Q&A with BTI Director Claudia Schmidt-Dannert

Q&A with BTI Director Claudia Schmidt-Dannert

Q&A with BTI Director Claudia Schmidt-Dannert

As the BioTechnology Institute’s new director, longtime faculty member Claudia Schmidt-Dannert aims to plant the institute firmly on the front lines of emerging needs and opportunities.

By Mary Hoff

Two decades ago, Claudia Schmidt-Dannert knew exactly where she wanted to be: at the frontlines of the intersection of biology and technology. And that meant joining the faculty of the University of Minnesota’s BioTechnology Institute. “BTI is actually one of the reasons I came to the University of Minnesota, because of this interaction between life sciences and engineering,” she says. “That’s very unique here.”

Named BTI director in January of this year, Schmidt-Dannert is working not only to strengthen interdisciplinary ties within the community as it recovers from disruptions due to the Covid pandemic, but also to firmly establish BTI’s position at the frontlines of biotechnology research and application during what could be the field’s most exciting times yet.

What do you hope to accomplish as director?

My focus is on keeping pace with biotechnology, really thinking about, “What are the next big things?” For example, biomanufacturing, biofabrication, new types of functional biomaterials for a range of applications—this is the future. We really must position ourselves very well in this space, make sure we are at the forefront of these types of efforts in biotechnology research, applied science, and development. We need to make sure we have the right people, resources and get people to collaborate across disciplines on these topics. We want to be spearheading new developments in biotechnology, looking at what biology can do to improve our future.

What strengths do you bring to the role?

I have a broad research background. I’m working both in fundamental areas of biotechnology but also in the engineering space, and my research spans from molecules to systems. I’m also very applied-minded. And I maybe bring a little bit more of a fresh perspective. We have a strong focus in bioremediation and environmental aspects of biotechnology. There are other and emerging focus areas in biootechnology that we should pay attention too and emphasize more. Also, I like collaboration and community-building. This is very important with a variety of stakeholders.

How important will BTI’s role in workforce training and strengthening Minnesota’s biotechnology be under your administration?

Most of our undergraduate and graduate students as well as postdocs will not follow an academic or medical career and instead many will seek out other employment in industry. There is high demand for skilled individuals from the biotechnology and biomanufacturing sector. We need to make sure that our students and postdocs are well prepared for these good-paying jobs. Over the past few years, BTI has collaborated with industrial partners on workforce development. I see this as an area that should be expanded. In addition, I feel strongly that meaningful biotechnology training should be incorporated at the undergraduate levels—where BTI can contribute. BTI also administers a small masters-level graduate program in microbial engineering that is aimed at students that want to go into industry. The student and postdoc-level workshop series as well as workshops offered through our NIH Biotechnology training program provide additional career relevant, professional skill sets.

Where do you see the big opportunities in the years ahead?

Biotechnology is very broad field, so there are many opportunities for different types of research. For example, synthetic biology is experiencing an influx of many new ideas in areas like materials sciences, sustainable biomanufacturing, artificial intelligence and computing. Addressing climate change, developing a circular bioeconomy, biomanufacturing and biofabrication—that’s where I see a lot of opportunities.

We also have very unique resources in Minnesota that go beyond our strong medical and agricultural industries. Northern Minnesota is rich in forests, water and minerals. My goal is to look at these resources as well as associated societal and environmental challenges associated with accessing these resources from a biotechnology perspective. I believe that there are many unique Minnesota-specific opportunities for biotechnology and bioeconomy development in our state.

What do you see as growth areas for the Institute?

I would like to continue building momentum and strength in synthetic biology. We have a research cluster in this area, but we have to further ramp up our expertise in this area. We are also lacking in certain cell-based manufacturing systems, especially for pharmaceuticals and biologics – we are not particularly strong in this area. Right now. we’re focused mostly on microbial systems with the new BRC [Biotechnology Resource Center] Microbial Cell Production Facility. But I also think mammalian cell cultures offer new opportunities for research. We need to bring in more young faculty with expertise in these areas.

Another goal is to build community, facilitate social interactions and provide more opportunities to exchange ideas among biotechnology research labs—crossing disciplines but also campuses. That was all put aside during Covid times, but it is very important. Without community, BTI is nothing but a collection of people. We’re going to have seminars followed by networking happy hours in both St. Paul and Minneapolis, not just by bringing in external speakers but having BTI labs give short talk to present their current research and where there research is headed. We are also reviving the graduate student and postdoc-led workshop series.

How will the Biotechnology Resource Center expansion benefit the University and for the state?

The new Microbial Cell Manufacturing Facility will have six times the pace of the current BRC, which will bring much needed capacity in microbial biomanufacturing to the University. Currently, the BRC is operating at capacity and even must turn down biomanufacturing projects and clients because of this. There is a huge demand for the types of the service the BRC offers in the preclinical space. The expanded BRC will therefore be able to serve much better the needs of UM researchers, industry, and academic partners. The “old BRC” offers opportunities for the development of new workforce training programs in biomanufacturing.

What are the big emerging societal needs that biotechnology can address, and how is BTI positioning to address them?

It is clear that we need to find drastically new ways of mitigating climate change, by developing new bio-based technologies for sustainable manufacturing, energy conversion, combating greenhouse gas emission or converting and sequestering carbon dioxide and for addressing environmental concerns. I see BTI as a catalyst and facilitator of research in these areas by bringing people together to tackle ambitious problems as teams with diverse cross-disciplinary skill sets.

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.”

Building New Metabolic Pathways

Building New Metabolic Pathways

By Kevin Coss

Microbes are nothing if not industrious. The metabolic pathways (linked series of chemical reactions) in these tiny organisms lead them to crank out a wide variety of molecules for all sorts of purposes — and that’s what has Mike Freeman’s attention.

“Some of these pathways are for chemical communication, some are for warfare, and others are completely unknown to us,” says Freeman, Ph.D., member of the University of Minnesota BioTechnology Institute and assistant professor of biochemistry, molecular biology, and biophysics. “A large part of what our lab does is looking at those genes and those pathways in unique organisms and studying them for the purpose of both basic science and biotechnology.”

Freeman’s research involves understanding how each piece of a biological system works and then combining and mixing those parts to “recircuit” pathways. This field, synthetic biology, aims to redirect microbes’ natural industriousness to produce a different, more desirable product. The intended purpose can span a wide range of applications, from producing compounds that help address bacteria’s growing resistance to antibiotics to developing molecules for use in the fragrance industry.

“You could use a microbe to do something it doesn’t already do in nature, for example, or engineer it to do it much better,” Freeman says. “We’re trying to put things together in unique ways to do what humans want, not what nature wants.”

Understanding the full scope of how a given pathway works, what it produces, and what larger purpose it serves requires a wealth of expertise. Fortunately, Freeman is part of the Synthetic Biology Research Cluster, which brings together faculty, postdoctoral fellows, staff, and students who study in the field to intermingle and learn from one another. This arrangement helps to spark collaborations that inspire new lines of research and enables the group to apply for larger grants with multiple principal investigators.

Freeman’s current research focus is on modifications that give molecules called peptides (smaller versions of proteins, with fewer pieces acting as “links” in their chain) more desirable properties. Peptide-based medications, such as the insulin used to treat diabetes, generally can’t be taken orally because stomach acids destroy the active compounds before they can provide any benefit. Modifying these peptides to remain stable through the digestive tract would open the possibility for peptide-based drugs to be taken as a pill — an option that makes it easier and more comfortable for patients to adhere to their medication schedule.

As another example, Freeman and his team are studying anti-cancer compounds derived from a specific type of fungus. Two promising varieties of peptides had previously been isolated from it, but the team went further in depth to study and isolate other “flavors” of these peptides with unique and useful characteristics. By optimizing the growing conditions in the lab for the fungi’s mycelia — the long, stringlike filaments that spread through the soil — they have been able to isolate a number of compounds from this fungus.

Apart from the medical field, a stronger understanding of synthetic biology could also help solve problems in manufacturing, agriculture, and other industries. While these solutions are appealing, what inspires Freeman the most about his research is the basic science — specifically, how much of it remains undiscovered.

In many other areas of science, researchers build upon a strong foundation of existing knowledge. Synthetic biology is different. It’s only recently that advances in genomic technology made it possible to study the workings and purposes of genes, proteins, and pathways at this level of detail.

“In some cases, the enzymes that we find, the pathways, the molecules have never been seen before in science,” he says. “Being able to explore these unknowns and add to the general scientific knowledge for humanity is what’s really satisfying to me.”

A Helpful Fungus Among Us

A Helpful Fungus Among Us

Mine wastewater bioremediation on Minnesota’s Iron Range

By Evan Whiting

When people think of fungi, they typically conjure images of mushrooms: portobellos, oysters, truffles, or shiitakes. But a mushroom—the fruiting body we see above ground—is merely the tip of the iceberg when it comes to fungi. Most fungi are comprised of a tangled network of small thread-like structures called hyphae. Others, like yeasts, are microscopic, consisting only of single cells.

In fact, there is a huge diversity of fungi out there—some experts estimate that there are over two million species of fungi living on Earth today. And they’re important members of modern ecosystems. Excellent scavengers and nutrient recyclers, many fungi also gather materials from their surroundings and can even capture and store environmental contaminants. Experts are actively working to understand the underlying mechanisms, but scientists, engineers, and industry professionals also see the potential for using fungi in bioremediation—the cleanup of environmental contaminants or pollutants using living organisms, usually microbes.

Dr. Cara Santelli, an associate professor of Earth & Environmental Sciences and a member of the University of Minnesota Biotechnology Institute, is an expert on bioremediation and the interface between microbes and minerals. Santelli and her colleagues investigate organisms with the potential for bioremediation of mining waste, including several species of fungi. One of her ongoing projects, funded by MnDRIVE Environment, involves a species of fungus native to northern Minnesota’s Iron Range, where high concentrations of metals in the wastewater from an inactive underground iron mine could, if left untreated, threaten ecosystems and natural resources on the surface.

Located near Lake Vermilion and the Boundary Waters Canoe Area Wilderness, the Soudan Iron Mine was once a prolific source of iron ore. In the 1960s, when mining operations shut down, the mine became a research and educational facility. But more than fifty years later, there are still lingering issues with toxic metals in the mine’s wastewater, which is currently treated with expensive ion-exchange filters. Luckily, there may be a cheaper, local, and ‘organic’ solution to this problem: bioremediation with a native species of fungus (Periconia sp.) that grows in the salty, metal-rich waters in the depths of the Soudan Mine. Periconia is capable of producing manganese oxide minerals that incorporate metal ions in their chemical structures, much like blocks in a microscopic game of Tetris.

Dr. Brandy Stewart, a postdoctoral researcher in the Santelli Lab, has been studying this fungal bioremediation system in detail. Stewart is an expert in biogeochemistry, or the interplay between chemicals, microbes, and their environment. With additional background in environmental consulting, she brings a wealth of knowledge and experience to this new project. Currently, Stewart studies the optimal growth conditions for the project’s focal fungus, as well as how efficiently it produces manganese oxide minerals using nearby metal ions from the surrounding brine.

The fungus needs a cocktail of nutrients to grow and remain healthy, but the actual wastewater from the mine might not be the ideal growth medium. Even for this mighty fungus, certain metals, like copper, can be toxic at higher concentrations, so Stewart has set out to facilitate the removal of these metals without hurting the fungus itself. She likens this to our own dietary choices: “If you ate nothing but doughnuts, you probably wouldn’t be very healthy, but if you ate well and got plenty of fruits and veggies most of the time, you could still have a doughnut every once in a while and be okay.”

Thankfully, the fungus seems to grow quite well in the suboptimal, mine-like conditions simulated in the laboratory, especially when grown in the presence of carpet fibers. These fibers may be acting as a sort of ‘scaffolding’ upon which the fungus can grow, or even as an additional food source for the fungus. Regardless, Stewart has found that the presence of carpet fibers dramatically improves the growth and productivity of the fungus, which creates a thick biofilm where the manganese oxide minerals form and accumulate . As revealed by X-ray fluorescence images, these minerals are often laden with captured metals, demonstrating the efficiency of this system for removing metals from wastewater.

 

Periconia sp

X-ray fluorescence imagery showing very similar groupings of manganese oxide minerals (left) and copper ions (right) along strands of Periconia sp. fungal hyphae growing in the lab. Courtesy of Brandy Stewart, UMN.

Although still in the experimental stages, Santelli and Stewart eventually hope to build larger bioreactors to scale up their fungal bioremediation system for applications in the Soudan Mine. These bioreactors may be able to help prolong the lifespans of the ion-exchange filters already in use—or potentially replace them, if they prove to be at least as effective at removing metals like copper, cobalt, and nickel from the mine’s wastewater. These metals are not just potential environmental contaminants; they’re also economically important for myriad purposes, including electronics and battery production. If enough of these metals could be efficiently captured in manganese oxides produced by fungi and later recovered, we could potentially capitalize on them.

And mining wastewater might be just the beginning, according to Santelli. There are large amounts of dissolved solids in many types of industrial wastewaters, so there is great potential for using fungi (and/or other microbes) for bioremediation of contaminants in wastewaters well beyond the Iron Range. With such a huge diversity of fungi out there, it’s only a matter of time until another helpful fungus among us becomes the next big hit in bioremediation.

Evan Whiting is a PhD Candidate in the Department of Earth & Environmental Sciences at the University of Minnesota and an affiliate writer in the University of Minnesota Science Communication Lab. He can be reached at whiti101@umn.edu.

Feature photo: Photomicrograph of Periconia sp. fungal hyphae. Courtesy of Brandy Stewart, UMN

Tapping the Talents of Enzymes

Tapping the Talents of Enzymes

BTI researchers are working to discover, understand, and improve our ability to enlist the help of molecules that catalyze life.

by Mary Hoff

Enzymes are the movers and shakers of the biomolecular world. A class of proteins found in every cell of every living thing, they bring together molecules that would otherwise be reluctant to interact so they can combine, exchange parts, or otherwise alter each other.

In nature, enzymes facilitate thousands of processes from photosynthesis to decomposition. Enzymes speed up chemical reactions thousands of times faster than the reactions would occur on their own. Over the millennia, humans have found ways apply this superpower to accomplish a variety of useful goals from making beer and cheese, to making our laundry whiter and brighter, to cranking out millions of copies of a sample of DNA to solve crimes or find long-lost relatives.

“And that’s just the beginning,” says Romas Kazlauskas, professor in the department of Biochemistry, Molecular Biology, and Biophysics. “Enzymes can also learn how to do different things. We’re trying to figure out which parts are important and why they’re important, then design something different to do a reaction that doesn’t occur naturally.” By identifying enzymes, improving understanding of how they work, and applying them to new tasks, Kazlauskas and BTI colleagues are taking advantage of the billions of years of evolution that produced these molecules to make medicines, degrade pollutants, speed industrial processes, and more.

 

Trash to Treasure Kazlauskas is working with an enzyme found in nature that degrades PET plastic. First synthesized in the 1940s, PET (a form of polyethylene) is widely used for beverage and food containers with some 70 million tons generated every year—and much of that ending up in landfills and the ocean. Current efforts to recycle the material can only produce lower-quality plastics.

“One idea is to break down to component parts and resynthesize fresh plastic that would be just as good as what you started with,” he says.

Sound like a job for an enzyme? Kazlauskas thought so, too. But the likelihood of finding a suitable one in nature was slim because PET didn’t exist for most of evolutionary history. Nevertheless, in a compost heap in Japan, researchers recently found an enzyme that bacteria use to break down the waxy part of plants that could also break down PET.

Kazlauskas, along with graduate student Colin Pierce and colleagues, is working on modifying that enzyme known as cutinase, to improve its ability to degrade PET. The goal, ultimately, is to be able to develop a commercially viable way to turn old PET into new plastics without experiencing the loss of quality. This would not only reduce the load of plastic waste, it would also reduce pressure to produce more plastic, often from fossil fuels.

Kazlauskas sees huge opportunities beyond PET for efforts to extend nature’s ability to degrade compounds. “There are a lot of cases where we start making stuff and putting it out in nature, and people say it doesn’t degrade,” he says. “We’re finding bugs that can degrade these forever chemicals.” he says. By advancing the ability to modify such natural enzymes to make them do the job even better, the hope is to avoid the buildup of undesirable, manufactured compounds in the environment and reduce the need to make more from raw materials.

 

Life on the Edge

Turning somersaults in a sulfurous hot spring or clinging tenaciously to life on a glacier, the organisms studied by McKnight Presidential Fellow Trinity Hamilton, associate professor in the department of Plant and Microbial Biology, are the stars in microscopic world’s version of “Survivor.” Having evolved within living things, most enzymes work best under fairly mild conditions with respect to things like temperature and acidity. But not all. In the hot springs of Yellowstone National Park, Hamilton is studying how microbes—and the enzymes they use to carry out the activities of daily life—can survive regular temperature fluctuations of 40 degrees Celsius (104 degrees Fahrenheit) or more. And, on the other end of the spectrum, she’s also looking at how other microorganisms that live on ice maintain their function at low temperatures in the absence of liquid water.

Hamilton studies, among other things, enzymes that facilitate photosynthesis and function well up to 72 degrees Celsius, and then suddenly quit. “We have no idea why,” she says. “It’s really hard to perform autopsies on microbes.”

The ability of bacterial enzymes to function at various temperatures is behind the process that makes it possible to sequence DNA using what is called the polymerase chain reaction (PCR) technique. The enzyme used for this was isolated from bacteria in a hot spring in Yellowstone National Park. A better understanding of how bacteria keep these proteins active under extreme conditions could open the door to advancing our ability to solve other human challenges like preserving food or thriving in the face of climate change.

Molecular Assembly Line 

For Michael Smanski, a McKnight land grant professor in the department of Biochemistry, Molecular Biology, and Biophysics, the focus is on bringing together enzymes from different sources to create an efficient work team that can produce a specific molecule.

Most recently he’s been focusing on serofendic acid, a molecule found in the blood of fetal calves. In the early 2000s, researchers in Japan discovered that serofendic acid could prevent the untimely death of neurons and potentially serve as a therapy for minimizing damage from Parkinson’s disease, strokes, and other neurological trauma. The problem? It occurs in such small quantities that it would take 1,000 calves to make a minute 3 milligrams of active substance—providing dismal prospects for practical use.

Biosynthesis and enzymes to the rescue. Using databases describing enzymes from different organisms and the type of work each does, Smanski and colleagues designed a molecular assembly line that could make serofendic acid from readily available feedstock chemicals. Then they introduced the corresponding genes into a bacterium, enabling it to make the desired product.

As any industrial engineer would know, populating an assembly line with ready workers is only part of the solution, however. For efficiency’s sake, it’s also important to have the right capacity at every step of an assembly process to ensure that partially made products don’t pile up, or a slow step doesn’t drag down everything else. To optimize production of serofendic acid, Smanski has been tweaking the activity levels of the various enzymes relative to each other.

Even as he’s working on a strategy to improve outcomes for individuals with brain disorders, Smanski is also discovering principles that can be applied more broadly to optimizing artificial biosynthetic processes.

Optimizing a process means testing multiple levels of expression for the specific gene that’s coding for each enzyme along the way. If the assembly line consists of 15 enzymes, and researchers want to test five levels of expression for each, that would require 5 15 power—more than 30 billion—individual trials. Using combinatorial mathematics, Smanski is devising a strategy for selecting from those millions of possibilities, a mere 100 or so that are most likely to succeed, making the optimization process far more manageable.

“As improvements in the technical aspects of genetic engineering make it easier to rewrite the genetic blueprints of living organisms, learning how to efficiently sift through all of the possibilities of what-to-write is becoming more important,” Smanski says. “We think that our work at the interface of combinatorial mathematics and genetic engineering will benefit any application that requires more than one or a few genes working together.”

 

Self-Assembling Scaffold

Bringing multiple enzymes together in an assembly line is far more easily said than done. The molecules involved in sequential steps must be physically located close enough to each other to be able to pass a product-in-the-making down the line. They also must be positioned correctly at their stations so they can accomplish their task.

Distinguished McKnight University Professor Claudia Schmidt-Dannert is on it. Rather than identifying enzymes to string together to accomplish a molecule-making task, she is working on the assembly line itself.

Her goal is to not only design a stable assembly line of enzymes able to make a useful product but to genetically modify a microorganism—say, the bacterium E. coli—so that it can produce it on its own. Such a self-assembling scaffold, she believes, could dramatically improve the function of molecular assembly lines, reducing the cost of producing pharmaceuticals and other useful products.

“If we stabilize enzymes, we can make reactions more efficient,” she says.

Schmidt-Dannert and colleagues recently received a patent for a self-assembling, modular scaffold that co-locates enzymes in a way that enhances their ability to efficiently produce desired molecules. Her current focus is on developing scaffolds as materials that can correctly self-assemble into 3-dimensional architectures to organize and support enzyme functions. This would allow the manufacture of a broad range of chemicals including pharmaceutically active molecules—a process that can be extremely difficult using conventional chemical synthesis methods. 

She’s also applying her strategy to making molecular assembly lines more economical by including enzymes that recycle required co-factors, which are molecules or metals that assist enzymes in assembling a molecular product.

“You need to recycle the [co-factors]. Otherwise, the process is too expensive,” she says. “A scaffold helps make that possible.”