The BioMachine

2008 saw surge in synthetic biology funding

2010-06-13T16:55:21Z

The Synthetic Biology Project run by the Washington DC-based Woodrow Wilson Center has produced a report on government funding for synthetic biology that shows the US powering ahead – with most of money arriving in just the past three years.

According to the report, Europe government funding for synthetic biology outpaced US for the first three years tracked – from 2005 to 2007 – but was then suddenly overtaken as US projects attracted a massive increase in money.

The 2008 spikes follow a period when a number of projects attracted public attention. The J Craig Venter Institute demonstrated that it was possible to transplant a genome from one related species of bacteria cell to another; the team at UC Berkeley cut a deal to deliver the fruits of its artemisinin-synthesis project to Sanofi-Aventis in exchange for an agreement for the antimalarial to be manufactured and sold at near cost; and a crop of biofuel specialists popped up describing how they would transform bacteria and algae to make alternatives to diesel and petroleum.

Some of the spike may also be due to a recategorisation of projects. Synthetic biology has a blurred boundary so it’s not difficult to rework project proposals and grants to accommodate it rather than older definitions such as genetic modification.

For example, since 2006, the US Department of Energy alone has spent more than $700m on synthetic-biology research. The report points out: “Sources with the Office of Biological and Environmental Research (BER) suggested the entire budgets of the Genomic Sciences Program and the Joint Genome Institute could be classified as synthetic-biology research.”

However, the report calculates that total US spending to date is lower, at $430m by assuming a more conservative level of funding from the DoE than the one proposed by the government agency: “We…cut its overall numbers in half.”

Medical and agriculture funding in the US lags biofuel work by a long way. The National Institute of Health has made $48m in awards since 2005 and the Department of Agriculture less than $3m. It was not clear how much the Department of Homeland Security and DARPA have spent. DARPA has only revealed a figure of $20m as a line item in its report for fiscal 2011.

Where funding for European funding falls is less clear as it is far more fragmented. But the project has said it wants to put together more detailed information as it continues to look at this area.

Will IP law choke synthetic biology work?

2010-06-06T16:28:09Z

Pointing to the 2007 PLoS Biology paper on intellectual property rights in synthetic biology co-written with Arti Rai, James Boyle of the Duke Law School has written in the Financial Times (and reprinted at The Public Domain blog) of his fears of the entire sector being locked up by patent and copyright claims by the likes of J Craig Venter.

One of the problems facing synthetic biology is that no-one is really quite sure which IP laws will affect it the most. It has the characteristics of software in some respects - although I believe some of these comparisons are overplayed and run the risk of misleading people as to how synthetic organisms will be designed - and patentable hardware in others.

US IP law may not even have the right infrastructure to deal with synthetic biology. Rick Johnson, who heads up an OECD group on synthetic biology, and who has called the field “an IP law professor’s dream final examination problem”, has argued that lawyers in this field should take a closer look at design rights, which are used in Europe and Asia but hardly at all in the US, as a means of protecting synthetic-biology inventions without the encumbrance that often goes with patents in biotechnology.

Boyle warns:

“Some of the patents being filed are astoundingly basic, the equivalent of patenting Boolean algebra right at the birth of computer science. With courts now reconsidering both business method and perhaps software patents, and patents over human genes, the future is an uncertain one.”

]]> Just finding them can be an issue. We know that the JCVI has filed a number of patents that cover the techniques the scientists used to construct and transplant the synthetic genome to ultimately create M mycoides-jcvi1.0. And many of them will be assigned to Synthetic Genomics, the company started by Venter and of which leading scientist on the project Hamilton Smith is also a director. However, the assignments are not there in all cases - you need to look for the scientists named as inventors to see which ones are likely to form the Synthetic Genomics patent pool.

At first glance, it looks as though Venter has avoided the reputational mistake made earlier in the project when the group decided to patent a candidate synthetic genome for the experiment: a derivative of M mycoplasma. This does contain some extremely broad claims for an organism with a minimal genome, providing lists of essential genes that such an organism is likely to contain. The patent writers did not take any chances, making claims for a bunch of genetic subsets apparently just in case they should turn out to be useful.

In the press conference to announce the success of the experiment to transplant the M mycoides-jcvi-1.0 genome, Venter claimed: “I have been quite comfortable claiming patents on discoveries.” He went on to confirm that patents have been filed on the techniques used for genome construction.

Venter’s claim of discomfort on patenting discoveries might elicit a hearty laugh from competing researchers. There are certainly patents in the Venter catalogue that cover things such as single nucleotide polymorphisms (SNPs) in the human genome. However, the technique patents may not prove to be all that useful if researchers decide that tuning existing genomes is going to be more successful in the medium term than trying to synthesise and stitch together DNA chains and then do a full reboot on a target cell.

Until science understands how all that DNA works within the cellular machine, trying to assemble a genome from scratch is not going to make much sense. This may change if it turns out to be easier to manipulate genomes in vitro than to alter living cells’ DNA. Right now, alternative techniques are having reasonable success in transforming organisms without recourse to the JCVI/Synthetic Genomics techniques. The foundational nature of these patents may be an illusion, unless another set turns up in the wake of the last experiment in the next few months.

The big problem is likely to be deciding where discoveries end and invention begins, assuming that Venter is as good as his word and is not using an excessively narrow definition of ‘discovery’. We are probably reaching the end of the period in which people attempt to patent individual genes and bits of them. The Myriad Genetics case has exposed them as undesirable.

Synthetic biology is less concerned with the activity of individual genes than with the emergent behaviour of combinations of them: the control algorithms created through the interactions between genes, promoters and transcription factors. This is an area where patent activity is likely to be high and one where it needs to be watched carefully: some may be similar to those that protect electrical circuits. Others may attempt to make much broader claims that cover entire families of ‘transcriptional logic’.

It is worth bearing in mind that genetic engineering has proceeded with some patents looming large. For example, everyone uses GFP despite this entire family of genetic elements being encumbered by patents. At the same time, Myriad showed how it is possible to lock development out of a sector with other patents. The problem is perhaps not so much to decide which patents should or should not be filed but to deal directly with abuses of the system.

iGem competitor launches

2010-06-03T20:51:41Z

The Yokohama-based Bioinformatics and Systems Engineering (BASE) division of Japan’s RIKEN research institute has launched its own take on the iGEM genetic-engineering competition, Nature reports.

In contrast to iGEM, which has no restrictions on entries other than they should use synthetic biology techniques and deliver any newly created genes to the BioBrick Registry, the GenoCon competition has a definite objective. For the one that has just launched, the aim is to transform thale cress (good old Arabidopsis thaliana) so that it digests the pollutant formaldehyde.

Masayuki Yamamura told Nature industrial groups don’t want to get involved with the BioBrick Registry because of the registry’s open-access provisions, which prevents patents being filed on genes that go into it. Participants in GenoCon will be able to keep sequences they use secret.

Using synthetic biology to design antibiotics

2010-06-03T20:36:02Z

The blog Lab Rat writes about a paper published in Nature Reviews Microbiology by Michael Kohanski and colleagues at Boston University that proposes the use of synthetic biology techniques to look at systems biology problems, something that Wendell Lim at UCSF has done in systems such as signalling networks and scaffold proteins.

The paper looks at the complexity of drug-target interactions and how a network-based approach, coupled with synthetically assembled combinations of genes introduced into bacteria using phages, could be used to probe how the cellular network behaves when hit by drugs and combinations of them.

From Lab Rat:

“By using synthetic genes to disrupt or alter the proposed antibiotic network novel drug targets could be discovered. If turned into a high-throughput system this would be far more useful than the current screening system which tests for a potential drugs interaction with a target, rather than the ability of this interaction to lead to cell death.”

The added genes might themselves form part of a longer-lasting antibiotic (or a family of them), Lab Rat concludes:

“Using combinations of drugs at lower concentrations, or aiding antibiotics by introducing them along with synthetic genes in bacteriophages allows an increased shelf-life of the drugs that we currently possess as well as providing potential systems to aid the discovery of new antibiotics.”

Life and Geneart

2010-06-01T19:39:46Z

Life Technologies has succeeded in buying a majority, 74 per cent stake in Geneart, the German maker of synthetic genes and DNA segments, propelling Life into the nascent synthetic-biology field.

“The burgeoning field of synthetic biology is filled with opportunities where many of Life Technologies’ genomic and sequencing products already play lead roles,” said Gregory Lucier, chairman and CEO of Life Technologies in a statement. “Just as Life Technologies is a pioneer in genetic sequencing, cloning and regenerative medicine, we will be able to directly participate and lead in synthetic biology by offering the tools our customers need to accelerate discoveries in this emerging field.”

Another day, another ethics initiative

2010-05-21T12:28:43Z

Prompted by the rebooting of a cell using a synthetically generated genome, US president Barack Obama has asked for a study of its implications from the Presidential Commission for the Study of Bioethical Issues.

Obama wants the report in six months and to “study the implications of this scientific milestone, as well as other advances that may lie ahead in this field of research”.

I wonder if they are going to point that this kind of thing has been going on for a while and that, although a total reboot is now possible, it’s unlikely to be the way that synthetic biology is done for a good while.

Rebooted with a synthetic genome (and some errors)

2010-05-20T21:16:26Z

The world’s most expensive cloning programme has completed with news that the J Craig Venter Institute has rebooted a cell with a genome originally generated by DNA synthesis instead of natural means. The question remains why do it, other than the capacity to generate headlines? (Because, if you squint a bit at what happened in the experiment, you can put “first synthetic cell” on a press release.)

A good proportion of bacterial genome, particularly a small one like Mycoplasma genitalium, which provided the template for the original “synthetic genome”, is made up of essential genes - DNA that codes for proteins and segments of RNA needed to keep the cellular machinery running. Things like ribosomes have stayed more or less unchanged for millions of years because they are central to Earth’s lifeforms.

There is a chance that sooner or later, someone will have a go at redesigning these enzymes to see if there are better alternatives. But, given the current state of understanding of biology, it’s not going to be tomorrow. So, for any practical synthetic biology, you are better off letting the existing biological infrastructure get on with doing its thing and work on ways to insert and delete genes at will.

That’s not to say it’s not worth finding out if it’s possible to create a functional genome from a code. Creating entire genomes from scratch sounds like a big project and it is, but it’s eventual value compared with techniques that rely on the existing cellular machinery are probably to going to have more use.

A joke cracked at the SB4.0 conference about DNA synthesis and whether more should be spent on it to get much longer sequences cheaply was that “the only customer is Ham”, referring to Nobel laureate Hamilton Smith, a leading member of the JCVI project. Everyone else was, more or less, happy to work with shorter, novel sequences bolted into an existing genetic chassis or to develop conceptually more laborious but cheaper, automatable ways to manipulate a genome.

Even a cursory look at the Science Express paper reveals the amount of work that went into the process of assembling the genome. DNA synthesis was comparatively straightforward and the team had already demonstrated that it was possible to reboot a cell with a foreign genome using existing, natural DNA, even though the process by which this rebooting happens still isn’t clear.

Even with all the care that went into synthesising and checking the DNA segments, errors crept in. And some were errors that biology has evolved out of the process. One killer error was a tiny change in one of the 11 segments of DNA that were ultimately stitched together to form a 1.1 million base-pair genome - the team had decided to move up from the smaller M genitalium because M mycoides was known to transplant successfully. One base pair went missing - and it happened to be in the DnaA gene, which is about as essential as it gets as it’s responsible for chromosome replication. No more generations of M jcvi without that.

That was fixed but other errors crept in, including a chunk of E coli DNA that turned up in the middle of the new genome. This was in a far less essential section of the genome as this was found in the successful rebooted cells. It may seem churlish to point this out but it’s worth recalling that many of the processes used to generate the complete synthetic genome relied on cloning techniques that have been around for a while and which themselves rely on natural processes. So, it’s not too surprising to find bits of the natural world turning. However, in an experiment that is meant to demonstrate how to take a code and write it into a cell, it’s far from desirable. Yet, in other techniques for genome editing, these processes would be far less destructive because they can be made work in concert rather than against the synthetic approach.

DNA lights up logic

2010-05-12T15:43:13Z

DNA has formed the backbone of self-assembling logic circuits designed by a team at Duke University. To communicate, the circuits employ light-emitting molecules already widely used by biologists in their own experiments.

Chris Dwyer, assistant professor of electrical and computer engineering at Duke’s Pratt School of Engineering, said the technique could be used to build intelligent but tiny biosensors as well as nanoscale encryption keys.

Dwyer said the logic is form of diode-diode logic, one of the earliest approaches to digital computation used in electronics. Although it cannot form all the possible Boolean logic gates, it can be used to build simple computers from AND and OR gates. In the Duke University scheme, the diodes of an electronic circuit are replaced with chromophores - light-absorbing elements - attached to segments of DNA.

DNA-linked chromophores, particularly those that fluoresce, are used widely in biological experiments as they make it easy to identify the locations of genetic elements within a cell. Theodor Förster found in 1948 that chromophores can pass energy to other, different chromophores close by through a coupling process. Biologists often use this in Förster or fluorescence resonance energy transfer (FRET) to show when molecules such as proteins are coupled together in complexes.

]]> In FRET experiments, the two chromophores used emit different wavelengths of light but only one is excited by a light source. Only when the two molecules are so close as to allow an energy transfer will the other chromophore light up. The logic circuits act as biological detectors by placing analyte receptors at a gate to bind to chemicals in a sample and, if they are present, disrupt the normal operation of the gate.

The Duke University researchers use a much more complex array of chromophores to pass signals to each other and, as a result, build logic gates. “The difference is that we chain them together,” said Dwyer.

“With diode-diode logic, you tie the outputs of two diodes together. Depending on the impedance you can make it function like an AND or an OR gate. Each donor-acceptor chromophore pairs that we can pattern is like a diode. If you share a common acceptor between two donors, it looks like an array of diodes tied to a single node. There is a really strong analogy to electrical circuits,” Dwyer explained.

“We can tune the gate’s behaviour by changing the positions on the grid to make the coupling efficiency greater or smaller. This gives us tunable ‘resistance’ for these diodes pairs. You can require all of them to be excited to give an output, which is used as an AND gate,” he added. “And if you bring them closer together any one can light up to produce an output, like an OR gate.”

Using nine different types of DNA fragment, the logic circuits designed by the Duke team form into grids that look like waffles in atomic-force microscopy images. Each individual waffle is 80nm across.

“The self-assembly process doesn’t require a patterned substrate. The sequences are designed such that they tie themselves together into a grid shape,” Dwyer explained. “It’s like taking pieces of a puzzle, throwing them in a box and, as you shake the box, the pieces gradually find their neighbours to form the puzzle.”

The most difficult part is designing the sequences to self-assemble, said Dwyer. Initial efforts to build arbitrary shapes from DNA focused on regular grids. To produce practical logic circuits, the sequences need to be less regular. “The structures we use now have complex addressability so that we can put down any molecule at any position on that grid.

“The new piece of the puzzle is that we can very precisely control the relationship between the donors and the acceptors. I don’t know any other way to get that kind of control,” Dwyer claimed. “This is work that has been building for 30 years.”

Dwyer said the self-assembly process, as with other DNA computer techniques, is error prone. But he argued that is it possible to focus on structures that deliver good results and that, in the future, sensors based on the chromophore-DNA logic could probably cope with 30 per cent error rates in construction.

“What this does is let you pack a lot of sensors into a diffraction-limited spot, just hundreds of nanometres across,” said Dwyer. By using this logic, many light-emitting sensors could fit into that space compared with conventional techniques that could only discriminate a few. “This lets you multiplex a bunch of things within that area, so it could improve the density of gene arrays.”

By performing logical operations withint the sensor, Dwyer said it should be possible to speed up diagnoses that today have to be done in a lab when multiple samples have to be analysed. “At a pharmacy or local level, that would have a dramatic impact in changing the business of healthcare. We are basically building nanoparticles that are 80nm on a side with a little computation inside that could impact a whole range of applications.”

“The real key is to bring in more sophisticated molecular beacons,” added Dwyer. With conventional FRET experiments, it is one chromophore for each analyte so that with ten different molecules, the maximum number that can be counted is ten. “We can put a binary encoding of those channels and instead of getting ten we get 2¹⁰ channels. We want to use the combinatorics of Boolean logic to conserve chromophores.”

Dwyer said applications could go beyond medicine. “One of the things we have thought of using it for is in the area of physically unclonable functions, to make a physically secure encryption key. It is basically impossible even with the best analytical chemical tools to discern the structure of chromophores within the array.”

Designing the structures today requires intense computation. “It is heavily computationally bound. It took 500 machines running 24/7 for a couple of weeks to solve a very small subset of the problem.”

Although the chromophore logic makes it possible to use a smaller number of chromophores, Dwyer said he would like to see more available to extend the computational range of these devices. Out of 600 known chromophores only about 40 are useful in biological work and, of those, only 20 are suitable for use in this type of logic circuit.

Up to now, there has not been a lot of demand for different chromophores. Although heavily protected by patents, not many researchers go beyond GFP and its relatives for FRET and similar experiments. And, as it’s not yet possible to design a chromophore on a computer - the work to create them is largely empirical - the research is expensive. However, if applications such as this one create a demand, more synthetic chemists may choose to work on an expanded library of chromophores.

Select committee likes DNA synthesis, a lot

2010-03-25T22:13:39Z

The UK House of Commons Science and Technology Committee has published its report on Bioengineering and synthetic biology plays a prominent part in the report alongside genetically modified (GM) crops and stem cells.

We found good indications that the UK is learning from past experiences in bioengineering when handling new emerging technologies, such as synthetic biology. The Government and Research Councils have recognised the value of synthetic biology early, and are providing funding. There is good activity in public engagement on synthetic biology. However we are concerned that while research is well funded there is not enough forethought about synthetic biology translation, for example developing DNA synthesis capability, which would provide the UK with an excellent opportunity to get ahead internationally. If this is not addressed, synthetic biology runs the risk of becoming yet another story of the UK failing to capitalise on a strong research base and falling behind internationally.

One of the problems pointed out to the committee during the evidence-gathering stage was that UK industry is not exactly well-positioned to benefit from synthetic biology. Although the pharmaceutical industry in the UK is comparatively strong, other sectors that could make use of materials produced using synthetic biology have been weakened by the flight of manufacturing from the country.

Ray Elliott, head of strategic projects at Syngenta, told the committee in January: “We have an interest in synthetic biology, but we are watching it. Most of it, at the moment, is happening in microbes but it could translate into plants. In terms of industrialisation, there are not many players in the UK who could take up synthetic-biology products.”

]]> Although it’s not essential to have the end-user of a microbe-grown cellulose plastic replacement in the same country as the people developing the technology, it makes life a lot easier if they are located close together. However, in electronics, companies such as ARM have carved out a solid niche with most of their customers sitting either on the West Coast of the US or in the Far East.

One way that the committee sees a way for the UK to gain an edge in industrialised synthetic biology is to fund a more advanced DNA-synthesis effort. Although it sounds like a good idea, I’d question whether this statement from the committee is true: “Given that there is widespread consensus that developing a national DNA synthesis capability would put the UK at the forefront of synthetic-biology translation…we recommend that the Government should invest in a national initiative to develop this capability.”

There’s a “widespread consensus” on this? Lord Drayson, the minister for science, gave one of the most bizarre answers to a question on DNA synthesis from the committee that demonstrates not only was he not on the same page, he hadn’t even read the same book. Bear in mind that Lord Drayson is a former roboticist and headed a pharmaceutical company, so should have some understanding of the state of play in DNA synthesis even if he hasn’t touched the stuff in a while. Robots play a key role in a number of the current techniques for building longish strands of DNA.

This is what he did say in response to whether the Technology Strategy Board might support companies building DNA synthesis machines:

“It will, but one must be measured in recognising that this has been described as a phase that moves from reading to writing the genetic code of life. That is a big deal that has some major ethical considerations. We need to be very clear about what that presents in terms of risks and challenges and go through an effective public engagement process to ensure that this does not get ahead of where the general public is in terms of the perception of the balance of risks and benefits.”

DNA synthesis technology per se is largely orthogonal to the ethical considerations. It’s what you write that’s important not how you write it. DNA synthesis is chemistry. Craig Venter is not playing God by synthesising a genome from scratch: he’s just working on the most expensive cloning operation in history. (I appreciate that the techniques being developed at the Venter Institute will show much of a synthetic genome can be generated from scratch, but the current experiment focuses on a genome that is already common in nature.)

All the time that the government is worrying about public engagement, people in the US and Germany are merrily pushing ahead on their own form of Moore’s Law in creating longer and longer strands of DNA. The relevant doubt that Paul Drayson should have faced with the question of building a national competency in DNA synthesis is how important it is as a technology to a research or industrial base.

The world is not overrun with DNA synthesis companies: you can practically count the important ones on the fingers of one hand. The thing about DNA manufacture is that you don’t really have to do it that often, and when you do, you don’t need very long bits. In fact, until people have learned to handle very long strands of synthesised DNA, the technology of synthesis isn’t all that useful. The biggest issue that Venter’s group has had in its project is in assembling the genome from its synthesised parts.

The DNA synthesised within a cell is surrounded by a whole host of chaperone proteins that stop it snapping. Stripped of these helpers, synthetic DNA is very much more fragile. So, there are good reasons for moving comparatively short chunks of DNA into the cellular environment quite quickly. It’s handy to be able to order individual genes or combinations of them from a company such as Geneart or DNA 2.0 rather than extracting them from a sample, but at 40 cents a base pair, this is already reasonably cheap and accessible.

Having asked a number of researchers about the relative importance of DNA synthesis, I’ve come to the conclusion that, very often, the synthesis of a single line of DNA is the wrong answer. Very often, the requirement is to build libraries of genetic sequences so that researchers can see which works best. Until science has a much better understanding of inter-gene interactions, directed evolution and selection works a whole lot better than pre-planning and synthesising.

What has happened so far is that some TSB funding has gone into technology being developed by ITI Life Sciences together with Ginkgo Bioworks in Massachusetts: this concentrates more on assembling sequences from pre-existing sequences in a more automated fashion than on synthesis per se. Other work outside the UK focuses more on editing than synthesis. Take the “DNA word processor” dreamt up at the Weizmann Institute in Israel. This is basically a giant robotic polymerase chain reaction (PCR) machine that takes up most of a lab. But it makes short work of combining, editing and deleting sequences that could take weeks to perform manually. It is also very suitable for creating genetic libraries. If this kind of work is what the select committee thinks of as DNA synthesis, then that’s good. But if their view is of a machine that turns a list of base pairs into one long double strand of DNA, they are looking in the wrong direction.

Having said that, the select committee presents a more realistic perspective on bioengineering than the current government. As with the recent Department of Business, Innovation and Skills (BIS) report on nanotechnology, the administration seems obsessed to the point of distraction with safety and public engagement issues. But if you wait long enough for those issues to be resolved, someone elsewhere in the world will have made those ethical decisions for you.

Moving towards the light

2010-03-19T08:25:14Z

A recent Nanosensors KTN seminar held at the National Physical Laboratory in Teddington provided an opportunity to show how biotech, nanotechnology and electronics are being combined in a new generation of portable instruments. Dion Klunder, a scientist at Philips Research, described the trade-offs that go into taking a technology that uses small particles and putting it into something that can be used in the field.

Although the original plan was to use the Magnotech system as a drug detector that could be used by police in the same way they would use a breathaliser, the emphasis has switched at Philips to speeding up the diagnosis of medical conditions, kicking off with heart attacks. Bedside staff can use instruments like that to work out quickly what treatment the patient needs.

“If possible, you want to stratify patients in the ambulance,” said Klunder. “In that way you can enable minimally invasive medicine.”

The reality today is that it takes a while to get the results back from a central laboratory. Although the actual tests are quick, the delay lies in the amount of time it takes to get the sample there and the result back, on top of the time that a sample may have to wait before being processed.

]]> “Even with a mild myocardial infarction, they [doctors] want the result in 20 minutes or less,” said Klunder.

The test for damage to a heart is well understood. When the muscle cells in the heart wall die they release some of the protein that makes up the muscle into the bloodstream. One of these protein components is troponin. Using antibodies that bind to troponin, it’s relatively straightforward to measure levels in a blood sample. The Philips technique moves that test from a laboratory environment to a handheld unit and a cartridge that contains a fluid chamber and the antibody.

Philips’ Magnotech system attaches the sensing antibody to magnetic beads — large in nanotechnology terms at 0.5µm across but that helps — so that they stick to molecules of troponin in the bloodstream. The magnetic beads are then attracted to the surface of the glass cartridge by a magnetic field generated by the instrument. This surface is coated with a second antibody designed to stick to a different part of the protein, if it’s present.

After a couple of minutes, to give time for enough of the antibodies to stick, the instrument reverses the magnetic field and any beads that do not have bound protein move away from the surface.

Rather than sense the presence of the beads using electromagnetic sensors, Philips opted for optical detection because that made it possible to put all of the electronics into the reusable instrument and keep the cost of the disposable cartridge to a minimum.

The key to the sensor is frustrated total internal reflection — a technique that’s been proposed as a way of building multitouch displays similar to those used on the iPhone but using light instead of body capacitance. The technique works by shining a light at a shallow angle onto the surface of glass or clear plastic. If the angle is shallow enough, then practically all of the light is reflected back — hardly any passes through the surface even though it’s transparent.

The ‘frustrated’ part comes in when you have an object on the other side of the surface. A quantum mechanical effect comes into play that interferes with the reflection because an evanescent field created by the light waves extends a short distance past the surface. An object in that field scatters some of the light so that some of it is not reflected directly.

This is the key to the touchscreen technology based on TFIR at New York University. A finger close to the surface scatters light so that detectors underneath pick it up. The Philips system measures how much the reflected light is affected by beads close to the surface.

“If a bead is present you get a lower reflected signal back. You don’t have to flow the beads away, just move them out of the evanescent field,” said Klunder. “It’s a very sensitive measure because you can detect almost individual particles.”

The optical detection technique puts a limit on the size of the protein that can be detected using the system — too long and you don’t get the interference effect. Short molecules also have problems, as it’s tough to get two antibodies to bind to them. This turned out to be a problem with measuring narcotics — those molecules are not big. So, Philips has chosen to focus on protein detection.

“This is a very nice technology and being commercialised now,” said Klunder. “We are collaborating with a French company, Biomémerieux, who are specialists in the field, because we are not experts in biochemistry.”

A further issue has been to increase the shelf life of the reagents stored in the cartridge. “The shelf life of antibody particles is typically a few months and there are no wet reagents onboard. If you don’t optimise this, the shelf life is a lot less than a month. And the temperature needs to be low,” said Klunder. “This is where you need industrial researchers. It is not something you can do in academia.”

What's the most common gene in the world?

2010-03-17T21:02:50Z

The title of the paper by a team from places as widespread as the University of Chicago, Cairo University and the Argonne National Laboratory gives the answer away, so I won’t repeat it here. The researchers mined genetic databases, including 2000 genomes and a large number of gene tags to predict which genes the most widespread in nature.

The answer is a bit unexpected, although there is a subtlety in the definition of the problem: it’s not the gene that results in the most protein, but the one best at “spreading its DNA around”.

How simple can useful RNA be? Very simple

2010-02-24T20:49:21Z

Since the discovery that RNA molecules can act as catalysts in chemical reactions, they have become prime candidates for being the kick start that life on Earth need billions of years ago. Although the conventional explanation is that proteins were cooked up in the primordial oceans and ultimately became parts of living organisms, there is no clear way to get from proteins appearing randomly to self-organising systems based on proteins.

Although proteins can make efficient catalysts, they have no clear way to reproduce. RNA is now a much more likely candidate as it can pass on genetic information and catalyse the reactions needed to do it. Although proteins are now responsible for most of the body’s catalysis, RNA ‘ribozymes’ are still in active and can be found at the heart of what are understood to be some of the most ancient cellular functions.

]]> RNA plays a key role in the translation process used to make proteins from a template encoded in RNA. The chances are, according to the ‘RNA World’ theory, that RNA made more RNA templates before life became complex enough to depend on a mixture of RNA and proteins. But this leaves the question of how a sufficiently complex ribozyme came about that could catalyse production, at the very least, copies of itself.

But, what if a self-replicating ribozyme could be very simple? How simple could it be? Publishing in PNAS, a team from the University of Colorado at Boulder has found a very simple ribozyme. It has just five bases but is able to catalyse reactions with other segments of RNA. It’s not very quick, but it works and, unlike previous work on simple RNAs, does not depend on metal ions for the catalytic activity.

The work by Professor Michael Yarus hints that RNA may put together proteins quite readily. “Essential intermediates in protein biosynthesis arise surprisingly easily in the presence of very short RNAs,” they write.

“The ultimate importance of these observations may lie partly in the unknown number of other reactions that can be accelerated by comparably small RNAs. This is because for each such minuscule RNA reaction, there is a prima facie case that it would become accessible even after the most primitive ribonucleotide polymerisation.”

It’s possible that this simple catalyst is a one-off, Yarus and colleagues warn. “On the other hand, it will be extraordinarily important to look for other tiny RNA active centres, now knowin they can exist.”

It makes the RNA World hypothesis look more likely and may help in the development of very simple synthetic cells for bioproduction.

GM problem? Add more evolution

2009-12-08T21:51:38Z

Amid the excitement around being able to synthesise and edit DNA directly, it's easy to forget about some of the older methods for altering a genome. Methods that are more acceptable in places such as Europe when genetic modification has an extremely bad image.

For a new breed of potatoes designed to only produce a starch suitable for treating paper as well as foodstuffs, a team at the Fraunhofer Institute in Germany used good old-fashioned breeding to get the job done. Well almost. Good old-fashioned selective breeding with the foot hard on the accelerator pedal, using directed-evolution techniques to speed up the process of producing viable variants.

There's nothing particularly new about speeding up the process. Although protesters look upon direct genetic modification as 'unnatural', it's worth noting that plant breeders have used chemical and radiation treatment for some years to induce mutations that speed up the process of moving the candidate genomes into new territory. However, because these techniques do not carry the tag 'GM', nor do they carry the stigma.

"We are working here with natural principles. In nature, sunlight triggers changes in the genome, With chemistry, we accomplish the same thing - only faster," said Jost Muth of Fraunhofer IME in the release put together by the institute.

Normally, you have to wait after a burst of cross-breeding and mutation to see what crops develop. Not in this case. As soon as the seeds germinated, samples of the leaves were taken and their genomes analysed directly to see which mutants had picked up desired traits.

The researchers analysed 2748 seedlings to find a genome that had the genetic profile they were aiming for: the ability to produce amylopectin exclusively. Luckily the potato already has an amylopectin-production gene, which reduces the amount of mutation that the potato has to go through. However, the aim was to find a mutant that could shut off the production of sister starch amylose, which the 'Tilling' potato could. This avoids the need to purify the starch after harvesting and separation.

This autumn, the team grew about 100 tonnes of potatoes with the required genome, and without specialised GM trials. "Special measures aren't necessary, because the Tilling potatoes are totally normal breeds that contain no genetically modified material," said Muth.

The name Tilling is derived from the name the team gave to the process: targeting induced local lesions in genomes, a technique developed in the late 1990s in Seattle.

In an artificial cell, what is a gene?

2009-10-21T20:34:57Z

The Innovation, Universities, Science and Skills Select Committee has published a set of UK government responses for its 'Evidence Check' programme on topics ranging from homeopathy to synthetic biology. Although the response from the Department of Health on the status of homeopathy in the health service is a little disconcerting, the most interesting response is from the Health and Safety Executive on possible future regulation over synthetic biology, particularly artificial cells.

The executive takes the view that most of the existing work on synthetic biology is already covered by regulations on work with recombinant DNA, which seems fair enough. However, the response adds:

"Future work may involve the creation of artificial cells, which would not fall within the scope of existing legislation. Consequently, a minor amendment is being proposed to the definition of GM as part of the development of a single regulatory framework for work with human and animal pathogens and GMOs. This will enable the regulations to cover artificial cells, should the technology develop in that direction. This change will be consulted on prior to the implementation of the new regulatory system."

The amendment for the single regulatory framework, the executive adds, is likely to extend the definition of genetic modification to include the "introduction of genetic material into a cell artificially created for that purpose, where the cell is then capable of replication or of transferring genetic material".

I can see two potential issues with this. One is what happens if the definition of artificial cell extends to bioreactors? Will that make the operation of biobreweries more difficult? And, more fundamentally, what does 'genetic material' mean in this context? Early artificial cells will doubtless use standard DNA but does the definition of gene cover synthetic nucleic acid strands, such as peptide nucleic acid or alternative 'genetic' systems based on alternative nucleic acids, or molecules with a similar function?

Two grants for Wilson Center

2009-09-23T06:47:44Z

The synthetic biology project based at the Woodrow Wilson International Center in Washington DC has picked up two grants from the US National Science Foundation.

One grant is to support a workshop that will host EU and US researchers looking at what synthetic biology can do, if anything, for sustainability. The University of Virginia will work with the Wilson Center on organising the workshop.

The second grant is to explore how online prediction markets - which have controversially been touted as ways to predict things from terrorist attacks to financial meltdowns - can be used to tap into the public mood on synthetic biology.

"Although online prediction markets have attracted significant interest from scholars and increasing application in corporate environments, little work has been done to apply these markets to critical issues in science and technology," said David Rejeski, director of the project at the Wilson Center in a statement.