Synthetic Biology, or SynBio for short, is a rapidly-growing field in science where existing systems and processes in biology are engineered for new purposes. With such a broad definition, advances in this field range from bacteria that make biofuels and microbes that clean up environmental pollutants, to rice that produces beta-carotene — a Vitamin A precursor and antioxidant usually found in carrots.
According to Jane Calvert, Professor of Science and Technology Studies at the University of Edinburgh, Synthetic Biology involves “engineering ideas being implied onto biology”. Likened to the digesting duck, Synthetic Biology today aims to:
- Understand biological systems in terms of the technology available to us, and
- Apply these resources; decipher, design, and redesign the building blocks of biology, with the ultimate aim of improving quality of life. And as the field continues to evolve, it diverts from the traditional focus seen in other scientific fields, which generally aim to characterize the natural world around us. SynBio leaves the theoretical to prioritize the potential; using biology as a vehicle for groundbreaking applications. As Science and Technology philosopher, Massimiliano Simons, from the University of Ghent eloquently puts it:
Instead of describing actual existing biological systems, the field aims to describe biological possibilities
While this branch has seen a sizable increase in interest over the years, the near-apocalyptic conditions invoked by COVID-19 on our modern society has catapulted it into the spotlight. The World Economic Forum considers SynBio as one of the key technologies to address the inefficiencies and non-sustainable practices existing today, and it is one of the pathways to success in its Great Reset Initiative. The SynBio market is expected to continue on this growth trajectory, with increased funding available and higher demand for new technologies that solve problems in medicine, pharmaceuticals, and the environment.
The possibilities truly are endless if SynBio can allow us to predict and modify biological processes — which are incredibly complex — the same way we can engineer computers. If we can successfully create new processes built off existing ones, this means we can also optimize existing processes, as more and more knowledge becomes available about them and technology continues to advance. This then begs the question: can Synthetic Biology be used to address inefficiencies in biological systems that have evaded elimination over the course of evolution?
Evolutionary Inefficiencies and Constraints
The implications of evolutionary theory are controversial. It requires an understanding of intricate, nuanced technicalities to fully grasp an ever-evolving picture about how life on earth works and has worked over billions of years. Nevertheless, whether accepted as probable or not, studying the natural world reveals inefficiencies that appear “overlooked” by evolution. These may come as a surprise, because a general perception of evolution and natural selection is the idea of “survival of the fittest” and that over time organisms continue to adapt and evolve to become better and better…but the reality — as explained in this article from the Australian Academy of Science — is that evolution doesn’t always lead to “the best outcome”. Two main reasons are given:
Firstly, selection can only act on the available genetic variation. A cheetah, for example, can’t evolve to run faster if there is no ‘faster’ gene variant available. Secondly, the body has to work with the materials it already has. It can’t make something out of nothing — that’s why winged horses are the stuff of myth.
Evidently, since nature can only work with what it has, a direct consequence is scenarios where systems are not as efficient as they could be. By “inefficiencies”, I am referring to features or processes that continue to exist in a population even though they don’t work as well as we expect them to, instead of being weeded out by the process of natural selection. While this is not a study of how these inefficiencies come about, I think an example might help to better set the scene.
Example of an inefficient enzyme — RuBisCO
RuBisCO is a naturally occurring enzyme believed to be the most common protein in the world. It is involved in ‘fixing carbon’, this is the process of converting carbon dioxide (CO₂) into a form of carbon that can be used by organisms for energy to help them build biomass, e.g. glucose. It is the main enzyme involved in carbon fixation, governing the Calvin-Benson-Bassham cycle, which is estimated to fix ~90% of carbon globally. However, as expressed in this paper by Tobias J. Erb and Jan Zarzycki — researchers at the Max Planck Institute interested in the biochemistry and synthetic biology of carbon conversion — it is a rather inefficient enzyme for a few reasons.
- It has a very slow turnover rate. This means that it takes relatively longer to turn the starting materials into the product; it’s rather slow at fixing carbon. Researchers speculate that this is because it needs to be more specific — it needs to tell CO₂ apart from oxygen (O₂) so that it reacts only with the first and not the second. Specificity is a characteristic of enzymes that usually comes at the cost of speed. But, despite this, for every five CO₂ molecules the enzyme reacts with, it also reacts with two O₂ molecules.
- The reaction with O₂ unfortunately leads to the production of a compound called glycolate-2-phosphate or 2-Phosphoglycolate or simply 2PG. 2PG is bad because it’s actually toxic to plant cells: it inhibits other enzymes. In order to get rid of it, a process called photorespiration occurs— where oxygen is used up and carbon dioxide is released, meaning plants are also losing CO₂. This limitation could be hindering the levels of crop production that could have been reached, because getting rid of the toxic product is energy intensive, basically draining energy from the plant that could have been channeled towards growth. This is a constraint.
For the purpose of this article, a constraint is a limitation that can prevent something else from happening to its full capacity. An evolutionary constraint is one that arose as a result of evolution. In the first point above, speed is sacrificed for accuracy in response to an evolutionary pressure. According to researchers, RuBisCO first evolved before the earth’s atmosphere had so much oxygen, so it didn’t need to worry about it. But with the change to the atmosphere and more oxygen present, a system was needed to ensure that the enzyme was not reacting with high levels of oxygen. This is an example of a current process being constrained by evolutionary pressure in the past.
While this is a system that has worked despite its inefficiencies in the past, the human population has grown tremendously over the 20th century, thanks to improved technologies. This growth is predicted to continue at an approximate rate of 1.7% per year, consequently requiring crop yields to double by the year 2050 in order to keep up with the increased demand. Since other components required for plants to fix carbon, including water and light, are typically abundant, the process of fixing carbon itself is a big limiting factor in crop yield. This situation calls for innovation in the agricultural sector, that would both support a growing human population, and be kind to the environment. Engineering the process of carbon fixation could be an answer to this problem.
This brings us back to the question from before: how exactly can synthetic biology play a role in addressing perceived inefficiencies in biological systems?
Synthetic Designs to Overcome Natural Constraints
While it might be beyond the scope of SynBio to attempt to alter the macro level of things, research has shown that on the micro and molecular levels, engineering can be used to enhance existing systems and overcome constraints. Here are two instances, the first related to the agricultural sector, and the second to medicine.
1. A Synthetic Pathway for the Fixation of Carbon Dioxide in vitro
Researchers were able to develop a system that improves carbon fixation by about 30%, by designing and engineering a new 17-enzyme system that isn’t constrained by evolutionary or environmental factors. To do this, they identified other carboxylase enzymes — enzymes that could also react with CO₂ — selected the most efficient, and performed a series of experiments to determine the order of the pathway. Through optimization steps, they were also able to minimize unfavorable side reactions. Optimization included “metabolic proofreading”, which involves using other enzymes to get rid of toxic by-products and other products that might get in the way or accumulate in the cell and interfere with processes.
Although this was a reductionist approach, and it was done in vitro, meaning we don’t know how the pathway will behave in a live organism (in vitro is the opposite of in vivo, which means done using a live organism, this experiment was done using purified enzymes and no live cells), this experiment demonstrates that it is possible to engineer enzyme pathways to improve yields. While it would take time to engineer such a complex system into a living cell, and even more time for a multicellular organism such as a plant, the implications of this study can still greatly benefit the agricultural sector.
2. Synthetic Immunology: Hacking Immune Cells to Expand Their Therapeutic Capabilities
Immune cells play the unique role of fighting off diseases and infections to keep us healthy. Despite diverse and impressive properties including killing and “eating” cells that may pose a threat and producing compounds to initiate an attack on foreign matter, these cells are still limited. In a review article from the Annual Review of Immunology, Kole T. Roybal and Wendell A. Lim evaluated existing ways to engineer immune cells and their related compounds to overcome more complex diseases that they may be unable to or have limited ability to address, such as cancer, or conditions that immune cells contribute to themselves, such as autoimmune diseases.
For instance, in one of the reviewed experiments, Levin et al. engineered an important cytokine, a small protein associated with cell signaling, involved in T-cell growth. As a key immune component in killing problematic cells, T-cells are essential to fight cancers, which are primarily caused by uncontrolled proliferation due to a regulatory failure in cells. By altering the protein structure of the cytokine IL-2, they created what they dubbed a “superkine” or “Super-2”, which had a new property IL-2 did not. Super-2 no longer needed a subunit called CD25 that previously limited the growth effects of IL-2 on T-cells. This is important because cancer cells are really good at suppressing the immune system, but using a cytokine-like Super-2 means T-cells can get an extra boost for activation and growth even in the presence of immune suppressants.
These studies highlight, at a very specific level, how biological engineering can be used not just to create new processes and properties, but also to enhance existing ones. As we continue to learn about how biological systems work, we would be able to develop more tools that allow us to by-pass natural constraints in these systems.
Applications and Implications — Why is this relevant?
This article by Tobias J. Erb et al. published in 2017 includes graphics that well summarize the applications of metabolic engineering. Starting with the natural metabolic processes, studying known enzymes and how they work, we could learn how to use these enzymes for other processes, “mix and match” enzymes to make new processes and systems, and possibly even develop new enzymes. This applies also to other proteins and components of biological systems.
If we can overcome constraints in biological systems, we would be a step closer to using synthetic biology as a tool to ensure a more sustainable future. From addressing limitations in agriculture to reducing the use of fossil fuels for the generation of ubiquitous compounds in our day-to-day life, each step forward in understanding and creating tools to engineer biology plays a key role.
More Resources on SynBio:
Dami Adebajo has recently completed a Bachelors in Biochemistry with a French Minor from the University of Waterloo, Canada, to which she will be returning for a Masters of applied science in Biochemical Engineering. Her interests are not limited to the world of biochemistry and bioengineering, however, as she is also interested in language and linguistics and how these shape our world. She enjoys exploring complex questions related to science, technology, and innovation.
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