Research Area: Cell Biology

New study solves an arthritis drug mystery

MIT biological engineers discover why a promising drug failed in clinical trials.

Anne Trafton | MIT News Office
March 6, 2018

Pharmaceutical companies once considered a protein called p38 a very attractive target for treating rheumatoid arthritis. Arthritis patients usually have elevated activity of this inflammation-producing protein, and in lab studies p38 inhibitors appeared to soothe inflammation. However, these drugs failed in several clinical trials.

A new study from MIT sheds light on just why these drugs did not work for arthritis. By untangling the complex interactions between different cell pathways involved in inflammation, the researchers discovered that shutting off p38 triggers other inflammatory pathways.

The findings demonstrate the importance of studying a potential drug’s impact on complex cellular systems, says Doug Lauffenburger, head of MIT’s Department of Biological Engineering and the senior author of the study. It’s also important to do these studies under environmental conditions that match those found in diseased tissue, he adds.

“You’ve got to make sure you understand the complexity of the intracellular networks, and beyond that, you need to think about the environment you put the cells in,” Lauffenburger says. “It’s easy to get different results in different contexts, so you need to study them under many different conditions.”

Former MIT postdoc Doug Jones is the lead author of the paper, which appears in the March 6 issue of Science Signaling.

A promising target

Rheumatoid arthritis, which afflicts more than 1 million Americans, is an autoimmune disorder that produces swollen and painful joints, primarily affecting the wrists and hands. This pain results from inflammation in the lining of the joints. Cells called synovial fibroblasts, which typically provide structural support for the joint lining, promote the inflammation and swelling in arthritic conditions.

Several years ago, scientists seeking new treatments for arthritis discovered that synovial fibroblasts from arthritis patients had very high levels of p38, and many pharmaceutical companies began working on p38 inhibitors. “The activity of this pathway was so strong that people tended to think that it was the best one to inhibit,” Lauffenburger says.

Despite their promise, p38 inhibitors failed in phase II clinical trials run by at least eight pharmaceutical companies. One of those companies, Boehringer Ingelheim, asked Lauffenburger to help them figure out why. Lauffenburger’s lab focuses on systems biology, a field that involves measuring the interactions of many cell components and then performing computational modeling of those measurements to predict cell behavior.

The researchers’ analysis revealed that the inflammatory pathway controlled by p38 interacts with several other pathways that can cause inflammation. These pathways, known collectively as stress pathways, produce inflammatory cytokines in response to events such as infection or injury.

The MIT team found that when p38 is extremely elevated, it suppresses the activity of these other inflammatory pathways. Therefore, when it gets turned off, the brake on the other pathways is released. Under these circumstances, inflammation remains high — the difference is that now it is controlled by other stress pathways.

“This is an insightful paper on redundancy in signaling and the need to understand compensatory mechanisms before spending billions on drug development. In that sense, it is a far more important insight than ‘just’ p38 inhibitors, and it makes clear again that animal efficacy models have severe limitations as tools to predict human efficacy,” says David De Graaf, CEO and president of Syntimmune, who was not involved in the research. “This paper outlines one very thoughtful and generic approach to answer complex questions about efficacy in ex vivo human model systems.”

Environment matters

Why was the MIT team able to see this phenomenon when others had not? Lauffenburger says one key is the environment in which the synovial fibroblast cells were studied.

Normally, cells studied in the lab are grown in a culture medium that offers them nutrients and molecules called growth factors, which keep the cells alive and proliferating. However, the MIT team found that under these conditions, a pro-growth pathway called MEK actually keeps p38 levels lower than in cells under stress. Because p38 is not as high, it doesn’t inhibit the other stress pathways as strongly, so when the cells are exposed to p38 inhibitors, the other pathways don’t soar into action and overall inflammation goes down.

“It looks like p38 inhibitors work well, if cells are in these growth factor environments,” Lauffenburger says.

However, the MIT team found that synovial fluid from arthritis patients is not a pro-growth environment but is full of inflammatory cytokines. They then decided to expose synovial fibroblasts taken from patients with arthritis and from healthy individuals to this inflammatory environment. In both healthy and diseased cells, p38 levels skyrocketed, producing more inflammation and shutting off other stress pathways.

One question still to be answered is whether p38 inhibitors could work against other diseases such as cancer, in which the cells targeted would likely be in a pro-growth environment. They are also being considered as potential treatments for other inflammatory diseases such as multiple sclerosis and Alzheimer’s. Lauffenburger says that their success will likely depend on what kind of environment the affected cells are in.

“A p38 inhibitor could work; you just have to know what the context is that the target cells are in. If you have the same kind of inflammatory cytokines there, then you might encounter the same problem” seen in arthritis, he says.

It’s also possible that p38 inhibitors could work against arthritis or other drugs if given along with drugs that shut off other stress pathways, but more research would be needed to investigate that possibility, Lauffenburger says.

The research was funded by the National Institutes of Health, the Army Research Office, and Boehringer Ingelheim Inc. The project was undertaken in collaboration with Professor Peter Sorger at Harvard Medical School; Brian Joughin at MIT and Anne Jenney at Harvard were also significantly involved in the work.

The Man Who Uncovered a New (Old) Way to Fight Cancer

Matthew Vander Heiden helped revive the forgotten— but critical—study of cancer metabolism.

Sam Apple | MIT Technology Review
February 21, 2018

Person in plaid shirt by windowOne 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.

Person pipets in lab hood
Daniel Schmidt, a postdoc in Vander Heiden’s lab, prepares cells to study how metabolism affects cancer cell proliferation. Credit: BUCK SQUIBB
Daniel 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.”

Scientists deliver high-resolution glimpse of enzyme structure

New finding suggests differences in how humans and bacteria control production of DNA’s building blocks.

Anne Trafton | MIT News Office
February 20, 2018

Using a state-of-the-art type of electron microscopy, an MIT-led team has discovered the structure of an enzyme that is crucial for maintaining an adequate supply of DNA building blocks in human cells.

Their new structure also reveals the likely mechanism for how cells regulate the enzyme, known as ribonucleotide reductase (RNR). Significantly, the mechanism appears to differ from that of the bacterial version of the enzyme, suggesting that it could be possible to design antibiotics that selectively block the bacterial enzyme.

“People have been trying to figure out whether there is something different enough that you could inhibit bacterial enzymes and not the human version,” says Catherine Drennan, an MIT professor of chemistry and biology and a Howard Hughes Medical Institute Investigator. “By considering these key enzymes and figuring out what are the differences and similarities, we can see if there’s anything in the bacterial enzyme that could be targeted with small-molecule drugs.”

Drennan is one of the senior authors of the study, which appears in the Feb. 20 issue of the journal eLife. JoAnne Stubbe, the Novartis Professor of Chemistry Emerita at MIT, and Francisco Asturias, an associate professor of biochemistry at the University of Colorado School of Medicine, are also senior authors. The paper’s lead authors are MIT research scientist Edward Brignole and former Scripps Research Institute postdoc Kuang-Lei Tsai, who is now an assistant professor at the University of Texas Houston Medical Center.

An unusual enzyme

The RNR enzyme, which is found in all living cells, converts ribonucleotides (the building blocks of RNA) to deoxyribonucleotides (the building blocks of DNA). Cells must keep a sufficient stockpile of these building blocks, but when they accumulate too many, RNR is shut off by a deoxynucleotide molecule known as dATP. When more deoxynucleotides are needed, a related molecule called ATP binds to RNR and turns it back on.

An unusual feature of RNR is that it can catalyze the production of four different products: the nucleotide bases often abbreviated as A, G, C, and T. In 2016, Drennan discovered that the enzyme achieves this by changing its shape in response to regulatory molecules.

Most of the researchers’ previous work on RNR structure has focused on the version found in E. coli. For those studies, they used X-ray crystallography, a technique that can reveal the atomic and molecular structure of a protein after it has been crystallized.

In the new study, Drennan and her colleagues set out to examine the human version of RNR. This protein’s structure, which turned out to be very different from the bacterial version, proved elusive using X-ray crystallography, which doesn’t work well for proteins that don’t readily crystallize. Instead, the researchers turned to an advanced form of microscopy known as cryo-electron microscopy (cryo-EM).

Until recently, cryo-EM typically offered resolution of about 10 to 20 angstroms, which might reveal the overall shape of a protein but no detail about the position and shape of smaller structural units within it. However, in the past few years, technological advances have led to an explosion in the number of structures achieving resolutions of about 3 angstroms. That is high enough to trace individual protein chains within the larger molecule, as well as internal structures such as helices and even side chains of amino acids.

Scientists already knew that RNR consists of two protein subunits known as alpha and beta. Using cryo-EM, the MIT team found that the human version of the enzyme forms a ring made from six of the alpha subunits. When ATP, which activates RNR, is bound to the enzyme, the ring is unstable and can be easily opened up, allowing the beta subunit to make its way into the ring. This joining of alpha and beta allows the enzyme’s active site, located in the beta subunit, to perform the chemical reactions necessary to produce deoxynucleotides.

However, when the inhibitor dATP is present, the ring becomes much more rigid and does not allow the beta subunit to enter. This prevents the enzyme from catalyzing the production of deoxynucleotides.

Designing drugs

Several cancer drugs now in use or in development target the human version of RNR, interfering with cancer cells’ ability to reproduce by limiting their supply of DNA building blocks. The MIT team has found evidence that at least one of these drugs, clofarabine diphosphate, works by inducing the formation of rigid 6-unit alpha rings.

This 6-unit ring is not found in the bacterial form of RNR, which instead assembles into a distinct ring containing four alpha subunits and four beta subunits. This means it could be possible to design antibiotics that target the bacterial version but not the human version, Drennan says.

She now plans to investigate the structures of other protein molecules that are difficult to study with X-ray crystallography, including proteins with iron sulfur clusters, which are found in many metabolic pathways. The microscopy work in this study was performed at the Scripps Research Institute, but when MIT’s new MIT.nano building opens, it will house two cryo-EM microscopes that will be available to the MIT community as well as other potential users in industry and academia.

“The technological advances that have allowed cryo-EM to get to such high resolution are really exciting,” Drennan says. “It’s really starting to revolutionize the study of biology.”

The research was funded by the National Institutes of Health.

Probing a critical player in cancer growth

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
Reading and writing DNA

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.

How some facial malformations arise

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

Person with red hair in bun stands outside with umbrella.

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 the Walter 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 the Centers 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
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
December 3, 2017

From DNA forensics to cancer metabolism

Person in black hat and purple shirt sitting in front of lab building.

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.’”

Photo credit: Raleigh McElvery
Sizing up cancer

Graduate student Zhaoqi Li investigates how cancer cells grow by harnessing exceptional chemical reactions

Justin Chen
January 11, 2018

Cancer cells use extreme measures to fuel their growth. In fact, researchers like Zhaoqi Li, a third-year graduate student, witness chemical reactions in these cells that would be impossible in the context of normal cells. In a petri dish, normal cells stop dividing once they cover the bottom of the dish and fit neatly together like mosaic tiles. In contrast, cancer cells continue to proliferate and pile haphazardly into small mounds. Within the human body, this abnormal growth — when combined with the spread of cancer cells throughout the body — interferes with organ function and causes death.

Li, a member of Professor Matthew Vander Heiden’s lab located in the Koch Institute, studies cancer metabolism. His work describes the chemical reactions cancer cells use to create energy and materials to make new cells such as membranes, proteins, and DNA. By tracking the flow of nutrients through cancer cells, Li and his labmates are learning how such cells change their metabolism to stimulate growth. These insights will help scientists develop new ways to treat the disease.

Cell metabolism comprises all the chemical reactions occurring in the cell, but researchers are particularly interested in a few reactions that aren’t required by normal cells but are critical for cancer growth. Stopping these reactions with drugs would disrupt the metabolism of cancer cells and hinder tumor development.

“Even though many people may not think of metabolism as a treatment target for cancer, this strategy has been used unwittingly for a long time,” Li says. “Many chemotherapies, such as antifolates, were originally used by doctors without knowing exactly how they worked. Since then, we’ve discovered that those treatments target metabolic pathways. By understanding the details of cancer metabolism we are hoping to design drugs in a more rational way.”

– –

Li might never have joined the Vander Heiden lab or studied cancer metabolism were it not for the unique structure of graduate training at MIT.

During their first year at MIT, graduate students are required to take four classes. Unlike their counterparts at many other PhD programs, they do not work in laboratories until their second semester. This allows students to focus initially on coursework — covering biochemistry, genetics, and research methodology — designed to build a foundation of knowledge. As a result, students discover new interests and develop the confidence to move out of their comfort zones. When it comes time to select a lab, they can choose from 56 spread across six locations, spanning a wide breadth of biological research.

Li could study how the brain forms memories, interpret X-rays to deduce protein structure, or even build miniature organs for drug testing. Before making his decision, he rotated in three laboratories. During each month-long rotation, he performed a small project allowing him to experience the culture of the lab and learn more about its research.

“The first two labs I visited were studying topics I was familiar with and thought were interesting,” he says. “But when I visited the Vander Heiden lab it was so different and caught me off guard. That’s why I eventually joined, even though I had never imagined myself working in a metabolism lab before.”

Diagram showing a metabolism pathway
Cellular metabolism is comprised of a network of interconnected biochemical reactions resembling a subway system. Zhaoqi Li compares normal and diseased cells to determine the differences in the way nutrients travel through this network. Credit: Justin Chen

– –

Although he is new to the community of researchers specializing in metabolism, Li has long known that he wanted to interact with the world through science. As an immigrant who moved from China to southern Tennessee at the age of six, Li struggled to learn English and began to view science as a universal language that transcended culture.

“My parents were also non-native speakers and the English as a Second Language classes in my elementary school were geared towards Spanish speakers, so I had a really hard time,” Li says. “I joke that the only reason I passed the first grade was because I was good at math.”

Li’s contrasting relationship with science and English continued as an undergraduate at Columbia University. There he majored in biochemistry and also studied literature of the Western Canon to fulfill his general degree requirements.

“I took four semesters worth of classes that started with Plato and ended with Virginia Woolf,” he says, “It was an eye-opening experience, but I never really loved it. I found biology more intuitive because it doesn’t rely on being familiar with a specific cultural lens. Most every society in the world values the scientific method to some extent.”

Li began working in a lab during his sophomore year at Columbia. To his surprise, he was mentored by a professor who valued his input and encouraged creative thinking. Li’s supervisor also introduced him to basic science — a type of research driven not by the desire to find a specific answer or cure, but by curiosity and the need to better understand the natural world.

– –

During his second semester rotation at MIT, Li searched for similarly open-minded environments, and was attracted to cancer metabolism because the field was relatively young.

“In other more established areas of biology, if you have a question someone has probably answered it in some capacity,” Li says. “The Vander Heiden lab was using new techniques so there was a lot of space to explore. Many questions I asked — even during my initial rotation —  didn’t have an answer, which was exciting.”

The great challenge confronting the metabolism field is translating decades’ worth of research on enzymes — proteins that manage chemical reactions — from the test tube to the cell and human body. By studying enzymes individually in the controlled setting of test tubes, researchers have documented almost all the chemical reactions that occur in the cell. When combined, these reactions look like a giant subway map where each stop, indicated by a dot, is a different molecule, and the line between stops represents a chemical reaction where atoms are added or subtracted. Some pathways are a straight line but others have nodes or intersections where a molecule can take part in several different reactions. Other pathways are circular where the molecule that starts the pathway is remade at the end so that the line circles back on itself.

Despite the ability to study chemical reactions in a test tube, scientists have struggled to understand what is actually happening in the complex environment of cells, which coordinate millions of reactions that not only affect each other, but are also influenced by outside stresses like nutrient deprivation.

To Li, using the metabolism map to figure out what chemical reactions are occurring and how atoms are moving through the cell is like using a subway map to track how people are traveling through a city.

“The map describes all the possible routes people could take,” Li says, “but you have to track the passengers to figure out where they are actually going. You could imagine people commuting into the city during the week and going to entirely different places on the weekend. There are a lot of different patterns of movement that you can’t infer just from looking at a map.”

To analyze what chemical reactions are occurring in the cell, Li utilizes cutting edge technology to track carbon atoms — an essential element that is required to build all components of the cell. By tagging carbon with an extra neutron, Li makes the experimentally altered atom heavier and distinguishable from naturally occurring carbon in the cell. Feeding cells nutrients like glucose made with heavy carbons allows Li to compare how molecules are broken down and used by normal and cancerous cells.

Person at lab instrument with sample“Returning to the subway map analogy, this labeling technique is similar to not only being inside the subway, but also giving everyone in Downtown Boston a red shirt,” Li says. “After 12 hours, we can look at the rest of the city. If we see a lot of red shirts in Allston, we would know that this particular route is really popular.”

In the case of glucose, Li and his labmates observed that normal cells break down the sugar to release energy and heavy carbons in the form of carbon dioxide. In contrast, cancer cells alter their metabolism so that the heavy carbons originally found in glucose are used to build new parts of the cells that are required for cancer cells to grow, such as membranes, DNA, and proteins.

Li’s observations demonstrate how cancer cells sustain abnormal growth by accumulating carbon. For his thesis project, Li has chosen to investigate one of the main tricks cancer cells use to hoard carbon atoms: a process known as carbon fixation. This type of chemical reaction, originally studied in plants performing photosynthesis, attaches carbon dioxide to other molecules. Li’s initial findings suggest that a protein, Malic Enzyme 1, helps cancer cells use carbon dioxide to build components required for growing and dividing.

“This is surprising,” he says, “because the textbook version of this enzyme actually catalyzes the reverse reaction in normal cells where carbon dioxide is removed from molecules.  Malic Enzyme 1 is an example of how cancer performs remarkable chemical reactions — who would have thought that cancer cells use carbon like plants do?”

Li is at the beginning stages of his research, and can’t predict where his project will take him. His current goal is to determine how cancer cells react when they are missing Malic Enzyme 1. Such loss could slow growth, but Li will have to perform experiments to be sure, since cancer is a resourceful and elusive target.

Like a detour rerouting travelers around a closed metro stop, cancer cells may further contort their metabolism, taking advantage of little-used or still unidentified chemical reactions to maintain growth. In the face of such adaptability, Li and his labmates believe the best course of action is to be as curious as possible to understand as much as they can about how cancer works. Working together, they discuss confounding results, adjust hypotheses, and design new experiments.

“It’s really encouraging to be part of Matt’s lab and the Koch Institute in general where researchers take a basic science approach,” Li says. “We try to keep an open mind because there’s probably no single thing that cancer cells depend on. Everyone’s work builds together to form a cumulative understanding.”

Photo credit: Raleigh McElvery
Chris A. Kaiser

Education

  • PhD, 1987, MIT

Research Summary

The Kaiser lab studied protein folding and intracellular trafficking in the yeast S. cerevisiae. Their work focused on the protein folding in the endoplasmic reticulum (ER), quality control mechanisms in the ER, and membrane protein sorting in Golgi compartments. They combined genetic, biochemical, and cell biological methods to gain an understanding of the molecular mechanisms underlying each of these processes. Chris Kaiser is no longer accepting students.