Code Breaker
By Lauren Cahoon
Julius Lucks unlocks the secret of RNA to advance human health.
Cornell Engineering Magazine
Julius Lucks is on to something. The professor of chemical and biomolecular engineering is making discoveries that have garnered attention; in the last two years alone, Lucks has received the 2012 DARPA young faculty award; a 2012 Gates Grand Challenge Exploration Grant; the 2013 Office of Naval Research Young Investigator Award; the NIH Director's New Innovator Award; and was named a 2013 Sloan Research Fellow. At the same time, his lab group has doubled in size, he's founded a seminal course on synthetic biology at Cold Spring Harbor Laboratory, and has just recently published some key discoveries in the journal ACS Synthetic Biology.
This wasn't always the case. In graduate school, Lucks found himself disheartened and doubting, and, were it not for the seasoned advice of a mentor, would likely have quit. The advice?
"This is all just a 'choose your own adventure' detective story," Lucks says. "Just see where this leads."
It's a good thing Lucks decided to take that advice, as his chosen adventure has led to key discoveries about one of biology's most important, yet frequently overlooked, molecules. While DNA typically gets the spotlight for holding the secrets of life, Lucks believes that it's time to introduce a new star.
"RNA does it all—it stores information, it propagates that information, it's the master molecule of life," he says.
By applying engineering principles to molecular biology, Lucks is uncovering not only new truths about what RNA does and what it impacts, but also potential shortcuts to engineering tailor-made biological pathways that could advance discoveries in human health and medicine.
Scientific serendipity
"Addicted to learning new things," Lucks studied chemistry as an undergrad at the University of North Carolina, following that with a masters in theoretical chemistry at Cambridge University. At that point, he took an interest in quantum physics, "so I figured I would go learn quantum physics from the people who discovered it," and threw himself into a masters and Ph.D. program in physics and a Ph.D. at Harvard University. After that, Lucks' thirst for knowledge led him to biology and a fascination with RNA, a path that seemed, at Luck's reflection, almost cosmically laid out for him. At Cambridge University, Lucks drank pints of ale at the very same pub where Watson and Crick first sketched out the physical structure of DNA—RNA's more famous cousin. While strolling along Cornell's oak-lined Tower Road, Lucks happened to spot a small plaque dedicated to Robert W. Holley, who won the Nobel Prize for his discovery of the structure of transfer RNA and linked DNA to protein synthesis. And last year Lucks developed a summer course at Cold Spring Harbor Laboratory, taught in a room down the hall from who else but—James Watson himself. "We don't tell the students that he's there," says Lucks. "It's a lot of fun once they realize that the elderly scientist in the office next door is the guy who discovered the structure DNA."
Whether it was destiny that led him to this field of study or pure happenstance, Lucks is making significant headway. Traditional biological models of RNA portray the molecule as a static, single-strand entity that transcribes the code from DNA into proteins. "Textbooks represent it as DNA going to a wavy line [representing RNA], which goes to protein," says Lucks. "But RNA is anything but a simple wavy line." Instead, Lucks explains that the molecule is more like a 'very long, sticky rope' that tends to ball up and fold in on itself. He uses an analogy of an old film reel projector, spitting out film that tends to snarl into tangles as it comes out. Those snarls, or folds, turn out to be instrumental in RNA function as well as overall gene expression. "Every RNA that's being made has an opportunity to fold in a particular way," says Lucks. "We want to 'make a movie' for every RNA molecule as it's getting spit out of that reel projector—that's our mission…if we can do that, we will definitely discover new things about biology."
Layers of code
DNA-to-protein code is not the only code involved in gene expression. Research has already uncovered epigenetics, in which certain genes in the DNA code are turned off or on by functional changes such as methylation or histone modification—but there is even more complexity to genetic expression, thanks to RNA. Lucks explains that the physical structure of RNA provides "another layer of code" for gene expression, selectively turning genes off and on. "New biology asks what this code is, and that's what we're trying to figure out," says Lucks.
One thrust of his quest to decipher this code involves a technique known as SHAPE-Seq, in which Lucks and his team chemically alter RNA molecules according to their shape, and then sequence the RNA to ultimately measure its structure. With every known structural tweak they make, Lucks and his group uncover an additional piece of the code that lies beneath the RNA structure.
Lucks is attacking the mystery from another angle as well; building an RNA-only genetic system from 'scratch'—one that is oversimplified and easy to control. Lucks hopes to someday be able to tackle biological issues via engineered, RNA-only genetic systems that he can 'program' to do exactly as he wants. "We're on a beautiful quest to create something that will act like a computer," says Lucks. "We're far off from doing that now, but we will do it."
Molecular Legos
By putting together these systems themselves, Lucks and his team are creating oversimplified versions of biology's genetic designs. "What we're doing with RNA does not exist in nature—but then again nature isn't an engineer. As engineers we want things that are simple, that fit together neatly like Legos."
Once these 'Lego-like' systems are available, a wide range of possibilities open up. The applications could include, in the near term, metabolic engineering—"making cells make things that we like and care about," as Lucks puts it. While there are E. coli bacteria that now produce insulin and yeast cells making crucial components for malaria drugs, Lucks believes that his engineered RNA systems could push these boundaries even further. By controlling engineered RNA systems, Lucks says that scientists will be able to balance metabolic pathways that previously would have been insurmountable roadblocks to certain processes—such as trying to make a mammalian protein in a bacterial cell.
In the long term, Lucks is planning to build a 'truly universal genetic circuitry'—an RNA system with a genetic passport to any type of cell, be it plant, mammal, yeast or bacterial—allowing much more efficient genetic engineering and design. He also hopes to utilize these universal RNA circuits to control cell differentiation. "Using this technique, you could grow tissues in the lab way easier," Lucks says. "By having a universal set of core building blocks, you could take a group of cells and make them turn into blood vessels or muscles."
Cold Spring Harbor crash course
In the meantime, Lucks and his group have made promising steps toward designer-made RNA systems. This past summer, Lucks and NSF Graduate Fellow Melissa Takahashi collaborated to help create the first Cold Spring Harbor Laboratory summer course on synthetic biology. The lab is renowned for summer courses and seminars that have sparked formative scientific discoveries in the field of molecular biology and have hosted Nobel Prize-winning scientists. Lucks' two-week course hosted sixteen select students as they conducted real synthetic biology research and experiments—most of whom were unfamiliar with RNA or molecular biology. "It was our dream in creating this course where students could do real research on a topic they've never heard about before," says Lucks.
His dream was realized. During the two-week course, the group proved one of Lucks' long-held theories—that RNA-only genetic circuits are faster compared to protein circuits. Using a cell-free transcription-translation system ("it's literally crushed up cells in a tube—a goop of cellular machinery that allows the RNA to do its thing so we can test its function,"), the group was able to prove that RNA circuits relay information faster. Specifically, at roughly five minutes per step—much faster than the protein circuits that naturally operate on hour time scales in cells. Lucks says this has exciting implications for things like stem-cell research, which requires weeks for differentiation to occur—but with an RNA-only circuit system would take only days.
"It was hugely inspirational that we were able to pull this off," says Lucks. "Hopefully it sets the tone for even greater things to come." It is this work, Lucks believes, that has attracted the recent deluge of awards. "A lot of these awards recognize high risk, high reward research," he says.
An open-door policy
When he's in the lab doing research, Lucks is fairly easy to spot, according to his students—thanks to his 'iconic' red sweatband he wears when he's in the thick of running experiments. "It's hilarious because it's so ridiculous," graduate student Kyle Watters says. "I've never seen him not wear it when doing anything in the lab." It's clear that Lucks has established camaraderie within his research group that seems to lead to scientific success.
"He is relentlessly enthusiastic about the research that we are doing," says postdoc James Chappell. "I can honestly say it's an absolute pleasure working for him. His door is always open, and he is always there to deal with challenges, push the work forward, and to celebrate the successes." Graduate student Melissa Takahashi agrees. "When you walk out of a meeting with him, you leave pretty excited about your work."
Lucks' enthusiasm for the work his group is doing is clearly genuine. "It's taken me a long time to connect all these different dots and begin to put the pieces of the puzzle together," he says, "but now, we are really creating the core pillars of this mission, and it's starting to click. We're going to have our moment in a few years when we show the world what we've discovered."
At the end of the day, Lucks has chosen an adventure with a big payout in the end—one that may be game-changing for everyone.