Huimin Zhao: A pioneer in synthetic biology

This profile originally appeared in the Spring/Summer 2016 issue of Mass Transfer, the magazine for alumni and friends of Chemical and Biomolecular Engineering at Illinois. 

Huimin Zhao
Huimin Zhao

Back when Huimin Zhao was a college student in the early 1990s, many people predicted that the 21st century would be the “century of biology,” much like the 20th century was called the “century of physics.”

A bright student with a range of interests, Zhao was intrigued by the promise and opportunities a “century of biology” could bring. Early into his undergraduate career, he followed his passion for biology and research and was able to participate in several research projects, first in immunology and later in molecular dynamics simulation related to drug design.

Now well into the 21st century, Zhao has become a pioneer in synthetic biology. He and members of his research group aim to harness the power of synthetic biology, developing and applying tools to address global challenges in human health and energy, and investigating the fundamental aspects of enzyme catalysis, cell metabolism, and gene regulation.

“It’s an exciting time” to be in this emerging synthetic biology field, Zhao said, given recent developments such as the iBioFAB, a “living foundry” developed at the University of Illinois, and the establishment of numerous synthetic biology centers around the world.

Zhao directs research labs in Urbana and Singapore, consults often with industry, and teaches Illinois chemical engineering students about biotechnology and bioengineering. He has published more than 230 research articles and delivered more than 260 plenary, keynote, or invited lectures around the world. He has over 20 patents that have been issued or are pending, some of them licensed by industry. Fourteen of his former graduate students and postdocs have become professors while the rest (more than 40) are pursuing industrial careers.

In April 2016, the Department of Chemical and Biomolecular Engineering celebrated Dr. Huimin Zhao’s investiture as the Steven L. Miller Chair in Chemical Engineering.

Early years

Zhao grew up in Haiyan, not far from Shanghai, where his father was a primary school teacher and his mother was a farmer. He left home at 13 years old when he was selected to attend a middle school about 20 miles away. From there, he and other top students enrolled at an elite high school. He then gained admission into the University of Science and Technology of China in Hefei.

Unlike many of his peers at the time, Zhao was able to participate in research early on during his undergraduate years. That experience—using computer modeling for drug design—cemented his decision to continue his studies and earn a Ph.D. He applied to about a dozen graduate schools in the United States and was accepted at the California Institute of Technology.

Because of his background in molecular simulations and interest in protein engineering, Zhao decided to join the lab of CalTech Professor Frances Arnold. Arnold pioneered a new field called directed evolution, which is essentially to interrogate and engineer biological systems by mimicking the Darwinian evolution process in the test tube. Mainly because of that contribution, Arnold became the first female scientist to be elected to all three national academies in the United States, an honor that less than two dozen scientists have achieved.

“I was lucky to be in that environment and develop a few technologies for direct evolution, using them to engineer enzymes to improve performance, so that they could be used as catalysts for making chemicals or drugs,” Zhao said.

Although he was interested in pursuing an academic career, while Zhao was finishing his Ph.D., Dow Chemical asked him to help establish the company’s industrial biotechnology program. After he completed his Ph.D., Zhao joined the company and was involved in hiring new scientists, setting up the lab, and negotiating research collaborations with other companies.

“As a scientist, though … I wanted to do the research myself. I had ideas I wanted to pursue,” he said.

After about two years with Dow, Zhao sought a job in academia. In 2000, he joined the University of Illinois, where he was impressed by the department’s early recognition of the importance of bioengineering and biotechnology. It’s been a great place for him to start and grow his career, said Zhao, who has fond memories of spending Thanksgivings with Charles Zukoski, Elio Eliakim Tarika Chair Emeritus, and his family.

New developments

When he first arrived at Illinois, Zhao’s work involved applying directed evolution technologies to the metabolic engineering field. His lab, initially called the enzyme and metabolic engineering lab, focused on engineering enzymes and whole cells for production of chemicals.

Currently his lab is focused on development and application of synthetic biology tools for the engineering of biological systems at different levels—protein levels, pathway levels, and whole cell levels. “We are exploring applications in several areas, some in industrial biotechnology to produce chemicals or biofuels,” he said.

In the past few years his lab also has been involved in the engineering of mammalian cells, including human cells, for gene therapy applications and to address some fundamental biology problems as well.

Last year the university received an $8 million grant from the National Institutes of Health to study nuclear structure as part of its 4D Nucleosome Initiative. The project, “Combined cytological, genomic, and functional mapping of nuclear genome organization” is headed by Andrew Belmont, University of Illinois Professor of Cell and Developmental Biology. The team of investigators also includes Zhao; Jian Ma, Associate Professor of Bioengineering; David Gilbert from Florida State University’s Department of Biological Sciences; and Bas van Steensel from the Netherlands Cancer Institute.

“We try to apply synthetic biology tools to study the chromatin structure and dynamics. What we want to do is develop genetic tools to label certain regions and then we can visualize the movement inside the cell. We can also use these tools for treating some genetic diseases as well,” such as cystic fibrosis, he said.

Zhao has also collaborated with Charles Schroeder, Associate Professor of Chemical and Biomolecular Engineering at Illinois, on observing the dynamics of TALE proteins, or, transcription activator-like effectors. They are exploring how TALE proteins can be used to treat sickle cell anemia, which is caused by a mutation in a link of the DNA chain.

“The genome editing field is growing rapidly, and we are aggressively pursuing research in this direction,” Zhao said.

Zhao leads the Biosystems Design theme at the Carl R. Woese Institute for Genomic Biology and is involved in the Illinois Biological Foundry for Advanced Biomanufacturing, or iBioFAB. It’s a computational and physical infrastructure that supports rapid design, fabrication, validation/quality control, and analysis of genetic constructs and organisms.

“If it works well, it really can revolutionize how people do biological engineering,” he said.

Another area of research is in drug discovery, uncovering novel natural products that could be used as antibiotics or anticancer drugs—and using the foundry to do so.

“Natural products are a very rich source of drugs and antibiotics. Almost 80 percent of our antibiotics we use are natural products or natural products derived,” he said. Since most antibiotics used now were discovered in the 1950s and 1960s, “there’s a huge need to discover new antibiotics, because microorganisms can develop resistance very quickly. That’s why, to address this challenge, we try to use synthetic biology tools to activate those silent gene clusters involved in the synthesis of natural products … and then do the biological assays to see what kind of activity they have. That’s also a very exciting area. In particular, we want to leverage the foundry so that we can discover not just one or two (natural products), but thousands of them,” Zhao said.

Zhao also wants to leverage the foundry for his study of mammalian cells.

“In mammalian biology, in the past it took at least six months to knock out a gene or develop a transgenic mouse. Now, with new gene editing tools based on TALEN or CRISPR (methods for genome engineering), we can develop those transgenic cell lines in a month,” he said.

Most recently, in collaboration with Gene Robinson, Director of the Carl R. Woese Institute for Genomic Biology, Zhao received a $2 million grant from the Defense Advanced Research Program Agency, or DARPA. In this project, he will develop an automated bee rearing system based on the foundry.

The new DARPA-funded project draws on Robinson’s background in honeybee genomics and Zhao’s expertise in advanced biomanufacturing to develop new tools to address the plummeting bee populations world-wide.

“At the present time honey bees can only be mass-reared in beehives with traditional beeswax honeycombs outside. But new evidence indicates that beeswax, once held up as a paragon of purity, actually absorbs many different environmental toxicants, posing as-yet unknown hazards to baby bees (brood) while they are being reared,” Robinson said.

“We will use advanced biomanufacturing to develop a high-throughput method of mass-rearing millions of honey bees in the laboratory. Developing this capacity will give investigators an unprecedented experimental platform to rear bees free from environmental toxicants, thus allowing them to test specific compounds for toxicity under controlled conditions,” he added.

In his Singapore lab, Zhao has been developing and applying synthetic biology and metabolic engineering to address challenges in advanced biomanufacturing, with a focus on sustainable manufacturing, nutrition, and healthcare. There is a great synergy between his two labs.

Even though he left industry as a full time employee more than 16 years ago, Zhao continues to engage with a variety of industries. His involvement has ranged from a few trips to companies to offer technical advice to longer term research projects and serving on scientific advisory boards for companies. He also is exploring options for starting new companies to translate his scientific discoveries and technologies for the public good.