Hacking Nature

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Mo Khalil and collaborators at BU’s Biological Design Center look for synthetic-biology solutions to the world’s biggest problems.

By Chris Berdik

In the summer of 1989, nine-year-old Ahmad “Mo” Khalil immigrated with his family to America from Riyadh, Saudi Arabia. As their plane descended into JFK Airport, Khalil and his younger brother Ayman pressed their faces against the window. They recognized the Manhattan skyline from movies and were slightly chagrined not to see Superman buzz past the Statue of Liberty. Other than Superman’s absence, there weren’t many other moments of cultural dismay for the Khalil boys, who otherwise adapted quickly to their adopted country.

“My brother and I were young and malleable,” says Khalil, now an assistant professor of biomedical engineering at Boston University. The two boys also had plenty of practice adjusting to new places. Prior to Riyadh, they had lived in Jordan, Dubai, and Greece, thanks to their father’s career as a globetrotting pharmaceutical sales executive. Along the way, the Khalil boys had attended international schools, learned English, and sampled the cuisine of many nations at their dinner table. And their new home in northern New Jersey (where a third brother, Karim, would be born) was well within the multicultural orbit of New York City.

But Khalil says his real key to acceptance by his American peers was sports. He played baseball and excelled at soccer for both club and school teams all the way through college at (nationally ranked) Stanford. That team orientation continues to serve him well today in the decidedly cross-disciplinary field of synthetic biology. Indeed, collaboration is at the heart of Boston University’s recently launched Biological Design Center (BDC), where Khalil is the associate director.

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Ahmad “Mo” Khalil. Photo by Dan Aguirre for Boston University Photography

Synthetic biology—or engineering biology, as it is sometimes called—offers immense promise, from growing organs for transplant to reengineering immune cells to kill cancer. But the field is very young, still in what Khalil likes to call the “tinkering” phase. The mission of the BDC, which will soon occupy the fourth and fifth floors of BU’s new Center for Integrated Life Sciences & Engineering building, is to bring together scientists who can “tinker” at every level of this ambitious enterprise—from genetic switches to cellular functions to multicellular systems—in the hope of building on one another’s discoveries.

More mature fields of engineering have developed reliable tools that can be used to create more complex devices, Khalil says. “For example, if I’m an electrical engineer and I want to build a computer, I don’t need to work at the level of designing my own transistor.” To reach that advanced stage in synthetic biology, “there needs to be time for tinkering,” Khalil says. “There needs to be time to play with as many of the biological components and bio-circuitry out there, to learn from them and what they can do.“

The mission of the [Biological Design Center]…is to bring together scientists who can “tinker” at every level…in the hope of building on one another’s discoveries.

Khalil, 36, has an infectious enthusiasm for synthetic biology, even the simplified version he doles out during a recent interview in his office. Wearing a tan, herringbone jacket, a checked shirt, and jeans on his wiry frame, he gesticulates and punctuates answers with exclamations like, “Right!” and “Oh yeah!”

At one point, Khalil waves toward a sleek espresso maker by his desk. It’s a multi-knobbed contraption of chrome and brushed nickel, complete with a glass warmer, milk frother, and magnetic stirrer.

“I use it to lure postdocs and grad students or anybody with an idea or data they want to show me, with an offer of free coffee,” he says. It’s a small gesture, but telling: Khalil is proactive about sharing knowledge and collaborating.

“Mo is one of those people whose first instinct is to say, ‘yes, let’s try it,’ as opposed to saying, ‘no, this is too complicated,’” says fellow BDC researcher Douglas Densmore, an associate professor of electrical and computer engineering who develops software to automate the creation of synthetic DNA and RNA molecules.

According to the BDC’s director, Christopher Chen, a professor of biomedical engineering, “not only does [Khalil] do his own exciting science, he also makes the people around him more energized about what they’re doing. He finds links between his work and a wide range of others’ interests, including mine.”

Chen points out that while the new lab space will be a focal point for engineering biology at BU, “the BDC is bigger than this new building,” and not every investigator working with the BDC will be moving within its walls.

As Khalil tells it, the seed idea for the BDC was planted during a lunch of pasta and panini at Scoozi in nearby Kenmore Square that he and other junior faculty had with the more senior Chen when the latter was being recruited by BU in 2013. At the time, the University’s synthetic biology efforts were anchored by Jim Collins, a pioneer in the field. In addition to Collins, who would leave for MIT in 2014, there was a nucleus of young, recently hired researchers who now form the core faculty of the BDC, including Khalil, Densmore, and Wilson Wong, an assistant professor of biomedical engineering.

“At that lunch, there was this new crew of people talking with Chris, a legend in the field of mechanobiology and tissue engineering,” Khalil says. “There was an ‘aha’ moment, when we realized that we were all thinking about similar ways to tackle very different problems.”

One way to phrase the shared approach: learning by building. For instance, you can learn a lot about how cells turn certain genes on and off by designing and testing different proteins known as “transcription factors,” that work like genetic switches. Once a biological mechanism can be built, it can be tweaked and eventually harnessed to help solve problems such as fighting disease and creating new energy sources.

Synthetic biology isn’t about using the building blocks of life to create something entirely new from scratch, says Khalil. It’s about employing the amazing powers that nature has evolved over billions of years. “We can tap into the fact that our immune cells are basically heat-seeking missiles for tumors, or the fact that plants can harness energy from the sun,” he says. “Let’s build on those evolved schemes and rewire them, because that’s where we’ll make the most impact.”

Once a biological mechanism can be built, it can be tweaked and eventually harnessed to help solve problems such as fighting disease and creating new energy sources.

For example, Wong’s lab is engineering immune cells, which are infused into cancer patients, to boost their safety and tumor-killing potency. Chen is investigating how best to create the blood vessels needed for synthetic heart and other tissue. And Khalil is making new RNA molecules (which carry DNA’s protein-making instructions) that can be used to help doctors quickly diagnose an antibiotic-resistant infection.

Khalil’s antibiotic-resistance research began when he was a postdoc with Collins, whose lab is a collaborator on the current project. The problem it confronts is huge. Due partly to the overuse of antibiotics, dangerous bacteria are mutating into drug-resistant strains at an accelerating rate that far outpaces the development of new drugs. Currently, it can take two to three days to test whether an infection is drug resistant, because the bacteria must be cultured and then hit with antibiotics to see what happens. Khalil and his team hope to cut that time down to a few hours by detecting bacteria’s initial genetic reactions to a drug, allowing a more precise and effective treatment. They will create a diagnostic tool with RNA engineered to produce a colorimetric or fluorescent signal if they encounter partner RNAs created by bacteria reacting to a drug.

There are different types of RNA that must interact in the chain of events that lead from the genetic code of DNA to the genetic expression of protein creation inside cells. Think of the synthetic RNA as genetic switches that only turn on when they bind with RNA that bacteria generate during a genetic response to an antibiotic attack. The first step in creating these switches is finding the precise sequences of RNA you’re targeting through a painstaking study of genetic reactions to different antibiotics by both drug-resistant and drug-susceptible bacteria.

“For some bacteria-drug combinations, we have a first set of genetic signatures,” Khalil says. “But for the larger set, it’s unknown.”

Much of this work is being done in the lab of a collaborator on the project, Caroline Genco, professor of integrative physiology and pathobiology at Tufts University. In early 2017, one of Khalil’s graduate students began working part time in Genco’s lab, which studies the bacteria being used to develop the sensor—a multi-drug-resistant strain of gonorrhea that the Centers for Disease Control and Prevention puts in the highest level of threats to public health and drug-resistant infections. This is where the talk of collaboration turns into action, says Genco.

“Collaboration isn’t just about Mo and me talking and writing a research proposal,” she says. “You need a person who can bridge both worlds and will do the actual work.”

After the researchers know what RNAs they are targeting, the next step is to design and synthesize the RNA switches that will bind to those targets and, in turn, trigger the fluorescence that will show up on the sensor. This is another big challenge, because there’s not just one RNA sequence that could possibly act as a switch, but several, which vary greatly in reliability. The process of finding the best option starts with computer modeling of candidate RNAs, Khalil explains, “and from there we synthesize the RNAs, put them into reactions, and screen them to see which give the best on and off properties.”

Minhee Park (ENG’18) and Khalil. Synthetic biology isn’t about creating something entirely new from scratch, says Khalil. It’s about harnessing the powers that nature has evolved over billions of years, to help solve problems such as fighting disease. Photo by Dan Aguirre for Boston University Photography

Synthesized RNA is made from a template of synthesized DNA, and in Khalil’s lab that process begins with Federal Express. Specifically, they order DNA strands from a biotech company that ships the genetic strands overnight. Khalil’s lab then uses custom-made enzymes to cut and paste the DNA into a new sequence. Next, they make a bunch of copies of the new DNA by putting it into a fast-multiplying organism such as E. coli. Finally, they isolate the DNA and sequence it so it can be checked for errors.

Ultimately, the researchers will create several RNA switches, each linked to a different drug on the menu of antibiotics a doctor might use to treat a patient. They will incorporate these switches into a diagnostic tool that can give doctors a color-coded assessment of an infection’s drug susceptibility within minutes.

While the longer-term tests of antibiotics using cultured bacteria will likely remain the gold standard for identifying drug resistance, Khalil says there’s a dire need for a faster diagnostic tool so that doctors can make a reasonably informed choice of prescription before their patients leave the hospital or clinic.

“What’s currently done is that a doctor makes a decision based on symptoms and relies on broad-spectrum antibiotics,” says Khalil, meaning the subset of antibiotics known to be effective on the broadest range of infections. “Those are generally effective, but not specific, so you’re fueling resistance.”

An issue of Cell magazine, on display in Khalil’s office. His wife, Katie Flynn, designed the cover, using a World War Two–era photo to illustrate the potential of synthetic biology. Photo by Cydney Scott for Boston University Photography

The most prominent decorations in Khalil’s office are the poster-sized prints of covers from journals in which he and his lab team have published, including a few designed by Khalil’s wife, Katie Flynn, a Boston architect. “She’s a reluctant cover artist,” Khalil notes. “She does it for me.”

The couple met at Stanford, where they lived in the same sophomore dorm and took a few of the same classes. Flynn majored in art, which had been one of Khalil’s abiding interests growing up, along with architecture. One of his watercolors, painted as a teenager while visiting family in Jordan, hangs in their dining room. It depicts a couple sitting in the desert and gazing down into a valley at the Sea of Galilee.

“I suspect what motivated him as a painter was precision,” she says. “He loves drafting. He likes getting the drawings just right. That painting is really precise.”

Both of Khalil’s brothers describe him as “well-rounded,” but not in the dabbling sense. When Khalil painted, he won awards. When he played sports, his teams won state championships. In high school, he was the valedictorian.

“Mo has this unique ability to go super-deep in a lot of different fields,” says their middle brother, Ayman, who manages a data analytics team for Apple. “He can sit down, hit the books, and memorize something, and at the same time, sit back and think abstractly and big-picture.”

Their youngest brother, Karim, who is now a mechanical engineering doctoral student at MIT, suspects that Khalil felt some pressure to succeed as the oldest son of immigrant parents. “They were willing to move across the world, to the United States, away from their family in the Middle East, to provide opportunities for success for their children,” he says. “I think that led Mo to want to be the best he could be, in everything.”

By the time Khalil enrolled at Stanford, his desire to make art had waned. Instead, he combined that interest in design with his talent for math and science and majored in mechanical engineering with dreams of building rockets. As an undergraduate, he interned at NASA’s Ames Research Center, and in his senior year, he was actively networking for a job at the Jet Propulsion Laboratory. That same year, however, he took a course that changed his trajectory.

The course, taught by a biomechanical engineer named Charles Taylor, focused on studying the cardiovascular system using the tools of engineering, such as modeling the fluid dynamics of blood flow.

“What I previously knew of biology was shaped by how it’s canonically taught, which often relies on memorization of proteins and pathways,” Khalil says. “But [Taylor] showed how you can take a complex biological system and understand it in terms of general functioning, so you can study it quantitatively and rationally, and that’s something engineers do really well.”

It was also personal to Khalil. When he was in high school, his dad endured emergency double bypass surgery, and Khalil was amazed to learn how Taylor could use simulations of blood flow on a computer to diagnose cardiovascular disease.

“He said, ‘this is a really exciting field with a lot of room for creativity and a lot of open-ended questions,’” Khalil recalls. Taylor advised him to apply to MIT for graduate school to pursue this new approach to biology, which he did. Two years after Khalil moved to Cambridge, Flynn enrolled at MIT too, for architecture. They married seven years later and now have two daughters, ages five and three.

While Flynn designs buildings and urban spaces for a living, she has occasionally used her artistic talents to illustrate the potential of her husband’s research. She recently designed a cover for the journal Cell, featuring a World War Two–era photo of women working at an assembly line. Along the belt, Flynn superimposed large spools of DNA colored red in contrast with the black and white image. It’s an apt metaphor for what Khalil hopes synthetic biology can become—standardized and reliable enough that smaller engineered parts, such as a genetic switch, can be snapped into place when building a larger, more complicated system.

“It’s quite rare that you’ll see one synthetic biologist develop something and another will just take it and build off it,” says Khalil. He hopes the BDC can help advance synthetic biology to the point where scientists can routinely build on each other’s creations. “The goal is to design a system that’s robust, so if you sent the blueprints to somebody else, they could replicate it, and it would work in all sorts of conditions.”

Synthetic biology as a field is like car manufacturing before Henry Ford, with vehicles largely built by highly skilled craftsmen in their own workshops. It was an industry filled with tinkering, in other words, until it matured and cars could be built using standard, interchangeable parts.

Nikit Patel (ENG’18) and Khalil. Khalil encourages collaboration with students and colleagues, sometimes drawing them into his office with an offer of high-end espresso. Photo by Dan Aguirre for Boston University Photography

Every Thursday afternoon, there’s a BDC social in a conference room stocked with snacks and drinks, which the affiliated labs take turns hosting. There’s also a monthly seminar and beer series, in which senior grad students or postdocs talk about their research.

“We all work on very different things, and we want to make sure every lab is aware of what the other labs are doing,” says Khalil. “As scientists, sometimes it’s easy to get hyper-focused on our own work, and this is a great chance to learn about other things, ask questions, and make connections.”

One recent seminar sparked a collaboration between the Khalil and Chen labs, focused on engineering receptors on the outside of cells to enable communication between them, a critical function for building multicellular systems.

“As scientists, sometimes it’s easy to get hyper-focused on our own work, and this is a great chance to learn about other things, ask questions, and make connections.”

These social hours and seminars are “small things,” Khalil admits, “but I think they can build off each other,” especially with the BDC in its new digs. When the building was being planned, the researchers met early and often with the architects to design a lab space that would be conducive to collaboration and to building an all-in-one creation space for robust, synthetic biology. “We had quite a bit of input,” Khalil says. For example, while there will be designated spaces for each lab, “we were able to take out walls for a more open lab environment, so researchers will be intermingling at all times.”

There will also be a large, automated DNA fabrication space with liquid-handling robots that will mix and match samples using code developed by Densmore’s group. The goal is making synthetic biology repeatable and replicable, says Densmore, who is lead investigator of the National Science Foundation’s “Living Computing Project,” a $10 million effort to create a toolbox of biological parts that can be used to engineer organisms.

Of course, “interdisciplinary” is a buzzword among researchers, one that’s easy to say and inviting to imagine but often hard to actualize. Khalil thinks the new, open lab spaces will help ensure that the BDC fulfills its collaborative promise. Mostly, however, he says it’s up to him and his fellow researchers to foster a “fun and creative culture,” where people are eager to innovate and work together.

“Many of us are still young and naïve, and I think that’s a good thing,” he says. “We’re open to new and interesting directions and collaborations. We’re still open to crazy ideas.”

This story originally appeared on BU Research.