT researchers spanning 18 departments, labs, and centers. J-WAFS hosted workshops for the proposers to present and discuss their initial ideas. These were winnowed down to a smaller set of invited concept papers, followed by the final proposal stage.

Today, J-WAFS is delighted to report that the inaugural J-WAFS Grand Challenge Grant has been awarded to a team of researchers led by Professor Matt Shoulders and research scientist Robert Wilson of the Department of Chemistry. A panel of expert, external reviewers highly endorsed their proposal, which tackles a longstanding problem in crop biology — how to make photosynthesis more efficient. The team will receive $1.5 million over three years to facilitate a multistage research project that combines cutting-edge innovations in synthetic and computational biology. If successful, this project could create major benefits for agriculture and food systems worldwide.

“Food systems are a major source of global greenhouse gas emissions, and they are also increasingly vulnerable to the impacts of climate change. That’s why when we talk about climate change, we have to talk about food systems, and vice versa,” says Maria T. Zuber, MIT’s vice president for research. “J-WAFS is central to MIT’s efforts to address the interlocking challenges of climate, water, and food. This new grant program aims to catalyze innovative projects that will have real and meaningful impacts on water and food. I congratulate Professor Shoulders and the rest of the research team on being the inaugural recipients of this grant.”

Shoulders will work with Bryan Bryson, associate professor of biological engineering, as well as Bin Zhang, associate professor of chemistry, and Mary Gehring, a professor in the Department of Biology and the Whitehead Institute for Biomedical Research. Robert Wilson from the Shoulders lab will be coordinating the research effort. The team at MIT will work with outside collaborators Spencer Whitney, a professor from the Australian National University, and Ahmed Badran, an assistant professor at the Scripps Research Institute. A milestone-based collaboration will also take place with Stephen Long, a professor from the University of Illinois at Urbana-Champaign. The group consists of experts in continuous directed evolution, machine learning, molecular dynamics simulations, translational plant biochemistry, and field trials.

“This project seeks to fundamentally improve the RuBisCO enzyme that plants use to convert carbon dioxide into the energy-rich molecules that constitute our food,” says J-WAFS Director John H. Lienhard V. “This difficult problem is a true grand challenge, calling for extensive resources. With J-WAFS’ support, this long-sought goal may finally be achieved through MIT’s leading-edge research,” he adds.

RuBisCO: No, it’s not a new breakfast cereal; it just might be the key to an agricultural revolution

A growing global population, the effects of climate change, and social and political conflicts like the war in Ukraine are all threatening food supplies, particularly grain crops. Current projections estimate that crop production must increase by at least 50 percent over the next 30 years to meet food demands. One key barrier to increased crop yields is a photosynthetic enzyme called Ribulose-1,5-Bisphosphate Carboxylase/Oxygenase (RuBisCO). During photosynthesis, crops use energy gathered from light to draw carbon dioxide (CO2) from the atmosphere and transform it into sugars and cellulose for growth, a process known as carbon fixation. RuBisCO is essential for capturing the CO2 from the air to initiate conversion of CO2 into energy-rich molecules like glucose. This reaction occurs during the second stage of photosynthesis, also known as the Calvin cycle. Without RuBisCO, the chemical reactions that account for virtually all carbon acquisition in life could not occur.

Unfortunately, RuBisCO has biochemical shortcomings. Notably, the enzyme acts slowly. Many other enzymes can process a thousand molecules per second, but RuBisCO in chloroplasts fixes less than six carbon dioxide molecules per second, often limiting the rate of plant photosynthesis. Another problem is that oxygen (O2) molecules and carbon dioxide molecules are relatively similar in shape and chemical properties, and RuBisCO is unable to fully discriminate between the two. The inadvertent fixation of oxygen by RuBisCO leads to energy and carbon loss. What’s more, at higher temperatures RuBisCO reacts even more frequently with oxygen, which will contribute to decreased photosynthetic efficiency in many staple crops as our climate warms.

The scientific consensus is that genetic engineering and synthetic biology approaches could revolutionize photosynthesis and offer protection against crop losses. To date, crop RuBisCO engineering has been impaired by technological obstacles that have limited any success in significantly enhancing crop production. Excitingly, genetic engineering and synthetic biology tools are now at a point where they can be applied and tested with the aim of creating crops with new or improved biological pathways for producing more food for the growing population.

An epic plan for fighting food insecurity

The 2023 J-WAFS Grand Challenge project will use state-of-the-art, transformative protein engineering techniques drawn from biomedicine to improve the biochemistry of photosynthesis, specifically focusing on RuBisCO. Shoulders and his team are planning to build what they call the Enhanced Photosynthesis in Crops (EPiC) platform. The project will evolve and design better crop RuBisCO in the laboratory, followed by validation of the improved enzymes in plants, ultimately resulting in the deployment of enhanced RuBisCO in field trials to evaluate the impact on crop yield.

Several recent developments make high-throughput engineering of crop RuBisCO possible. RuBisCO requires a complex chaperone network for proper assembly and function in plants. Chaperones are like helpers that guide proteins during their maturation process, shielding them from aggregation while coordinating their correct assembly. Wilson and his collaborators previously unlocked the ability to recombinantly produce plant RuBisCO outside of plant chloroplasts by reconstructing this chaperone network in Escherichia coli (E. coli). Whitney has now established that the RuBisCO enzymes from a range of agriculturally relevant crops, including potato, carrot, strawberry, and tobacco, can also be expressed using this technology. Whitney and Wilson have further developed a range of RuBisCO-dependent E. coli screens that can identify improved RuBisCO from complex gene libraries. Moreover, Shoulders and his lab have developed sophisticated in vivo mutagenesis technologies that enable efficient continuous directed evolution campaigns. Continuous directed evolution refers to a protein engineering process that can accelerate the steps of natural evolution simultaneously in an uninterrupted cycle in the lab, allowing for rapid testing of protein sequences. While Shoulders and Badran both have prior experience with cutting-edge directed evolution platforms, this will be the first time directed evolution is applied to RuBisCO from plants.

Artificial intelligence is changing the way enzyme engineering is undertaken by researchers. Principal investigators Zhang and Bryson will leverage modern computational methods to simulate the dynamics of RuBisCO structure and explore its evolutionary landscape. Specifically, Zhang will use molecular dynamics simulations to simulate and monitor the conformational dynamics of the atoms in a protein and its programmed environment over time. This approach will help the team evaluate the effect of mutations and new chemical functionalities on the properties of RuBisCO. Bryson will employ artificial intelligence and machine learning to search the RuBisCO activity landscape for optimal sequences. The computational and biological arms of the EPiC platform will work together to both validate and inform each other’s approaches to accelerate the overall engineering effort.

Shoulders and the group will deploy their designed enzymes in tobacco plants to evaluate their effects on growth and yield relative to natural RuBisCO. Gehring, a plant biologist, will assist with screening improved RuBisCO variants using the tobacco variety Nicotiana benthamianaI, where transient expression can be deployed. Transient expression is a speedy approach to test whether novel engineered RuBisCO variants can be correctly synthesized in leaf chloroplasts. Variants that pass this quality-control checkpoint at MIT will be passed to the Whitney Lab at the Australian National University for stable transformation into Nicotiana tabacum (tobacco), enabling robust measurements of photosynthetic improvement. In a final step, Professor Long at the University of Illinois at Urbana-Champaign will perform field trials of the most promising variants.

Even small improvements could have a big impact

A common criticism of efforts to improve RuBisCO is that natural evolution has not already identified a better enzyme, possibly implying that none will be found. Traditional views have speculated a catalytic trade-off between RuBisCO’s specificity factor for CO2 / O2 versus its CO2 fixation efficiency, leading to the belief that specificity factor improvements might be offset by even slower carbon fixation or vice versa. This trade-off has been suggested to explain why natural evolution has been slow to achieve a better RuBisCO. But Shoulders and the team are convinced that the EPiC platform can unlock significant overall improvements to plant RuBisCO. This view is supported by the fact that Wilson and Whitney have previously used directed evolution to improve CO2 fixation efficiency by 50 percent in RuBisCO from cyanobacteria (the ancient progenitors of plant chloroplasts) while simultaneously increasing the specificity factor.

The EPiC researchers anticipate that their initial variants could yield 20 percent increases in RuBisCO’s specificity factor without impairing other aspects of catalysis. More sophisticated variants could lift RuBisCO out of its evolutionary trap and display attributes not currently observed in nature. “If we achieve anywhere close to such an improvement and it translates to crops, the results could help transform agriculture,” Shoulders says. “If our accomplishments are more modest, it will still recruit massive new investments to this essential field.”

Successful engineering of RuBisCO would be a scientific feat of its own and ignite renewed enthusiasm for improving plant CO2 fixation. Combined with other advances in photosynthetic engineering, such as improved light usage, a new green revolution in agriculture could be achieved. Long-term impacts of the technology’s success will be measured in improvements to crop yield and grain availability, as well as resilience against yield losses under higher field temperatures. Moreover, improved land productivity together with policy initiatives would assist in reducing the environmental footprint of agriculture. With more “crop per drop,” reductions in water consumption from agriculture would be a major boost to sustainable farming practices.

“Our collaborative team of biochemists and synthetic biologists, computational biologists, and chemists is deeply integrated with plant biologists and field trial experts, yielding a robust feedback loop for enzyme engineering,” Shoulders adds. “Together, this team will be able to make a concerted effort using the most modern, state-of-the-art techniques to engineer crop RuBisCO with an eye to helping make meaningful gains in securing a stable crop supply, hopefully with accompanying improvements in both food and water security.”

Seychelle Vos and Hernandez Moura Silva named HHMI Freeman Hrabowski Scholars

The program supports early-career faculty who have strong potential to become leaders in their fields and to advance diversity, equity, and inclusion.

Lillian Eden | Department of Biology
May 9, 2023

Two faculty members from the MIT Department of Biology have been selected by the Howard Hughes Medical Institute (HHMI) for the inaugural cohort of HHMI Freeman Hrabowski Scholars.

Seychelle Vos, the Robert A. Swanson Career Development Professor of Life Sciences, and Hernandez Moura Silva, an assistant professor of biology and core member of the Ragon Institute of MGH, MIT and Harvard, are among 31 early-career faculty selected for their potential to become leaders in their research fields and to create diverse and inclusive lab environments in which everyone can thrive, according to a press release.

Freeman Hrabowski Scholars are appointed to a five-year term, renewable for a second five-year term after a successful progress evaluation. Each scholar will receive up to $8.6 million over 10 years, including full salary, benefits, a research budget, and scientific equipment. In addition, they will participate in professional development to advance their leadership and mentorship skills.

The Freeman Hrabowski Scholars Program represents a key component of HHMI’s diversity, equity, and inclusion goals. Over the next 20 years, HHMI expects to hire and support up to 150 Freeman Hrabowski Scholars — appointing roughly 30 scholars every other year for the next 10 years. The institute has committed up to $1.5 billion for the Freeman Hrabowski Scholars to be selected over the next decade. The program was named for Freeman A. Hrabowski III, president emeritus of the University of Maryland at Baltimore County, who played a major role in increasing the number of scientists, engineers, and physicians from backgrounds underrepresented in science in the United States.

Seychelle Vos

Seychelle Vos studies how DNA organization impacts gene expression at the atomic level, using cryogenic electron microscopy (cryo-EM), X-ray crystallography, biochemistry, and genetics. Human cells contain about 2 meters of DNA, which is packed so tightly that its entirety is contained within the nucleus, which is only a few microns across. Although DNA needs to be compacted, it also needs to be accessible to, and readable by, the cell’s molecular machinery.

Vos received a BS in genetics from the University of Georgia in 2008 and a PhD from University of California at Berkeley in 2013. During her postdoctoral research at the Max Planck Institute for Biophysical Chemistry in Germany, she determined how the molecular machine responsible for gene expression is regulated near gene promoters.

Vos joined MIT as an assistant professor of biology in fall 2019.

“I am very humbled and honored to have been named a HHMI Freeman Hrabowski Scholar,” Vos says. “It would not have been possible without the hard work of my lab and the help of my colleagues. It provides us with the support to achieve our ambitious research goals.”

Hernandez Moura Silva

Hernandez Moura Silva studies the role of immune cells in the maintenance and normal function of our bodies and tissues, beyond their role in battling infection. Specifically, he looks at a specific type of immune cell called a macrophage and its role in the proper function of white adipose tissue — our fat. White adipose tissue in a healthy state is highly populated by macrophages, including very abundant ones known as “vasculature-associated adipose tissue macrophages,” which are located around the blood vessels. When the activity of these adipose macrophages is disrupted, there are changes in the proper function of the white adipose tissue, which may ultimately link to disease. By understanding macrophage function in healthy tissues, Hernandez hopes to learn how to restore tissue homeostasis in disease.

Hernandez Moura Silva received a BS in biology in 2005 and an MSc in molecular biology in 2008 from the University of Brazil. He received his PhD in 2011 from the University of São Paulo Heart Institute. Silva pursued his postdoctoral work as the Bernard Levine Postdoctoral Fellow in immunology and immuno-metabolism at the New York University School of Medicine Skirball Institute of Biomolecular Medicine.

He joined MIT as an assistant professor of biology in 2022. He is also a core member of the Ragon Institute.

“For an immigrant coming from an underrepresented group, it’s a huge privilege to be granted this opportunity from HHMI that will empower me and my lab to shape the next generation of scientists and provide an environment where people can feel welcome and encouraged to do the science that they love and be successful,” Silva says. “It also aligns with MIT’s commitment to increase diversity and opportunity across the Institute and to become a place where all people can thrive.”

New peptide modulators of the pro-apoptotic protein BAK

Biophysical characteristics such as peptide binding affinity and kinetics do not determine cell death function

Lillian Eden | Department of Biology
May 9, 2023

Billions of times a day, every day of our lives, cells receive signals to initiate the process of cell death. This strategic cell death, also called apoptosis, is one of the tools multicellular organisms use to maintain tissues and regulate immune responses: damaged, old, or superfluous cells are given the green light to, as it were, turn out the lights for the last time.

Programmed cell death is both extremely powerful and extremely regulated: for example, the careful culling of cells between our digits during embryonic development reveals fingers and toes. When programmed cell death goes awry, however, it can have serious consequences. Cells left unchecked can divide unstoppably and aggressively, leading to cancer. Dysregulated apoptotic pathways have also been implicated in neurodegenerative diseases like Alzheimer’s, where unrestrained cell death may play a part in the severity of the disease.

MIT Professor H. Robert Horvitz ‘68 shared a Nobel prize in 2002 for his foundational research on the genetics of programmed cell death and organ development in the nematode, a microscopic roundworm. Horvitz discovered that ced-9, a key gene in programmed cell death in nematodes, was similar in structure and function to the human gene bcl-2.

Targeting members of the BCL-2 protein family has already shown promise in the fight against cancer. For example, approved by the FDA in 2016, the oral drug Venetoclax is a BCL-2 inhibitor used to treat certain types of leukemia.

In a study published online Jan. 26 in Structure, Fiona Aguilar PhD ‘22 (Keating lab) and collaborators focused on a member of the BCL-2 protein family called BAK. When it is active, BAK promotes mitochondrial outer membrane disruption, leading to cell death, and is therefore referred to as a pro-apoptotic protein. But precisely how BAK becomes activated – or inhibited – is unknown.

“A greater understanding of BAK activation is interesting both from a fundamental biochemical and biophysical perspective as well as from the more translational one of BAK as a potential therapeutic target,” says lead author Fiona Aguilar.

BAK exists in two different forms: an inactive monomer and an active oligomer. A few activators of BAK (BIM, truncated BID, and PUMA) have already been identified and these proteins bind directly to BAK, leading to the model that binding of activators trigger changes in protein shape that allow BAK to transition from the inactive to active forms. To further explore this idea, Aguilar identified and characterized a number of other peptides that bind to and regulate BAK. To identify new peptide binders, the team used cell-surface display screening and computational protein design methods, including techniques developed by Keating lab alum Gevorg Grigoryan– dTERMen and TERMify – that use protein structural data to generate new protein sequences likely to bind a protein of interest.

In total, Aguilar et al. discovered 10 diverse new peptide binders of BAK that regulate its function.

Interestingly, some of the BAK-binding peptides inhibited activation rather than promoting it. Aguilar et al. found that inhibitors and activators of BAK shared many characteristics including structure as well as binding affinity and kinetics – the strength and rate that binders associate with and dissociate from BAK.

Newly identified activators had sequences both dissimilar from one another and from the previously known BAK activators BIM, truncated BID, and PUMA. The similarity of the sequence was not necessarily a good indicator of activation or inhibition. For example, an inhibitor and an activator differed by just two amino acids.

Aguilar and colleagues solved the crystal structures of two inhibitor-BAK complexes and one activator-BAK complex and found that the activator interacted with BAK with similar geometry as the two inhibitors. Also, the two inhibitors have only about 40% sequence identity, but bind very similarly to BAK.

Amy Keating, the senior author on the study, says “Fiona was tireless in identifying new peptides, testing their interactions with BAK, determining their functions, and solving structures to look for differences between activators and inhibitors. We were surprised that peptides with such different behaviors shared such common interaction properties.”

Although the puzzle is not yet solved, Aguilar believes the “transition state” between inactive and active forms of BAK is key.

“We think of activators as peptides that preferentially bind to the BAK transition state, whereas inhibitors are those that preferentially bind to the monomeric state,” Aguilar says. “Overall, we should be thinking more about the transition state, what steps are necessary to reach the transition state, and how to target the transition state.”

This study also added two sequences in the human proteome – BNIP5 and PXT1 – to the repertoire of known BAK binders. Not much is known about these sequences, Aguilar says, but the fact that they activate BAK could indicate that they may play a role in apoptotic pathways that have not yet been determined.

“The finding is something that people in the field are pretty excited about,” Aguilar says.

Ultimately, work remains to establish what characteristics of the binders determine their function, and how binding to BAK triggers the conformational changes that activate or inhibit this complex protein.

“It’s still unclear what it is about these sequences that trigger the allosteric network leading to BAK activation, but at least for now we can rule out the hypothesis that binding mode, affinity, and kinetics fully determine how this occurs,” Aguilar says.

Aguilar suggests that it will be interesting also to explore how these peptides interact with BAX, another pro-apoptotic protein in the BCL-2 family that is both structurally and functionally similar to BAK.

Fiona Aguilar is lead author and Amy Keating is senior author; Bob Grant and graduate students Sebastian Swanson, Dia Ghose, and Bonnie Su contributed. Collaborators Stacey Yu and Kristopher Sarosiek, from the Harvard T.H. Chan School of Public Health, helped with cell-based experiments. The research was funded by a National Institute of General Medical Sciences award, the MIT School of Science Fellowship in Cancer Research award, the John W. Jarve (1978) Seed Fund for Science Innovation (MIT) award, an award from the National Cancer Institute, a National Institute of Diabetes and Digestive and Kidney Diseases award, and Alex’s Lemonade Stand Foundation for Childhood Cancers award.

Third annual MIT Research Slam showcase highlights PhD and postdoc communication skills

Biology grad student Neha Bokil (Page lab) won audience choice and runner up prizes.

MIT Career Advising and Professional Development
May 3, 2023

An 80,000 word PhD thesis would take many hours to present. MIT Research Slam competitors get three minutes.

The finalists of the 2023 MIT Research Slam competition met head-to-head on April 19 at a live, in-person showcase event. Four PhD candidates and five postdoc finalists competed for the judges’ and audience’s vote. The contestants put their skills to the test as they took on the challenge of communicating why their research matters to a live audience in only 180 seconds. This follows the format of the 3-Minute Thesis research communication competition embraced by over 200 universities around the world. Aside from the thrill of competition, these events provide opportunities for trainees to develop and showcase their research communication skills.

During the weeks leading up to the event, participants joined training workshops on pitch content and delivery, and had the opportunity to work one-on-one with educators from the Writing and Communication Center, English Language Studies, Career Advising and Professional Development, and the Engineering Communication Labs, all of which co-sponsored and co-produced the event.

The event was masterfully emceed by Deanna Montgomery, Communication Lab manager at the Department of Electrical Engineering and Computer Science (EECS). “The MIT Research Slam is a wonderful celebration of both research and communication,” she says. “I was honored to serve as the emcee of the first in-person Research Slam Showcase and have the opportunity to share the stage with this group of talented researchers and creative communicators.​”

Eric Grunwald, director of English language studies and part of the Research Slam planning team, reflects: “The Research Slam is a wonderful opportunity for any research trainee who is looking for more training in academic communication. I think it is also particularly useful for second-language PhD students and postdocs who want to think through how to best present their work to a diverse English-speaking audience. Telling the story of their research in a way that is interesting, understandable, and important, all in three minutes — and getting feedback and revising and revising — is an invaluable practice. Some competitors report that they’ve gone on to use their Research Slam pitch and slide in successful job talks. So it’s really a no-lose proposition for second-language students.”

A panel of accomplished judges gave feedback after each of the talks: Bruce Birren, director of the Genomic Center for Infectious Diseases, Institute Scientist; Suzanne Lane, director of the Writing, Rhetoric, and Professional Communication (WRAP) program; and Brittany Trang, STAT News and Science Reporting Fellow with the Knight Science Journalism Program at MIT.

“It was great to learn about so much interesting research from such accomplished speakers,” Trang says. “The participants really made me think about what makes a good presentation and made it hard to choose winners.”

At the end of the night, Eric Wang was the judges’ choice in the PhD category, and Neha Bokil was the runner-up. Bokil also won the hearts of the viewers and walked away with the Audience Choice Award.

In the postdoc class, Dirk Lauinger took the top honor, and Alaa Algargoosh took both second place and the Audience Choice Award. After the competition, Dirk reflected: “I really enjoyed the Research Slam. It was fun to meet other people and learn about their research. I had met Chris Rabe, another finalist, a couple months back at another event and was interested in learning more about his research. We buddied up to train for the slam together and this was a nice opportunity to get to know each other better. Thanks to the preparatory sessions, I learned about the Writing and Communications Center (WCC) at MIT. What a great discovery. It was a lot of fun to bounce ideas off the WCC staff. Training for the slam also helped me take a step back and see the bigger picture of my research, which was very helpful for a fellowship application I wrote last month.”

The first-place finishers received a $600 cash prize, while the runners-up and audience choice winners each received $300.

Last year’s winner in the PhD category, Leonard Broussard, will represent MIT at the Ivy+ level of the 3MT competition.

A full list of slam finalists and the titles of their talks is below.

PhD students:

  • Neha Bokil, Department of Biology, “Why Our Sex Chromosomes Matter”
  • Bradley Turner, Management: Economic Sociology, “The Storytelling Entrepreneur Has No Clothes: Risks and Rewards of Narrative Pitching”
  • Eric Wang, Institute for Medical Engineering and Science, “A vaccine that works against any COVID variant”
  • Sadie Zacharek, Department of Brain and Cognitive Sciences, “Neuromarkers of Social Anxiety Disorder”

​​      Postdocs: 

  • Alaa Algargoosh, Media Lab, “Aural Affect: The impact of acoustic environments on emotions, experience and well-being”
  • Hanna de Jong, Department of Biology, “Reading the sugar alphabet”
  • Dirk Lauinger, MIT Sloan School of Management, “Vehicle-to-Grid: Mobile energy storage from electric vehicles”
  • Chris Rabe, Environmental Solutions Initiative, “Understanding Environmental Justice Exclusion in Higher Education”
  • Sharmelee Selvaraji, Bioelectronics Group, Research Laboratory of Electronics, “‘Gut feelings’ of Parkinson’s disease”

Research Slam organizers included Diana Chien, director of MIT School of Engineering Communication Lab; Simona Rosu, senior assistant director of postdoctoral career and professional development at MIT Career Advising and Professional Development (CAPD); Elena Kallestinova, director of MIT Writing and Communication Center; Alexis Boyer, assistant director of graduate career services with CAPD; and Amanda Cornwall, associate director of graduate student professional development with CAPD. Deanna Montgomery, Communication Lab manager at MIT EECS was the emcee. Prizes were sponsored by MIT Career Advising and Professional Development.

The measuring tape heard round the world

Professor Emerita Nancy Hopkins and journalist Kate Zernike discuss the past, present, and future of women at MIT.

Phie Jacobs | School of Science
May 1, 2023

On a recent evening at MIT, over a hundred people gathered at Boynton Hall for a conversation with Amgen Professor of Biology Emerita Nancy Hopkins and journalist Kate Zernike. The topic of discussion was Zernike’s book, “The Exceptions: Nancy Hopkins, MIT, and the Fight for Women in Science,” which made its official debut at the end of February.

“The Exceptions” centers on Hopkins’ remarkable life and career and tells the story of 16 “exceptional” female scientists on the MIT faculty, who, with Hopkins as their unlikely leader, became heroes in the fight for gender equality. As a result of their work, in 1999 MIT publicly admitted to discriminating against its female faculty, a move that forced academic institutions across the country to reckon with pervasive sexism in science. Kate Zernike, now a correspondent at The New York Times, was a reporter at The Boston Globe at the time and was the first to break the story of MIT’s historic admission.

The discussion, which fittingly took place on International Women’s Day, began with an introduction from Nergis Mavalvala, the Curtis and Kathleen Marble Professor of Astrophysics and dean of the School of Science, who sponsored the event with the Department of Biology. After welcoming attendees, both in-person and virtual, she shared an anecdote about the tools that scientists use to measure things. “I’m an experimental physicist,” she explained. “My entire research career has been spent measuring very, very precise distances.” As a result, Mavalvala was fascinated with one particular incident from Hopkins’ career, which is chronicled in chapter 15 of “The Exceptions.”

In 1973, Hopkins became an assistant professor at MIT’s Center for Cancer Research, which would later become the Koch Institute for Integrative Cancer Research. She spent more than a decade mapping RNA tumor virus genes before switching research fields to develop molecular technologies for working with zebra fish. The work required funding, equipment, and — most importantly — more space in which to house her fish tanks. But Hopkins’s male colleagues routinely took up more than their fair share of all of those resources. After more than 10 years at MIT, Hopkins still had less laboratory space than any other senior faculty member in the building. The head of the cancer center refused to believe that things were so unequal, so one night in 1993, Hopkins got down on her hands and knees with a measuring tape and proved it.

Mavalvala, whose research depends on precise measurement, found herself particularly affected by the story. “I have this newfound regard for the lowly measuring tape,” she declared.

“The story struck me, in a way that I think you more than any other audience can appreciate, as very MIT,” Zernike recalled to the attendees. This sort of thing could only happen, she thought, at an institution whose Latin motto translates to “mind and hand.”

When Zernike’s editor tipped her off that something was happening at MIT regarding gender discrimination, she had initially been skeptical. It was 1999, and so many doors had already been opened for women — surely the fight for equality was pretty much over. If few women pursued careers in science, perhaps they just weren’t interested. Science, after all, was a meritocracy.

Hopkins had spent much of her career assuming the same thing. For decades, she dealt with subtle and blatant instances of discrimination. She was told she could not teach genetics on the grounds that students wouldn’t trust information coming from a female professor. Despite years of hard work and numerous ingenious discoveries, she struggled to obtain tenure. And she simply wasn’t getting the same respect, money, or space that the men on the faculty did.

Hopkins eventually joined forces with 15 other women on the MIT science faculty to bring the issue of gender discrimination to light. After four years of work, and with the unexpected endorsement of the university administration, they produced the 1999 “A Study on the Status of Women Faculty in Science at MIT.”

The results of the study suggested that science was not, in fact, a meritocracy. Women were interested in pursuing degrees and careers in science, but they encountered barriers every step of the way. Between blatant acts of discrimination as well as unconscious bias, it was simply more difficult to make it as a woman in science.

Zernike adored that these women had addressed the problem the same way they would a science experiment — with rigorous data analysis and an MIT mindset. But she was equally fascinated by MIT’s response to the study results — their willingness to admit shortcomings, and their dedication to making things better. “In my business,” said Zernike, “that’s known as a man-bites-dog story.”

Though Zernike chose the title her book to refer to the 16 “exceptional” female scientists who had the courage to openly acknowledge and fight back against discrimination, she also said it could apply as well to the Institute’s administration, which admitted wrongdoing and made significant changes as a result. “I would say that MIT itself is the exception for having done this,” Zernike said.

Following her remarks, Zernike was joined on stage by Hopkins for a conversation about the writing of “The Exceptions.” Hopkins described knowing early on that her story and the stories of the 15 other female faculty members were exceptional and that they would need an “exceptional writer.” “You have to have a rigorous New York Times reporter,” she joked. “Somebody who gets the dirt.”

The event ended with an audience Q&A session, during which audience members, including current MIT students, expressed frustration with the continued impact of sexism in science, and Zernike and Hopkins discussed the work that still remains to be done to achieve equality.

MIT’s Program in Women’s and Gender Studies hosted a similar discussion on April 26. Moderated by Ruth Perry, professor emerita of literature, the event featured a panel including Zernike; Hopkins; Leigh Royden, the Cecil and Ida Green Professor of Geology and Geophysics in the Department of Earth, Atmospheric and Planetary Sciences; Lorna Gibson, the Matoula S. Salapatas Professor of Materials Science and Engineering, a professor of mechanical engineering and MacVicar Fellow in the Department of Materials Science and Engineering; and Sangeeta Bhatia, the John J. and Dorothy Wilson Professor of Health Sciences and Technology and a professor of electrical engineering and computer science. The event was co-sponsored by the School of Humanities, Arts and Social Sciences’ programs in History, STS, Literature, and Comparative Media Studies/Writing.

Desmond Edwards ’22 awarded 2023 Paul and Daisy Soros Fellowship for New Americans

Fellowship funds graduate studies for outstanding immigrants and children of immigrants.

Julia Mongo | Office of Distinguished Fellowships | MIT Career Advising and Professional Development
April 25, 2023

MIT graduate students Kat Kajderowicz and Shomik Verma, alumni Desmond Edwards ’22 and Steven Truong ’20, and Vaibhav Mohanty, an MD-PhD student in the Harvard-MIT Program in Health Sciences and Technology, are among the 30 recipients of this year’s Paul and Daisy Soros Fellowships for New Americans.

The P.D. Soros Fellowships for New Americans program honors the contributions of immigrants and children of immigrants to the United States. The program recognizes the potential of immigrants to make significant contributions to U.S. society, culture, and academia by providing $90,000 in graduate school financial support over two years.

Students interested in applying to the P.D. Soros Fellowship may contact Kim Benard, associate dean of distinguished fellowships in Career Advising and Professional Development.

Desmond Edwards ’22

Desmond Edwards graduated from MIT in 2022 with a double major in biological engineering and biology and a minor in French. As a National Science Foundation GRFP Fellow and Jamaica’s first Knight-Hennessy Scholar, Edwards is currently a PhD student in microbiology and immunology at Stanford University’s School of Medicine, where he researches immunity to infectious diseases. He intends to lead a scientific career not only contributing to groundbreaking academic research, but also ensuring that the fruits of this research have their maximal benefit to society through public policy, outreach, and education.

Born and raised in Jamaica, Edwards lived in rural St. Mary and attended school in urban Kingston. His constant childhood illnesses prompted his interest in better understanding human disease and his desire to develop novel therapeutic options for their treatment and prevention. At MIT, Edwards conducted host-pathogen research in Professor Rebecca Lamason’s lab, focusing on characterizing mutants of interest and developing novel genetic tools for use in the tick-borne pathogen Rickettsia parkeri. As an Amgen Scholar, he also worked with Professor Viviana Gradinaru at Caltech to engineer solutions for a novel gene therapy for Rett syndrome, a neurodevelopmental disorder primarily seen in girls.

Interested not only in the technical details of scientific research but also in its societal impact, Edwards has dedicated himself to serving the community through roles in the MIT Biotech Group, student representation and advocacy, and teaching and mentorship. For his academic achievements and commitments to community and nation-building, he was awarded a 2022 Prime Minister’s National Youth Award for Excellence, the highest national award bestowed on Jamaicans between the ages of 15 and 29 by the Prime Minister of Jamaica.

Kathrin (Kat) Kajderowicz

Kat Kajderowicz is a neuroscience PhD student in the Department of Brain and Cognitive Sciences at MIT. She is co-advised by professors Sinisa Hrvatin and Jonathan Weissman at the Whitehead Institute for Biomedical Research and is researching how cells from hibernating organisms can survive cold temperatures to engineer human cells to do the same. Kajderowicz envisions her work improving organ transplantation and therapeutic hypothermia technologies. She hopes to someday lead a research group developing technologies that allow humans to safely enter and exit “hibernation-like” stasis for medical treatment purposes.

Kajderowicz grew up in Chicago’s large Polish-immigrant community. Her parents fled communist Poland in the early 1980s, arriving in the United States with no savings, college degrees, or knowledge of English. Kajderowicz’s mother worked as a housekeeper, while her father worked in construction. As undocumented immigrants fighting to obtain green cards, they spent most of their savings on the American naturalization process and rarely sought medical care because they couldn’t afford insurance and feared deportation. To help financially, Kajderowicz began working as a golf caddie at age 14. Her golf clients connected her with shadowing and interning opportunities at technology and biotechnology companies and hospitals, which inspired her career interests.

As an undergraduate at Cornell University, Kajderowicz worked at the Lab of Ornithology, where she built computational pipelines to better understand songbird communication. During undergraduate summers at Harvard University, she worked on comparative genomics and population genetics projects using plants, fruit flies, and butterflies. As a post-baccalaureate researcher at Harvard Medical School, she built imaging tools to visualize the development of different types of mouse retinal neurons.

In 2020, Kajderowicz’s father passed away from metastatic lung cancer. Kajderowicz served as his caregiver and medical proxy. Her greatest source of comfort was her hospital waiting room community. Inspired by the power of communities, Kajderowicz founded DNA Deviants, a 2,000-plus member biotechnology group that hosts podcasts on Twitch to discuss breakthrough research and organizes career mentorship programs.

Vaibhav Mohanty

Vaibhav Mohanty is pursuing an MD-PhD in the Harvard-MIT Program in Health Sciences and Technology, where he is earning a second PhD (in chemistry). His goal is to extend his physics-based theories of evolution to understand how molecular-level structural changes in proteins can induce changes in evolutionary fitness of viruses and cancers. Mohanty aspires to develop novel therapeutic approaches to combat diseases subject to evolution on fast timescales, and to treat patients with such diseases.

Mohanty was born in Durham, North Carolina, and grew up in Charleston, South Carolina. His parents emigrated from Odisha, India, to the United States to pursue academic research careers in biology. Accepted to Harvard College at age 15, Mohanty graduated in 2019 with a master’s degree in chemistry (theory) and a bachelor’s degree summa cum laude in chemistry and physics and a minor in music. He was inducted into the Phi Beta Kappa academic honor society and received a 2018 Barry Goldwater Scholarship for his physics research. As an undergraduate and master’s student, Mohanty’s published research papers spanned a number of interdisciplinary topics across the sciences and even music, including diffusion MRI physics, time-dependent quantum mechanics of graphene, and mathematical and geometrical models of voice leading in music theory. In 2022, Mohanty earned a PhD in theoretical physics as a Marshall Scholar at the University of Oxford’s Rudolf Peierls Centre for Theoretical Physics, where he worked in the Condensed Matter Theory Group to use statistical physics and spin glass theory to investigate fundamental properties of biological evolution.

In addition to being a scientific researcher, Mohanty is an award-winning classical and jazz music composer, arranger, pianist, and saxophonist. His large wind ensemble and chamber works are distributed and performed regularly around the United States and in many parts of the world. He actively performs as a jazz pianist.

Steven Truong ’20

Steven Truong graduated from MIT in 2020 with a double major in biological engineering and writing. He was inducted into Phi Beta Kappa and Tau Beta Pi and was also named a Barry Goldwater Scholar. As a Marshall Scholar in the United Kingdom, Truong completed an MPhil in computational biology at Cambridge University and an MA in creative writing at Royal Holloway, University of London. Currently, he is an MD-PhD student at Stanford University. In his future career, Truong aspires to help solve and treat metabolic disorders such as diabetes. He hopes to make these discoveries accessible — especially for communities traditionally underrepresented and underserved in medicine — as a physician-scientist, science communicator, and storyteller.

Truong was born in St. Paul, Minnesota, to Vietnamese refugees. His parents and relatives pooled their resources to start a family-owned nail salon. Truong spent his evenings after school at the salon, where he assisted in the business’s operations and finished homework between helping customers. In his free time, he avidly read science fiction and fantasy, which evolved into a passion for science. Truong eventually realized he could use science to address diabetes, a disease that affects much of his family and community.

During his undergraduate years at MIT, Truong worked in the Langer-Anderson Lab to develop smart insulins, and in the Lauffenburger Lab to study the link between the immune system and diabetes. With funding from MIT’s Undergraduate Research Opportunities Program, he started a study investigating the genetic basis of diabetes with colleagues at the University of Medicine and Pharmacy at Ho Chi Minh City. The data from this study were published, associating single nucleotide polymorphisms to Type 2 diabetes in Vietnamese individuals. Truong and his colleagues eventually secured a grant to expand their studies through the National Foundation for Science Technology and Development. The grant currently funds Vietnam’s largest genome-wide association study, which he co-leads.

Shomik Verma

Shomik Verma is pursuing a PhD in mechanical engineering at MIT with Professor Asegun Henry, where he is working on energy storage to make variable renewable energy sources such as solar more reliable, and on a next-generation power plant based on thermophotovoltaic power conversion. After his PhD, Verma hopes to use his skill set to decarbonize industry and make cheap, clean, and reliable energy available to all.

Growing up in Sugar Land, Texas, Verma maintained a deep connection to Indian culture. There was a strong emphasis on education, and he spent many weekends at math competitions with fellow Asian Americans. Verma started noticing some interesting patterns at the math competitions he attended — oil and gas companies would often sponsor them, and the conversations his petroleum engineer father had with his friends often turned to the geopolitics of energy. Verma was struck by the realization that he lived in the oil and gas capital of the world, with parents who were from the coal capital of India. He was caught between two worlds — the fossil fuel industry that enabled his way of life, and the growing threat of global warming he learned about in school.

When Verma lost his uncle to black lung, he decided it was time to devote his life to clean energy. While studying mechanical engineering at Duke University, he helped lead the Duke Electric Vehicles team to two Guinness world records for fuel efficiency, for both battery electric and fuel cell vehicles. In the U.K., as a Marshall Scholar, he completed an MPhil in materials science and conducted research at Imperial College London and the University of Cambridge, working on improving the efficiency of solar cells.

Yamashita elected to American Academy of Arts and Sciences for 2023

The prestigious honor society announces more than 250 new members, including MIT Biology Professor Yukiko Yamashita.

MIT News Office
April 24, 2023

Eight MIT faculty members are among more than 250 leaders from academia, the arts, industry, public policy, and research elected to the American Academy of Arts and Sciences, the academy announced April 19.

One of the nation’s most prestigious honorary societies, the academy is also a leading center for independent policy research. Members contribute to academy publications, as well as studies of science and technology policy, energy and global security, social policy and American institutions, the humanities and culture, and education.

Those elected from MIT in 2023 are:

  • Arnaud Costinot, professor of economics;
  • James J. DiCarlo, the Peter de Florez Professor of Brain and Cognitive Sciences and director of the MIT Quest for Intelligence;
  • Piotr Indyk, the Thomas D. and Virginia W. Cabot Professor of Electrical Engineering and Computer Science;
  • Senthil Todadri, professor of physics;
  • Evelyn N. Wang, the Ford Professor of Engineering (on leave) and director of the Department of Energy’s Advanced Research Projects Agency-Energy;
  • Boleslaw Wyslouch, professor of physics and director of the Laboratory for Nuclear Science and Bates Research and Engineering Center;
  • Yukiko Yamashita, professor of biology and core member of the Whitehead Institute; and
  • Wei Zhang, professor of mathematics.

“With the election of these members, the academy is honoring excellence, innovation, and leadership and recognizing a broad array of stellar accomplishments. We hope every new member celebrates this achievement and joins our work advancing the common good,” says David W. Oxtoby, president of the academy.

Since its founding in 1780, the academy has elected leading thinkers from each generation, including George Washington and Benjamin Franklin in the 18th century, Maria Mitchell and Daniel Webster in the 19th century, and Toni Morrison and Albert Einstein in the 20th century. The current membership includes more than 250 Nobel and Pulitzer Prize winners.

The Human Genome Project Turns 20: Here’s How It Altered the World

"It simply changed the way that people thought that biology could be done."

Ed Cara | Gizmodo
April 11, 2023

On April 14 2003, scientists announced the end to one of the most remarkable achievements in history: the first (nearly) complete sequencing of a human genome. It was the culmination of a decade-plus endeavor that involved thousands of scientists across the globe. Many people hoped the accomplishment would change the world for the better.

For the 20-year anniversary of this historic event, we took a look back at the Human Genome Project and its impact. How did it shape science moving forward? How many of the expected goals have been reached since? And what lies ahead for the study of genetics?

A genome is the entire set of genetic information that makes up an organism. This information is packaged into sequences of DNA we call genes, which in humans are spread along 23 pairs of chromosomes. Only a small portion of these genes contain the instructions for coding the many proteins essential for life, but much of the rest is still thought to be important to our functioning. As scientists would eventually confirm, one copy of the human genome has around 3 billion base pairs of DNA. The sheer magnitude of the effort needed to map all this wasn’t lost on the researchers involved in the project, especially given the technology available decades ago.

“There’s been lots of analogies that people have put forward—like us being Lewis and Clark. We didn’t really have a map,” said Richard Gibbs, founder and director of the Baylor College of Medicine Human Genome Sequencing Center in Texas, one of the major institutions involved in the project.

Gibbs and his many colleagues knew they had to make compromises. Despite the advancements in sequencing technology since the official start of the project in 1990, they couldn’t fill in every gap with their current tools. And the first human genome was a composite of several blood donors in the U.S., not a single person. Along the way, private company Celera entered the picture, promising that it would complete a separate genome project using its own techniques even faster. Ultimately, both groups finished ahead of schedule around the same time, with the first draft sequences released in 2000, though Celera announced its success a few months earlier.

Regardless of the victor, the feat certainly did usher in a new era of genetics research—one that has seen great leaps in speed and efficiency since 2003.

“I think the very most important accomplishment in the past 20 years has been the advent of next-generation sequencing. The ability to perform sequencing in a massively parallel way, so that you could do it far more quickly and cheaply,” said Stacey Gabriel, director of the Genomics Platform at the Broad Institute of MIT and Harvard, another major research site involved in the Human Genome Project. “And that has come with all of the associated advancement in our computational abilities, too, to really be able to take that data and analyze it at a massive scale as well.”

The original project cost $2.7 billion, with most of the genome being mapped over a two-year span. Nowadays, the current speed record for sequencing a genome is around five hours (more often, though, it takes weeks), and this past fall, the company Illumina unveiled a machine that it claims will cost as little as $200 per sequence, down from the recently typical $600 cost.

Greg Findlay leads the Genome Function Laboratory at the Francis Crick Institute in the UK. His team is one of many around the world that is building on the work of the original project. They’re currently trying to identify and understand how certain variants in tumor-suppressor genes can raise our risk of cancer.

“So what my lab tries to do is actually understand what variants do to the genome. That is, we want to know exactly which variants cause disease and why they cause disease. Right now, we’re focused on certain genetic changes that lead to cancer, and I think this particular field has really been revolutionized by the Human Genome Project,” Findlay said. “We now know there are many, many different genetic paths by which cells can turn into cancer. And we know this, because we’ve been able to actually sequence the DNA in so many different tumors repeatedly, across all different types of cancer, to see what are the mutations that actually lead to cancer forming.”

Perhaps equally important was the project’s impact on scientific collaboration. The effort directly led to an international agreement meant to ensure open access to DNA sequences. It also made clear that great things could be possible when large groups of scientists worked together, according to Gibbs.

“It simply changed the way that people thought that biology could be done,” he said. “It built a model for team science that was not there before.”

Even at the time, though, the project knowingly left some things unfinished. They had mapped roughly 92% of the genome by 2003, but it would take almost 20 more years for other scientists to track down the remaining 8%. This missing “dark matter” of our genome could very well provide new clues about how humans evolved or our susceptibility to various diseases.

Much of the genetic information collected and analyzed since the project ended has come from white and European populations—a disparity that hampers our ability to truly understand the impact of genetics on everyone’s health. But scientists today are working on bridging that gap through initiatives like the Human Pangenome Project, which will sequence and make available the full genomes of over 300 people intended to represent the breadth of human diversity around the globe.

“There’s genetic variation that exists across all the world’s populations. And if you only use variations from a sliver of the world’s populations, and you try to apply that to everybody else, it just doesn’t work very well, because we all have different backgrounds,” said Lucinda Antonacci-Fulton, one of the project’s coordinators and director of project development & new initiatives at Washington University in St. Louis’s McDonnell Genome Institute. “So the more inclusive you can be, the better off you are in terms of treatments that you want to bring into the clinic.”

As important as genetics research has been, some of the expectations fueled by the Human Genome Project likely were too lofty. In 2000, for instance, President Bill Clinton claimed that the project would “revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases.” While we do continue to discover new gene variants that strongly predict the odds of developing a specific disease or trait, there are countless others that we’re still in the dark about. Elsewhere, it’s become clear that our genome often only plays a small or negligible role in why we get sick or experience something in a particular manner. So although the project has helped unlock some of the mysteries of the world, there are so many more questions out there about why we are the way we are, and our genes are probably not going to provide a neat answer to many of them.

“I think where things are oversold, sometimes, is with this notion that just because the human genome is done, you’re going to be able to read it off for some sort of deterministic answer—where finding genes for disease becomes like falling off a log,” Gabriel notes. “But often human disease, especially the diseases that impact us the most, these are not simple genetic diseases. They’re multifactorial. They’re combinations of your genes, your behavior, exposure to the environment, sometimes just bad luck.”

None of this is to sell short the potential of genetics. Hans Lehrach, a former director at the Max Planck Institute for Molecular Genetics in Germany, was one of the first researchers involved in the Human Genome Project. He’s also one of many scientists who believe that we’ll someday be able to cheaply and easily scan a person’s genome at a moment’s notice and that this information, along with other aspects of our molecular make-up, will help guide the specific drugs or interventions doctors prescribe—a concept known as personalized medicine. Notably, the treatment of some cancers is already influenced by the variants that underlie their growth. Some experts even argue that widespread whole genome sequencing should start as early as birth, and there are already small-scale programs in the U.S., UK, and elsewhere testing out its potential benefits and risks.

“Not knowing about your genome is a bit like crossing the street while closing your eyes because you don’t want to see a bus coming. If we don’t sequence our genomes, the buses keep coming anyway—it just lets us open our eyes and maybe see the kind of danger that we can escape or do something about,” Lehrach said.

The Human Genome Project truly has changed the scientific landscape, but we’re still only at the very beginning of seeing the world that it’s made possible.

Balance between proteins keeps sperm swimming swiftly

Developing sperm cells swap out histones for proteins called protamines to coil DNA tightly enough to fit inside the hydrodynamic shape ideal for the task of swimming swiftly to an egg in order to fertilize it. If the balance of protamines in the sperm is wrong, however, the sperm may become misshapen and die, making the animal infertile. Whitehead Institute Member Yukiko Yamashita and former graduate student Jun Park have discovered why this imbalance causes infertility in the fruit fly.

Greta Friar | Whitehead Institute
April 10, 2023

Sperm must swim swiftly to an egg in order to fertilize it, and so they have evolved hydrodynamic shapes. Most of the space in the head of sperm cells is taken up by the DNA they carry, so the cells coil up their DNA super tightly to stay small and streamlined. In most cell types, DNA is coiled around proteins called histones. These do not package DNA tightly enough for sperm, so when a sperm cell is developing, it swaps out histones for another type of protein called protamines that coil DNA very tightly.

Many species, including humans, mice, and flies, have multiple types of protamines. If the balance between the different types is wrong, then the sperm’s DNA may not be packaged correctly and it may become misshapen and die, making the animal infertile. Whitehead Institute Member Yukiko Yamashita and former graduate student Jun Park have discovered why this imbalance causes infertility in the fruit fly (Drosophila melanogaster). The finding, published in the Proceedings of the National Academy of Sciences on April 10, showed a mechanism that balances different types of protamines to ensure male fertility.

Mst77F is a major fruit fly protamine. Yamashita and Park determined that the fruit fly protamine Mst77Y, which is related to Mst77F, can interfere with the function of Mst77F. Fruit flies usually make a lot of Mst77F and a little of Mst77Y. The researchers found that when expression of the Mst77Y gene is too high, especially when expression of Mst77F is low, it disrupts the process of DNA packaging, leading to infertility.

How does Mst77Y interfere with Mst77F? The researchers discovered that this is because the Mst77Y gene makes faulty protamines. There are multiple copies of Mst77Y on the fly’s Y chromosome. They likely evolved from a copy of Mst77F, which is not on a sex chromosome. However, the different versions of Mst77Y have lost or altered parts that they need in order to function, so unlike the Mst77F protamine, Mst77Y protamines likely cannot coil DNA tightly around themselves. In spite of the fact that the Mst77Y protamines do not work correctly, they are dominant: when they are present, the sperm cell will use them over the functional Mst77F protamines.

“Mst77Y is a half-broken tool,” says Yamashita, who is also a professor of biology at the Massachusetts Institute of Technology and a Howard Hughes Medical Institute investigator. “It is able to take the place of the working tool, Mst77F, but not to do its job, so when too much Mst77Y is present, the sperm cell does not have enough working tools in place to compact its DNA.”

The researchers also figured out how sperm cells keep expression of Mst77F high and Mst77Y low: with the help of a protein called Modulo. In order for an RNA read from a gene to be made into a protein, it needs to have a tail added to it made up of a string of adenines—one of the four building blocks that make up RNA. Modulo makes sure that the cell preferentially adds this tail to the RNA coding for Mst77F. Although Yamashita and Park did not determine the exact mechanism by which Modulo ensures this preferential treatment, they did observe that Modulo and the Mst77F RNA group together in the same part of the cell, the nucleolus, whereas Mst77Y does not.

Altogether, these findings explain why and how fruit fly sperm cells carefully balance the levels of these two protamines. However, the research raises the question, what are sperm cells using the non-functional Mst77Y protamines for? Yamashita and Park can only speculate, but the answer may have to do with their observation that high levels of Mst77Y killed off more X-chromosome bearing sperm than Y-chromosome bearing sperm. Past research has suggested that protamines may be involved in a process called meiotic drive, which animals can use to skew the sex ratio of their offspring. This new work is not only consistent with that hypothesis, but provides a possible mechanism to explain how protamines contribute. The researchers note that they did not see a strong effect on the sex ratio of offspring in this experiment, but hope that this work could set the stage to understand the role of non-functional protamines in meiotic drive.

“At the cell level, we were able to show that there’s some basis for this protamine to be involved in biasing whether X or Y chromosome bearing sperm survive,” Park says. “An interesting next question would be to see if there are certain conditions in which this mechanism more clearly acts as a driver at the level of offspring’s sex ratio.”

Notes

Park, Jun I., George W. Bell, and Yukiko M. Yamashita. 2023. “Derepression of Y-linked multicopy protamine-like genes interferes with sperm nuclear compaction in D. melanogaster,” PNAS 120 (16). https://www.pnas.org/doi/10.1073/pnas.2220576120