This article and interview is a guest post by Elle Whitlock, a student in Rob Dunn’s course on the Future of Life.  Elle hopes to later pursue a career as a mathematician and to contribute to research that directly impacts the people and communities around her. She is interested in the intersection between physical and social sciences and wants to help create better treatment plans for those struggling with mental disorders as well as raise awareness about the dangers of vaping and other forms of addiction.

Albert Keung (AK) is an assistant professor at North Carolina State University in the Department of Chemical and Biomedical Engineering. Through the University’s Synthetic and Systems Biology program, Keung Lab research focuses on areas such as information storage in DNA and understanding neurodevelopmental and neurological disorders through organoid-based models.

Julius Lucks (JL) is an Associate Professor at Northwestern University in the Department of Chemical and Biomedical Engineering. As part of Northwestern’s Center for Synthetic Biology, Lucks Lab studies RNA structures and functions and applies this knowledge to engineer diagnostics with medical and environmental applications.

Xiao-Jun Tian (XT) is an assistant professor at Arizona State University in the School of Biological and Health Systems Engineering. Under the university’s research area of Synthetic Engineering and Systems Bioengineering, Tian Lab addresses design principles such as cell communication and regulation to create treatments for complex diseases.

Introduction

When researching this field, I was surprised to find that there is not just one definitive answer to ‘What is synthetic biology?’ Rather, and as readers will see through the following interviews, the details of synthetic biology are interpretational, although its overarching themes are consistent. It was not until 1970 that the field’s name was coined, but since then the advancements in the field have led to synthetic biology being tied to work in a multitude of industries with other disciples. The field has been developing alongside the growth of interdisciplinary work which took off in the 1980s, and it is through collaboration that technology and ideas behind the field have become more accessible and reliable. I chose these three experts because they conduct research that contributes to biomedical advancements, and there seems to be a lot of interest in the intersection of these two areas. Given the current crisis due to Covid-19, alternatives to traditional ways of addressing infectious diseases, as well as other health issues, have become a spotlight for global discussion. Synthetic biologists work to create new ways to treat, diagnose, and even understand problems like these and many others. That is why I am curious about this field, how it is developing, what potentials and limits it holds, and what we should be cautious about moving forward with this technology as the field continues to be incorporated into our lives.

Understanding the Field

Can you define synthetic biology for those who might not have heard of it?

AK: This is a very tough question to answer because so many people have different definitions of it. I tend to think of synthetic biology as the creation of any sort of system that is inspired by biology. A keyword here is system, meaning that the simple manipulation of a single type of molecule or gene I would not consider synthetic biology. Rather the integration of multiple parts that lead to some higher level or emergent function is what I think defines synthetic biology.

JL: Synthetic biology is about discovering the engineering principles by which natural organisms and biology function, and using those principles to re-use, repurpose, and re-engineer biological systems for impactful applications.

XT: Synthetic biology is a new area of research that uses biological parts to build novel circuits or devices for various applications, such as cancer diagnosis and treatment.

Keung, working with multiple cell types can you speak on what different biological systems uniquely offer to the study of synthetic biology?

AK: One thing is that different biological systems offer many different ‘parts’ or modules with diverse functionalities, from fluorescent proteins to sticky adhesive molecules, to signaling components and genes. The other is that different biological systems have different advantages or make certain types of questions easier to answer. For example, yeast grows very quickly and can be genetically engineered very rapidly but are unicellular and may not express and fold proteins from higher-order organisms that well. In contrast, human cell lines are reflective of human genetics but grow slowly, are more difficult to manipulate genetically.

Is there a priority of what cell functions should be harnessed? In other words, do some functions have more applications than others, and how do you judge the weight they carry?

AK: Hrm, tough to answer. There are so many applications, so many cell functions. I think the focus at this point should be to continue exploring and understanding the diversity of functions so we have the best possible toolbox we can have in addressing applications.

Lucks, you use bacterial cell extracts to help develop your biosensors, are there any specific reasons you use these cells as opposed to other cell systems as part of your research? Why are the biosensors created based on these cells, cell-free?

JL: We are very interested in ways that we can monitor the health of ourselves and our environment. For example, roughly 2 billion people around the planet lack access to clean water. Why? Part of that is that humans can’t see, smell, or taste many water contaminants. So, what are we going to do about it? Laboratory instruments are good, but they cost too much and require too much expertise to ‘scale’ to 2 billion people. So, we need something simpler to use, and that costs way less. We turn to bacteria because it turns out they are sensitive to some of the same toxic compounds that we are. To detect these bacteria have evolved molecular machines called ‘biosensors’ – think of them as molecular taste buds. Normally the bacterial biosensors bind to toxins and express genes that help the bacteria get rid of the toxin, for example, a protein pump to pump the toxin out of the cell. Synthetic biologists understand the principles of these biosensing reactions, and we have figured out how to ‘rewire’ them so that the biosensors trigger the production of genes that create visible signals – for example, fluorescent proteins. We can then use these biosensors to detect water contaminants directly. Cell-free synthetic biology comes in to make this whole process cheap and easy to use – by extracting the cellular machinery that enables biosensors to work and putting them in a test tube, we don’t have to worry about the complications of using live organisms in the field. It turns out you can also freeze-dry these reactions (like you would make astronaut ice cream …) so that they can be used by a ‘just add water’ approach. It’s pretty amazing!

How it Impacts the Future

What are some key wicked problems surrounding the biological world we could potentially answer through synthetic biology or would you like to see answered, and what implications would such discoveries have?

AK: There are so many! Cancer, environmental toxins, autism, and neurodevelopmental disorders, and also acute traumas like brain injuries, wounds, infections, etc. Synbio can play a role in all of these. Certainly it is not the only solution, a large amount of work from core research fields in each of those areas and in their biological disciplines is required, and the interplay between synbio, other engineering disciplines, with fundamental and clinical disciplines will be required. I think the implications of synbio in particular is that we may be able to expand how we think about treatments or therapies to one that is more bio-bio matched rather than bio-inorganic matched. 

XT: I would say it is cancer metastasis, which causes 90% of cancer death, but it is difficult to predict and control. I believe that synthetic biology will hold a promise for it.

What new functions in biological systems would you like to see in the future, or that you think will be most beneficial to society as a whole, and why?

AK: I think certainly new functions would be nice, but I think I’d like to see an increasing focus on reliability and robustness of synthetic biology functions/systems. For example, if you design a new circuit in a cell, how does it function in a population of cells? Does it work the same way in 50%, 90%, 100% of the cells? 

JL: In the next few years we’ll see major synthetic biology advances in diagnostics and therapeutics that will benefit humanity. We are also seeing the growth of a new sustainable bio-manufacturing capability where products can be made much more sustainably than through traditional chemical means. I’m also very excited about the intersection of synthetic biology and materials science – within the next decade we are going to see the emergence of ‘smart’ materials: clothes that can sense aspects of your physiology and self-adjust accordingly, smart building materials that can detect the presence of toxins in the air and then synthesize materials to purify them out. Combined, my hope is that these technologies will allow us to live more healthy lives in harmony with our environment so we can also take care of our planet.

XT: What I most want to see is the success of using engineered bacteria for cancer treatment. 

Do you believe there will be a shift from traditional medication to new forms of diagnostics and therapeutic treatment created through synthetic biology? If so, when do you believe this shift may occur and is there a certain type of disease(s) you believe the technology would be best suited for?

JL: Yes. The first thing you’ll see is synbio-based pathogen detection, building off of the work by companies like Mammoth Biosciences and Sherlock Biosciences. These will then be adapted to all sorts of viruses and pathogens. After this, I think you’ll start to see a general awareness for the need to know about what is in your environment and you’ll start to see synbio-based tests for things like lead, pesticides, antibiotics, and other harmful water compounds. Full disclosure, I’m co-founder of a startup called Stemloop that is working on some of this.

Has Covid-19 given you any insights into combating or understanding diseases through synthetic biology for the future? If so, can you elaborate on what you have learned and how it can be applied?

AK: Directly, no. I think the most important areas for Covid have been understanding the disease itself through immunology and virology. Synbio can play a role in detection and testing but due to regulatory necessities, it’s not quite there yet where it could play a role. I think perhaps what it does suggest is that we could imagine if synbio were more mature, our response and ability to deal with Covid could be stronger, so developing our capabilities to do synbio based testing, vaccine development, surveillance, etc. would be very helpful.

JL: COVID-19 highlighted that existing diagnostic technologies do not scale well. It highlighted the need for low-cost, easy-to-use, point-of-use technologies. It’s motivated us to adapt our technologies to detecting COVID-19.

XT: I would say the fast diagnosis. It will be critical to develop a reliable diagnostic tool for early detection of a new pandemic disease or virus in a multiplexed way.   

How can biosensing be expanded in the future? Is there a limit to how fast certain detections can occur? What forms could indicators come in? What developments would you like to see?

JL: I would like to see the range of compounds that can be sensed to expand. For example, there are some dangerous water contaminants called PFAS and PFOA that we currently can’t sense with biosensors. I would also like to see detection times get down into the minutes. It would be amazing if Apple Watches of the future contained our biosensors so that people with specific health conditions could get the information they need to live full and healthy lives.

When do you see biosensing in the environmental world becoming the mainstream? What issues do you believe are most crucial in addressing, and why do you think they should be addressed through synthetic biology as opposed to other methods?

JL: Synbio offers some of the cheapest, easy-to-use, and accessible technology for sensing environments and ourselves. It’s really important that we think about equity with new technologies – who can get access, who can afford access, and is it easy enough for everyone to use. Cell-free synbio technologies are one of the few that can really make a difference from an equity lens. To that end, I’d like to see issues with poor water quality be addressed first since it can affect our lives in many ways, and the burden right now is on those that are less affluent. Whether you need to know if there is lead in your water in Chicago, or if you know if your well is contaminated with high levels of fluoride in India, everyone has a right to know. I’m hoping solving these very serious challenges will create more general global awareness that there are quality issues for almost everyone and that these technologies can help.

What relationship will synthetic biology, and the biotechnology it establishes, create with other species in the future? How may it affect their ecosystems, evolution, and or lifespan?

AK: Much of synbio will be relatively contained to laboratories or production facilities. For things that edit human germlines or embryos…that is a difficult topic because most scientists would agree those things should not be done, but it will require the broader public to institute laws governing these actions. 

There is another area that is probably going to have the most direct impact on ecosystems…gene drives which are genetic circuits that copy themselves from one chromosome to another. These can effectively ‘drive’ a synthetic gene through a population of mosquitos, or rodents, etc. at a rate faster than mendelian inheritance. Again, these need to be regulated in some way, and widespread efforts to disseminate scientific information and invest in education will help societies and governments develop plans for this.

JL: This is a tricky question and depends on how synbio proceeds. I personally think we should proceed cautiously, and constantly evaluate the ethics of whether or not specific technologies should be developed or if we should not develop them because they risk large scale ecological changes. I’m hoping that by training more responsible synthetic biologists and educating society at large we can work on these challenges together.

The Future of the Field

Over the course of your career in the field, have there been any key turning points when it comes to the procedures, technology, or ideas behind the practice and how have they impacted you and your work?

JL: In 2014, Jim Collin’s lab showed that cell-free gene expression reactions can be freeze-dried. This was revolutionary – it enables reactions to be made, freeze-dried, and then easily stored or transported anywhere in the globe. It really made it so that these biotechnologies can be cheap and scalable and enable anyone to use them. This really motivated us to get into the field of synthetic biology diagnostics!

What are the advantages and disadvantages of working in a relatively new field? Can you provide specific examples of how drawing from other disciplines, enhanced or hindered your approach?

AK: Engineering provides some formal ways to model systems, methods that have been thought through and matured extensively in engineering disciplines. So, you can benefit from all of that prior work and thought, and it can help you understand some aspects of synbio without reinventing the wheel. However, in other cases, synbio may have aspects where direct analogies to traditional engineering systems may not be appropriate.

JL: It’s incredibly exciting. My background is in chemistry, theoretical physics, biology, and bioengineering and I draw on all of it constantly. Our group has chemical engineers, biologists, and applied mathematicians that are part of it at various points, and we collaborate with a huge number of scientists, social scientists, artists, business students, etc. The more people and ideas at the table the better. It can be hard though since new fields don’t ‘fit’ in traditional categories. It just means you have to work harder to convince others that this is an exciting and impactful area!

XT: Working in a relatively new field is not easy because you need to understand many different new things, such as terminologies and technologies. However, you can always bring in a different perspective into the field.

What potential barriers do you see in the future in terms of the ethics of synthetic biology? What are the ethical boundaries you think we should keep in mind?

JL: It’s hard to write about specifics here because there is A LOT of work to be done. Basically, we need to be thinking about ethics every step of the way. It’s a big part of our new NSF-funded training program in synthetic biology at Northwestern.

XT: An incomplete understanding of the biological system will become a critical potential barrier. For example, when we are able to delete one gene using new technology such as CRISPR to cure one disease, but we are not sure if the deletion of this gene could cause other potential problems in the long-term, we need to consider ethics.

What holds the field of synthetic biology back?

AK: There has and will continue to be exciting progress in synthetic biology, and bringing knowledge of the field to the broader public and exciting young scientists, engineers, as well as those in the social sciences and humanities to think about synthetic biology will be very important. Your efforts here are a great contribution to this!

JL: We need more people to know about synthetic biology, which is why I’m grateful for your article.

Conclusion

Synthetic biology creates technology that relies on naturally occurring biological resources being manipulated in innovative ways, in hopes of being more effective and efficient. It can be used to address existing issues and further understand the world around us, which in turn allows for even more discoveries. As the principles and methods become further established through research, so too will the extent to which we realize the full potential it holds in application. Whether it be tools, methodology, or purpose, it must be expanded upon by a variety of perspectives other disciplines offer. Reflecting on the abundance of opportunities this field offers, it is important to keep in mind that it will be necessary to create measures to ensure that the implications of its technologies are fully recognized before they are implemented in our future.

Glossary

• Organoid- Artificially grown cells that resemble an organ.
• Fluorescent- Produces light.
• Metastasis- Secondary growths from the original cancer site.
• Physiology- Study of functions and parts of a living system.
• Germline- Sex cells that allow species to reproduce, i.e. egg and sperm cells.
• Embryos- Developing human offspring two to eight weeks after fertilization.
• Chromosome- In the nucleus of living cells, it carries genetic information via genes composed of DNA.
• Mendelian Inheritance-Traits inherited by one gene controlled by two alleles, for organisms that reproduce sexually, one parent passes one allele, the other another.
• CRISPR- Technology that allows for DNA sequences to be altered, and in turn can alter gene function.

Sources

Burgess, Shawn. “Germ Line.” Genome.gov, National Human Genome Research Institute, www.genome.gov/genetics-glossary/germ-line.

Collins, Francis S. “Mendelian Inheritance.” Genome.gov, National Human Genome Research Institute, www.genome.gov/genetics-glossary/Mendelian-Inheritance.

Noorden, Richard Van. “Interdisciplinary Research by the Numbers.” Nature News, Nature Publishing Group, 16 Sept. 2015, www.nature.com/news/interdisciplinary-research-by-the-numbers-1.18349.

Rugnetta, Michael. “Synthetic Biology.” Encyclopædia Britannica, Encyclopædia Britannica, Inc., 20 Apr. 2016, www.britannica.com/science/synthetic-biology.

Vidyasagar, Aparna. “What Is CRISPR?” LiveScience, Purch, 21 Apr. 2018, www.livescience.com/58790-crispr-explained.html.