The Aerospace Engineers of Biology
Reetwan Bandyopadhyay
Fall 2021
Humanity’s experience with stargazing has transformed significantly throughout the past centuries. From Copernicus’s theory of the heliocentric universe in 1543, the creation of the Hubble telescope in the 1920s, to NASA’s current Artemis mission which plans to send astronauts to the moon in 2024, we have made incredible leaps and bounds in terms of our knowledge of and relationship with space.
A major factor driving this transition is the gradual advent of the field of aerospace engineering. Originally, in the days of Copernicus and Galileo, it was astronomers that dealt mainly with the questions of the final frontier. However, as our knowledge and technology improves, we gain the ability to ask new questions: What does the Great Spot on Jupiter look like to a physical passerby? How far does the Kuiper Belt and Oort Cloud stretch from Pluto? Is it possible for a human to set foot on Earth’s moon? To answer these questions, we had to take our learnings from the study of astronomy and weaponize them, so to speak. It is this endeavor that led to the field of aerospace engineering, and subsequent milestone creations like Sputnik, the space shuttle, and the SpaceX Falcon rocket.
A similar process of weaponization has taken place in the field of biology over time. A journey that began with the discovery of the cell by the likes of Hooke and Leeuwenhoek in the 17th century grew over time to yield groundbreaking innovations like the development of the polio vaccine by Jonas Salk in the 1950s. Today, scientists and researchers have accessed the ability to take benchtop basic science discoveries and mold them into potent therapeutic tools. Consider the production of insulin, for example. In this case, the gene that codes for the production of the insulin protein is inserted into the genome of yeast or bacteria. effectively turning them into factories of insulin production (Smith, 2019).
These types of innovations fall under the umbrella of the field of synthetic biology. Synthetic biology is understood as the fusion of engineering and biology principles to design and build novel biomolecular components, networks, and pathways (Khalil et al, 2010). Synthetic biologists function as the aerospace engineers of biology, utilizing their knowledge of basic biological concepts to construct intricate tools that help produce cheaper drugs, novel cancer therapeutics, robust experimental systems, diagnostic tools, and world-saving vaccines.
DNA Synthesis and Assembly
At its core, synthetic biology is based on the reconfiguration of native genomic structures. Synthetic gene technology has improved by leaps and bounds since the 1970s, when human insulin was produced in E. coli bacteria. Today, gene networks can be constructed to emulate digital circuits and devices (Frieland et al, 2009). Their construction is aided by a directory called The Registry of Standard Parts. This registry is a collection of genetic tools that can be used interchangeably in order to create circuits, devices, and systems in synthetic biology. At a very high level, it can be thought of as a big box of biological “Legos”, which can be selectively pieced together to build a more complex final product. On the registry itself, each component (promoters, terminators, protein-coding regions, etc.) has a designated symbol that researchers can browse when looking for the components they will need for their projects/studies.
In addition to The Registry of Standard Parts, scientists use a type of technology called BioBricks in order to construct synthetic gene circuits. BioBricks are plasmids containing a genetic element from the Standard Registry that are flanked by restriction sites. There are two restriction sites on the left, EcoRI and XbaI, and two on the right, SpeI and PstI. In the BioBrick assembly shown in the diagram below, the blue part is cut out of the plasmid on the left with the enzymes EcoRI and SpeI. The resulting fragment is called the insert because it will be inserted into the plasmid containing the other part of our desired gene circuit.
In a separate reaction, a gap is cut in the plasmid containing the green part using EcoRI and XbaI. Using gel electrophoresis, the insert for the blue part and the cut plasmid containing the green part are purified and the unwanted fragments discarded. The purified insert and cut plasmid are mixed under the right conditions to allow the E sticky ends to come together and the S sticky ends to come together with the X sticky ends. Once this happens, the DNA backbone is re-ligated. By iterating this process using elements from the registry of standard parts, entire genetic circuits can be constructed.
Living Therapeutics
One of the most impactful products of advances in the field of synthetic biology is the development of living therapeutics. Cells that have had synthetic gene circuits incorporated into their native genomes, in a process analogous to that described above, can control the localization, timing and dosage of therapeutic activities in response to specific diseases (Cubillos-Ruiz, 2021). One example of this is the genetic engineering of gut microbiota. These microbes can be engineered with biological sensors, circuits, and outputs for diagnostic and therapeutic function. For example, scientists have used synthetic biology techniques in order to develop “natural probiotics”, or bacteria that have been edited to have the ability to alter the composition and metabolism of the gut microbiota. These engineered microbes have been used to treat Clostridium infections, inflammatory conditions like obesity and inflammatory bowel disease, and neurological conditions like anxiety and depression (Landry et al, 2021).
Another application of synthetic biology in the development of living therapeutics is chimeric antigen receptor T-cell therapy, or CAR T-cell therapy for short. In CAR T-cell therapy, T cells are isolated from a patient’s blood and then genetically engineered to produce a gene for a man-made receptor that has affinity for specific cancer cell antigens. Once the engineered T cells are given back to the patient, they will track down and kill the cancer cells in the patient’s body (American Cancer Society).
Vaccine Development
In 2009, scientists at the pharmaceutical giant Novartis teamed up with collaborators at the J. Craig Venter Institute and Synthetic Genomics to use synthetic biology techniques to turn a genetic sequence from a novel virus into a potential vaccine in a matter of days. In 2011, researchers tested this vaccine platform in response to a mock influenza pandemic, which paid off massively in 2013 when an outbreak of avian flu overtook the world (Dolgin, 2020).
Synthetic biology has been embraced once again by vaccine makers, as can be seen with Moderna and Pfizer BioNTech’s mRNA COVID-19 vaccines. According to Richard Kitney, PhD, a professor from Imperial College London, “both vaccines were designed and implemented using synthetic biology techniques. With these vaccines it was possible to design them to specifically mimic the virus at a molecular level and hence to provide the body’s immune system with a direct template to which the immune system could react” (Macdonald, 2021). Moving forward, this modular template will be highly useful as scientists and physicians fight the many mutated forms of COVID-19 that are spreading quickly across the world.
The field of synthetic biology holds unbridled potential to augment the human experience. Further study will undoubtedly lead to groundbreaking new diagnostic modalities, cellular therapeutics, vaccines, and more. Just as modern aerospace engineers continue to push the boundaries of the human reach into the final frontier by leveraging their knowledge of the basic sciences, synthetic biologists too will continue to push limits, using the basic building blocks of biology and chemistry to create intricate and elegant designs that will help propel our civilization forward.
References
[1] Dolgin, E. (2020). Synthetic biology speeds vaccine development. Nature Portfolio.
https://www.nature.com/articles/d42859-020-00025-4
[2] Smith, D. G. (2019). Biohackers With Diabetes are Making Their Own Insulin.
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[3] Khalil, A. S., et al. (2010). Synthetic biology: applications come of age. Nature Review
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[4] Frieland, A.E., et al. (2009). Synthetic Gene Networks That Count. Science, 324(5931).
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[6] Landry, B. P., et al. (2021). Engineering diagnostic and therapeutic gut bacteria.
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[7] CAR T-cell Therapy and Its Side Effects. American Cancer Society.
[8] Macdonald, G. J. (2021). Vaccine Makers Could Benefit from Synthetic Biology.
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