Research Area: Genetics

Department of Biology welcomes three new faculty members

Recent additions bring diverse expertise and cultural perspectives to research community.

Raleigh McElvery | Department of Biology
July 25, 2017

On July 1, MIT Department of Biology welcomed three new faculty members. Since they were all born outside the continental U.S., these newcomers add to the diversity of cultural experiences and contribute to the global face of science at MIT and its affiliated institutions around Kendall Square. The triad also enhances the department’s diverse array of research initiatives. Their interests are as far-reaching as their roots, and range from investigating genetic diseases and cancer immunotherapy to exploiting parasite vulnerabilities.

“When creative individuals with distinct perspectives and approaches come together in an innovative environment like MIT, the possibilities for scientific collaboration and accomplishment are exceptional,” says Alan Grossman, head of the department. “I couldn’t be more pleased to welcome three such outstanding and accomplished individuals into our research community.”

Eliezer Calo

Eliezer Calo is no stranger to MIT. Although he grew up on a farm more than a thousand miles away in the mountains of Carolina, Puerto Rico, Calo first set foot in MIT’s Building 68 11 years ago — and hasn’t wavered in his decision to become a biologist since. In 2006, as part of the MIT Summer Research Program (MSRP), Calo spent 10 weeks studying under Professor Stephen Bell, examining DNA replication. At the time, Calo was a chemistry major at the University of Puerto Rico, but returned post-graduation to MIT’s Department of Biology, earning his PhD while serving as both a teaching assistant for MIT’s course 7.01 (Introduction to Biology) and MSRP program assistant.

“MIT is very unique,” he says. “I’ve done research at multiple institutions, and yet nothing quite compares. Here, the impossible is made possible.”

After completing his postdoctoral training at Stanford University, Calo returned to Cambridge, Massachusetts, this past January as an assistant professor and extramural member at the Koch Institute to head his own lab — exploring the ways in which errors in cellular organelles called ribosomes can lead to disease.

Ribosomes are vital to the translation of genetic code into the molecules integral to life, but are far less often acknowledged for their role in embryonic development. Calo suggests that when ribosomes are not constructed correctly, they are unable to carry out their cellular duties, hindering cell growth and causing developmental disorders. Calo is interested in one condition specifically: Treacher Collins syndrome, which stems from a mutation in a single gene that impedes proper ribosomal assembly. He will soon transfer his experiments from cell cultures to a new model system — zebrafish — in order to further unravel the relationship between ribosome structure and disease.

“The research I do now is purely based on my interest in understanding how cells work,” Calo says. “Specifically, how the mechanisms controlling growth and proliferation operate. These are essential processes that led to the emergence of multicellular organisms, and thus to our own existence.”

Stefani Spranger

One building over in MIT’s Koch Institute, newly-appointed Assistant Professor Stefani Spranger will work to harness the body’s own defense force to pinpoint and eradicate cancer. Spranger carried her passion for immunotherapy across seas from Munich, Germany. As the daughter of two engineers, Spranger was raised on science. “My parents fostered my curiosity,” she says, “which led to my initial motivation to go into science: to figure out how things work.”

While earning her bachelor’s and master’s degrees from the Ludwig-Maximilians University of Munich, Spranger discussed publications focusing on two clinical trials that used engineered immune cells to combat malignant melanoma. These publications ignited Spranger’s enthusiasm for immune-based therapies, which in turn spurred her doctoral and postdoctoral training at the Helmholtz-Zentrum Munich in the Institute for Molecular Immunology and the University of Chicago, respectively.

While Spranger’s education helped hone her immunology research skills, she is excited to experience a more varied academic environment encompassing a range of disciplines. “I was drawn to MIT because of its diverse faculty and the breadth of research interests,” she says.

Spranger’s lab will employ tumor models in mice to determine how cancer and immune cells interact. In particular, she aims to discern the many factors related to the cells, tissues, and environment that could affect the immune system’s anti-tumor response. Ultimately, Spranger hopes to contribute to new treatments that trigger the body’s defense to thwart cancer.

Sebastian Lourido

Trained as both an artist and a scientist, Sebastian Lourido works to counter an entirely different kind of invader spreading biological mayhem: parasites. Originally from Colombia, he was recently named assistant professor of biology, joining the cohort of 15 faculty members at the Whitehead Institute for Biomedical Research — one of just 28 individuals to ever receive this appointment. The title may be new, but this is familiar turf for Lourido. He became a Whitehead Fellow in 2012, after receiving his PhD in microbiology from Washington University in St. Louis and a bachelor’s in studio art and cell and molecular biology from Tulane University. A pioneer in more ways than one, Lourido formed his own lab as a fellow rather than following a more conventional postdoc path.

Lourido spent much of his childhood exploring his mother’s genetics lab, where he analyzed practically anything he could fit under a microscope. “That experience solidified my excitement for the invisible mechanisms that make up the living world,” he says. “I can’t remember a time when I didn’t know that genetic information was carried in our cells in the form of DNA, and passed from one generation to the next.”

Constantly seeking ways to merge his artistic endeavors with scientific ones, Lourido leverages his creativity to glean insight into the systems and structures that constitute life.  He probes a group of microscopic invaders known as Apicomplexan parasites, revealing their weaknesses in order to devise potential treatments. Lourido’s team was the first to perform a genome-wide functional analysis of an apicomplexan — gaining deeper understanding of the genes and molecules key for the invasion process. In 2013, Lourido received the National Institutes of Health (NIH) Director’s Early Independence Award, and with it a five-year grant to investigate motility in one kind of parasite, Toxoplasma gondii. This same interloper is also the subject of Lourido’s two-year NIH-funded project, for which he is the principal investigator.

Lourido has found the MIT community both welcoming and inclusive. Even as he was interviewing for his new position, he was struck by the collaborative, collegial, and nurturing environment.

“This level of engagement permeates the other elements of our community — students, postdocs, and staff scientists — who drive the exciting research happening every day at MIT,” he says. “There are many forces that shape the diversity of our campus, and we need to be vigilant and work hard to continue to encourage and support scientists from different backgrounds, experiences, and cultures.”

STEX event showcases innovations in fitness technology and science

Entrepreneurs, researchers, and industry experts build connections at workshop.

Rob Matheson | MIT News Office
June 26, 2017

Many MIT-affiliated startups are innovating in the burgeoning fitness technology and science space, aiming to promote healthier lifestyles and help optimize athletic performance.

Novel products from these startups include a smart chair that fights back pain and diabetes, a sleeve that monitors muscle-movement data that users can share in the cloud, a wristband that tracks blood oxygen levels for greater performance, and even a so-called anti-aging pill.

A workshop hosted June 22 by the MIT Office Corporate Relations’ (OCR) MIT Startup Exchange (STEX) program brought together some of these MIT entrepreneurs and industry experts to showcase their innovations and foster connections that could lead to new business opportunities.

Held throughout the year, the three-hour STEX workshops include lightning presentations from MIT-connected startups; brief talks from academic innovators, industry experts, government representatives, and venture capitalists; startup presentation and demonstration sessions; and an interactive panel discussion.

At last week’s event, eight entrepreneurs pitched their fitness-tech products — several rooted in MIT research — to a crowd of around 80 entrepreneurs, researchers, and industry experts in the OCR headquarters on Main Street, in Cambridge, Massachusetts. The academic keynote speaker was MIT Novartis Professor of Biology Leonard Guarente, who took the opportunity to demystify the science behind his startup Elysium Health’s “anti-aging pill,” which is made of compounds that aim to thwart age-related cell damage, which can lead to inflammatory and heart diseases, osteoporosis, and diabetes.

STEX events aim to stimulate discussion, foster collaboration, and build partnerships between MIT-connected startups and member companies of MIT’s Industrial Liaison Program (ILP). The series covers a broad range of topics: a recent workshop focused on energy storage, while upcoming events will focus on synthetic biology, robotics and drones, cancer therapies, renewable energy, world water issues, and 3-D printing.

“Fitness, wellness and nutrition are very exciting areas, and MIT founders are very active in the space. We certainly have industry coming to campus interested in all of these technologies and products coming from them,” Trond Undheim, who directs STEX and is the organizer of the event, said in his opening remarks.

Presenter Simon Hong, a researcher in the McGovern Institute for Brain Research at MIT, and CEO of smart-chair startup Robilis, said last week’s STEX workshop provided “an opportunity to interact with potential stakeholders.”

Based on neuroscience research, Robilis developed StandX, a chair with two automated moving halves, side by side. The halves alternate — one dropping down and the other staying straight — making the user sit down on one half while standing on the opposite leg. The frequent alternation prevents stress on the spine caused by sitting in one position for extended periods, and the chair’s design encourages proper posture. The movement also interrupts prolonged sitting, which is associated with diabetes.

During a startup demonstration session midway through the event, Hong’s station was crowded with attendees looking to try out the chair. In the end, he walked away with a few contacts interested in helping with production and in introducing him to potential investors. “I was quite satisfied with the event,” Hong told MIT News. “It is in a way a networking event, and good things tend to happen quite unexpectedly during many, many interactions with people.”

Apart from providing a venue to spread the word about his wearables, the event enabled Alessandro Babini MBA ’15, co-founder of Humon, to connect with larger organizations in the space. Humon, a wearable targeted at endurance athletes, attaches to a muscle, where it monitors blood oxygen levels by shining a light into the skin and analyzing changes in the light that indicate less or more oxygen.

“It was interesting to get an understanding about what big brands seek in partners, what they’re looking to invest in, and what they’re working on now,” Babini told MIT News. “Big corporations have a lot of customers and a big influence on where the market is going.”

Another interesting MIT spinout, figure8, presented a wearable that captures 3-D body movement that can be analyzed by the user or shared with an online community — like a “YouTube” of movement data.

The wearable is a small sleeve made from novel sensor-woven fabric that fits over the arm or leg to track joint and muscle movement. It lets users map the movement of muscle, bone, and ligaments. Put on a knee, for instance, the wearable can map individual ligaments, which is valuable for, say, monitoring the anterior cruciate ligament (ACL). One application is in physical therapy, so athletes can track injuries as they heal.

Users can also map their movement to others. Dancers, for instance, can use the sensor to match their movements to those of others during training. The startup is also developing a platform that lets users upload and share that data in the cloud.

“Before YouTube, no one thought about video as something you can share, upload, and download as a commodity,” said co-founder and CEO Nan-Wei Gong, an MIT Media Lab researcher, during her presentation. “We’re trying to create a system for everyone to collect this motion [data] they can upload and download.”

Other startups that presented included: Kitchology, Fitnescity, Digital Nutrition, Food for Sleep, and SplitSage.

In his keynote, Guarente explained the science and history behind Elysium’s “anti-aging” pill, called Basis, which he himself has been taking for three years. He noted the pill doesn’t necessarily make people feel more youthful or healthier, especially if they’re already healthy. “You should just fall apart more slowly,” Guarente said to laughter from the audience.

Years ago, Guarente and other MIT researchers identified a group of genes called sirtuins that have been demonstrated to slow the aging process in microbes, fruit flies, and mice. For instance, calorie-restricted diets, long known to extend lifespans and prevent many diseases in mammals, is key in activating sirtuins. “It turns out there are compounds that can do the same thing,” Guarente said.

It was later discovered that one of those compounds is abundant in blueberries and that an enzyme called nicotinamide adenine dinucleotide (NAD) is essential in carrying out the activity of sirtuins. But NAD deteriorates with age. “If there’s not enough NAD, you don’t activate sirtuins. Metabolism and DNA-repair goes awry, and a lot of things go wrong,” he said.

However, in the NAD synthesis pathway, NAD’s precursor, called nicotinamide riboside (NR), can be injected into an organism, where it would move efficiently into cells and be converted into NAD.

Basis is a combination of NR and the sirtuin-activating compound from blueberries.

Last year, Elysium conducted a 120-person trial. The results indicated that the pills were safe and led to an increase and sustainability of NAD levels. More trials are on the way, and the startup is growing its pipeline of products. It has not yet been shown whether Basis can extend life-span in humans.

“We could really make a difference in people’s health,” Guarente said at the conclusion of his talk. “And it would add to all the … medical devices and DNA analysis and motion sensors, so that people can begin to do what they want to do, which is to take charge of their health.”

The investor speaker was David T. Thibodeau, managing director of Wellvest Capital, an investment banking company specializing in healthy living and wellness. The industry speaker was Matthew Decker, global technical leader in the Comfort and Biophysics Group of W.L. Gore and Associates, the manufacturing company best known for Gore-Tex fabrics.

Panelists were Guarente, Decker, Thibodeau, and Josh Sarmir, co-founder and CEO of SplitSage, an MIT spinout that is developing an analytics platform that can detect “sweet spots” and “blind spots” in people’s fields of vision to aid in sports performance, online advertising, and work safety, among other applications.

STEX has a growing database of roughly 1,200 MIT-affiliated startups. Last year, OCR, in close partnership with ILP, created STEX25, an accelerator for 25 startups at any time that focuses on high-level, high-quality introductions. The first cohort of 14 startups have gone through the accelerator, gaining industry partnerships that have led to several pilots, partnerships, and lead client relationships.

Microbe generates extraordinarily diverse array of peptides

In marine bacteria, evolution of new specialized molecules follows a previously unknown path.

David L. Chandler | MIT News Office
June 22, 2017

It’s one of the tiniest organisms on Earth, but also one of the most abundant. And now, the microscopic marine bacteria called Prochlorococcus can add one more superlative to its list of attributes: It evolves new kinds of metabolites called lanthipeptides, more abundantly and rapidly than any other known organism.

While most bacteria contain genes to pump out one or two versions of this peptide, Prochlorococcus varieties can each produce more than two dozen different peptides (molecules that are similar to proteins, but smaller). And though all of Earth’s Prochlorococcus varieties belong to just a single species, some of their localized varieties in different regions of the world’s oceans each produce a unique collection of thousands of these peptides, unlike those generated by terrestrial bacteria.

The startling findings, published this week in the journal Proceedings of the National Academy of Science, were discovered by former MIT graduate student Andres Cubillos-Ruiz, Institute Professor Sallie “Penny” Chisholm, University of Illinois chemistry professor Wilfred van der Donk, and two others.

“This is incredibly significant work,” says Eric Schmidt, professor of medicinal chemistry at the University of Utah, who was not involved in the research. “The authors show how nature has evolved methods to create chemical diversity. What really sets it apart is that it examines how this evolution takes place in nature, instead of in the lab. They examine a huge habitat, the open ocean. This is amazing,” he says.

“No one had seen the true extent of the diversity in these molecules” until this new study, Cubillos-Ruiz says. The first hints of this unexpected diversity surfaced in 2010, when Bo Li and Daniel Sher, members of van der Donk’s and Chisholm’s labs respectively, found that one variety of Prochlorococcus could produce as many as 29 different lanthipeptides. But the big surprise came when Cubillos-Ruiz looked at other populations and found that the same organisms, in a different location, produced similarly great numbers of the peptides, “and all of them were completely different,” he says.

After considerable study examining the genomes of many Prochlorococcus cultures and pieces of DNA from the wild, the researchers determined that the way the extraordinary numbers of lanthipeptides evolve is, in itself, something that hasn’t been observed before. While most evolution takes place through tiny incremental changes, while preserving the vast majority of the genetic structure, the genes that enable Prochlorococcus to produce these lanthipeptides do just the opposite. They somehow undergo dramatic, wholesale changes all at once, resulting in the production of thousands of new varieties of these metabolites.

Cubillos-Ruiz, who is now a postdoc at MIT’s Institute For Medical Engineering and Science, says the way these genes were changing “wasn’t following classic phylogenetic rules,” which dictate that changes should happen slowly and incrementally to avoid disruptive changes that impair function. But the story is a bit more complicated than that: The specific genes that encode for these lanthipeptides are composed of two parts, joined end to end. One part is actually very well-preserved across the lineages and different populations of the species. It’s the other end that goes through these major shakeups in structure. “The second half is amazingly variable,” he says. “The two halves of the gene have taken completely different evolutionary pathways, which is uncommon.”

The actual functions of most of these thousands of peptides, which are known as prochlorosins, remain unknown, as they are very difficult to study under laboratory conditions. Similar compounds produced by terrestrial bacteria can serve as chemical signaling devices between the organisms, while others are known to have antimicrobial functions, and many others serve purposes that have yet to be determined. Because of the known antimicrobial functions, though, the team thinks it will be useful to screen these compounds to see if they might be candidates for new antibiotics or other useful biologic products.

This evolutionary mechanism in Prochlorococcus represents “an intriguing mode of evolution for this kind of specialized metabolite,” Cubillos-Ruiz says. While evolution usually favors preservation of most of the genetic structure from the ancestor to the descendants, “in this organism, selection seems to favor cells that are able to produce many and very different lanthipeptides. So this built-in collective diversity appears to be part of its function, but we don’t yet know its purpose. We can speculate, but given their variability it’s hard to demonstrate.” Maybe it has to do with providing protection against attack by viruses, he says, or maybe it involves communicating with other bacteria.

“Prochlorococcus is trying to tell us something, but we don’t yet know what that is,” says Chisholm, who has joint appointments in MIT’s departments of Civil and Environmental Engineering and Biology. “What [Cubillos-Ruiz] uncovered through this molecule is an evolutionary mechanism for diversity.” And that diversity clearly must have very important survival value, she says: “It’s such a small organism, with such a small genome, devoting so much of its genetic potential toward producing these molecules must mean they are playing an important role. The big question is: What is that role?”

In fact, this kind of process may not be unique — it may be just that Prochlorococcus, an organism that Chisholm and her colleagues initially discovered in 1986 and have been studying ever since, has provided the wealth of data needed for such an analysis. “This might be happening in other kinds of bacteria,” Cubillos-Ruiz says, “so maybe if people start looking into other environments for that kind of diversity,” it may turn out not to be unique. “There are some hints it happens in other [biological] systems too,” he says.

Christopher Walsh, emeritus professor of biological chemistry and molecular pharmacology at Harvard University, who was not involved in this work, says “The dramatic diversity of prochlorosins assembled by a single enzyme … raises surprising questions about how evolution of thousands of cyclic peptide structures can be  accomplished by alterations that favor large changes rather than incremental ones.”

According to Schmidt, “There are many possible practical applications. The first is fairly clear: By using this natural variation, the same process can be used to design and build chemicals that might be drugs or other materials. More fundamentally, by understanding the natural process of generating chemical diversity, this will help to create methods to synthesize desired applications in cells.”

The research team also included former graduate student Jessie Berta-Thompson and postdoc Jamie Becker at MIT. The work was supported by the Gordon and Betty Moore Foundation, the National Science Foundation, and the Simons Foundation.

How cells combat chromosome imbalance

Biologists discover the immune system can eliminate cells with too many or too few chromosomes.

Anne Trafton | MIT News Office
June 19, 2017

Most living cells have a defined number of chromosomes: Human cells, for example, have 23 pairs. As cells divide, they can make errors that lead to a gain or loss of chromosomes, which is usually very harmful.

For the first time, MIT biologists have now identified a mechanism that the immune system uses to eliminate these genetically imbalanced cells from the body. Almost immediately after gaining or losing chromosomes, cells send out signals that recruit immune cells called natural killer cells, which destroy the abnormal cells.

The findings raise the possibility of harnessing this system to kill cancer cells, which nearly always have too many or too few chromosomes.

“If we can re-activate this immune recognition system, that would be a really good way of getting rid of cancer cells,” says Angelika Amon, the Kathleen and Curtis Marble Professor in Cancer Research in MIT’s Department of Biology, a member of the Koch Institute for Integrative Cancer Research, and the senior author of the study.

Stefano Santaguida, a research scientist at the Koch Institute, is the lead author of the paper, which appears in the June 19 issue of Developmental Cell.

“A downward spiral”

Before a cell divides, its chromosomes replicate and then line up in the middle of the cell. As the cell divides into two daughter cells, half of the chromosomes are pulled into each cell. If these chromosomes fail to separate properly, the process leads to an imbalanced number of chromosomes in the daughter cells — a state known as aneuploidy.

When aneuploidy occurs in embryonic cells, it is almost always fatal to the organism. For human embryos, extra copies of any chromosome are lethal, with the exceptions of chromosome 21, which produces Down syndrome; chromosomes 13 and 18, which lead to developmental disorders known as Patau and Edwards syndromes; and the X and Y sex chromosomes, extra copies of which may cause various disorders but are not usually lethal.

In recent years, Amon’s lab has been exploring an apparent paradox of aneuploidy: When normal adult cells become aneuploid, it impairs their ability to survive and proliferate; however, cancer cells, which are nearly all aneuploid, can grow uncontrollably.

“Aneuploidy is highly detrimental in most cells. However, aneuploidy is highly associated with cancer, which is characterized by upregulated growth. So, a very important question is: If aneuploidy hampers cell proliferation, why are the vast majority of tumors aneuploid?” Santaguida says.

To try to answer that question, the researchers wanted to find out more about how aneuploidy affects cells. Over the past few years, Santaguida and Amon have been studying what happens to cells immediately after they experience a mis-segregation of chromosomes, leading to imbalanced daughter cells.

In the new study, they investigated the effects of this imbalance on the cell division cycle by interfering with the process of proper chromosome attachment to the spindle, the structure that holds chromosomes in place at the cell’s equator before division. This interference leads some chromosomes to lag behind and get shuffled into the two daughter cells.

The researchers found that after the cells underwent their first division, in which some of the chromosomes were unevenly distributed, they soon initiated another cell division, which produced even more chromosome imbalance, as well as significant DNA damage. Eventually, the cells stopped dividing altogether.

“These cells are in a downward spiral where they start out with a little bit of genomic mess, and it just gets worse and worse,” Amon says.

“This paper very convincingly and clearly shows that when chromosomes are lost or gained, initially cells can’t tell if their chromosomes have mis-segregated,” says David Pellman, a professor of pediatric oncology at Dana-Farber Cancer Institute who was not involved in the study. “Instead, the imbalance of chromosomes leads to cellular defects and an imbalance of proteins and genes that can significantly disrupt DNA replication and cause further damage to the chromosomes.”

Targeting aneuploidy

As genetic errors accumulate, aneuploid cells eventually become too unstable to keep dividing. In this senescent state, they start producing inflammation-inducing molecules such as cytokines. When the researchers exposed these cells to immune cells called natural killer cells, the natural killer cells destroyed most of the aneuploid cells.

“For the first time, we are witnessing a mechanism that might provide a clearance of cells with imbalanced chromosome numbers,” Santaguida says.

In future studies, the researchers hope to determine more precisely how aneuploid cells attract natural killer cells, and to find out whether other immune cells are involved in clearing aneuploid cells. They would also like to figure out how tumor cells are able to evade this immune clearance, and whether it may be possible to restart the process in patients with cancer, since about 90 percent of solid tumors and 75 percent of blood cancers are aneuploid.

“At some point, cancer cells, which are highly aneuploid, are able to evade this immune surveillance,” Amon says. “We have really no understanding of how that works. If we can figure this out, that probably has tremendous therapeutic implications, given the fact that virtually all cancers are aneuploid.”

The research was funded, in part, by the National Institutes of Health, the Kathy and Curt Marble Cancer Research Fund, the American Italian Cancer Foundation, a Fellowship in Cancer Research from Marie Curie Actions, the Italian Association for Cancer Research, and a Koch Institute Quinquennial Cancer Research Fellowship.

New model could speed up colon cancer research

Introducing genetic mutations with CRISPR offers a fast and accurate way to simulate the disease.

Anne Trafton | MIT News Office
May 1, 2017

Using the gene-editing system known as CRISPR, MIT researchers have shown in mice that they can generate colon tumors that very closely resemble human tumors. This advance should help scientists learn more about how the disease progresses and allow them to test new therapies.

Once formed, many of these experimental tumors spread to the liver, just like human colon cancers often do. These metastases are the most common cause of death from colon cancer.

“That’s been a missing piece in the study of colon cancer. There is really no reliable method for recapitulating the metastatic progression from a primary tumor in the colon to the liver,” says Omer Yilmaz, an MIT assistant professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and the lead senior author of the study, which appears in the May 1 issue of Nature Biotechnology.

The study builds on recent work by Tyler Jacks, the director of the Koch Institute, who has also used CRISPR to generate lung and liver tumors in mice.

“CRISPR-based technologies have begun to revolutionize many aspects of cancer research, including building mouse models of the disease with greater speed and greater precision. This study is a good example of both,” says Jacks, who is also an author of the Nature Biotechnology paper.

The paper’s lead authors are Jatin Roper, a research affiliate at the Koch Institute and a gastroenterologist at Tufts Medical Center, and Tuomas Tammela, a research scientist at the Koch Institute.

Mimicking human tumors

For many years, cancer biologists have taken two distinct approaches to modeling cancer. One is to grow immortalized human cancer cells known as cancer cell lines in a lab dish. “We’ve learned a lot by studying these two-dimensional cell lines, but they have limitations,” Yilmaz says. “They don’t really reproduce the complex in vivo environment of a tumor.”

Another widely used technique is genetically engineering mice with mutations that predispose them to develop cancer. However, it can take years to breed such mice, especially if they have more than one cancer-linked mutation.

Recently, researchers have begun using CRISPR to generate cancer models. CRISPR, originally discovered by biologists studying the bacterial immune system, consists of a DNA-cutting enzyme called Cas9 and short RNA guide strands that target specific sequences of the genome, telling Cas9 where to make its cuts. Using this process, scientists can make targeted mutations in the genomes of living animals, either deleting genes or inserting new ones.

To induce cancer mutations, the investigators package the genes for Cas9 and the RNA guide strand into viruses called lentiviruses, which are then injected into the target organs of adult mice.

Yilmaz, who studies colon cancer and how it is influenced by genes, diet, and aging, decided to adapt this approach to generate colon tumors in mice. He and members of his lab were already working on a technique for growing miniature tissues known as organoids — three-dimensional growths that, in this case, accurately replicate the structure of the colon.

In the new paper, the researchers used CRISPR to introduce cancer-causing mutations into the organoids and then delivered them via colonoscopy to the colon, where they attached to the lining and formed tumors.

“We were able to transplant these 3-D mini-intestinal tumors into the colon of recipient mice and recapitulate many aspects of human disease,” Yilmaz says.

More accurate modeling

Once the tumors are established in the mice, the researchers can introduce additional mutations at any time, allowing them to study the influence of each mutation on tumor initiation, progression, and metastasis.

Almost 30 years ago, scientists discovered that colon tumors in humans usually acquire cancerous mutations in a particular order, but they haven’t been able to accurately model this in mice until now.

“In human patients, mutations never occur all at once,” Tammela says. “Mutations are acquired over time as the tumor progresses and becomes more aggressive, more invasive, and more metastatic. Now we can model this in mice.”

To demonstrate that ability, the MIT team delivered organoids with a mutated form of the APC gene, which is the cancer-initiating mutation in 80 percent of colon cancer patients. Once the tumors were established, they introduced a mutated form of KRAS, which is commonly found in colon and many other cancers.

The scientists also delivered components of the CRISPR system directly into the colon wall to quickly model colon cancer by editing the APC gene. They then added CRISPR components to also edit the gene for P53, which is commonly mutated in colon and other cancers.

“These new approaches reduce the time frame to develop genetically engineered mice from two years to just a few months, and involve very basic gene engineering with CRISPR,” Roper says. “We used P53 and KRAS to demonstrate the principle that the CRISPR editing approach and the organoid transplantation approach can be used to very quickly model any possible cancer-associated gene.”

In this study, the researchers also showed that they could grow tumor cells from patients into organoids that could be transplanted into mice. This could give doctors a way to perform “personalized medicine” in which they test various treatment options against a patient’s own tumor cells.

Fernando Camargo, a professor of stem cell and regenerative biology at Harvard University, says the study represents an important advance in colon cancer research.

“It allows investigators to have a very flexible model to look at multiple aspects of colorectal cancer, from basic biology of the genes involved in progression and metastasis, to testing potential drugs,” says Camargo, who was not involved in the research.

Yilmaz’ lab is now using these techniques to study how other factors such as metabolism, diet, and aging affect colon cancer development. The researchers are also using this approach to test potential new colon cancer drugs.

The research was funded by the Howard Hughes Medical Institute, the National Institutes of Health, the Department of Defense, the V Foundation V Scholar Award, the Sidney Kimmel Scholar Award, the Pew-Stewart Trust Scholar Award, the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund, the American Federation of Aging Research, and the Hope Funds for Cancer Research.