These ‘biofoundries’ use DNA to make natural products we need

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Biology is an astonishing builder. Think of the complexity and organization required to construct a giant redwood, or to form the extreme tensile strength of a spider web, or the on-mass ability of ancient microbes to change the Earth’s atmosphere.

Scientists today are harnessing this building power in the field of engineering biology to achieve bespoke biological functions for many different and new applications. The convergence of biological understanding, data science and the tools of molecular biology, combined with an ability to synthesize DNA to order, have enabled us to transform cells into “mini-factories” for the production of products useful to humans.

For example, silk from a spider’s web is a material that has been optimized by spiders over millennia, as it is lightweight yet extremely strong, and fantastic at catching prey. Using knowledge of the genetic code, scientists can now instruct specialized microbes to make spider silk in quantities otherwise impossible. Such silk can now be manufactured into fabrics for adventure wear and into armoury for military defence.

The ability to exploit this amazing building capacity is now being accelerated by the new field of engineering biology, which applies engineering principles such as standardization, modularization and robustness to the genetic engineering of complex living systems for specific applications. New robotic workflows and technology platforms are being established, resulting in different types of laboratories focused solely on accelerating and prototyping biological designs for engineering-biology applications. Such facilities today are called biofoundries, and they are being rapidly established worldwide.

At the core of biofoundries is the Design-Build-Test-Learn (DBTL) cycle, which involves computational design of DNA genetic parts, physical assembly of designed DNA parts, prototyping and testing performance of designs in living cells followed by applying modelling and computational learning tools to inform the design process. Iterations of the DBTL cycle result in genetic designs that aim to fulfil the design specifications.

The infrastructure within current biofoundries varies, but is based primarily around high-throughput liquid-handling robots that allow millions of computer-controlled liquid manipulations, automating many of the processes needed to genetically engineer living systems. Coupled to this are also high-throughput biological measurement instruments that provide the data needed to inform the biodesign process. These biodesign and prototyping facilities are analogous to those developed for computers in the 1970s that led to the ICT revolution and as such are key to a future global biomanufacturing capability and the prospects for a sustainable bioeconomy.

Image: Syncti.org

Uniquely, biofoundries can prototype engineered microbes to convert waste from one industrial process into an input for another, opening doors for sustainable manufacturing difficult to reach without biology. Such engineered microbes can then, for example, convert methane gas released from flues into protein-rich biomass for animal feed in adjacent biorefinery facilities. Another example is the highly efficient production of fatty acids and diesel from glucose by metabolically engineered bacterium, which opens up the possibility of not relying on plant oil or animal fat to produce biodiesel.

Development of such efficient microbial cell factories can be streamlined within biofoundries. Other applications include microbial cell factories producing commodity chemicals, bioplastics, protein-based foods and antibiotics to name but a few, as part of a transition to more sustainable bio-based manufacturing systems using engineered cells. Applications also extend to low-cost bio-based sensors and diagnostics that can be rapidly prototyped and optimized before deployment. These include new environmental biosensors for detecting water contamination like arsenic and lead, as well as disease, in resource-poor environments.

Other healthcare applications include novel vaccine prototyping, the development of new cell-based therapies for cancer treatment and the engineering of living probiotic drug delivery and disease detection systems. For instance, our body’s communities of microbes offer new therapeutic interventions where, for example, communities within our gut can be engineered to maximize nutrient absorption and disease detection, while regulating the intimate relationship between gut, mental and immunological health. All of these applications require engineered cells or communities of engineered microbes that can be designed, prototyped and developed within biofoundries.

With this extraordinary capability to engineer biology comes an acknowledgment of the need for additional security awareness. While knowledge coupled with a biofoundry has potential to underpin these amazing biological solutions, some capabilities may enable those with nefarious intent. To mitigate this possibility, scientists and engineers must actively consider the security implications of their work and, when necessary, take proactive steps to address additional risks. Under one mechanism for this, biofoundries have arisen at numerous sites globally with the intention of positively impacting society and enabling economic growth and stability. A globally networked system of biofoundries will form a collaborative community to help ensure that biofoundries are responsible, open, transparent and safe in their activities.

A global alliance of public-funded, non-commercial biofoundries, called the Global Biofoundry Alliance (GBA), has recently been established and launched in Kobe, Japan in May 2019. The GBA provides an opportunity for knowledge-sharing and open technology development to increase discovery, but also for developing common standards and reference materials. Each biofoundry is unique and typically has a degree of specialization in the cell type and process it employs. Working together also enables the expansion of the cell type portfolio to best ensure an appropriate “chassis” (used to define a cell for a specific application) is identifiable with an existing knowledge base on which to build bespoke solutions. Familiarity with the expertise offered at each facility highlights those best skilled for addressing particular challenges across the diverse sectors of medicine, materials, chemicals, fuels, food and the environment. A shared understanding of expertise and capabilities offered will also open the door to the possibility of unique international collaborations to develop chemicals, materials and healthcare applications of global importance.

The unification of the global biofoundries into an open-technology alliance also offers scalability for rapid progress in large projects beyond the capability or capacity of any single entity. The frequency of this requirement is likely to increase as costs for DNA synthesis decline, and researchers adopt even more ambitious goals in the face of ever-more complex challenges. A networked alliance of compatible biofoundries enables streamlined exchange of people and expertise to collaborate in addressing these challenges. As collaborations are best suited in pre-existing relationships, the alliance offers the opportunity for such an extended network of individuals to develop such relationships in the event a collaboration of global importance is required.

One potential scenario where global collaboration might be crucial would be an unforeseen global pandemic. Biofoundries could then collaborate for large-scale vaccine production and the Alliance could be harnessed to help. It also offers unparalleled training and sharing opportunities, including exchange programs, open technology development and collaborative testing of common protocols. These facilities are now training young researchers in technologies that will dominate the research landscape and underpin biomanufacturing in the years to come.

Biofoundries offer a unique opportunity to harness the amazing building power of biology. There is a plethora of new materials, sustainable products and novel therapies awaiting development, which can transform the world and change the face of global and sustainable biomanufacturing. A global alliance of biofoundries will also ensure that this productive potential is maximised for all and ensures a state of readiness towards unforeseen global disease threats.

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Why are scientists building a synthetic yeast genome?

 

 

 

For most of us, brewer’s yeast conjures up images of all the delicious things we make with it – bread, beer and wine.

Key points

  • Australian scientists are part of a consortium building the world’s first synthetic yeast genome
  • Better understanding how to build synthetic genomes gives us the potential to redesign a whole organism’s genome from scratch
  • We could use designer genomes to design microbes to do things that would be industrially or environmentally useful

Known scientifically as Saccharomyces cerevisiae, Brewer’s yeast has greatly contributed to humanity’s happiness, according to synthetic biologist Ian Paulsen of Macquarie University.

But there are a lot more reasons to raise a glass to this single-celled microorganism, beyond the role it plays in providing something to put in that glass in the first place.

“It’s also increasingly useful as an industrial workhorse for the production of bioethanol,” Professor Paulsen said.

What’s more, yeast has the potential to help us produce biological versions or replacements for a whole range of other important chemicals we currently produce from oil.

That makes it something of a darling in the growing field of synthetic biology — and one of the most studied organisms on the planet.

“Synthetic biology is very much about trying to understand more about how the natural world works, and just being able to exploit that to do useful things,” said Claudia Vickers of the University of Queensland and director of CSIRO’s Synthetic Biology Future Science Platform.

“If we can use biology to replace those petrochemical-based industries and processes, then we can develop sustainable, environmentally friendly, renewable processes.”

For example, we could design and construct novel biological systems in microbes that could convert waste into biofuel, bioplastics and other high-value chemicals.

But for that to happen we need to better understand how yeast works.

And that’s where Professor Paulsen’s work comes in.

He’s one of the leaders of the Australian team that is part of an international effort to build the first synthetic yeast genome.

They’re calling it yeast 2.0.

What is a synthetic genome?

Every one of us, and indeed every living thing, has our own natural genome. It’s encoded by DNA and makes us what we are — it’s our complete set of genes and genetic material.

On the other hand, a synthetic genome is one that scientists have completely redesigned on a computer. Then they can chemically synthesised the DNA and replace the natural genome of an organism with the redesigned, chemically synthesised genome.

With synthetic genomes, the vision is to redesign a whole organism genome from scratch, Professor Paulsen said.

Or at least, that’s the theory anyway. It’s proving a little trickier in practice; so far scientists have only been able to make some synthetic bacteria genomes.

In 2010, scientists at the J. Craig Venter Institute announced they had successfully synthesised the genome of bacteria Mycoplasma mycoides and transplanted it into a Mycoplasma capricolum cell that was then able to self-replicate.

Six years later, they announced a new, more streamlined version of the M. mycoides genome, creating what’s known as a minimal genome.

A minimal genome is the minimum collection of genes and DNA components that give you a functional genome and make life possible, Dr Vickers said.

For example, you might have some genes that are redundant because more than one does the same job. Or highly repetitive regions of DNA, sometimes called junk DNA, which can be removed.

The yeast 2.0 project is our first attempt at making a synthetic eukaryote genome, which is many times more complex than a bacterial genome.

“Eukaryote is a classification of creatures that covers everything from single-celled yeasts to plants to animals to humans,” Professor Paulsen said.

It’s a distinct group from bacteria, which are a type of prokaryote.

So, how are scientists building yeast 2.0?

Yeast has 16 separate chromosomes and within the international consortium building the genome, each team is responsible for at least one chromosome.

These individual chromosomes will then be combined to form the full synthetic genome.

“What’s proven to be by far the most time-consuming is not the design, not the building, but it’s the testing and fixing it,” Professor Paulsen said.

The team are working from a complete design of the chromosome, and then are chemically synthesising what they’re calling “megachunks” of the DNA, which are about 50,000 base pairs in size.

(DNA is made of four different units or bases — adenine which binds with thymine, and guanine which binds with cytosine, to form base pairs.)

To put that in perspective, each of these megachunks represents maybe two or three per cent of the chromosome.

Each megachunk of synthetic DNA replaces the native DNA, as the team works stepwise across the whole chromosome until it’s all synthetic.

“The real problem is … maybe about a quarter of the time the new megachunk that we’ve put in dramatically breaks the yeast,” Professor Paulsen said.

Faced with a massively less healthy organism, the team then have to work out which of the changes they made are responsible for messing it up.

“One of the surprising things is you can actually make really large changes and they’ll often have no detrimental effects,” Professor Paulsen said.

“And you can make really tiny changes that you think, ‘well this isn’t going to do anything’, and that has these massive health decreases in our semi-synthetic yeast.”

Ultimately, the team want to design a synthetic version of yeast that’s as robust as the original.

“We want the final synthetic yeast to be as healthy as the native yeast, meaning it can grow at the same rate, and on the same substrates as the native yeast can grow on,” Professor Paulsen said.

But they’re not just making a carbon copy of nature’s original design. The final synthetic yeast genome will be about 80 per cent the size of the native yeast genome, with many regions of so-called junk DNA removed.

“Our first design is a much more ambitious design in that we’re actually deleting a whole bunch of stuff, and making a whole range of other changes, but we’re not removing any genes,” Professor Paulsen said.

And he hopes this will give them more insight into the dos and don’ts of editing genomes.

Is this creating artificial life?

Depending on how you define it, scientists have been creating artificial life or modified organisms since the 1970s, Professor Paulsen said, and “we haven’t ended the world yet”.

He sees designing completely synthetic genomes from scratch as the next step forward from traditional techniques that only change an organism one gene at a time.

But both he and Dr Vickers are very aware of the significant ethical issues that surround their work, and the need to secure broader community support and engagement.

“If we don’t develop technologies that people are willing to use, then why are we developing those technologies, and where’s the benefit that we’re seeing out of them?” Dr Vickers said.

That’s a very valid concern when you consider the enormous potential of synthetic biology, said Josh Wodak of the University of New South Wales, who researches the societal implications of science and technology.

For him, one of the biggest consideration when it comes to synthetic biology is dual use, or the potential for the science to be misused.

“If people are creating essentially synthetic lifeforms, bacterial, microbial lifeforms, it stands to reason that they will evolve, mutate and adapt with time.”

It’s impossible to know how such lifeforms will behave in the field.

“One of the scary things about synthetic biology is that a lot of the tools and the equipment can actually be gotten for very, very cheap,” Dr Wodak said.

This raises the risk of citizen biohackers getting themselves into trouble or people using the technology for nefarious purposes.

“[If] synthetic biology is one of the conceptual toolkits we’re gong to use to face down the enormous environmental challenges of the 21st century, that does mean it’s probably got more chance to wind up in the hands of people we would prefer it to not do,” Dr Wodak said.

Professor Paulsen acknowledged that it’s not possible to rule out any technology being conceivably misused. But he stressed that academic researchers are using the same safeguards that they would in any other project.

And he said it’s work that is having real world impact in a positive way.

“I think the synthetic community in general, certainly see synthetic biology as a powerful tool for addressing many of humanity’s current problems.”

Dr. Vickers agrees.

“A lot of the problems that we’re trying to solve are unsolvable using other technologies,” she said.

And for now, designing a synthetic genome for an organism to take over the world remains firmly in the realm of science fiction.

“If I was an evil mad genius and I wanted to make an organism to destroy the world, the good news is that there’s no way we would know how to do that at this point in time, or at any conceivable point,” Professor Paulsen said.