Interview

3 Questions for Dr. Francesca Ceroni

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In our newest edition of the '3 Questions for' interview format, we spoke to Dr. Francesca Ceroni, located at the Department of Chemical Engineering of Imperial College London. As a Junior Research Fellow, she is making use of bacterial and mammalian synthetic biology to make a difference in bioproduction and biomedicine. Additionally, Dr. Ceroni is also active in the iGEM competition, both as a judge as well as a supervisor.

When and why did you move into the field of synthetic biology?

I had just graduated in Pharmaceutical Biotechnologies when I met a Professor in the Faculty of Engineering at the University of Bologna
that was looking for an advisor for the Bologna iGEM team.
Synthetic Biology sounded so interesting to me that I decided to give it a try; I was also happy to work with other students in an interdisciplinary environment.
That was it: Synthetic Biology just captured my interest and passion from that moment on and I continued in the field for my PhD, post doc and ... the present.

What is the single most important piece of advice that you would give to a current PhD student or a post-doc?

I would suggest to try to work with people you like, that show vision... choose very well the environment, the people, the once you want to deal with.
That will make a difference in your career.


In which areas do you see the main challenges and opportunities for synthetic biology?

I think there are many challenges, but the one I consider the most difficult to tackle is the complexity of biological systems that impacts on the reliable engineering we want to achieve. We have gone a long way into the understanding and characterisation of the systems we work with, but there is a lot to do and so much diversity to take into account as well.

3 Questions for Prof. Hyun Youk

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Our newest instalment of the "3 Questions for" interview series features Prof. Hyun Youk from Delft University of Technology in the Netherlands. His research makes use of quantitative methods as well as models and theory to understand the interactions between molecules and cells and discover common design principles. Here, he speaks about his transition from physics to biology and his view on the field of synthetic biology.

 

When and why did you move into the field of synthetic biology?

I never considered myself as a full-fledged synthetic biologist and I certainly haven't done any significant work in synthetic biology. But I have used and my group routinely uses tools of synthetic biology to modify and complement endogenous signalling pathways with engineered signalling circuits, with the goal of better understanding those endogenous pathways or what cells can do. On the other hand, my group doesn't build synthetic circuits to create logic gates, devices, desired dynamics, and practical applications. That’s why I hesitate to call myself a synthetic biologist in the conventional sense.

Instead, I can say when and why I moved into biology from physics.  At the core, I'm a physicist who’s been very interested in understanding how inanimate molecules - the same ones that make up many non-living systems - give rise to features that we associate with life in one scenario but not so in another scenario. This tells us that dynamics, not the molecular content, are what determines whether something is living or not and that we don’t really understand the principles that underlie these dynamics (keep in mind that even a dead cell can contain DNA so “ all living things contain DNA and non-living things don't” is not the answer). This question of what distinguishes the living from the non-living has stayed with me since 2006 when I started learning and doing biology. In 2006, I enrolled in MIT’s physics graduate program. As a beginning PhD student, my original intention was to join a cold-atomic physics group there. But I had a year of fellowship money to try other fields before formally committing to a lab. At first, I did an internship in a nanotechnology lab that studied how electrons moved through quantum dots. But that group’s PI let me go after a month - this is a gentrified way of saying “I was fired” -  because he thought that I wasn’t good and that I kept messing up a senior PhD student’s experiments. That was a low point for me because I had just started the PhD program and I had never been fired before. My options then were to just finish taking the required courses (in the American PhD programs, you had to take courses) and eventually join the atomic physics group after 9 months or try my hands at a different field.

In my daily commute to the nanotechnology lab, I passed by the biophysics lab of Alexander van Oudenaarden. I had no idea what he was working on, and I didn’t even understand the words in the title of his group's papers and posters that were posted outside his lab. My last course in biology was more than six years ago in high school, which was mostly about Mendelian genetics and ecology and almost nothing about molecular biology. At this point, as physics student, I also didn’t know what a pipette was, how RNA was different from DNA, and what the central dogma of molecular biology was. But what struck me about my morning commute through the hallway of Alexander’s group was how happy people seemed in his group. I routinely heard laughters coming out of the lab as I walked by. Before approaching Alexander for an unpaid internship, I first borrowed Alberts' book on molecular biology from a library. I found the book (and I still do) very difficult to read because biology textbooks were and still are written in styles that are very distinct from those of the physics and math textbooks that I was used to.  Even though I barely made through a page in any of the chapters in Alberts’ book, I found that I could pose for myself very simple questions about living systems while reading the book and that these questions, posed by someone without any biology background, were largely meaningful and still weren’t answered yet. That really hooked me on biology. So I asked Alexander for an internship and he generously gave me the chance. Since then I fell in love with biology, questions about life which could border on philosophy, and doing experiments with my own hands. I never looked back since then and I’m very grateful to Alexander to this day for giving me a chance and keeping me in his lab for the next 4 years.

Aside from the positive lab culture and the fact that I could pose “simple" questions, such as “how does a cell ’know’ this and not that", to which deep answers didn’t exist yet, the final clincher for me was the revelation that I could quantitatively address those simple questions about living systems with my own hands at the lab bench. Through my internship in Alexander’s lab, I found that I could resolve these questions about cells by designing “simple” experiments, doing them, and then having the results of those experiments tell me the next steps. I have found and still find this process to be similar to the process one uses in proving mathematical theorems through a series of logic, which I also enjoy doing, or how a detective would narrow down the list of suspects. I very much enjoy this hard-to-describe “funnelling” process that narrows down a complex biological system or a grand question about life into concrete conclusions. Aside from these grander points, I also found myself enjoying even the little things like pouring agarose gels, running PCR, aliquoting media, making master mixes, pasting gel pictures into my lab notebooks, etc.  In retrospect, I find that this aspect - enjoying even the seemingly little things in day-to-day bench activities - were indispensable for whatever success I’ve had in research.

So that’s my non-linear path to biology. I've revealed these details here to remind readers who are students that some small event - in my case, being fired from an internship - can literally have a life-changing consequence and that like in research, serendipity and seemingly devastating failures can actually lead to a very positive outcome in a scientist's career. I also think that my story is just one of many like it and that it shows one should not be afraid to enter a field that one knows nothing about. If you’re really fascinated by the question, then I say you should go for it.

 

What is the single most important piece of advice that you would give to a current PhD student or a post-doc?

My first advice is to take anyone’s advice, including mine, with a grain of salt. There’s no one shoe that fits everyone. With this caveat, my advice for PhD students is different from one that I’d give to postdocs.

If you’re a PhD student, keep in mind that your goal is to learn how to develop a story backed by data and then tell that story through writings and talks. In many countries, you have four years to develop and tell a story. Be very critical of your own work. Learning this is also an important part of a PhD. Once you know how to develop and tell a story, then you’ll find these are useful skills in any other field of science as well as outside of science (keeping in mind that you don’t have to stay in academia or in science after a PhD - leaving academia is not a “failure”). You can keep a text document and slides that you constantly update with new results. The idea is that the text will evolve into a manuscript and the slides evolve into slides for a talk that you can give to anyone about your work. When you first start a project, the text and slides will be empty, contain vague items, and a messy outline. But as you get new results, they will evolve. You’ll find that you’ll need to delete some paragraphs or slides because the story has changed. You’ll rearrange some slides because their order no longer makes sense according to the evolving story that you want to tell. The process of rearranging, deleting, and as a result, planning the next experiments is the process of learning how to do science. I think this is what every PhD training should be about.

If you're a postdoc who’s looking to run your group one day, I think you need to think about if there are questions that your own group will want to pursue that are unrelated to your current postdoc work while, at the same time, having the postdoc work being helpful in pursuing those questions (e.g., same organism with similar techniques). What you do in your own lab does not have to be a natural extension of your postdoc work. Don’t let a decision that you made years ago on where to do a postdoc dictate the next 10-20 years of your life. A luxury that we have in systems and synthetic biology, while not exclusive to these fields, is that we’re often driven by abstract concepts and are not tied to a particular pathway, mechanism, biological process, or an organism. So you can chart a course for your lab that really is distinct from what you did during your postdoc. But I think you can be strategic about doing this. For example, doing follow-up studies of your postdoc work may let you publish soon (1-3 years) after beginning your lab. In the meantime, you can explore a new area that really excites your group and if that new direction works out, then your lab can start publishing in that field after 4-5 years and start shifting into that new area, if you’d like. I think this strategy can let your group avoid the publication draught of the first few years that starting labs often experience while also having the time to develop a new line of research if that’s what you’d really like to do. On the other hand, there’s nothing wrong with more gradually extending your postdoc work and having that be the focus of your own lab. Again, no one shoe fits everyone. The most important thing is to dream big about what your lab will have contributed after 5- 10 years.

 

In which areas do you see the main challenges and opportunities for synthetic biology?

I think the biggest challenge for me is understanding biology well enough to build systems that mimic or extend natural systems. In my experience, no circuit that I or my group has built ever worked out the way that we thought that it would. These apparent “failures” yielded surprising findings and formed the bases of projects and publications in my PhD, postdoc, and now in my group. Think of how the repressilator led to, unsuspectingly, a vivid demonstration of noise in gene expression. That study helped in launching the burgeoning field of stochastic gene expression. For me, I think the challenges and opportunities are the same: Not understanding biological systems well enough and trying to perturb them has and will lead to discoveries about how cellular processes work, whether they be evolved or hand-made. I think this will be an ever-lasting challenge and opportunity that will outlive the technological limitations that we have now (e.g., cost-effectively writing DNA of an arbitrary length letter by letter and integrating it anywhere inside a cell of any type).

3 Questions for Prof. Sven Panke

This time the "3 Questions For" series features Prof. Sven Panke from ETH Zürich in Switzerland. Prof. Sven Panke currently holds a position as Professor at the Department of Biosystems Science and Engineering. His research focuses on the design of novel bioprocesses for the pharmaceutical and chemical industry.

 

When and why did you move into the field of synthetic biology?

I moved into Synthetic Biology in the early 2000s, when the topic was about to emerge in Europe. The engineering vision behind it displayed a very big attraction to me, even if it was clear from the very beginning that a simple transfer of engineering principles from classical engineering disciplines to biology would not work. However, the engineering narrative and the DNA synthesis methods seemed to promise a major improvement about earlier biological engineering methods. Another important factor was iGEM – a totally novel way of communicating a field to students and making them enthusiastic about it.

Since then, I stayed in Synthetic Biology because I think that it remains the most promising route to better strains in industrial biotechnology and in many neighboring fields, generating visionary projects that can capture the imagination of scientists from many different backgrounds.

 

What is the single most important piece of advice that you would give to a current PhD student or a post-doc?

Consider ignoring the advice of senior colleagues.

 

What do you think is presently the major limiting factor for progress in the field of synthetic biology?

I am not sure that I can name one factor that is more important than others. think that one major limiting factor is the time it takes to integrate of all the qualitative knowledge that we have accumulated over the years in computationally supported design platforms. We are making considerable advances there, but the process will, I fear, take another 10 years. I also think that we are becoming very good at certain aspects of synthetic biology, e.g. pathway optimization, but in the end this is only a certain aspect of the overall path from idea to real world impact – I think many projects still fail at an entirely different level, such as “this enzyme does not work in my chassis strain”, for whatever reason. And we should not forget that even if you have a good strain, you are still far away from having a good process. Finally, at some point we will return to the discussions that we had already once before, whether genetic engineering/synthetic biology is safe enough to be used outside contained facilities. The outcome of this discussion will have, I think, a strong impact on the future of synthetic biology outside of medicine.

 

Introducing DOULIX: A Bio-Engineering Platform from Explora Biotech

Synthetic biology hinges on the ability to build biological systems from the bottom up using biological parts. Plasmid design is crucial and with so many parts to choose from, assembling compatible parts can be a bottleneck in Syn Bio workflows. To address this, Explora Biotech have recently launched Double Helix Technologies (DOULIXTM) – a toolkit to design, validate and synthesise custom constructs for synthetic biology.

This is a 3-step process:

1.      Design. Using their free online design platform, users can design a custom plasmid from their library of parts (‘biomodules’) or from your own custom sequence to assemble into a vector of choice.

2.      Validation. The software guides you through a design validation to avoid common design flaws.

3.      Synthesis. You can order ready-to-use full length constructs, or order individual Biomodules to assemble yourself.

It looks good on paper, so we got in touch with Davide De Lucrezia from DOULIX to find out more.

 

Q. What do you think are the current bottlenecks of synthetic biology projects?

We feel that the lack of in vivo standardization of standard biological parts is the main bottleneck. Without reliable in vivo data, any simulation will run on wobbling data and will inevitably be of little help to experimental synthetic biologists.

 

Q. How does DOULIX aim to circumvent these issues?

We started a challenging project to measure in vivo activity of most commonly used standard biological parts called DOULIX GrandChallenge. Together with the LIAR EU project (http://livingarchitecture-h2020.eu/) we aim to provide the SB community with rock-solid in vivo data to be used for simulation and model refinement. These data will be available through DOULIX’s database and used by our multiscale simulation platform to be released in 2018. Together with our synthesis platform, we hope to provide the SB community with a comprehensive toolkit that allows them to move seamlessly from design to fabrication.

 

Q. What is the average turn-around time for de novo constructs from DOULIX?

Individual dsDNA can be delivered in as little as 5 working days and full-length circular constructs of up to 10 kbp are usually delivered in 15 working days.

 

Q. Are the Biomodules all optimised for E. coli, or are other (and if so which?) expression systems catered for?

To date, most of our Biomodules are optimised for E.coli chassis. However, we are glad to announce to EUSynBioS a new partnership with Agilent that will tremendously expand our Biomodule collection to include parts optimised for Yeast and mammalian cells.

 

Q. What is the advantage of DOULIX over designing constructs ourselves?

With DOULIX you can finally use in vivo validated Biomodules so you can focus on construct/circuit design rather than part validation. I think that DOULIX is a substantial step ahead toward abstraction and decoupling in SB, something we really need if we want to unlock the full potential of SB.

 

Q. How do you see DOULIX expanding to serve the Synthetic Biology community in the future?

The next big thing is our DOULIX simulator, an integrated simulation platform for multiscale modelling using in vivo data. We expect it to have a big impact on the SB workflow. Yesterday we used the old genetic engineering approach of trial-and-error, today we are using the Synthetic Biology approach of design-build-test. But as for tomorrow we envision a time when we will confidently simulate before we built, saving time, money and delivering safer drugs, greener products and greater knowledge. Tomorrow, we envision the dawn of constructive biology.

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DOULIX are kind sponsors of EUSynBioS. For more information about Explora Biotech and DOULIX, visit https://www.explora-biotech.com/ and https://www.doulix.com/ or contact info@doulix.com.

10,000 Genes for the Synthetic Biology Community: Twist Bioscience Partners with the BioBricks Foundation

With exponential discoveries taking place every day, we are in an exciting era of biology as researchers unlock the potential of DNA.”

Emily M. Leproust, Ph.D., CEO of Twist Bioscience

 

"Most of biotechnology has yet to be imagined, let alone made true.”

Drew Endy, Ph.D., associate professor of bioengineering at Stanford University and president of the BioBricks Foundation

 

As Synthetic Biology leaps forward from its infancy into its formative years, we’ve seen the price and time of DNA synthesis dropping to the extent that we are now rarely constrained by availability of the ‘parts’. As Prof. Endy alludes to, our greatest roadblock will soon be the limits of our imagination. Twist Bioscience’s (www.twistbioscience.com) recent partnership with the BioBricks Foundation (www.biobricks.org) is a major step forwards towards this vision. The partnership aims to make 10,000 genes freely available to the research community – with us as the SynBio community suggesting which genes should be made. Once built by Twist Bioscience, the genes will be shared with the community by the BioBricks Foundations. This represents the first time that multiple genome-equivalents of synthetic DNA will be made available at no cost to the research community – a major milestone for Synthetic Biology.

We got in touch with Emily Leproust, CEO of Twist Bioscience to find out more.

 

Q. Synthetic Biology is a very fast moving field – how do you think the challenges now compare to 5 years ago?

Five years, ago, synthetic biology required painstaking work to achieve results. Synthesizing DNA could only be done in the smallest of quantities. Gene editing was held back by a myriad of technical and biological impediments.

Since then, Twist Bioscience has changed the way DNA is synthesized. Our silicon-based manufacturing process has led to cost-effective, rapid, high-quality and high throughput synthetic gene production. This, in turn, expedites the design, build and test cycle in many industries – pharmaceutical and biotech, industrial chemicals, agricultural biotech, academia and even digital data storage.

In addition, the discovery of the CRISPR gene-editing technique, with its ability to guide precise, directed changes to genomic DNA is making it much easier for researchers to manipulate DNA. They can now cut sequences and repair DNA where needed. Thus, the process of gene editing has become easier and cheaper. The emergence of CRISPR has ushered in a new era of genetic investigation.

The challenge going forward is to leverage the great potential that these technologies offer us to continue to develop breakthroughs in fields such as personalized medicines, pharmaceuticals, sustainable chemical production, improved agriculture production, diagnostics, DNA data storage, and more. We’ve already seen incredible advances with coats and shoes now made from spider silk, tires and carpet made in sustainable ways, new methods of food production, and I believe we’ve only seen the tip of the iceberg.

 

Q. What is the rough timeline for this project – when will the genes will become available to the research community?

The BioBricks Foundation will moderate a free and open online forum that allows researchers anywhere to suggest which genes should be built. Genes gaining enough "up votes" that are determined to be of public benefit may then beprioritized for selection by BBF. Twist Bioscience will manufacture the genes for BBF. Twist Bioscience has already received and manufactured the first order of genes.

 

Q. Is the project designed to span SynBio in a range of host organisms, or will it be focusing on genes for mammalian/ yeast/ bacterial expression systems?

Suggestions for gene use can come from all fields of biology.

 

Q. What is your vision for Synthetic Biology 10 years from now, and how are can Twist Bioscience help us get there?

I believe that synthetic DNA can improve sustainability by making products in a different way - for example, we can make plastics today without starting from the petrochemicals in oil, by using yeast or e.Coli to create the same materials. Also, synthetic DNA already has, and will continue to, play an important role in the development of new medicines, diagnostic tools and precision therapeutics. The third area of tremendous importance is food safety.  With synthetic biology, there are ways to drastically improve food security by engineering both crops or even the symbiotic bacteria in the soil to benefit all. This could play a role in the developing world as well as the United States, Europe and Asia.  

Overall, the ‘50s were about aerospace (satellites, planes), the ‘70s about semi-conductors, the ‘80s about computers, the’ 90s about software and ‘00s about the Internet. We are now in the biology era, and biology and specifically synthetic DNA will have a massive impact and create tremendous value. At Twist Bioscience, we provide the material necessary to accelerate research and look forward to playing a key role in this exciting time.

 

 

Twist Bioscience are a kind sponsor of the EUSynBioS annual Symposium in Madrid 31s August – 1st September. For more information on the partnership with the BioBricks Foundation, visit www.twistbioscience.com or www.biobricks.org.

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Emily Leproust

CEO and Founder, Twist Bioscience