Written by Merrill Meadow | Video by Ceal Capistrano
February 27, 2018
TabulaSynthase The blog of Whitehead Institute; bringing together ideas and perspectives from the Whitehead community and beyond.
As Rudolf Jaenisch and Rick Young sit side-by-side in conversation, a long reptilian skull is perched behind them. Its intact teeth still menacingly sharp, it was a “salty,” a carnivorous, ferocious, salt water crocodile from the north Australian coast. The skull is both a piece of natural history and the perfect souvenir for two scientists who appear most happy when taking on some new and not-wholly-calculable risk—whether as pioneering researchers or globe-trekking adventurers.
Though born half-a-world apart—Jaenisch in Wölfelsgrund, Germany; Young in Pittsburgh, Pennsylvania—the two have collaborated virtually since each arrived at Whitehead in 1984, leveraging shared passions for discovery research and for exploring the Earth’s least-travelled paths. And they have found a potent-but-unexpected synergy between their scientific ventures in Cambridge and their sometimes-risky expeditions to spots such as Chile’s Patagonia, the Namibian desert, and the Himalayas.
Young has developed ground-breaking technology to map human genome regulatory circuitry and discovered core circuitry of human embryonic stem cells; an educator and bio-tech entrepreneur, as well as bench scientist, he’s been recognized as one of the top 50 leaders in science, technology and business. Jaenisch, a National Medal of Science (NMS) recipient, developed technology to create mice with virtually any genetic mutation an investigator wants to study, and is uncovering “druggable” aspects of the mechanisms underlying infectious, autoimmune, and neurological diseases. Together, the two have pursued the investigations underpinning a dozen of the world’s most cited research papers—including a series of studies that laid the groundwork for understanding the genetic control of stem cell pluripotency.
To paraphrase the NMS award announcement, Jaenisch embodies fearlessness even as he explores the very frontiers of human knowledge. “That’s right on the mark,” Young muses. “The key trait that Rudolf exhibits in both science and travel is that he is fearless.”
“Yes, but I often rely on Rick to get me out of trouble,” Jaenisch jokes, recalling an experience from their trip through the Namibian desert seven years ago. On a whim, they decided to climb a granite mountain that seemed to rise straight out of the desert. Local guides said it was a three-day climb; Jaenisch and Young calculated they could do it in one, if they started well before dawn and finished before dusk (to avoid night-hunting leopards). And so they did, but not without incident. Just after their mid-day break, feeling a concern he couldn’t define, Young insisted that they start back down, even though they were close to the summit. “We argued about it for a while, because I really wanted to reach the top,” Jaenisch says. “But one of our standing rules is that whatever we do, we do together, and Rick was adamant about not going to the top, so we turned around.” Even so, their return proved dicey. They had to minutely ration their water for the last six hours; and Jaenisch was virtually crawling by the time they reached their vehicle. “Rick was probably right,” he says, wryly.
“On our treks, Rudolf has no sense of danger, whereas I’m the guy who gets a little anxious sometimes,” Young says. Those protestations aside, his anxiety sounds like the internal voice of the experienced pilot that he is, used to making instinctual calculations, quickly. And the fact that Young is only somewhat less inclined to risk-taking becomes clear when he discusses his choice on their Australia trip to go for a morning run beside waters harboring fast-running salt crocs.
Helping each other get out of challenging situations—such as when they and fellow climbers were caught in a blinding snow-storm on a Himalayan peak—has created both deep trust and fine-tuned understanding of each other’s capacities. As a result, explains Young, “When we’re back at Whitehead doing science, we have very good instincts about what we can accomplish together and we’re not afraid to do things that are, scientifically, very risky.”
While they make no specific plans to discuss science on their trips—they make as few advance decisions as possible about what they’ll do during a trip—science naturally arises, and some of their most important projects have resulted from these free-wheeling conversations. The most recent include a major research initiative on gene control in diabetes and a proof-of-principle study on a Rett syndrome treatment.
“These trips—whether climbing mountains, kayaking the open ocean, or hiking barely explored forests—are all about four things: exploring places we’ve never seen, learning something new, testing our physical capacities, and wholly unplugging from the rest of the world,” Jaenisch explains.
“We go with our eyes, ears, and minds wide-open. In that context, especially with someone who you really trust, it’s natural that good ideas emerge and that some of them be quite risky. But the science that’s emerged from our excursions has been a wonderful serendipity.”
Matthew Vander Heiden helped revive the forgotten— but critical—study of cancer metabolism.
Sam Apple | MIT Technology Review
February 21, 2018
One day last October, MIT biology professor Matthew Vander Heiden showed up in one of his trademark plaid shirts to teach his undergraduate course on cancer biology. As usual, he peppered his lecture with questions, filling six sliding chalkboards with arrows mapping cellular pathways; he had to erase the boards halfway through class to make room for more notations. But what might have seemed like an ordinary lecture was far from ordinary in one respect: although Vander Heiden was explaining some of the most fundamental aspects of how tumors grow, most of what he was teaching his students would have been absent from nearly every introductory course on cancer biology a decade ago. The science Vander Heiden discussed that afternoon amounted to a once-lost but recently rediscovered chapter in the history of cancer research.
What he didn’t mention in class is that he’d played as large a role as anyone in bringing it back.
That lost chapter focuses on metabolism, and how cancers use nutrients for energy and as building blocks for new cancer cells. It began with a discovery in the early 1920s that most cancers stuff themselves with glucose and then use it in an unusual way. Whereas normal cells typically break down glucose by burning it with oxygen, cancer cells extract much of its energy through fermentation—essentially the same process microorganisms use to make yogurt, beer, and other foods. Indeed, early-20th-century researchers noticed that cancer cells seemed to behave more like yeast than the cells of an animal. But though it would briefly become a major school of cancer research, metabolism fell by the wayside in the 1960s as researchers turned their attention to how cancer-causing genes signal cells to divide.
Cancer metabolism research appeared to be dead, until Vander Heiden helped launch its revival around two decades ago. Today it’s among the hottest areas of the field, spawning conferences, journals, and promising new therapies. And it has fundamentally changed the way many researchers understand cancer and its origins.
Modest revolutionary
Metabolism’s downfall as a research area in the late 20th century was largely a reflection of the faddish nature of science. It didn’t help that Otto Warburg, the German scientist who discovered the unusual metabolism of cancer cells, was so arrogant that much of the scientific community disliked him. So it’s probably a good thing that Vander Heiden, a down-to-earth type who’s been known to downplay his own role on research papers to give his students and postdocs first-author billing, has been so central to the metabolism revival.
Vander Heiden, 45, grew up in Port Washington, Wisconsin, a small town on Lake Michigan once known for its lawnmower factories, and he lives up to every stereotype of his background. “He carries his Midwestern sensibilities with him everywhere he goes,” says his wife, Brooke Bevis, a biologist and the operations manager for Vander Heiden’s lab at MIT’s Koch Institute for Integrative Cancer Research. “I finally made him give up my old 1995 Honda Civic just a few years ago.”
When Vander Heiden enrolled at the University of Chicago in 1990, medicine was already on his mind. His younger brother had suffered from a rare blood disorder as a child, and Vander Heiden spent much of his own childhood hanging around children’s hospitals. But he had little thought of becoming an academic scientist until he began a work-study job washing out equipment in a University of Chicago biology lab. The work was not glamorous but came with a perk: the graduate students in the lab would let Vander Heiden make solutions for them and show him how they did their experiments.
After graduating, he enrolled in Chicago’s MD-PhD program and landed in the lab of Craig B. Thompson. Today Thompson is the president and CEO of the Memorial Sloan Kettering Cancer Center, but at the time he was studying immunology, looking at how the body eliminated huge numbers of immune cells once they were no longer needed.
When Vander Heiden arrived in Thompson’s lab in 1996, part of the explanation was already understood. Those cells would simply commit suicide, a process known as apoptosis. It was also known that a family of proteins named Bcl-2 could stop a cell from committing suicide—and that they appeared to do so through their impact on mitochondria, tiny organelles known as the powerhouses of the cell for their role in energy production.
Vander Heiden had just joined a cutting–edge immunology lab interested in protein signaling. Yet he had been asked to investigate how Bcl-2 proteins affect mitochondria, a relic of the old, outdated metabolism research. When it became clear that no one in the lab knew much about metabolism, Vander Heiden reread the relevant sections of his undergraduate biochemistry textbook. He also teamed up with Navdeep Chandel, a metabolism researcher at Northwestern University who was then a graduate student in a University of Chicago cellular physiology lab.
When another lab showed that proteins released from the mitochondria could trigger apoptosis, Vander Heiden and -Chandel got an important clue: the decision to commit suicide could now be traced directly to the mitochondria. And yet the deeper question of what was happening inside them remained mysterious until the two researchers arrived at an answer, thanks to a series of elegant experiments designed by Vander Heiden (whom Chandel calls “a world-class experimentalist”) to study how molecules moved through the mitochondrial membrane. They discovered that the release of the mitochondrial proteins was a sign of a failing powerhouse, a notice to the cell that a brownout was under way so it was time to abort. But brownouts weren’t inevitable; the Bcl-2 proteins, like emergency workers called to the scene of an imminent disaster, could resuscitate the metabolic function of the mitochondria and keep things from getting to that point. The suicide signal, in turn, would never be released.
Daniel Schmidt, a postdoc in Vander Heiden’s lab, prepares cells to study how metabolism affects cancer cell proliferation. Credit: BUCK SQUIBBDaniel Schmidt, a postdoc in Vander Heiden’s lab, prepares cells to study how metabolism affects cancer cell proliferation.
BUCK SQUIBB
For Vander Heiden, this was a “watershed moment.” Among other things, it meant that metabolic enzymes weren’t merely supplying energy from food. Metabolism was governing the most fundamental decision a cell has to make—whether to live or die. That meant it had to be interwoven into the signaling cascades that molecular biologists studied. His feeling at the time, he recalls, was “Oh my goodness. We don’t really understand metabolism.”
Vander Heiden might not have envisioned himself delving into research areas that had been discarded decades earlier, but what was more surprising was how little research was then being done in an area that was “as fundamental as you get in terms of how biology works,” he says. “I looked around and no one was studying it.”
Thompson, recognizing the opportunity, shifted the focus of his lab to metabolism. Vander Heiden, meanwhile, continued to pursue Thompson’s broader question of how the body eliminates unwanted immune cells. He already knew that growth factors, messages sent from one cell to the next, kept cells from committing suicide, but how the signals delivered their survival message remained unclear. What he discovered in a series of studies carried out in the late ’90s followed perfectly from his previous research. Growth factors kept cells alive by giving them permission to eat. Without that permission, a cell soon faced an energy crisis, and the mitochondria released their death signals.
The takeaway was clear: our bodies eliminate unwanted cells by starving them to death.
Solving the metabolism mystery
As Vander Heiden’s MD-PhD program was coming to an end, he hadn’t yet begun to focus on cancer, but its possible links with his research on cell suicide were intriguing. Cancer cells were the other side of the coin—cells that were resistant to suicide, that no longer cared about instructions from other cells. So in 2004, after completing a residency in oncology at Brigham and Women’s Hospital in Boston, he was anxious to investigate cancer metabolism for his postdoc research.
Finding the right lab wasn’t easy. At the time, telling leading researchers he wanted to study how cancer cells consumed glucose was like approaching a high-tech manufacturer and announcing you wanted to study the trucks that brought fuel to the factory. It sounded, Vander Heiden says, “like a really ridiculous thing.”
Vander Heiden eventually found a home in the Harvard lab of Lewis Cantley, who now directs the Meyer Cancer Center at Weil Cornell. His research in Cantley’s lab would help solve one of the central riddles of cancer metabolism: why cancer cells are so ravenous for glucose. Researchers had once assumed that cancer cells were turning to fermentation because they’d lost the ability to use oxygen properly and needed some other way to produce energy. But Vander Heiden’s research on a mutated form of the enzyme pyruvate kinase showed something else. Rather than being used for energy, much of the glucose was being shunted into pathways used to build new molecules. What a growing cancer needs most of all from its food, the research suggested, is more spare parts—raw materials for making new DNA, membranes, and proteins.
Rethinking chemotherapy
Vander Heiden’s research with Cantley would also lead to his involvement with Agios Pharmaceuticals, the company behind one of the most promising new drugs to emerge from the metabolism revival. (Cantley says he played a major role in building the company’s science in its early days.) The drug, AG-221, treats acute myelogenous leukemia, a cancer of the blood and bone marrow. It works by blocking the product of a mutated form of the mitochondrial enzyme IDH-2. Approved by the US Food and Drug Administration in August, it has been hailed as the first real advance for the disease in 30 years.
The approval of AG-221 isn’t the only thing generating excitement in the cancer world. Unlike almost all other cancer drugs, AG-221 doesn’t kill the cancer cells but, rather, allows them to develop out of their deranged state into noncancerous, mature, functioning cells. That a single metabolic enzyme could have such profound effects on which genes are expressed in a cell is now one of the many signs that changes in metabolism are not just a response to the needs of a growing cancer. Often, they may actually be causing the cancer itself. It represents a major shift in thought: many cancer-causing genes long known for their ability to signal cells to keep dividing have now been shown to have additional roles in signaling cells to keep eating. Some researchers now believe the overeating typically comes first, driving the transformations that follow.
Since his arrival at MIT and the opening of his lab at the Koch Institute in 2009, Vander Heiden has treated cancer patients and continued to search for better therapies. In recent years he has focused on improving understanding of chemotherapy. Though typically thought of as general poisons, most chemotherapy drugs work because they disrupt metabolic functions. That much has long been known, but less clear is why a particular drug works for some cancers and not for others, even when two cancers carry the same mutations.
It was while explaining to his undergrad cancer biology students how targeted drugs work that Vander Heiden first thought of an answer. As a cancer doctor, he knew that chemotherapies are often chosen on the basis of where in the body a tumor first arose, but what was it about this location that made the difference?
Vander Heiden’s research in mice now suggests that the answer may lie in which foods are available to the cancer as it forms. Melanoma and colon cancer, for example, often have the same mutations, and yet, as he explains, because the two cancers “grow in very different places in the body,” they likely “have access to different nutrients.” He adds, “It has nothing to do with the genetics.” If he turns out to be right, it could lead to a fundamental change in how oncologists think about which drugs to give their patients.
As Vander Heiden turns his attention to old chemotherapy drugs, rethinking why and how they work, he is once again looking to the past for new insights on cancer. It might be more than a coincidence. As Bevis, his wife, says, the outdated Honda Civic isn’t the only item he has struggled to let go of. “The list goes on and on,” she says. “He hates waste and will use items long after someone else would have replaced them with a newer, shinier model.”
Alissandra Hillis ’18 has spent all four years at MIT in the same cancer metabolism lab, deciphering the basic science behind pancreatic cancer.
Raleigh McElvery
February 19, 2018
Senior Alissandra Hillis attributes her appetite for the basic sciences to her craving for fundamental knowledge. She’s spent her four years at MIT in the same lab, committed to unraveling the molecular mechanics of pancreatic cancer — the fourth leading cause of cancer death for both men and women, given that symptoms do not often appear until the disease is quite advanced.
“I was always very curious growing up,” she says. “I taught myself how to read at a very young age, just because I wanted to know about things and how they worked. But I didn’t become interested in biology and chemistry specifically until I came to MIT and started taking my General Institute Requirements.”
In doing so, Hillis became enthralled by the prospect of breaking down life into its most fundamental, biological units to decipher cellular function and disease. Originally a Course 7 major with a chemistry minor, she declared Course 5-7 (Chemistry and Biology) as soon as it became available in the fall of 2017 — applying her study of biochemistry and cell metabolism to cancer research.
“When I was quite young, my grandfather was diagnosed with stomach cancer, and ended up having almost three quarters of his stomach removed,” she says. “I was too little to really understand the severity of the situation, but as soon as I came to MIT I started to wonder what was going on at a cellular level. Most people today know someone who is fighting cancer, and yet we’re still lacking effective treatments for its most severe forms.”
Hillis joined Matthew Vander Heiden’s cancer metabolism lab the first semester of her freshman year, and has been there ever since.
“Professor Vander Heiden does an excellent job of tailoring the research project to the individual, and there is no hierarchy among lab members,” she says. “I really liked it from the onset, so I stayed.”
For nearly two years, Hillis has been investigating the role of one enzyme, pyruvate kinase muscle isozyme M2 (PKM2), in pancreatic cancer. PKM2 is responsible for catalyzing the final step in glycolysis, which is required to create the energy that fuels cells. Glycolysis is also important in tumor metastasis and growth, since cancer cells demand energy in order to proliferate.
Cancer cells often preferentially express PKM2 over other types of pyruvate kinases such as PKM1. This spurred William Israelsen PhD ’14, a former graduate student in the Vander Heiden lab working in breast cancer models, to delete the PKM2 gene and see what happened. Since PKM2 is critical for glycolysis, and cancer cells require energy to proliferate, he anticipated that removing PKM2 would hinder energy production and thus disrupt tumor development. To his surprise, he found the opposite: deleting PKM2 actually accelerated tumor formation and promoted liver metastasis in mice.
In his 2014 paper, Israelsen concluded that PKM2 might permit cancer cells to maintain their “plasticity,” shifting from one specialized role to another even after they’ve fully matured. In the absence of PKM2, he proposed PKM1 might take over PKM2’s influential role.
Hillis wondered if she could replicate Israelsen’s breast cancer results in a model for pancreatic cancer, especially given the conflicting findings in human data regarding PKM2 expression in the latter. Some studies suggest that high PKM2 expression correlates with accelerated disease, whiles others indicate just the opposite: that high PKM2 expression is associated with better survival rates.
“Going into the project, we were expecting similar effects in both pancreatic and breast cancer models because both cancers preferentially express PKM2, and we were using the same method of PKM2 deletion, just bred into a different cancer model,” Hillis explains. “We anticipated that PKM2 deletion would accelerate pancreatic tumor size and tumor genesis, and decrease the mouse’s lifespan. But we’ve noticed that these effects — if they exist — are very much attenuated in the pancreatic cancer model; there is only a slight decrease in lifespan and increase in tumor size without PKM2.”
Right now, her working hypothesis holds that PKM2’s influence varies depending on the tissue in question. This might explain why her own results don’t exactly parallel what Israelsen found in his breast cancer model. For instance, the method they were using to delete PKM2 is quite effective in the breast and pancreatic cells themselves, but less so in the dense scar-like tissue characteristic of pancreatic tumors in particular. It’s possible, she thinks, that this fibrous tissue may still express some PKM2 even post-knockout, perhaps hindering both a drastic decrease in lifespan and increase in tumor size.
Hillis hopes piecing together PKM2’s mechanism of action will help us better diagnose — and eventually treat — certain cancers. Her most recent results were published in the November 2017 issue Cancer & Metabolism.
Although Hillis enjoys tackling the more fundamental questions concerning cancer, she’s also interested in translating this work from bench to bedside. That’s why she decided to intern with David Ting at the Massachusetts General Hospital Cancer Center this past summer.
“I wanted to try a different type of research before applying to graduate school,” she says. “The Department of Biology frequently sends out emails about job opportunities, and there was one advertising that the Ting lab was looking for a research technician.”
Although she was still a junior at the time, she contacted Ting — an MIT alumnus with a dual degree in 7A and 10 — and together they fashioned a summer position just for her, studying the role of miniscule, fluid-filled transportation structures called exosomes in cancer development and diagnosis.
“That was the first time I’d worked with samples from actual patients,” she says. “Many of the assays were the same, but I felt closer to a clinical application than I ever had before. I really enjoy doing the foundational work to identify the basic problem, but there’s definitely something to be said for experiencing research targeted at creating a diagnostic tool. I can see the pros and cons of both approaches.”
As Hillis begins her final semester at MIT, she’s continuing her work in the Vander Heiden lab, while also finishing up the requirements for her HASS concentration in legal studies. She’s still set on pursuing a PhD in cancer biology, but the propensity to ask tough questions that drew her to science in the first place has led her to realize that the questions she raises in her own research have ramifications far beyond her lab bench. Taking policy-oriented classes in addition to her science-related ones has inspired her to pursue a law degree in conjunction with her PhD — weaving together her love for science with a newfound interest in the rules and regulations that govern how science is funded, performed, shared, applied, and monetized.
“I really enjoy doing research, and that’s something I probably will continue to do,” she says, “but I also want to influence science-related regulations, which is something I couldn’t possibly do without a law degree. I would still be heavily immersed in science, while applying the subjects I love in new and exciting ways.”
Photo credit: Raleigh McElvery
Whitehead Institute researchers are using a modified CRISPR/Cas9-guided activation strategy to investigate the most frequent cause of intellectual disability in males.
Nicole Giese Rura | Whitehead Institute
February 15, 2018
Fragile X syndrome is the most frequent cause of intellectual disability in males, affecting one out of every 3,600 boys born. The syndrome can also cause autistic traits, such as social and communication deficits, as well as attention problems and hyperactivity. Currently, there is no cure for this disorder.
Fragile X syndrome is caused by mutations in the FMR1 gene on the X chromosome, which prevent the gene’s expression. This absence of the FMR1-encoded protein during brain development has been shown to cause the overexcitability in neurons associated with the syndrome. Now, for the first time, researchers at Whitehead Institute have restored activity to the fragile X syndrome gene in affected neurons using a modified CRISPR/Cas9 system they developed that removes the methylation — the molecular tags that keep the mutant gene shut off — suggesting that this method may prove to be a useful paradigm for targeting diseases caused by abnormal methylation.
Research by the lab of Whitehead Institute for Biomedical Research Founding Member Rudolf Jaenisch, which is described online this week in the journal Cell, is the first direct evidence that removing the methylation from a specific segment within the FMR1locus can reactivate the gene and rescue fragile X syndrome neurons.
The FMR1 gene sequence includes a series of three nucleotide (CGG) repeats, and the length of these repeats determines whether or not a person will develop fragile X syndrome: A normal version of the gene contains anywhere from 5 to 55 CGG repeats, versions with 56 to 200 repeats are considered to be at a higher risk of generating some of the syndrome’s symptoms, and those versions with more than 200 repeats will produce fragile X syndrome.
Until now, the mechanism linking the excessive repeats in FMR1 to fragile X syndrome was not well-understood. But Shawn Liu, a postdoc in Jaenisch’s lab and first author of the Cell study, and others thought that the methylation blanketing those nucleotide repeats might play an important role in shutting down the gene’s expression.
In order to test this hypothesis, Liu removed the methylation tags from the FMR1 repeats using a CRISPR/Cas9-based technique he recently developed with Hao Wu, a postdoc in the Jaenisch lab. This technique can either add or delete methylation tags from specific stretches of DNA. Removal of the tags revived the FMR1 gene’s expression to the level of the normal gene.
“These results are quite surprising — this work produced almost a full restoration of wild type expression levels of the FMR1 gene,” says Jaenisch, whose primary affiliation is with Whitehead Institute, where his laboratory is located and his research is conducted. He is also a professor of biology at MIT. “Often when scientists test therapeutic interventions, they only achieve partial restoration, so these results are substantial,” he says.
The reactivated FMR1 gene rescues neurons derived from fragile X syndrome induced pluripotent stem (iPS) cells, reversing the abnormal electrical activity associated with the syndrome. When rescued neurons were engrafted into the brains of mice, the FMR1 gene remained active in the neurons for at least three months, suggesting that the corrected methylation may be sustainable in the animal.
“We showed that this disorder is reversible at the neuron level,” says Liu. “When we removed methylation of CGG repeats in the neurons derived from fragile X syndrome iPS cells, we achieved full activation of FMR1.”
The CRISPR/Cas-9-based technique may also prove useful for other diseases caused by abnormal methylation including facioscapulohumeral muscular dystrophy and imprinting diseases.
“This work validates the approach of targeting the methylation on genes, and it will be a paradigm for scientists to follow this approach for other diseases,” says Jaenisch.
This work was supported by the National Institutes of Health, the Damon Runyon Cancer Foundation, the Rett Syndrome Research Trust, the Brain and Behavior Research Foundation, and the Helen Hay Whitney Foundation. Jaenisch is co-founder of Fate Therapeutics, Fulcrum Therapeutics, and Omega Therapeutics.
New cancer research initiative eyes individualized treatment for patients.
Koch Institute
February 1, 2018
Details matter — perhaps most noticeably in the fight against cancer. Some patients respond to a given anticancer therapy, and some do not. A new initiative at MIT takes aim at those details, and the name of the game is precision.
The recently launched MIT Center for Precision Cancer Medicine (CPCM) is housed within MIT’s Koch Institute for Integrative Cancer Research and headed by physician-scientist Michael B. Yaffe, the David H. Koch Professor of Science and professor of biology and biological engineering. The center brings together leading Institute faculty members to focus on key research themes to accelerate the clinical translation of novel cancer discoveries, treatments, and technologies.
Engineering approaches to the clinic
While other institutions have begun efforts in precision medicine as well, the MIT Center for Precision Cancer Medicine stands out for using engineering approaches to solve complex clinical challenges in cancer treatment that are rooted in biology. In particular, the CPCM combines understandings of biological circuitry — along with engineering, computational, and mathematical techniques (as well as genomic ones) — to focus on signaling networks and pathways that are aberrantly regulated in cancer cells. This strategy is supported by the fact that most state-of-the-art molecularly targeted cancer therapies are focused on these key pathways.
At its core, the CPCM is driven by both internal and external collaboration, and is devoted to translational research to help the substantial number of patients who do not respond well to traditional cancer therapies — for example, those with triple-negative breast cancer, ovarian cancer, non-small cell lung cancer, or advanced prostate cancer.
To improve outcomes for these patients, CPCM investigators are focused on four key areas of research. First among these is identifying and targeting the processes, signals, and mechanisms that determine an individual patient’s response to chemotherapy. Recent discoveries by CPCM researchers include mechanisms that cancer cells use to repair chemotherapy damage that should have killed them, to hide from drugs in protected “niches” in the body, or to grow when and where they should not.
CPCM members are also working on a second research pillar, which involves finding ways to use existing FDA-approved cancer drugs more effectively, particularly in carefully designed combinations. Combination therapies are currently used in the clinic to treat some cancers, yet the discovery process for these has been largely empirical. By contrast, CPCM investigators are integrating their knowledge of cancer biology, understandings of drugs’ mechanisms of action, and sophisticated analytical techniques, to identify or design specific combinations that work synergistically to disarm and then destroy cancer cells.
“We believe we can significantly alter cancer patients’ outcomes by determining the right combination of therapies and the right sequence of drugs for the right patients,” says Yaffe. “We’re also concentrating on innovative ways to give these drugs, like time-staggered dosages and nanoparticle delivery.” He notes that, as part of their analyses of drugs and combination regimens currently administered in the clinic, CPCM members expect to identify combinations of drugs that are not as efficacious when given simultaneously as when given sequentially, at specific intervals. Yaffe stresses that these will be important findings that could help reduce the toxicity of treatment by not exposing people to multiple drug toxicities at the same time.
In parallel with their efforts to use existing drugs more effectively, CPCM investigators are also working to identify compounds, materials, and approaches that can engage key “undruggable” genetic and molecular targets and disrupt processes driving drug resistance. The “undruggable” label often refers to the fact that a target protein or molecule lacks a site to which drugs can bind, and thus is not considered a good drug target by the pharmaceutical industry. However, using novel chemistry approaches, CPCM researchers have made early inroads against several such high-value cancer targets, including specific transcription factors and RNA-binding proteins. The center will continue and expand these efforts as the third part of its research platform, including collaborations with industry.
Finally, the fourth component of the CPCM’s efforts will be harnessing MIT’s particular expertise in big data analysis and tools to begin new and expedite existing cancer research efforts. For example, the researchers plan to use data analytics to identify selective panels of biomarkers that can be used to prioritize which of their drug combinations, treatment protocols, and formulations are best suited to a particular patient’s tumor.
Getting discoveries out the door
“Patients will be the ultimate beneficiaries of the work of the new MIT Center for Precision Cancer Medicine,” says Tyler Jacks, director of the Koch Institute and the David H. Koch Professor of Biology. “This research is, by its nature, imminently and rapidly translatable. By concentrating efforts on which patients will benefit from particular existing drugs or combinations of drugs, there is a relatively small step from laboratory to a treatment that is benefitting a cancer patient.”
While work on combinations of approved therapies, like that at the CPCM, may be more rapidly translatable than other cancer research, it can be challenging for industry to pursue, particularly when those drugs hail from multiple companies. Overcoming this disjuncture is one of the goals behind the establishment of the MIT Center for Precision Cancer Medicine, which was made possible by a generous gift from an anonymous donor.
Yaffe and his CPCM colleagues are committed to finding viable routes to move their cancer research into the clinic, particularly through collaborations between CPCM members, hospitals, and industry. Logistically, this means more work for the center’s research groups, including advanced laboratory and preclinical studies, safety and scale-up studies, and clinical-grade manufacturing, as well as staff to carry it out. Woven into these efforts, CPCM investigators will tap into MIT’s celebrated tradition of entrepreneurship and, even more so, the Institute’s expanding network of clinical collaborators. The philanthropic investment behind the center will provide stable financial support for the researchers’ endeavors.
The new hub in town
In addition to supporting the research of member investigators, the CPCM offers a robust training ground for young engineers and scientists interested in precision medicine. Moreover, it will serve as the hub of precision cancer medicine research at MIT and beyond, connecting with researchers across the MIT campus and partnering with clinical investigators in Greater Boston’s noted health care centers and around the country.
Five outstanding cancer researchers make up the center’s founding faculty:
Michael B. Yaffe, MD, PhD, director, MIT Center for Precision Cancer Medicine; David H. Koch Professor of Science, professor of biology and biological engineering
Efforts are currently underway to recruit an assistant director and a scientific advisory board.
As part of its charge, and key to spurring the new collaborations in precision cancer medicine that are its focus, the MIT Center for Precision Cancer Medicine will also convene lectures, events, and scientific exchanges and symposia, the first of which is slated for the fall.
Department of Biology kicks off IAP seminar series with a lecture by synthetic-biology visionary George Church.
Raleigh McElvery | Department of Biology
January 31, 2018
Thanks to the invention of genome sequencing technology more than three decades ago, we can now read the genetic blueprint of virtually any organism. After the ability to read came the ability to edit — adding, subtracting, and eventually altering DNA wherever we saw fit. And yet, for George Church, a professor at Harvard Medical School, associate member of the Broad Institute, and founding core faculty and lead for synthetic biology at the Wyss Institute — who co-pioneered direct genome sequencing in 1984 — the ultimate goal is not just to read and edit, but also to write.
What if you could engineer a cell resistant to all viruses, even the ones it hadn’t yet encountered? What if you could grow your own liver in a pig to replace the faulty one you were born with? What if you could grow an entire brain in a dish? In his lecture on Jan. 24 — which opened the Department of Biology’s Independent Activities Period (IAP) seminar series, Biology at Transformative Frontiers — Church promised all this and more.
“We began by dividing the Biology IAP events into two tracks: one related to careers in academia and another equivalent track for industry,” says Jing-Ke Weng, assistant professor and IAP faculty coordinator for the department. “But then it became clear that George Church, Patrick Brown, and other speakers we hoped to invite blurred the boundaries between those two tracks. The Biology at Transformative Frontiers seminar series became about the interface of these trajectories, and how transferring technologies from lab bench to market is altering society as we know it.”
The seminar series is a staple in the Department of Biology’s IAP program, but during the past several years it has been oriented more toward quantitative biology. Weng recalls these talks as being relegated to the academic sphere, and wanted to show students that the lines between academia, industry, and scientific communication are actually quite porous.
“We chose George Church to kick off the series because he’s been in synthetic biology for a long time, and continues to have a successful academic career even while starting so many companies,” says Weng.
Church’s genomic sequencing methods inspired the Human Genome Project in 1984 and resulted in the first commercial genome sequence (the bacterium Helicobacter pylori) 10 years later. He also serves as the director of the Personal Genome Project, the “Wikipedia” of open-access human genomic data. Beyond these ventures, he’s known for his work on barcoding, DNA assembly from chips, genome editing, and stem cell engineering.
He’s also the same George Church who converted the book he co-authored with Ed Regis, “Regenesis: How Synthetic Biology Will Reinvent Nature and Ourselves,” into a four-letter code based on the four DNA nucleotides (A, T, C, and G), subsisted on nutrient broth from a lab vendor for an entire year, and dreams of eventually resurrecting woolly mammoths. He’s being featured in an upcoming Netflix Original documentary, so when he arrived at the Stata Center to give his lecture last week he was trailed by a camera crew.
According to Church, the transformative technologies that initially allowed us to read and edit DNA have grown exponentially in recent years with the invention of molecular multiplexing and CRISPR-Cas9 (think Moore’s Law but even more exaggerated). But there’s always room for improvement.
“There’s been a little obsession with CRISPR-Cas9s and other CRISPRs,” said Church. “Everybody is saying how great it is, but it’s important to say what’s wrong with it as well, because that tells us where we’re going next and how to improve on it.”
He outlined several of his own collaborations, including those aimed at devising more precise methods of genome editing, one resulting in 321 changes to the Escherichia coli genome — the largest change in any genome yet — rendering the bacterium resistant to all viruses, even those it had not yet come into contact with. The next step? Making similarly widespread changes in plants, animals, and eventually perhaps even human tissue. In fact, Church and his team have set their sights on combatting the global transplantation crisis with humanlike organs grown in animals.
“Since the dawn of transplantation as a medical practice, we’ve had to use either identical twins or rare matches that are very compatible immunologically, because we couldn’t engineer the donor or the recipient,” said Church.
Since it’s clearly unethical to engineer human donors, Church reasoned, why not engineer animals with compatible organs instead? Pigs, to be exact, since most of their organs are comparable in size and function to our own.
“This is an old dream; I didn’t originate it,” said Church. “It started about 20 years ago, and the pioneers of this field worked on it for a while, but dropped it largely because the number of changes to the genome were daunting, and there was a concern that the viruses all pigs make — retroviruses — would be released and infect the immunocompromised organ recipient.”
Church and his team successfully disrupted 62 of these retroviruses in pig cells back in 2015, and in 2017 they used these cells to generate living, healthy pigs. Today, the pigs are thriving and rearing piglets of their own. Church is also considering the prospect of growing augmented organs in pigs for human transplantation, perhaps designing pathogen-, cancer-, and age-resistant organs suitable for cryopreservation.
“Hopefully we’ll be doing nonhuman primate trials within a couple of years, and then almost immediately after that human trials,” he said.
Another possibility, rather than cultivating organs in animals for transplant, is to generate them in a dish. A subset of Church’s team is working on growing from scratch what is arguably the most complicated organ of all, the brain.
This requires differentiating multiple types of cells in the same dish so they can interact with each other to form the complex systems of communication characteristic of the human brain.
Early attempts at fashioning brain organoids often lacked capillaries to distribute oxygen and nutrients (roughly one capillary for each of the 86 billion neurons in the human brain). However, thanks to their new human transcription factor library, Church and colleagues have begun to generate the cell types necessary to create such capillaries, plus the scaffolding needed to promote the three-dimensional organization of these and additional brain structures. Church and his team have not only successfully integrated the structures with one another, but have also created an algorithm that spits out the list of molecular ingredients required to generate each cell type.
Church noted these de novo organoids are extremely useful in determining which genetic variants are responsible for certain diseases. For instance, you could sequence a patient’s genome and then create an entire organoid with the mutation in question to test whether it was the root cause of the condition.
“I’m still stunned by the breadth of projects and approaches that he’s running simultaneously,” says Emma Kowal, a second-year graduate student, member of Weng’s planning committee, and a former researcher in Church’s lab. “The seminar series is called Biology at Transformative Frontiers, and George is very much a visionary, so we thought it would be a great way to start things off.”
The four-part series also features Melissa Moore, chief scientific officer of the Moderna Therapeutics mRNA Research Platform, Jay Bradner, president of the Novartis Institutes for BioMedical Research, and Patrick Brown, CEO and founder of Impossible Foods.
Sixth year graduate student Zoë Hilbert investigates how C. elegans react to changes in their environment — and how these changes affect physiology, gene expression, and behavior
Raleigh McElvery
January 30, 2018
Sixth year graduate student Zoë Hilbert is sure of many things. After performing her first dissection in third grade, she was sure she liked science. Before she started college, she was sure she wanted to major in a biology-related discipline. And as she finished her final year at Columbia University, she was sure she would leave the East Coast immediately upon graduation. What she did not anticipate, however, was falling in love with the Cambridge biotechnology hub, applying to MIT for graduate school, and switching fields from biochemistry to genetics.
“I’m incredibly grateful for the MIT first-year program, because dedicating the fall semester solely to taking classes gave me a background in subjects I didn’t take in college,” Hilbert says. “I’d never taken genetics before, and now here I am in Dennis Kim’s lab — a genetics lab.”
Hilbert was enthralled by evolution from an early age, in particular the idea that entire organisms and their proteins change over time in response to internal and external pressures. She recalls becoming “obsessed” with the small and seemingly unremarkable stickleback fish, after she learned that researchers could map the evolution of physical features like additional belly fins or extra armor to variations in specific genes.
“When it came time for the first years to write our National Science Foundation proposals, we had the opportunity to work with a faculty member,” she recalls, “and I chose Dennis because one of the project ideas he’d listed was in a similar vein to the stickleback research. Coming into it, I didn’t know anything about his work or even his model system, but I ended up joining the lab after second semester rotations.”
The Kim lab investigates how the roundworm Caenorhabditis elegans reacts to changes in their environment — and how these changes not only affect physiology and gene expression, but behavior as well.
Today, Hilbert is as enamored by C. elegans as she once was with stickleback fish. With minimal prodding, she’s happy to rattle off their numerous advantages: they’re transparent, so there’s no need to do dissections to look inside; they’re ideal for studying development and the nervous system, because scientists have already charted all the cells in the body and how the neurons communicate; and they’re low-maintenance and easy to keep in lab. The list goes on.
But most pertinent to Hilbert is the fact that — like most species of animals — the two sexes of C. elegans, males and hermaphrodites, often behave differently in similar situations due to differences in gene expression. Take mating, for example.
Hermaphrodites are capable of self-fertilization, and can produce up to several hundred identical progeny over the course of several days. Males are much less common and unable to reproduce on their own, but by mating with hermaphrodites they can introduce some genetic variety into their offspring. Because males must locate a hermaphrodite in order to pass on their genetic material, they’ve developed some specific behaviors to find their mate. And that’s where Hilbert’s work comes in. She makes males choose between the two things they need most: food and mate.
There comes a time in every adult male’s life when finding a mate takes precedence over continuously eating, as younger worms are wont to do. If he is placed in a plate of yummy bacteria by himself, he runs away — not because he’s full, but because he’d rather spend his time searching for a mate. However, if he is placed in a plate of food along with a tempting hermaphrodite, his urge to escape is suppressed and he remains long enough to mate.
That said, C. elegans mating is not always so cut and dry. Researchers understand that a male’s behavior is also food-dependent. If you place a starving male on the plate of food, he no longer prioritizes mating over feeding, and will remain in the food instead of seeking a mate. He is constantly evaluating his priorities, which are heavily influenced by the situation at hand and — as Hilbert discovered — when and where certain genes are expressed.
“We’ve spent a lot of time monitoring how the expression of daf-7 changes in different food and mating situations,” Hilbert says. “When you starve the male, you suppress the gene and as a result you also suppress the fleeing behavior.”Hilbert demonstrated several years ago that this male-specific behavior is controlled by a gene known as daf-7, which encodes a signaling molecule and is expressed in two specific neurons in the male. (No expression is normally seen in the hermaphrodite.) Curiously, the same gene in the same two neurons is also turned on when any worm — male or hermaphrodite — comes across a pathogen, sending a “WARNING: consume at your own risk” signal, and prompting the worm to avoid the noxious bacteria.
Expression appears to be dependent not only on nutritional state (hungry or full), but also environment (food and/or mate) and sex (since males express daf-7 differently than hermaphrodites).
“All these factors and signals are converging on this one gene,” Hilbert says. “It’s really quite incredible.”
The neurons that express daf-7 are “sensory,” and traditionally viewed as funnels to higher neural centers where information is processed and behaviors are generated. However, Hilbert’s data suggest this information processing is happening right there, directly within these neurons via changes in gene expression without waiting for instructions from on high.
What Hilbert finds particularly intriguing is that the worms rely on just one molecular pathway to dictate behavior in two very different situations: mating and pathogen avoidance. Although the worm flees food in both situations, precisely why one gene is implicated in two distinct settings remains a mystery. Hilbert is still asking herself, For what benefit?
She intends to spend her final semester at MIT tying up loose ends and conducting follow-up experiments to extend the work from her recent paper in the January 2017 issue of eLife, on which she was first author. She’s screening for molecules that could impact whether or not daf-7 is expressed, honing in on chemicals and signaling molecules used by neurons to communicate with one another.
“I’d advise prospective grads to be willing and open to change your mind about what you want to do,” she says. “I was really into protein biochemistry when I first arrived at MIT, and was really surprised when I fell in love with a discipline that was completely different from my initial interests.”
As Hilbert applies to academic postdoctoral positions, she’s still set on fulfilling her longtime dream of heading out West. She’s sure she’d like to end up someplace like California, Washington, or Utah, but only time will tell.
Photo credit: Raleigh McElvery
Study explains why mutations that would seemingly affect all cells lead to face-specific birth defects.
Anne Trafton | MIT News Office
January 24, 2018
About 1 in 750 babies born in the United States has some kind of craniofacial malformation, accounting for about one-third of all birth defects.
Many of these craniofacial disorders arise from mutations of “housekeeping” genes, so called because they are required for basic functions such as building proteins or copying DNA. All cells in the body require these housekeeping genes, so scientists have long wondered why these mutations would produce defects specifically in facial tissues.
Researchers at MIT and Stanford University have now discovered how one such mutation leads to the facial malformations seen in Treacher-Collins Syndrome, a disorder that affects between 1 in 25,000 and 1 in 50,000 babies and produces underdeveloped facial bones, especially in the jaw and cheek.
The team found that embryonic cells that form the face are more sensitive to the mutation because they more readily activate a pathway that induces cell death in response to stress. This pathway is mediated by a protein called p53. The new findings mark the first time that scientists have determined how mutations in housekeeping genes can have tissue-specific effects during embryonic development.
“We were able to narrow down, at the molecular level, how issues with general regulators that are used to make ribosomes in all cells lead to defects in specific cell types,” says Eliezer Calo, an MIT assistant professor of biology and the lead author of the study.
Joanna Wysocka, a professor of chemical and systems biology at Stanford University, is the senior author of the study, which appears in the Jan. 24 online edition of Nature.
From mutation to disease
Treacher-Collins Syndrome is caused by mutations in genes that code for proteins required for the assembly and function of polymerases. These proteins, known as TCOF1, POLR1C, and POLR1D, are responsible for transcribing genes that make up cell organelles called ribosomes. Ribosomes are critical to all cells.
“The question we were trying to understand is, how is it that when all cells in the body need ribosomes to function, mutations in components that are required for making the ribosomes lead to craniofacial disorders? In these conditions, you would expect that all the cell types of the body would be equally affected, but that’s not the case,” Calo says.
During embryonic development, these mutations specifically affect a type of embryonic cells known as cranial neural crest cells, which form the face. The researchers already knew that the mutations disrupt the formation of ribosomes, but they didn’t know exactly how this happens. To investigate that process, the researchers engineered larvae of zebrafish and of an aquatic frog known as Xenopus to express proteins harboring those mutations.
Their experiments revealed that the mutations lead to impairment in the function of an enzyme called DDX21. When DDX21 dissociates from DNA, the genes that encode ribosomal proteins do not get transcribed, so ribosomes are missing key components and can’t function normally. However, this DDX21 loss only appears to happen in cells that are highly sensitive to p53 activation, including cranial neural crest cells. These cells then undergo programmed cell death, which leads to the facial malformations seen in Treacher-Collins Syndrome, Calo says.
Other embryonic cells, including other types of neural crest cells, which form nerves and other parts of the body such as connective tissue, are not affected by the loss of DDX21.
Role of DNA damage
The researchers also found that mutations of POLR1C and POLR1D also cause damage to stretches of DNA that encode some of the RNA molecules that make up ribosomes. The amount of DNA damage correlated closely with the severity of malformations seen in individual larvae, and mutations in POLR1C led to far more DNA damage than mutations in POLR1D. The researchers believe these differences in DNA damage may explain why the severity of Treacher-Collins Syndrome can vary widely among individuals.
Calo’s lab is now studying why affected cells experience greater levels of DNA damage in those particular sequences. The researchers are also looking for compounds that could potentially prevent craniofacial defects by making the cranial neural crest cells more resistant to p53-induced cell death. Such interventions could have a big impact but would have to be targeted very early in embryonic development, as the cranial neural crest cells begin forming the tissue layers that will become the face at about three weeks of development in human embryos.
The research was funded by the National Institutes of Health, Howard Hughes Medical Institute, and March of Dimes Foundation.
December 14, 2017
Lab coat meets legislation
Undergraduate Courtney Diamond combines biology and policy to tackle real-world challenges
Raleigh McElvery
Undergraduate Courtney Diamond arrived at MIT determined to be an oncologist. Five years later, she’s leaving with a broader focus on human health, grappling with real-world, biomedical problems by way of public policy rather than medicine or research.
Although Diamond had completed her requirements for a degree in biology at the beginning of her senior year, she decided then to add a second major: Course 17 (Political Science), and with it a fifth year of study at MIT.
“I came into MIT wanting to be a doctor, but the more I thought about it the less it felt like medical school would be a good fit,” she says. “I spent a long time narrowing my interests within the realm of human health, and recently realized there was another dimension to that interest related to public policy, which was also this common thread among my extracurriculars.”
Diamond grew up in a small town in Massachusetts called Millbury, not too far from MIT, which she describes as special to her but “rather unremarkable” in most other ways — with the exception of one particularly zealous and articulate high school biology teacher. His infectious enthusiasm sparked Diamond’s passion for the life sciences, but over the course of her senior year this interest became far more personal. It was around that time that her mother developed breast cancer, and Diamond resolved to be an oncologist.
“My mom had been diagnosed once before with a different kind of cancer, cervical cancer,” she says. “But I was in sixth grade back then, and assumed she was just at home resting. By the time the breast cancer rolled around, I was old enough to understand that most people are lucky to survive cancer once. But twice?”
Her mother has since entered remission, and the year Diamond began at MIT her interests matured away from a career in medicine and towards biomedical research. In April 2014, she applied to the MIT Undergraduate Research Opportunities Program (UROP). “I wanted to figure out which part of biology excited me — which area I really wanted to drill down on,” she recalls.
She began working with a postdoctoral fellow in Professor Darrell Irvine’s lab at the Koch Institute for Integrative Cancer Research, tackling research questions related to cancer immunology. Diamond’s job was to analyze murine tumors as they developed over time, in order to understand how they were affected by changes to their cellular environments.
After a year, Diamond took a break from research in order to focus on her classes. But she didn’t stay away for long.
“I’ve had a life-long obsession with Australia,” she says, “and in the fall of my sophomore year, I told my advisor, Professor Bob Horvitz, that my dream was to study biochemistry in Melbourne.” One email and two hours later, she received an offer from theWalter and Eliza Hall Institute for Medical Research to spend a summer abroad in Jeff Babon’s lab. “It turns out the director of the Institute did his postdoc at MIT, and liked the UROP system so much he decided to bring it back to Australia,” she explains.
There, Diamond helped to unravel the structure of a protein complex known as JAK-STAT. This complex is involved in many diverse processes — from cell proliferation and programmed cell death to immunity — making it critical to understand how the different molecular components of the complex fit together to influence function.
When she returned to MIT, Diamond decided to maintain her focus on structural biology. She completed her thesis in Professor Thomas Schwartz’s lab, studying the Y complex, a component of the nuclear pore — a channel that allows mRNA and other molecules to pass into the cell’s nucleus. Diamond helped creat a library of fluorescing antibodies that could adhere to the Y complex, allowing her to visualize its position within the nuclear pore. After a year, she opted to broaden her interests by taking classes outside her major.
One of those classes, recommended by a friend, was in political science: 17.309 (Science, Technology, and Public Policy), taught by Professor Kenneth Oye. During one of his lectures, Oye made a quip about a small Massachusetts town called Millbury.
“I came up to him after class to ask him, ‘Did you know I’m actually from there?’ and he thought it was the funniest thing,” she says. “That initial, informal interaction led to more meaningful conversations, and I ended up working with him on a few projects.”
Today, she is pursuing a final UROP with Oye, looking at technologies and policies related to synthetic biology. At Oye’s weekly working group of graduate students and postdocs, she debates the possible repercussions of using gene editing techniques like CRISPR-Cas9 to control the transmission of certain traits throughout a given population. For example, what would happen if mosquitos in the regions where malaria is most prevalent carried a gene encoding malaria resistance — would that eradicate the illness? But might there be unintended, negative consequences?
As part of a separate project, Diamond is researching U.S. consent and privacy policies in the realm of health information technology. She’s also hard at work on her political science thesis, focusing on ways to incentivize companies and researchers to develop new and more effective antibiotics to combat antimicrobial resistance.
Diamond is now applying for public health consulting jobs, and she plans to pursue graduate training in epidemiology, followed by a master’s in public health. Long-term, she sees herself at theCenters for Disease Control and Prevention or the World Health Organization.
“I mean, that’s the current plan,” she says. “Check back in with me in two years.”
Photo credit: Raleigh McElvery
Carolyn Lanzkron discovered bench science while attending community college with her son, and followed her newfound passion to MIT
Raleigh McElvery
December 3, 2017
From DNA forensics to cancer metabolism
Carolyn Lanzkron discovered bench science while attending community college with her son, and followed her newfound passion to MIT
Raleigh McElvery
Carolyn Lanzkron spent 20 years as a stay-at-home mother raising five children before starting at MIT. Life has taught her patience, which she, in turn, has tried to pass on to her kids: “A successful person falls down many times and gets up — just pick a direction and move forward.”
Those were the same words she told her teenage son back in 2011 when she encouraged him to attend community college.
“I figured I would just take a few courses with him,” she says. “He enjoyed his chemistry classes, so I was looking at the chemistry offerings, and on the wall there was a poster for Dr. Bruce Jackson’s unique Forensic DNA Science program.” Lanzkron was intrigued, and decided to enroll.
The students aided Jackson with real cases, and were given dedicated lab space and materials to follow their curiosities, as well as design their own inquiries. The program was based on a peer-mentoring model, and Lanzkron was appointed chief of peer mentors and forensic case manager. Under Jackson’s tutelage, she worked on lineage cases tracing ancestry and criminal cases for defense and prosecution.
“I was hoping my son would join me in a chemistry class, but he wasn’t so interested in having his mom as a lab partner — go figure,” she says. “But we carpooled to school together for a year, and by that time I’d developed a love for bench science.”
After two years, Lanzkron had completed her degree, but it wasn’t enough. So she applied to several institutions within her carpool radius, including MIT. Like all transfers here, she began as a sophomore.
“I love bench science because I really appreciate the combination of being part of a team and solving a big, important question, but at the same time having tasks in my day that allow me to focus on small details — like keeping track of the labels on my tubes,” she says. “That balance works really well for me; it satisfies my need for a quest while still having control over a small environment.”
She’s turned her attention from DNA forensics to cancer metabolism, an interest which has become far more personal over the past year. Last spring, Lanzkron’s mother was diagnosed with lung cancer, and Lanzkron took a leave of absence to care for her.
“Right now, my mother is doing really well, and we are enjoying a window of stability,” Lanzkron says, “which has allowed me to come back to MIT and finish my degree.”
Although Lanzkron is not currently in a lab, lest that period of stability suddenly end, she’s worked in several over the course of her three years at MIT. She began in Jean Francois Hamel’s chemical engineering lab, adapting an adherent cell line to grow in a suspension-like culture in various bioreactors using microcarriers.
Later, Lanzkron joined David Sabatini’s lab in the Whitehead Institute for Biomedical Research, aiding two separate projects: one spearheaded by then-postdoc Yoav Shaul, and the other led by MD-PhD student Walter Chen.
Chen was hard at work developing a new method for profiling undamaged mitochondria, while Shaul had discovered a unique set of 44 metabolic genes that were upregulated in certain cancers that expressed mesenchymal markers (which he called the “Mesenchymal Metabolic Signature,” or “MMS”), indicating that those cells were acquiring cancerous characteristics. Lanzkron collaborated with Shaul as he worked to further characterize the metabolic requirements and behavior of the MMS. She also helped him refine his web-based gene analysis tool, Metabolic gEne RApid Visualizer (MERAV), which queries a database comprising ∼4,400 microarrays, representing human gene expression in normal tissues, cancer cell lines, and primary tumors.
The summer after Shaul completed his postdoctoral training, Lanzkron interned in his lab in at the Hebrew University of Jerusalem at Hadassah Ein Kerem through the MISTI/Israel program, to continue working with him on these projects.
“When I went to Israel, my husband stayed in Boston and took care of the kids,” she recalls. “Without family responsibilities, I could work in lab around the clock, and that was great. I was actually able to finish things up, prepare them for the next day, and cover for other people and really focus; I look forward to being able to do that again as the kids get older.”
Lanzkron admits these aren’t the only aspects of the MIT undergraduate experience she’s missed — not just because she lives off campus and can’t meet at odd hours of the night to collaborate on problem sets — but also because she’s a generation and a half older than her classmates.
But in some ways she considers this an advantage. For instance, she now has the tools to guide her own children through today’s college process.
“I no longer have this outdated view of what it’s like to apply to schools and navigate the SAT,” she says. “Granted, MIT is not your average school. It’s been quite the ride to be at the community college where I had to bring my own masking tape to complete the gel trays because we didn’t have any sealing rings — I didn’t even know there was such a thing as a seal back then. And to go from that to the MIT Department of Biology and the Whitehead Institute where the resources are phenomenal, it’s just mind blowing. I have learned so much from both situations — having to make do, and having an abundance of resources.”
While Lanzkron intends to graduate this spring, her future plans depend on her mother’s health.
“I picked my classes this semester so that I could take her to her cancer treatment,” Lanzkron says, “so, though I’m ultimately planning to go to graduate school, right now things are still in flux.”
While maintaining this school-family balance would be inconceivable for most, Lanzkron takes her personal and academic responsibilities in stride.
“Honestly I’m so happy here at MIT,” she says. “I tell my kids, ‘Don’t get too worked up about the college process. You’ll get where you need to go — the starting point almost doesn’t matter; what matters is what you do when you get there.’”
One day last October, MIT biology professor Matthew Vander Heiden showed up in one of his trademark plaid shirts to teach his undergraduate course on cancer biology. As usual, he peppered his lecture with questions, filling six sliding chalkboards with arrows mapping cellular pathways; he had to erase the boards halfway through class to make room for more notations. But what might have seemed like an ordinary lecture was far from ordinary in one respect: although Vander Heiden was explaining some of the most fundamental aspects of how tumors grow, most of what he was teaching his students would have been absent from nearly every introductory course on cancer biology a decade ago. The science Vander Heiden discussed that afternoon amounted to a once-lost but recently rediscovered chapter in the history of cancer research.
