Røros Airport, January 2009: American scientist Craig Venter, the most renowned biotechnologist in the world, has just landed in his private jet. In the arrivals hall waits SINTEF researcher Trygve Brautaset, who has engaged the research star to give a talk here in Røros, in the Norwegian mountains.
SINTEF’s Trygve Brautaset is inserting lengths of “foreign” DNA into cells in order to make bacteria or algae behave in a different way from what they originally evolved to do.
Photo: Thor Nielsen
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Like Craig Venter, Trygve Brautaset and his colleagues at SINTEF work in the discipline known as synthetic biology. Both groups are working on the industrial use of microorganisms – to which they have given new properties.
Venter’s goal is to end up with a synthetic bacterium that can efficiently use sunlight and CO2 from the air to create fourth-generation biofuels. Although he is not there yet, he has taken the first step by showing an astonished world that he has managed to replace all the genetic material of a bacterium with man-made DNA.
For their part, Brautaset and his colleagues have replaced only a small proportion of the genetic material in “their” bacteria. But they have also independently designed parts of the genetic material that they insert, which they have produced with the aid of computers and advanced chemistry.
“If you think of bacteria in terms of fruit, then Venter and his group have turned oranges into apples, while we are satisfied with chang-ing the flavour and colour of oranges – to stay with the metaphor. What we do is to modify individual bacteria to give us new organisms that can produce substances from which people can benefit. They could become the raw materials used in industrial production, such as dyes, enzymes, plastic-like materials and antibiotics. We call our bacteria ‘cell factories’,” says Brautaset.
The SINTEF scientist explains that both Venter and they basically do not work with anything synthetic. “All the ‘building blocks’ we use already exist in nature. What we do is to mimic what happens with natural evolution, just very much faster and with clear goals.”
The battle for sugar
We are standing with Trygve Brautaset in SINTEF’s genetics lab on the Gløshaugen campus in Trondheim. Around us, young people in white lab-coats concentrate over pipettes as they move almost invisible quantities of reagents from flask to flask.
This scientific community has just passed a milestone: in competition with five other international research groups, the SINTEF research team has been given the leadership of a project run by the European Science Foundation. In other words: they have passed through an unusually narrow eye of the needle. Together with scientists from the five other countries, Brautaset’s group intends to create a bacterium that has never before existed. If they succeed, they will help to ease the world’s supply of a much needed resource: sugar.
How SINTEF scientists change a bacterium:
A bacterial species is grown to obtain enough material to work with. The bacterium’s mini-chromosome is cleaned out and split up. The desired gene is separated out. The properties of the gene are changed and placed into a new mini-chromosome. The new mini-chromosome is placed into the bacterium by means of an electric current, and the new mini-chromosome thus replaces the original mini-chromosome. The bacterial properties have now been changed.
Illustration: Raymond Nilsson
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“Synthetic biology can become one of the most useful tools known to mankind.”
Senior Scientist Trygve Brautaset
For bacteria use sugar as food when they are put to work by industry. And with a global population of almost 7 billion, sugar is scarce. “The challenge we have been given by the European Science Foundation is to modify certain bacteria so that they can use methanol as food instead of sugar,” explains Brautaset.
In 2005, experts from SINTEF succeeded in altering a bacterium that produces the amino acid lysine – an essential component of animal feed. The new bacterium can now subsist on the natural gas methanol and still make its coveted product.
“If we can modify some bacteria to consume natural gas instead of sugar, it will be very beneficial for Norway, since we now have an excess of methanol,” says Brautaset with a smile.
DNA building blocks
All around us there is hectic activity in the laboratory, where a large number of microorganisms – Norway’s smallest farmed animals – live under controlled conditions. Their “keepers” have a job that requires surgical precision and untiring patience. They isolate the DNA and “cut and paste” the genetic material by means of enzymes. Between these walls, genetic manipulation and cloning are as mundane as newspapers and coffee cups.
“Modifying living organisms is a painstaking process. Each small step has involved several days of work,” explains Trygve Brautaset. “What is fascinating is that we never see what we are working with. The tiny building blocks we use are not visible to the naked eye. Therefore, we spend more than half of our time testing to see whether we have actually obtained results. This is the only way we can tell whether or not we have succeeded.
What happens now?
But how can we actually redesign a living organism? Brautaset explains: “Synthetic biology is a matter of inserting bits of ‘foreign’ DNA into cells to get a bacteria or algae to behave differently from what it originally evolved to do.”
It all began with recombinant DNA technology – a discipline that emerged in the 1970s. For a long time, this field involved entering a bacteria and “cutting out” one or more of its genes. The clipped genes were then “pasted” into the genetic material of a different species of bacterium to give the new host one or more new properties.
Here is how Craig Venter created artificial life
1. The entire DNA of the bacterium Mycoplasma mycoides was first decoded – i.e., the order of the building blocks of genetic material was read.
2. The code is copied into a computer, and specific changes are made. Purchased DNA fragments are altered according to the new recipe. One fragment is encoded for immunity to antibiotics.
3. The modified DNA fragments are inserted into yeast cells that glue them together in the correct order.
4. This synthetic DNA is inserted back into the bacterium, which divides into two daughter cells – one with natural, unaltered DNA and one with synthetic DNA.
5. Antibiotics are used to kill the bacteria with unaltered DNA. The bacteria with synthetic DNA survives and reproduces.
6. In a few hours all traces of the original bacteria have been erased, while bacteria with synthetic DNA continue to grow. Voila – new artificial life!
Illustration: Raymond Nilsson
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Facts about genes, chromosomes and DNA
Illustration: Raymond Nilsson
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The next step in the development of the field began when it became possible to create synthetic genes. In recent years it has become possible to assemble the building blocks of genetic material according to a recipe that we draw up ourselves, with the help of computers and chemical manufacturing equipment. This has enabled us to paste synthetic genes into the genetic material of the host cell. Now gene technologists to an even greater extent than before can change the properties of the host bacterium.
What Brautaset and his group are doing is to create one or more artificial genes from scratch, based on nature’s own building blocks, and then insert them into the genetic material of the new bacterium. When Craig Venter made his world-famous bacterium – synthetic Synthia – he took yet another step ahead.
A completely new organism
Venter created a completely new organism by using a bacterium as a “map” for his work. He was able to design, manufacture and paste together a complete set of synthetic genes – that is, a complete synthetic chromosome – in a host bacterium. To build it he used a very simple yeast cell as a tool to assemble chromosomes from lengths of synthetic DNA and copy this artificial chromosome. He then extracted the new chromosome from the yeast cell and inserted it into a bacterial cell. The result was that the artificial chromosome took over from the natural chromosome and formed a completely new bacterium.
This scientific achievement led to Time Magazine naming him as one of the planet’s “10 people who mattered” in 2010.
“All this is pure chemistry, but very resourceintensive. Venter is incredibly talented and ambitious. In addition, he has powerful backers, which means that he can both attract the very best people to his team and fund the whole effort. Quite hypothetically, it might be possible to create synthetic cells from higher animals and humans with completely new properties at some point in the future,” says Brautaset.
Billions of possibilities
While Brautaset has been drawing and explaining things to us, we have moved over to the chemistry block a few hundred metres from the gene lab, where we find a brand-new laboratory that will speed the work of the Trondheim scientists. The laboratory is equipped with a wide range of instruments and robots that all perform long series of microscopic procedures. Thousands of samples of bacteria are manipulated and tested automatically and simultaneously round the clock. On the floor below the new laboratory, the raw materials for the scientists – the bacteria – are cultivated. Here there are rows of fermentation reactors, where micro-organisms are grown and bacterial colonies are closely monitored as they are propagated on a large scale.
The laboratory at SINTEF’s Department of Biotechnology is cultivating thousands of different colonies of bacteria. They must be sorted in order to grow individually. This robot does the job. The robot arm contains a camera and a “pick head” with 96 points. The diameter of the tip is about 1 mm.
Photo: Thor Nielsen
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“This field has been developing at an accelerated pace in recent years, and can be compared with developments in ICT, which doubles its calculation capacity every year,” says Brautaset. Every year, the genetic material of thousands of species is being mapped, providing researchers with billions of genes to choose from.
One reason for this is that machines now do work in record time that previously took thousands of hours of manual labour. But this process is not cheap. A single machine may well have a price tag of several million kroner, and progress requires a wide range of robots and computers.
Are we gambling with nature?
The prospects for the creation of new and useful organisms seem to be huge. But more and more people are warning against tampering too much with nature. In Tromsø, one of them, Terje Traavik, is research director at GenØk – Centre for Biosafety, which was set up to encourage the safe use of gene technology. He believes that unexpected properties will emerge when we modify existing organisms in laboratories.
“Mutations and gene transfer are both random processes. This is the essence of evolution and biology. The risk that we will come across unanticipated properties is ever-present, so that it is very important to be cautious when working in this field. Our main task is to carry out research on biosafety, based on worst-case scenarios. So far we are the only independent research institute in the world that focuses primarily on biosafety research,” says Traavik.
Craig Venter created a completely new organism by using a bacterium as a “map” for his efforts, and was able to design, build and paste together a complete synthetic chromosome in a host bacterium.
Photo: J. Craig Venter Institute
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Continuous debate
Trygve Brautaset is largely in agreement with Traavik regarding the precautionary principle, and he believes that GenØk fulfils an important function: “Our visions and our potential to create entirely new life forms have ethical, political and religious aspects that must be taken seriously.”
Brautaset believes that the ethical debate about the consequences and risks associated with biotechnology has been an ongoing process since recombinant DNA technology was introduced in the 1970s, and he does not regard synthetic biology as fundamentally novel, but rather a further, and natural step in the field of biotechnology.
“I quite agree that we need a continuing debate about this, and I see that both the EU and the European Science Foundation require ethical considerations to be integrated into all projects in synthetic biology that are currently being advertised.”
Brautaset and his fellow scientist Alexander Wentzel are currently in the final stages of writing a major application for EU funding in synthetic biology, together with several industrial and academic partners from all over Europe. If the project is funded it will place SINTEF in an important position on the international synthetic biology map.
The SINTEF scientist recalls his conversations with Craig Venter in the sharp winter sun in Røros: “Both of us understand that people may be anxious when they hear what we are doing. But if it is exploited responsibly, synthetic biology can become one of the most useful tools known to mankind.”
Christina Benjaminsen and Svein Tønseth
