Cheese is an everyday artifact of microbial artistry. Discovered accidentally when someone stored milk in a stomach-canteen full of gut microbes, acids, and enzymes thousands of years ago, cheesemaking evolved as a way to use good bacteria to protect milk from the bad bacteria that can make us sick, before anyone knew that bacteria even existed. In our modern world, with antimicrobial hand sanitizer dispensers in every elevator lobby, cheeses and other microbe-rich foods lie at the heart of a post-Pasteurian debate over the positive impact of microbes on our health and happiness.
With rising antibacterial resistance and appreciation for how bacteria maintain our digestive and immune health, attempting to strike a balance between cultivating helpful bacteria and keeping dangerous bacterial infections at bay is more important than ever. Biotechnology and synthetic biology will likely play a role in developing healthy bacterial communities, with designer bacterial ecosystems engineered to improve human and environmental health. However, before we can have the domesticated biotechnology that scientists like Freeman Dyson predict, we must first re-domesticate the microbes that have evolved with us over many thousands of years.
Cheesemaking, microbial ecosystems, microbiology, and biotechnology each present examples of complex mixed cultures. All bring diverse groups of lifeforms together into intricate ecologies of competition and collaboration, impacting our culture and our environment. Heather Paxson, an anthropologist who studies the microbial politics of artisanal cheesemaking writes, "To speak doubly of cheese cultures–bacterial and human–is thus no idle pun." What can these different cultures offer each other? Can scientists and biological engineers learn from human cultures as readily as they do from microbial cultures? Indeed, can those oft-battling "two cultures" of the arts and sciences work together through something as simple as cheese to ease the friction at the interface of human and bacterial cultures?
Cheese begins when Lactobacillus bacteria naturally present in raw milk or added as a starter culture break down lactose into high concentrations of lactic acid. The same acid that cramps your muscles during exercise will curdle the milk, separating the squishy proteins and fats away from the liquid whey. Rennet, an enzyme mixture found in the stomach lining of young veal and certain types of mold, is added to further break down the milk proteins, hardening the curds so that they can be pressed, washed, aged, and processed into the hundreds of types of cheeses we can choose from today.
Different cheeses are distinguished by the source and quality of the milk (cow, sheep, goat; grass-fed, raw, low-fat) and how they are aged and processed, but they can also be separated by the microbes involved in their production. Lactobacillus isn’t the only microbial species that’s used to curdle milk–Swiss cheese’s characteristic holes come from carbon dioxide exhaled by the bacteria Propionibacterium freudenreichii, a major contributor to the smell of the human armpit. Cheese microbes aren’t limited to bacteria, different species of fungus from the genus Penicillium give us not only the antibiotic penicillin, but also provide blue cheese with its stinky blueness and brie cheese its soft white rind.
Most cheese rinds don’t just harbor single species, however, but complex biofilms, communities of bacteria and fungi that deposit themselves on the cheese surface and grow in dense layers as the cheese ages in dark, humid caves. Cheeses are washed, brined, and stored in different ways to cultivate unique microbial communities and thus unique cheese flavors.
In these and other microbial communities we see most clearly that no microbe is an island. Bacteria and fungi in the cheese rind communicate with each other and share nutrients in intricate ways that we are only beginning to understand. Beyond cheese, every surface around us—the soil, air, and water, and even our own bodies—are full of complex ecosystems of microbes interacting with each other and with other microbes in our environment and in our food. Cheese rind offers a simplified system in which to study complex microbial interactions, a model that Rachel Dutton, a Bauer Fellow at the Harvard FAS Center for Systems Biology, is using in order to uncover details of how microorganisms cooperate in nature. With only tens of species working together instead of the hundreds or thousands that could be present in more complex environments, cheese rind offers scientists the ability to combine different scales of experimental understanding. Large-scale gene sequencing can be mixed with more classical microbiological experiments on one or more bacterial species working in isolated cultures, providing a deeper understanding of the biology of microbial communities.
Studying bacteria like the laboratory workhorse E. coli in pure cultures has allowed microbiologists to untangle thousands of the chemical reactions that make up the cell’s metabolism over many decades. Despite exhaustive study, however, almost one third of the more than 4000 genes in the E. coli genome still have unknown functions. Many of these genes seem to be entirely unnecessary to the cells growing in isolated laboratory conditions–deleting them from the E. coli genome one at a time has no effect on how well the cells can grow in a test tube. It’s likely that many of these seemingly unnecessary genes are actually used by the bacteria in their more natural context, surrounded by, competing, and communicating with hundreds of other microbial strains and species.
99% of these other strains can’t be isolated and grown in the lab at all: they need the dynamic microbial environment to live, making it hard to understand how they are individually contributing to the microbial ecosystem. Sequencing all of the microbes present in places as diverse as the Sargasso Sea to the human tongue has allowed us to identify the full extent of the microbial diversity in these environments but many details are missing. Projects from systems biology like Dutton’s analysis of cheese can add a valuable layer of complexity to what we can learn from sequencing alone.
Synthetic biology too can address the complexities of how microbes work together in mixed cultures. "Synthetic" can refer to things that aren’t found in nature but also can refer to how those things are made; synthesis brings two or more things together to make something new. Synthetic biology experiments putting cells or cell components together in a new biological context can provide us with clues about how biological systems work in nature or provide tools for new biological experiments. Wendell Lim and Michael Elowitz address this new frontier for the study of biology in a recent commentary in Nature, "Build life to understand it":
Conventionally, biologists have sought to understand life as it exists. Increasingly, however, from stem-cell reprogramming to microbial factories, researchers are both describing what is and exploring what could be. An analogous shift occurred in physics and chemistry, especially in the nineteenth century. Like biology, these fields once focused on explaining observed natural processes or material, such as planetary motion or ‘organic’ molecules. Now they study physical and chemical principles that govern what can or cannot be, in natural and artificial systems, such as semiconductors and synthetic organic molecules.
Synthetic biology and systems biology are working together in many exciting new ways to probe microbial cooperation, building mathematical models of how different strains of bacteria can share metabolites in a harsh environment or "wiring" new bacterial logic gates using the systems that bacteria use to communicate. By bringing together different engineered strains and even different species we can explore how microbes communicate in nature and create new functions impossible for species working alone.
Beyond the two cultures
Moreover, as a relatively new field that combines the efforts of engineers and biologists, synthetic biology itself shows how complex mixtures of academic cultures can potentially lead to something larger than the sum of its parts. Like different bacterial species that each contribute a unique ability to the function of the community, each researcher brings their own viewpoint, their own approach to the development of the field. These different viewpoints make synthetic biology what it is, but can also lead to interesting "culture clashes" as different groups learn to communicate and work together. Lim and Elowitz describe such clashes in their article:
Although traditional disciplinary boundaries are dissolving, the cultural differences between scientists and engineers remain strong. For biologists, genetic modification is a tool to understand natural systems, not an end in itself. Thus, making biological systems ‘engineerable’ — a goal of engineers in the field of synthetic biology — can seem pointless. Many biologists wonder why engineers fail to appreciate the intricate, beautiful and sophisticated designs that occur naturally. Engineers are often equally perplexed by biologists. Why are they so obsessed about the details of one particular system? Why don’t they appreciate the value of replacing a complex and idiosyncratic system with a simpler, more modular and more predictable alternative? These misunderstandings can make for fascinating conversations, but they can also prevent mutually beneficial synergies.
Here too we can learn from microbial communities, where competition plays an important role. Spirited debates on what "counts" as synthetic biology and what research will be most valuable can be useful for distinguishing the new field and developing a strong research program only as long as we don’t let such debates distract from positive work being done by members of the group. Often these debates also highlight how difficult it is to separate out individual strands from a complex community. It’s not just engineers on one side and biologists on the other but rather all sorts of blurred in-betweens–in between science and technology, pure and applied research, organic and electronic. Synthetic biology is using engineering to probe questions in basic science, making new connections between the bacterial and computational world, using new science to develop new biological technologies. C.P. Snow warns us in The Two Cultures and the Scientific Revolution (PDF) "The number 2 is a very dangerous number: that is why the dialectic is a dangerous process. Attempts to divide anything into two ought to be regarded with much suspicion." Splitting a complex issue into just two opposing and independent factions can be as dangerous and limiting as a biological monoculture. By encouraging debate and collaboration from many sides and intermediate interests we can build stronger communities.
Indeed, engineers and biologists aren’t the only people with strong and complicated interests in the future of synthetic biology. As the brand new report from the president’s bioethics commission (PDF) is being discussed on blogs around the world, the future of this new field and how it will impact technology and society is on a lot of people’s minds. How does synthetic biology fit into that suspiciously binary split of science and culture? How can we incorporate other people’s voices and concerns into new scientific and technological developments?
I spent November thinking a lot about these questions, working explicitly in-between the two cultures of art and science in order to address the future of synthetic biology. As a Synthetic Aesthetics resident I had an opportunity unheard of for most science PhD students, I got to spend the month learning and working with artists, designers, and social scientists, trying to find a common ground from which to build a better synthetic biology.
Synthetic Aesthetics residencies pair synthetic biologists like me with artists and designers, and I had the pleasure of working with Sissel Tolaas, someone who describes herself not as an artist, but as a "professional in-betweener." Her work on smell, how we communicate about and through odors is as much chemistry as it is art. She combines a powerful ability to identify smells with specialized knowledge of what combination of molecules will exactly replicate that particular complex scent. We spent two weeks in my lab in Boston and two weeks in her lab in Berlin, exploring the ways that we both isolate and recreate the natural world through biological or chemical means, our methods, our goals, our intentions.
In cheese we found a perfect "model organism." Stinky and full of bacteria, cheese has a lot to offer someone who studies difficult smells and someone who studies bacterial communities. Cheesemaking is itself a culture/science hybrid, an art form forged out of biological materials, creating a cultural object treasured by culinary cultures through millennia.
Our residency is over, but our project has only just started. Will cheese or the way we eat it change as we learn more about microbial communities and can better engineer them? Will our relation to our food and our bodies change with an increased appreciation for the millions of non-human cells that make up our personal ecosystem? Can we design biology better with an appreciation for all the mixed cultures involved, both human and microbial?
About the Author: Christina Agapakis is a PhD student at the Harvard Medical School studying synthetic biology and an aspiring engineer, designer, artist, and writer. She blogs at Oscillator and tweets @thisischristina.
The views expressed are those of the author and are not necessarily those of Scientific American.
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