Brock Siegel first came to recognize the true power of enzymes as he completed a Ph.D. in physical organic chemistry at the University of Illinois, Urbana-Champaign. The small organic molecules he was synthesizing in order to model an enzymatic reaction required a temperature of 200°C for activity, whereas the enzyme itself functioned at room temperature. He reasoned that any catalyst that could accomplish at 20°C what his model systems could only manage at 200°C "knew a whole lot more about chemistry than I did," Siegel says. So he steered his academic career toward studying how enzymes make and break molecular bonds to "convert enzymes into catalysts for organic transformations that had nothing to do with biology." But this was back in the '70s, and Siegel's early concept of rational enzyme engineering was hampered by a dearth of tools and knowledge.

Leaving academia for industry, Siegel helped launch a start-up company in the mid-'80s that used the novel tools of genetic engineering to develop enzymes that are still in use today in detergents. In the '90s, he went on to help develop automated DNA synthesis and sequencing technology, unknowingly paving the way for his oldest son's career in synthetic biology. His son, Justin Siegel, now 29, recently completed a Ph.D. during which "he developed the first computationally designed enzyme catalyst for a stereoselective bimolecular reaction" that doesn't exist in nature, writes David Baker, one of his Ph.D. supervisors, in an e-mail to Science Careers. "It's a convergence of technologies that have all ... finally gotten good enough that rational engineering of proteins has really kind of come back," the younger Siegel says.

Early immersion

This Science Careers article is a tie-in to Science magazine’s special issue on synthetic biology.

By age 5, Justin had spent hours with his dad making soaps and freezing things with liquid nitrogen in the garage. He was already serious about a chemistry career. But Brock Siegel detected in his son a natural knack for seeing three dimensionally and designing new computer configurations. As a teenager, Justin "would spend hours, hours poring through the literature to find the highest-speed processor and the best graphics card and the mathematics cards" so that he could build new computers with better graphics. At the time, his father was working at Applied Biosystems, helping to develop the company's pioneering automated DNA sequencing machines. Brock often took Justin along to the office, where Justin exchanged ideas with computational engineers and scientists.

When he was a high school student, Justin began doing summer internships at Applied Biosystems, automating data analysis for the production of DNA human identification kits. Justin says the project taught him the importance of trial and error in research. Meanwhile, Applied Biosystems's sister company Celera Genomics was launched to join the race to sequence the first human genome, using Applied Biosystems's latest-generation sequencing machines and a DNA pool that included blood samples from Siegel.

Nature or nurture

In 2001, Justin went on to study biochemistry at the University of California, Davis. He immediately joined the laboratory of Kenneth Burtis, identifying DNA-repair enzymes by crossing flies with genes knocked out. Intrigued by the molecular details of how enzymes worked, he next joined the lab of Michael Toney, where he set out to understand how electrons and protons move during catalysis by analyzing how mutations in the enzyme's functional site affected the reaction mechanism. But soon he "got distracted," he says, by a course taught by Vladimir Filkov that got him thinking about applying computational tools to his research. Collaborating with Toney and Filkov, Justin wrote a computer program identifying the structural and functional components of two different classes of enzymes and coming up with a list of the mutations that would convert one class of enzymes into the other.

By the time he graduated, in 2005, Justin had decided he wanted to design novel enzymes that are able to carry out interesting organic reactions, echoing Brock Siegel's earlier idea. Both father and son say the parallel is fortuitous. But Justin had advantages his father lacked: knowledge of the enzyme's DNA sequence and protein structure and advanced computational tools. While doing a Ph.D. with David Baker and Michael Gelb at the University of Washington, Seattle, Justin rationally engineered an enzyme that catalyzes the Diels-Alder reaction, a reaction that doesn't occur in nature but won its original inventors the 1950 Nobel Prize in chemistry.

To produce the enzyme, Justin teamed up with Alexandre Zanghellini, who at the time was a computational programming student in Baker's lab. Zanghellini did much of the computational work while Justin tweaked the models. "We started up with roughly 1019 different computational models, and through lots of computational algorithms and filtering, we narrowed it down to roughly 80 genes that we thought were reasonable to try," Justin says. By then, DNA synthesis had become so cheap that Justin was able to order all 80 genes from synthesizing companies. He then produced the enzymes using bacteria and tested their catalytic activity in assays, using mass spectrometry to detect an increase in the reaction's product. Two of the young scientists' enzymes showed significant activity, leading them to be the first two authors on a Science paper.

About halfway through his Ph.D., Justin helped launch a synthetic biology company called Bio Architecture Lab. Together with Yasuo Yoshikuni, a postdoc who had joined Baker's lab with the idea for the company, Justin developed a business plan aiming to use synthetic biology to go from seaweed to sugar to completely novel gasoline-like molecules. "I spent 10 to 20% of my time at the company, mostly doing computational research, trying to think about the best way to engineer enzymes to complete those pathways," Justin says. Facing time pressures, Justin left the company after about a year. He defended his thesis last April.


CREDIT: Justin Siegel
Justin Siegel in the laboratory.

A lifelong collaboration

Siegel the elder believes he started paving the way for his son's research well before he embarked on his industry career. As a photochemistry undergraduate at Syracuse University in New York state, Siegel helped develop fluorescent dyes, which proved to be one of the essential components that made automated DNA sequencing possible, he says.

Later, as Justin developed his own career and started using DNA amplification and sequencing as major tools in his research arsenal, father and son "would have fabulous -- and still do have fabulous -- conversations" about techniques, Siegel says. Of course, over the years the dynamics of the conversations have changed. "He's now the teacher and we enjoy being colleagues," Brock Siegel says. "Between my network and his network, we often need an introduction to somebody that the other can provide, or we need information that the other can get."

In 2009, Siegel the elder also came to Baker's lab for a few weeks' sabbatical, working on a three-dimensional description of orotate decarboxylase, the enzyme he studied back in his Ph.D. days, with Justin's help. "Thirty years later, lots of enzymology has now been done, the structure of this enzyme has now been solved, and he wanted to go back and [test] how his mechanisms hold up," Justin says.


CREDIT: Mary Levin/University of Washington
Siegel and members of the 2010 iGEM team at the University of Washington. The team won a medal for the 'Best Health or Medicine Project.'

Training the next generation

Another motivation Siegel has passed on to his son is getting young people interested in science as early as possible. "People spent a lot of time mentoring me when I was very young, and so I feel obliged almost to do the same to the current young students," Justin says. To date, he has mentored more than 40 high school and undergraduate students, mainly through the annual iGEM competition in which students try their hands at synthetic biology under the supervision of senior researchers.

"It's really prepared me on how to run a laboratory," says Justin, who will start applying for faculty positions this year. He says his goal is to "really go out and start seeing how far we can push rational protein design using current technologies." His Ph.D. supervisor believes an independent position is within reach. "Justin ... is already a world expert in this area, so there is no need in his case for additional training before starting his independent career," Baker says.

As usual, his father is one step ahead of him, Justin says. In recent years, Siegel has left Applied Biosystems to help Illumina and later Complete Genomics put new sequencing technologies onto the market. One of these days he's going to catch up to his father, Justin says, though for now he's happily taking advantage of all the tools his father has been developing over his career. Meanwhile, Siegel the elder says, "I am able to live my science in seeing what Justin is doing."

Elisabeth Pain is contributing editor for Europe.

10.1126/science.caredit.a1100090