Synthetic Cells and Biofactories

Synthetic Cells and Biofactories

Kate Adamala and the Build-a-Cell consortium look to synthetic biology for insight into the origins of life and a source for vital raw materials.

By Bernard Cook III

Your phone, your food, and the fuel that powers your car all depend on oil-derived petrochemicals. But experts anticipate oil reserves will run dry as early as 2070, forcing industries dependent on petrochemicals to look for alternatives that would fundamentally change the way they do business–and the way we live.

But scientists like Kate Adamala (BTI/Genetics, Cell Biology and Development) see another path forward. They envision a world where oil reserves disappear but one where we’ll still be able to meet our need for petrochemicals. Their solution? Create more life.

Adamala, a chemical engineer by training, is working to build living organisms from nonliving chemical components. These “synthetic cells” can help scientists explore the origin of life, accelerate drug discovery, or provide a renewable source of resources, like petrochemicals.

At its core, a synthetic cell is an organism that exhibits lifelike qualities. Much like a car, which is a collection of metal parts until arranged in the right way, cells are chemical bundles organized in a particular manner. Adamala constructs synthetic cells in her lab by encapsulating nucleic acids, amino acids, and ribosomes (the building blocks of cellular life) within a protective lipid coating. This method, known as the “bottom-up” approach, offers a key advantage: complete control over the cell’s components.

Natural cells can also be engineered to perform specific functions, but they’re resistant to change, and coaxing them into producing large quantities of desirable chemicals comes at a cost. When scientists engineer cells to create petrochemicals, for example, the build-up of those chemicals can damage the cell. “No self-respecting cell will make those chemicals because it’s toxic to them.”

Synthetic cells, however, are a blank slate. “Because we make them from scratch, they don’t have the baggage of 4 billion years of evolution,” Adamala remarks. They can be manufactured to do what scientists want them to do (like churning out petrochemicals). But, even with this level of control, there are still compromises. Adamala likens this to canine domestication. “I want my dog to sit on my lap and keep me warm in the winter. And he does that, but he cannot go out and hunt … so that’s the trade-off we made.”

Before synthetic cells can support a robust biomanufacturing economy, scientists like Adamala also need to resolve the physics of how cells self-replicate. To date, researchers have yet to determine how to make synthetic cells reproduce on their own–a crucial step toward using these organisms as in mini, living biofactories.

Like many scientists, Adamala grew up watching science fiction films and was fascinated by the search for life beyond earth. She earned her Ph.D. in astrobiology, but synthetic biology allowed her to explore her passion while producing tangible benefits for society. “The synthetic cell engineering field presented itself as everything I always wanted. It has connections to origins and astrobiology, so I can still say I’m looking for life on Mars! But it’s also incredibly applicable. It could solve some of the biggest problems our economy is facing now.”

Adamala isn’t the only scientist excited about this approach to cell engineering. The Build-a-Cell consortium, co-founded and led by Adamala, intends to construct a network of scientists sharing ideas, data, success stories, and failures–not unlike open-source software platforms that depend on shared knowledge to drive innovation. Adamala is hopeful that by uniting researchers via Build-a-Cell, they’ll get there sooner rather than later.

Once we unlock their potential, synthetic cells could produce fuel for our cars, fibers for clothing, and fertilizers to increase crop yields. They may also accelerate biomedical discovery or offer a glimpse into the life of our earliest ancestors. One day, they may even enable us to survive on Mars.

The DNA Solution

The DNA Solution

Synthetic biology is poised to revolutionize everything from health care to climate change—and Michael Smanski is making the most of it.

By Mary Hoff

The exploding yeast and fluorescent fish are interesting, for sure. But for Michael Smanski, the real attraction of synthetic biology is the chance to work at the cusp of a new era in biology—one that holds promise for improving food production, medical care, climate change adaptation, pollution cleanup and more.

Living things use DNA as a template for creating proteins, which in turn control the processes that make life possible. Synthetic biology creates new forms of DNA and enlists microbes, plants, or other organisms to use these new forms to produce products or functions beneficial to humans.  

“Twenty years ago, the field of biology went through an interesting phase change that was catalyzed by the Human Genome Project: the ability to read DNA. And it touched every area of biology,” says Smanski, McKnight Land Grant professor in the College of Biological Sciences “The phase change we’re going through now is even more exciting than that—and that’s the ability to write with DNA. It’s changing biology from a descriptive science, where we’re trying to learn about nature, to an engineering science, where we can ask, ‘What can life be programmed to do?’”

In Smanski’s case, the answer to that question appears virtually boundless. Trained as a biochemist and bacteriologist, he came to the University in 2014 because of its strength in both engineering and the natural sciences. In the few short years since, both synthetic biology and his research have expanded dramatically. Assembling a team of postdoctoral fellows and graduate students with expertise in computer science, chemistry and engineering as well as biology, he began exploring strategies for creating DNA-based assembly lines that microbes could use to make materials useful for humans.

In one line of research, he and his colleagues have been working to optimize a bacteria-based system that produces drugs to treat disorders such as stroke or Parkinson’s disease. In another, he has led development of a novel strategy for ensuring that engineered organisms can’t produce viable progeny with their wild relatives (hence the exploding yeast).

More recently, Smanski has begun applying synthetic biology to more complex organisms, such as vascular plants, insects, and vertebrates. By modifying their genomes to incorporate useful traits while also removing their ability to breed with unmodified relatives, he’s creating innovative strategies for controlling disease-causing and ecosystem-disrupting pests without resorting to poisons.

“We have a few projects in plants to try to translate this for agriculture,” he says. Novoclade, a University biotech startup he helped found and for which he serves as chief technology officer, is exploring applications for controlling mosquitoes and stopping the spread of invasive carp (hence the fluorescent fish).

Some of the biggest challenges related to his work are not about altering molecules and coaxing them to perform desired tasks. Rather, they relate to the kinds of issues entrepreneurs encounter with any new technology: making sure they’re addressing real needs; identifying and mitigating potential unintended consequences, complying with regulatory constraints, listening and incorporating input from various stakeholders, scaling, and more. So, for instance, he’s involved in a national Manufacturing Innovation Institute called BioMADE that’s working to bridge the large and often unwieldy gap between being able to do something in a laboratory and being able to do it on a commercial scale. And he’s consulting with the Minnesota Department of Natural Resources, tribal governments, and others to ensure their concerns are addressed and their needs are met with his carp work.

“We think a lot about translating these technologies to the field and trying to do it responsibly, because we don’t want to develop a technology that the public doesn’t want,” he says. “We’re not just teaching people, we’re learning from them in ways that helps guide the direction that we take.”

As he sets his sights on new directions, Smanski is excited about the College of Biological Sciences’ recently announced efforts to make the University of Minnesota an international hub for frontline synthetic biology research and development. 

“We’re excited to see the details emerge,” he says. “There are so many interesting directions that the field can take right now”—from advancing and applying the new tools to engineering a person’s cells to fight cancer, to reducing waste in food production, producing materials to replace climate-disrupting fossil fuels, developing crops that can thrive in the face of climate change and more.

As far as what’s next for the Smanski lab—even Smanski himself suspects it’s beyond imagination.

“Throughout my career and throughout the time frame of my lab, we let the science take us in the most interesting directions,” he says. “We’re going to keep going where the science leads us.”

Ludmilla Aristilde

Ludmilla Aristilde

Ludmilla Aristilde

Associate Professor, Civil and Environmental Engineering and (by courtesy) Chemical and Biological Engineering
Faculty Fellow, Center for Synthetic Biology
University of Minnesota

Multi-Omics Investigation of Carbon Flux Networks in Environmental Bacteria of Biotechnological Relevance

Abstract:

Biological conversion of organic wastes into valuable products represents an important component of a sustainable energy portfolio towards decreasing our reliance on petroleum-based chemical production. Critical to this effort is a fundamental understanding of the metabolic networks that control carbon utilization by environmental bacteria, which provide an array of potential biological platforms to develop new chassis for biotechnological targets.

Dr Aristilde and her team has developed 13C-metabolomics approaches coupled with other omics techniques to unravel the metabolic flux networks in bacterial species isolated from soils, plant roots, and wastewater streams. We combine high-resolution fingerprinting of metabolites and metabolic reactions with genome-based predictions, proteomics analyses, and fluxomics modeling.

This walk will present multi-omics investigations to obtain new insights on the metabolic mechanisms underlying carbon flux routing in Pseudomonas putida, Priestia megaterium (formerly known as Bacillus megaterium), and Comamonas testosteroni. Guiding principles to identify target pathway candidates for metabolic engineering will also be highlighted. 

Sean Elliot

Sean Elliot

Sean Elliot
Boston University

3:30 September 22, 2022
239 Gortner
Reception to follow

Redox Enzymes of Carbon Transformation, through an electrochemical lens

Abstract:

This seminar will use iron-sulfur cluster proteins and enzymes as examples to illustrate how a far-ranging series of redox-active metalloproteins can be examined through an electrochemical lens, to understand the role that specific redox couples play in complex enzymatic mechanisms and biological pathways. The main focus will be the impact and interplay of ferredoxin — small, ubiquitous iron-sulfur cluster redox relays — upon the function of members of the oxo-acid:ferredoxin oxidoreductase (OFOR) enzyme superfamily will be discussed. OFORs are essential players in the carbon cycle, and are considered to be reversible enzymes. However, like hydrogenases and other reversible enzymes, the design features that nature has employed to modulate the ‘bias’ of reactive toward either oxidation or reduction is unclear. And, like hydrogenases, understanding the redox couples of OFORs has proven challenging historically. Here, a combination of electrochemical and spectroscopic studies will be presented as a series of OFOR enzymes from varying biological sources and pathways will be compared and contrasted.

Art Edison

Art Edison

Art Edison 

University of Georgia

September 29, 2022
3:30 PM, 151D Amundson Hall
East Bank

Unique Strengths of NMR Metabolomics:  In vivo metabolism and improved compound identification

Metabolomics is an important component of systems biology research in biology and biomedicine. Two major technologies are widely used in metabolomics research, mass spectrometry and NMR spectroscopy. Both have their own strengths and weaknesses. Recently, LC-MS has gained in popularity, thanks largely to its high sensitivity and ability to detect 10s of thousands of features.

In this talk, I will highlight some of the unique strengths of NMR metabolomics, most notably approaches to study metabolic dynamics in real-time in cells or microorganisms. I will also discuss the difficulty that the entire field faces in confident metabolite identification and will present recent approaches to better combine NMR with LC-MS and computational chemistry to improve compound identification.

Edison, A. S.; Colonna, M.; Gouveia, G. J.; Holderman, N. R.; Judge, M. T.; Shen, X.; Zhang, S. NMR: Unique Strengths That Enhance Modern Metabolomics Research. Anal Chem 2021, 93 (1), 478-499. DOI: 10.1021/acs.analchem.0c04414.