Chris Edwards

Gene genies

2010-02-18T22:11:39Z

Wild corn is sorry looking stuff. It’s hard to tell it from a weed at first glance and, as University of Cambridge plant scientist Jim Haseloff points out, that’s not a surprise. “Most crop species are weedy species that have been through selective breeding processes over the past 10,000 years,” he says.

The Earth is host to some 20,000 known edible plant species out of an estimated quarter million species in total. Of that 20,000 a mere 10 per cent are grown in any volume by farmers. And just three account for the bulk of the biomass we actually eat, says Haseloff: rice; corn; and wheat.

Genetically, there is not very much difference between wild corn and what farmers plant today, even after the revolution in yields provided by hybrid corn and other crops developed during the Green Revolution of the mid-20th Century. It may seem churlish to make this point but plants are quite inefficient at converting sunlight and carbon dioxide into the carbon skeleton needed to grow roots and leaves. RuBisCO, a protein complex that lies at the heart of the photosynthesis process, is notoriously inefficient as an enzyme, although some researchers argue that RuBisCO is about as good as it can get.

]]> RuBisCO evolved in a very different atmosphere to the one that the Earth today possesses – largely thanks to the descendants of the first organism to make RuBisCO. That early atmosphere was loaded with carbon dioxide. A form of RuBisCO reworked to cope better with an oxygen-rich atmosphere could lead to much faster growing, high-yielding plants. Ideas like this encourage researchers to look much more closely at how plants and crops grow. Haseloff’s work, for example, concentrates on the way that plants regulate their growth in the hope of using new DNA to maximise the production of the edible parts.

Optimising plant yield is vital according to a growing number of politicians who, having spent years in Europe at least negotiating over ways to stop farmers growing things are now issuing warnings about “food security” as the global population continues its relentless surge towards 9 billion people on the planet by 2050.

At the Oxford Farming Conference at the beginning of the year, UK secretary of state for the environment, food and rural affairs Hilary Benn said: “Food security is as important to this country’s wellbeing – and that of the world’s – as energy security. Securing both must be our priority.”

UK Government chief scientist John Beddington declared at the Oxford Farming Conference: “We need a new and Greener Revolution, improving production and efficiency through the food chain within environmental and other constraints. Techniques and technologies from many disciplines, ranging from biotechnology and engineering to newer fields such as nanotechnology, will be needed.”

Theodor Friedrich, an agriculture expert with the FAO says: “With our conventional way of going about agriculture we are facing limitations. Production is not keeping pace with population. Our traditional approach to agriculture is reaching a ceiling – we hit a wall.”

Some conventional techniques turn out to be counter-productive, says Friedrich: “In tropical countries by applying more fertiliser, the yields actually go down.”

Other means are needed. Beddington said research could aim for ambitious goals of improving not just nitrogen fixation by plants but the photosynthentic potential of crops. The changes could be through more efficient, reworked enzymes such as RuBisCO. “These are likely to be global in nature and give the UK research base an opportunity to engage in cutting-edge research with other key global players.”

But that cutting-edge research might never make it to market. For more than ten years, European Union states have presided over a situation where genetically modified (GM) crops are potentially legal but rarely used.

Reticence to apply GM goes way beyond Europe. The FAO World Summit on Food Security held last November had no mention of GM on its agenda, a very different stance from that taken when the FAO published its 2004 State of Food and Agriculture report, in which the organisation said it supported the use of biotechnology. It was a move that prompted a letter from 800 representatives of a variety of non-governmental organisations (NGOs) to write a letter to FAO director general Jacques Diouf.

The report Food Security and Agricultural Mitigation in Developing Countries makes no mention of GM or other genetic-engineering techniques, although an earlier report on technology prepared for the autumn High-Level Expert Forum in Rome said GM might be a component of future food development. The report warned its potential advantages had to be weighed against public opposition.

In the closing press conference of the Food Security Summit also held in Rome, Diouf did not address GM directly but said talks at the conference did focus on “the contribution of technology to agricultural development, to research resistant varieties, that will deal with stress and drought particularly in the framework of climate change, salinity or whatever”.

Improved food production would revolve around an effort that combines many techniques, he added: “We therefore needed to bring research organisations together to discuss this”.

The reticence among the public to embrace GM may help improve its performance, which has been patchy. David Dawe, senior food systems economist with the FAO says one of the problems with technology is that it can focus too readily on large farming operations and take a long time to put into action properly. “For the small farmer, if it takes years of learning, it’s no use to him.”

There are other problems with commercial GM crops, which so far have focused on herbicide tolerance and pest control and which tend to suit the large plantations found in the US and South America. For example, crops augmented with the Bt gene produce a protein that kills caterpillars that would otherwise feed on them. Roundup Ready crops developed by Monsanto are engineered to not be affected by the company’s own weedkiller.

Christian Fatokun, geneticist at the Nigeria-based International Institute of Tropical Agriculture (IITA), says: “Some of the GM [crops] in use today may not be particularly attractive to Africa, for example, if you may take a crop like Roundup Ready soybean. Here, in Africa, you see farmers growing soybean with other crops in the field.

“So, if you spray Roundup, you are going to kill the crops – only soybean will remain. Nobody wants that kind of tech,” says Fatokun. “But there are crops that are useful in Africa and those are the ones to which we should give trials to see how they can be of benefit to farmers, the consumers and the communities as well.”

For many tropical farmers, blockbuster engineered crops are not the answer. Boru Douthwaite, impact and adoption specialist with the IITA, uses an example from the Green Revolution where one variety of rice wound up being planted on some 11 million hectares, “making it the most widely planted rice variety ever. However, problems emerged when millions of rice farmers all moved from growing a number of their traditional varieties to just one or two genetically homogeneous varieties. Some of the resistance that the breeders had given the improved varieties against pests and diseases broke down within three to five years, leading to huge crop lossses”.

Douthwaite explains: “In evolutionary terms, the cause of the problems was not with the novelties per se, but with the selection and diffusion mechanisms that led to them to be adopted so widely without considering the consequences. This has been a salutary lesson: reductionist science that isolates problems and ignores contexts and scale issues can come horribly unstuck even in relatively simple ecosystems.”

Work carried out by groups such as the IITA, many of which cooperate through the Consultative Group on International Agricultural Research (CGIAR) has shifted away from trying to apply single techniques and to find ways to get farmers to adopt only the ones that work on their own fields. Rather than supply huge quantities of seeds direct, the aim is to produce plants with the right traits that can then be cross-bred with suitable local species.

Caroline Herron, a scientist working at the IITA Tanzania, says biotechnology “is probably the only way we can get true resistance” to the brown streak disease that afflicts cassava. This project received in January a $2.4m grant from the Bill and Melinda Gates Foundation to use a technique called marker-assisted selection to help breeders make sure the local seeds they produce have the right resistance traits.

As a geneticist at Duke University, Professor Thomas Mitchell-Olds is working on drought-resistant rice that will use a similar distribution mechanism: “My focus is on natural variation. I work with breeders one the one hand and lab biologists on the other to understand how we can improve production for small farmers.”

GM on its own is unlikely to hold the answer to crops that are more productive in the long term. But the focus on GM versus non-GM is a potentially damaging view. As Professor Douglas Kell, chief executive of the Biotechnology and Biological Sciences Research Council, explained to MPs from the Science and Technology Select Committee in January: “We need a changed regulatory regime. We need to be basing regulation on the agricultural results themselves, not the method by which they are produced.”

This feature formed part of a special issue on food in Engineering & Technology. You can read more at the IET site.

Basestation says 'you're all busted'

2010-02-04T17:06:35Z

Who's keeping an eye on the kids when you're not home? If David Nowicki, vice president of marketing for Airvana, has his way, it will be their mobiles. At the Femtocells World Summit held in London last year, unveiled what he called the 'boyfriend buster' - a detector for people who protective parents don't want their daughters to take home when they are not around.

The boyfriend buster is no more than software running on a cellular basestation designed for the home. Being a basestation, this femtocell - named because it covers a smaller range than the picocells used in shopping centres and microcells in city streets - notices which phones come into range and if they are allowed to register, lets those phones make calls through it. The femtocell can, potentially, do more with that information, possibly letting the concerned dad know by text message or email that the wrong cellphone has turned up at the house or that, with 30 strong signals in the house, the family pile may be home to a Facebook party.

The boyfriend buster is just one service that people such as Nowicki think will consumers will use. There will be femtocells that synchronise users' phones as they arrive home, transferring contacts and diary appointments between their handsets and their home computers. Or the unit may turn the hallway lights on as you walk up the garden path on the way home.

]]> Manish Singh, vice president of product-line management at Continuous Computing, says: "There is a whole range of services that have been talked about. In principle, they boil down to the same basic elements. They will be services that benefit from information about location, presence and context."

For time being at least, people are looking to the femtocell for something a little more mundane but important to them: the ability to use a cellphone in their own home.

After one national newspaper carried a story on silicon supplier Picochip and its work on femtocell components, the company received a number of phone calls and emails from people wanting to find out where they could buy the hardware to sort out their dodgy coverage, recalls director of communications Andy Gothard.

"People want five-bar coverage," says Gothard. "And there is a price people will pay to get it."

Simon Saunders, chair of the femtocell industry group Femto Forum says the US has become the first competitive market for femtocells with AT&T, Sprint and Verizon offering products. And the main selling point being used by those companies is to bring coverage to the home. Verizon's femtocell is advertised as the Wireless Network Extender.

The femtocell can work beyond the range of the wireless network because it uses the fixed-line Internet infrastructure. Although many homes may be just about within range of a standard mobile telephone cell, calls made using a femtocell passes through a wired DSL connection to the internet and from there passes into the mobile operator's fixed-line network.

With access to a 1Mb/s DSL line, operators can more easily demonstrate what users can do with mobile data. "People hear about the headline datarates on mobile networks and wonder whether they can be achieved," says Saunders. "Often they can't on the outdoor network."

Because the phone and the femtocell communicate at very short range - power usage tends to increase as you approach the edge of a macrocell - Saunders says users can achieve high datarates on their mobiles without running down their battery. They can't go beyond the garden, but they can at least surf from wherever they are in the house. And it can demonstrate to users the benefits of using the more advanced data services, in turn driving consumption.

The concept of the femtocell has taken several years to become established. "The challenge has been to get from being able to do a demo, which is what we did four or five years ago, and deploying out there with real handsets. You can't put a best-effort technology into the telecom world. And each of those real-world handsets have their own peculiarities," explains Will Franks, chief technology officer of femtocell specialist Ubiquisys.

By the end of 2009, a small collection of operators in the US, Japan and Europe had started to sell femtocell products to their customers. "We are seeing what we were hoping for. There are nine networks using femtocells at the moment," says Saunders.

"We continue to see stronger adoption in America, followed by Japan and Europe," says Singh.

Japan is the one market where additional services will be important to selling femtocells early on. "3G coverage there is good. But the ability to recognise that you are in your home is a great opportunity for providing new services," says Saunders.

In 2010, that number could increase dramatically: close to 60 operators around the world are currently performing trials and people within the industry expect them to follow companies such as NTT Docomo, SFR and Vodafone into supplying femtocells.

"We are not having to explain what a femtocell is anymore," says Franks, whose company sells femtocell technology to hardware makers and operators. "There are quite significant deployments either underway or starting quite soon."

"We are expecting 2010 to be the crossover year for femtocells. When we hit the mass market," Saunders claims.

The femtocell is emerging into an environment where, in many cases, there is already a wireless hub. WiFi has become a standard feature on DSL routers. Not only that, WiFi is appearing on a growing number of mobile phones. However, according to analyst firm ABI Research, WiFi support on mobile phones is likely to stay restricted to smartphones such as the Apple iPhone and the various models of Symbian- and Android-based hardware. Cheaper featurephones will carry cameras and run browsers but will not necessarily have a WiFi interface.

"All 3G phones can use a femtocell," says Saunders.

There is a more subtle problem with WiFi: setting it up. Creating a secure WiFi network generally involves wading through several pages of forms generated by a webserver running on the router. It is not a simple process for those unused to terms such as SSID, default channel or WPA Passphrase.

Saunders says: "Femtocells offer simplicity of configuration compared to other devices because it is carrier managed. Setup is a real barrier to people if they haven't, or even if they have, had the experience of installing a WiFi access point. We made it a requirement for femtocells that they are truly zero-touch.

An open question is how operators will charge for the femtocell. In the US, Verizon wants around $250 for its Network Extender, although it provides discounts to high-tariff customers. As more operators enter the market, experts expect to see a wide range of offerings, from free with a contract to a one-off charge in the way that Verizon works.

Franks says: "There are plans at some of the operators to do this on a differential tariff basis, where call charges are different at home compared with being away. When you are at home, for example, data may be completely uncapped and calls may be as well."

Although femtocell hardware remains separate to other consumer devices, operators selling bundled services are likely to favour a move to a gateway style design that incorporates other hardware. "We see the femto function getting collapsed more and more into residential gateways and even TV set-top boxes," says Singh.

However, operators may prove wary of providing setup support for Ethernet and WiFi to the home user. "The question remains: will the wireless operator take on that burden and, if so, why?" asks Singh, noting that operators do not want to provide hardware that results in a massive increase in expensive support calls and 'truck rolls' to customers' homes. He add: "There is the question of whether we will see strategic partnerships emerge between wireless and wireline operators."

Saunders sees two changes being important for the femtocell business this year. "First and foremost that it is not something just known in the industry, that if you haven't got one, someone you know has. And it should reach beyond the coverage-based proposition to provide a richer usage environment."

Singh concludes: "This is the year when the femto take-off should take place."

This feature was written for the Communications section of Engineering & Technology. You can read the main copy and additional boxouts here.

How low can you go?

2010-01-24T16:58:19Z

Last summer, Len Jelinek, director and chief analyst at iSuppli, stuck his neck out and called the end of Moore's Law as an economic driver in 2014. Pause for a moment over that claim. It was not that Moore's Law would not necessarily end in 2014 but the economic imperative for scaling the dimensions further on silicon would come to a screeching halt. Development per se need not stop. The problem is that rising cost could so easily outweigh the advantages of going further than the 20nm or 18nm node.

It should probably be called the Moore-Noyce Law because it was Bob Noyce, Moore's colleague at Fairchild and then Intel, who came up with the pricing model that meant Moore's Law became the key to predicting a market sector driven by deflation. But if that pricing model - which has typically meant close to a halving in production cost with each generation shift - begins to fail, then the reasons for pushing ahead on scaling also break down.
]]> Intel technologists are more bullish about the future than Jelinek. Senior Intel engineer Kelin Kuhn says the company can see a way to 15nm and beyond. The company has a high-volume business that depends on continued scaling - and a continued demand for compute horsepower - but Intel has a public roadmap that extends out to the middle of the decade, with no stop sign at 2015. By that point, Intel expects to introduce an 11nm process.

Five years ago, NEC developed a transistor that was just 5nm long and which switched from conducting to conducting slightly less as the leakage was so high. But it had a performance curve that confirmed transistor behaviour, demonstrating that a 5nm transistor could be made, even if it might not be desirable.

Jelinek's argument was made on the basis of cost: "The usable limit for semiconductor process technology will be reached when chip process geometries shrink to be smaller than 20nm, to 18nm nodes. At those nodes, the industry will start getting to the point where semiconductor manufacturing tools are too expensive to depreciate with volume production. That is, their costs will be so high, that the value of their lifetime productivity can never justify it."

Non-recurrent engineering wafer costs are already pricing users out of the most advanced nodes. For RF specialist Elonics, a 130nm provides the best fit because the company's analogue circuits will not shrink very even with a halving of the process geometry. And, as CEO and founder David Srodzinski points out, the wafer cost of a 45nm process is three times that of the process the company uses today. Unless you can take the benefit of smaller circuit sizes - something that is only more or less guaranteed for digital circuitry - a move to 45nm is a very costly option. This increase in wafer cost is one of the reasons why Jelinek sees a gradual falling away of chipmakers as process development moves ahead.

Many system-on-chip (SoC) designs have now reached the point where the decision to integrate is no longer easy. Very often, it is worth having two chips in a design because that offers the flexibility to adapt to changing market circumstances. For example, with a split applications and baseband processor, a phone manufacturer has more options. And the baseband processor may not benefit from integrating the surrounding analogue circuitry because, even with a shift to a more advanced process, the chip winds up getting bigger, not smaller.

Conversely, while there is a demand for memory greater compute power - and if that power can be provided by deploying more and more processor cores - companies such as Intel as going to keep making those parts, and using process scaling as long as they can to bring the cost down.

The end of Moore's Law has been forecast so often that the claims are generally treated only slightly more seriously than predictions of the world's imminent end. You don't have to wait long for someone to tell you that, in the 1980s, a bunch of researchers reckoned 1µm was the limit. The story is relayed in much the same way history teachers tell of Victorian fears that riding in cars at more than 30mph would tear people's heads off.

However, one important point about Moore's Law is that it isn't very detailed. When Moore plotted some graphs and extrapolated in the mid-1960s, there wasn't any such thing as a 'process node'. There was no International Technology Roadmap for Semiconductors (ITRS) to tell you what the half-pitch measurement for the first metal layer was expected to be from year to year.

Moore explained later that the actual reduction in size of the transistors and circuits was responsible for just one-third of the increase in chip function per dollar every two years. It started off as a doubling every year but this soon levelled out to two by the time Moore gave his more detailed analysis of the graph he drew in the mid-1970s. The other two-thirds came from an increase in chip size and improvements in design techniques. Although the electronics industry was one of the first to employ computers for design, most layout was done by hand on sheets of plastic even ten years into the Moore's Law period.

What has happened since is that the one-third down to shrinkage in two dimensions now accounts for the bulk of the biennial improvement in density. So, it's easy to equate Moore's Law with process technology. But there is no reason for things to stay that way. The original graph only plots two things: 'number of components per function' versus time. There is no declaration of how any of that is actually to be achieved.

As a result, as long as the industry keeps delivering cost reductions, no matter how they are achieved, no-one is going to look that closely at whether they are adhering to Moore's 30-year-old definitions. Inventor Ray Kurzweil has used that to extrapolate the curve out in both directions, into the dim and distant past of the thermionic valve and the punched card, and forward into as-yet untried technologies - and very few are as promising as silicon right now. From Kurzweil's point of view, all that matters is the exponential progression.

One strong candidate for extending the life of silicon beyond the end of 2D scaling is to move into the third dimension (see box 'Build high').

The key question is: how much will scaling have slowed by 2020? A number of technologists believe that there will be a hiatus after the introduction of 22nm processes for the simple reason that the shift to 18nm will demand infrastructural changes, such as the replacement of 193nm lithography with extreme ultraviolet (see box 'Billionaires' club').

"The industry could stick at 22nm for some time," says Jen-Hsun Huang, CEO of nVidia.

It does not mean process development will stop, just that what engineers do to improve density will change. Instead of simply making the transistors ever smaller, companies may work on tweaking devices for performance or allow for improvements in density through better design. "We could call it 22F, F for fast," quips Sani Nassif, manager of tools and technology at IBM's Austin research lab.

Although it is a reasonably safe bet that 2D scaling in silicon will be running out of steam by the end of the decade, it is possible that progress will have slowed to the point that the smallest practical silicon transistors are yet to be made. It only takes an extension from a two- to a three-year cycle for 2020's leading-edge process to have gate lengths substantially longer than NEC's experimental 5nm device. But new, stacked memory technologies are likely to have arrived that keep density apparently on-track, despite a slowing in progress in 2D.

Moore's Law is dead. Long live Moore's Law.

This feature was written for a 2020-focused issue of Engineering & Technology. The IET site has this together with some additional boxouts that ran in this edition.

Technology behind the Games

2010-01-06T09:32:40Z

When the first snowboarder catches air and turns in the half pipe cut into the side of a Canadian mountain in February's Winter Olympic Games, the obstacle between them and a gold medal is a row of human judges. But the day is coming when machines will be able to decide whether the move was good, or the athlete fluffed it.

For the past 70 years, the Olympic organisers have slowly brought more and more technology to try to make sure the gold medal goes to the right person.

It used to be so simple. In the 1930s, a technician from the Swiss watchmaker Omega turned up with 27 stopwatches that had to be used for all the Games. To time the cross-country skiing event, judges had to synchronise two timers and then send one of the judges off on their skis to the start line to write down the time each contestant started off.
]]> In the 1940s, the Winter Olympic Games saw the first electronic sensors, or magic-eyes as they were dubbed then. They were just on the finish line to sort out the winners in contests where having a human press the stop button on a watch was no longer good enough. Since then, electronic eyes have spread all over the Winter Games courses. But it's taken 50 years to get here. When gold medals are at stake, no-one but the competitors likes to take chances.

"Very often I get asked 'what's new at the Games?' But we use very tried and true technologies that are mainstream. We want to be sure nothing goes wrong," says Ward Chapin, senior information officer for the Vancouver Winter Olympic Games organising committee.

Even with the computer network, a mini-Internet of 600 servers - cities are run with fewer - no-one is taking chances. For years, computer maker Sun Microsystems has been beavering away, getting the network ready so that it can deliver gigabytes of video and data.

Barry Caswell, head of IT at the Vancouver games, says: "Any score you read has come across this. It has to be ready for February: you cannot miss a date at the Olympics. So you have to test, test, test."

The machines cannot miss anything. At these speeds, bobsleighs and luges pass the finish line, a split second difference could separate the winner from the losers and human reactions are not enough. So, light sensors along the track watch for the carts as they whizz by. In the bobsleigh, the competitor even starts and stops the timer by passing through light beams.

With systems like this installed, no-one can blame the judges. "Ok, you can have a cell that doesn't work, but there is no human judgement." says Christophe Berthaud, head of Olympic timing at Swiss-based watch manufacturer Omega.

Measuring distances and times is easy for computers. What about the sports that need human judgement such as ice hockey and figure skating? Even these now get computerised help.

Judges used to have to wave coloured cards around as though they were on Strictly Come Dancing to show their scores so someone could tot them up and work out who won. Even when electronic buttons came in so the numbers would light up on the big screen rightaway, the way judges worked out the scores the same way.

To let judges make better decisions, some now have super slow-motion replays to analyse, just like the third umpire in cricket. Shot at a definition that would not be out of place in a movie multiplex, these replays let speed-skating judges work out if an athlete has tripped another, or if a figure skater has messed up a landing. Critics argue that bringing in these slow-motion post-mortems has made the judging too focused on technical tricks and not on the overall performance.

What technology has made worse, it can fix. Keen Australian snowboarder and scientist Jason Harding has been working with athletes and judges to come up with a way of getting computers to take over the job of watching for mistakes so the people with the scorecards can focus on the art of the half pipe. Harding and colleagues stuck lightweight motion sensors, just like those in a Wii nunchuk, to the athletes themselves. They transmit how they move to a computer which pieces together the moves. It will take years for this kind of technology to make it to the Olympics - it takes time to be trusted after all - but it's one more way that technology can make sure the right people win gold.

This is the main body copy for the feature that appeared in the January 2010 issue of Flipside.

Sweden's pirate party sails to success in European elections

2009-06-10T23:00:01Z

A wave of revulsion against a law that targets filesharers has swept the Pirate party into a seat at the European parliament.

Not even in existence when the last European elections took place, the Pirate party managed to secure 7% of the national vote in Sweden, beating the country's Eurosceptic party, June List, which suffered a collapse in its vote.

Two events have taken copyright to the fore in Sweden, which has the highest penetration of high-speed broadband-fibre connections in Europe. In April, the Swedish government brought into force the EU's intellectual property (IP) enforcement directive, which demands that internet service providers turn over traffic data to copyright holders who are trying to track down filesharers. Later that month, a court sentenced The Pirate Bay's owners to a year in jail on top of awarding damages of SKr30m (£2.5m).

Following the case, the Pirate party, which campaigns for patents to be scrapped and copyright to last just five years instead of 70, trebled its membership to more than 45,000.

You can read the rest at the Guardian website.

Evolution's war on design

2009-03-19T21:45:57Z

"I think I may have been one of the first people to have their picture taken with fecal matter," jokes Professor Andrew Ellington of the University of Texas at Austin. Ellington was not the model for a piece of concept art or an undergraduate prank but the willing model for an experiment that set out to demonstrate how living organisms could be made to behave like photographic film. They developed the image on a glass plate full of bacteria, reprogrammed by adding extra DNA to them.

Ellington is a little embarrassed to have his own image recorded by a landmark experiment in synthetic biology and points to one of Charles Darwin made using the same technique later on. "In the US, we actually celebrate Darwin Day because we have to. Our picture of Chuck is a kind of homage," Ellington explains, referring to the running battle between creationists and devotees of intelligent design against the "evilutionists".
]]> The work at Ellington's lab among others may pay Darwin greater homage than a copy of a 150-year-old image. It is showing that intelligent design is a lot harder to achieve than simply letting the processes evolution run their course.

A few thousand miles away from Ellington's base in Austin, scientists from the Massachusetts Institute of Technology (MIT) decided that the time had come to bring engineering discipline to the science of biology. The view of Professor Tom Knight and former students such as Drew Endy, who has gone on to head up his own lab at Stanford on the west coast of the US, and Ron Weiss of Princeton University, is that biology can be engineered. For them, genetic engineering is a misnomer: little more than tinkering with pre-existing genomes and hoping that something useful pops out. They see synthetic biology as the way to design in specific traits simply by piecing DNA strands together in a molecular jigsaw puzzle.

There are many aspects of biology that remain a mystery but Knight argues: "There is a whole set of people who have the outlook that biology is inherently complicated that every system will have to be handcrafted. I just reject it. Yes, we are in a very primitive state right now. But I think in another five years we will have a very robust and contained set of components that will let us put components together and it will change the world."

Synthetic biology is where life science meet engineering head-on and is arguably the most cross-disciplinary part of biology right now. Many of its practitioners are not life scientists by training. Knight started as an electronics engineer and crossed over into synthetic biology when he realised that conventional methods for making circuits were running out of steam.

"The fundamental problem in microelectronics is not that you can't make the transistor but the device, once you make it, is not going to be under control. You can try to fix it but the problem is that the devices are being fabricated with a statistical process. You stand back with a shotgun and blast dopants at it and hope for the best. That is not going to work in this century," claims Knight. "You need to put atoms where you want them. That is chemistry and not physics and the best kind of chemistry is biochemistry."

Ellington has a conventional biochemistry background but his main collaborator is a computer programmer, Zack Booth Simpson, who moved from games developer Electronic Arts to designing life.

"Zack likes to talk about how, when building his systems, he did it in a top-down fashion," says Ellington. But biology requires a different approach. "What we do with molecules, we are building from the bottom up. For that, you have to have lots and lots of self-organisation."

The engineers bring a different perspective, says Knight: "There is a joke you can tell. The biologist goes into a lab and discovers a process is twice as complicated than he thought and says: 'I can write a paper about that'. The engineer goes into and says: 'Damn, how do I get rid of that?'"

The key to engineering with synthetic biology lies in self organisation. Beyond a certain level of complexity, Ellington explains, top-down design fails to work. But nature has proven able to construct complex systems using comparatively simple 'programs', if you regard the DNA that encodes them as a kind of instruction set.

Professor John Mattick, director of the centre for molecular biology and biotechnology at the University of Queensland points to how little DNA it takes to provide all the information required to make a human being. "After a few glasses of wine, I like to say that biology can IT a thing or two," he says, pointing to the fact that the human genome requires only about 6Mb of storage. "That is not as much code as there is in Windows, but I can walk and talk."

The way that DNA stores information intrigues Professor Ron Weiss of Princeton University. A computer scientist by training, he told scientists at a Royal Society of Chemistry seminar on synthetic biology last autumn: "Twelve years ago, I became fascinated by the notion that we might be able to program cells with the ease with which we program computers."

"One thing that happens in living systems is this idea of emergent systems. You have elements that engage in localised decision making. But out of that interesting global behaviour emerges," says Weiss.

Some of the experiments conducted by Weiss provide hints as to the way in which animals form spots and stripes on their coats through chemical signals exchanged by cells, and ultimately to the way that organs form. He started by trying to coax cells into producing coloured rings on the surface of a petri dish. "It's not too difficult to engineer on paper. It took about 20 minutes to put the slide together in Powerpoint. But it took three years to do the implementation.

"One of the reasons we wanted to do this was to work out whether we could program spatial patterns by design and, based on these patterns, have the cells differentiate into bone, muscle, cartilage or organs: engineer tissues in ways that are not possible unless you reprogram the cells."

Weiss's team developed a mathematical model based on an idea put forward by Alan Turing and from that came up with a set of genes, one of which provides the recipe for a protein that makes a fluorescent dye, that would interfere with each other. "We did a simulation on a lawn of virtual cells in the computer. We found you can form a variety of patterns: dots, lines and so on."

A movie of the experimental systems compresses 40 hours of relative inaction into a few seconds that show how patterns such as stripes form on an otherwise undifferentiated lawn of cells. "For ten hours, nothing happens. Then the cells start to make decisions about the kinds of cell they should be. We are building a model to understand the differences between the domain sizes and the original predictions but I think there is good correlation between the model and the experiment.

"While I am not claiming that we can build the coat of a cheetah or a giraffe, there is some correlation between the lawn of bacteria and what we see in nature," Weiss claims, pointing to the eventual aim. "Can you take an initial cell and form structures that are useful in a medical setting? We are trying to program tissue generation. We would like to put cells in the appropriate places and have them make decisions based on communication between them so they know what to do."

One of Weiss's initial targets is Type I diabetes, a condition where the immune system turns on insulin-producing cells in the pancreas. "We would like to engineer a system where we start with stem cells and maintain in a patient the level of these beta cells," he explains.

The immune response will still kill off beta cells. Weiss's plan is to engineer into stem cells a control loop that monitors how many of the cells are present and, if the level drops below a threshold, have them divide and differentiate to make more insulin-producing cells. In effect, the team would create a genetic program to control the stem cells.

The process is trickier than it sounds. Early experiments found that the cells produced an all-or-nothing response. The cells synchronised to each other, making the decision to convert to beta cells all at once. The population of cells simply collapsed.

Weiss tweaked the program and added an oscillator with the sole function of breaking symmetry in the system. "With an oscillator, some of the cells go out of synchronisation. So not all of the cells make the decision to commit to become beta cells at the same time," he explains.

The progress so far has been promising. "We have implemented about 80 per cent of the elements that we need for the system," claims Weiss, who reckons within five years, the approach could be trialled.

One big potentially big advantage of using synthetic biology to make beta-cell factories is that it makes it possible to use the patient's own cells. Not only can the stem cells have the beta-production logic inserted into their genome, the stem cells themselves can be derived from normal cells using the same kind of genetic reprogramming. The portion of the DNA that leads to stem cells differentiating into other cell types could be deleted, once the parts of the genome responsible for those process have been identified.

Once altered in a test tube - Weiss says he is wary of trying to do such complex gene therapy in the body - they would be injected back into the patient. A further change might be to have the cells commit suicide should they wind up outside the pancreas. "We would have part of the design there to get the cell's to recognise where they were," he explains, using the absence of chemicals peculiar to the pancreas to provide the kill signal.

Given the progress of efforts such as Weiss's, it is easy to believe that writing software in DNA is not all that much different from writing embedded code for a microcontroller. Recent research has shown how much control theory can inform biology. The Circadian rhythms that control how plants grow and give us jetlag are readily modelled as control loops, although scientists differ on how complex those loops are.

Unfortunately for the scientists, not everything goes to plan. Living organisms have the nasty habit of working around the modifications made by scientists. Or, as Ellington sums up: "Cells suck."

Lingchong You says the idealised picture of synthetic biology, one that makes the technology looks tractable is to picture a wall between the logic circuit that scientists want to implement and the rest of the cell. A word that often crops up in these discussions is 'chassis': the cell into which you insert the genetic logic simply accepts the changes and provides all the necessary support machinery.

"The chassis is an attractive metaphor but not a very good one," argues Professor Victor de Lorenzo of the National Centre of Biotechnology in Madrid. "We can't take the chassis, ignore it and put something on top."

"There is no such thing as modularity," claims Alexander Ninfa of the University of Michigan, although he has worked with colleagues on a technique that could make genetic subsystems interfere with each other less than they do today.

"The reality," You explains, "is that there are hidden interactions between the circuit and chassis which result in unexpected behaviour. When we write our mathematical models they are not taken into account."

Very often, the circuit simply fails to operate. More surprisingly, the experiment can seem to work but for all the wrong reasons. In one case, You wanted to build a genetic circuit that acted as a bistable switch. But, after performing some other experiments to confirm the results, You discovered that the cell was showing the right behaviour but not because of the action of the new genetic circuit. The new DNA had caused the cells to grow in a way that resembled the behaviour that You wanted.

In many cases, a genetic circuit's effect on growth is what causes it to fail. This is where evolution makes its presence felt, particularly in fast-evolving organisms such as bacteria.

"I find cells annoying because they are evolving entities," says Ellington, recalling how one experiment was stymied by the adaptiveness of living cells. A protein that the cells were supposed to make was so toxic that the ones in which the circuit worked grew very slowly. The cells that grew and replicated more efficiently were those where the circuit did not work properly. The cell simply evolved the genetic circuit out of the way.

"The cell has a resistance to implantation of proteins that are not part of its normal makeup," says de Lorenzo.

Evolution is a major headache for synthetic biologists who hope to be able to bolt genetic circuits together using readymade parts and subsystems. The BioBricks Foundation, a founded by scientists from Harvard University, MIT and the University of California at San Francisco, aims to collect DNA with known functions in a public registry and is defining standards for how those components should be made. In principle, bioengineers will be able to pick and mix parts from the library to put together more complex functions. But the tendency of cells to reject the engineering if it turns out to damage their growth remains a problem.

De Lorenzo contrasts the approach taken by those brought up on the MIT school of synthetic biology and one that takes evolution into account, methods that are more common in European labs. He sees evolution as something to be harnessed: it can be used to improve the efficiency of a synthetic genetic circuit and get around the problems that plague proponents of a purely rational-design approach.

"You can make the new system isolated," says de Lorenzo, pointing to the use of subcellular partitions as a way of keeping toxic proteins out of the way of the main part of the cell. Nature uses this very technique to stop cells poisoning themselves. "Or you can let the system evolve by itself the very behaviour that you want it to have."

De Lorenzo wants a protein that changes colour in the presence of 2-4-dinitrotoluene, a common component of landmines. A bacterial colony that produces this protein sprayed on field would show the location of buried landmines to observers in a helicopter flying overhead using the chemical vapour rising through the soil to trigger the reaction. De Lorenzo's problem was that no such protein exists in nature.

In principle, it should be possible to design enzymes on a computer to perform specific tasks, such as convert a foodstuff into fuel. Conceptually, you take the shape of a target chemical and design a protein that wraps neatly around its major features. A change in shape as the protein wraps around might be enough to cause the colour shift or expose a fluorescent marker.

Unfortunately, not enough is yet known about the mechanics of these reactions. Protein folding remains an area of active research that has millions of computers crunching through quantum molecular simulations every night in the hope it will reveal how it happens in nature.

Professor Alfonso Jaramillo of the Ecole Polytechnic near Paris has come up with simpler models of protein folding to try to make it easier to put together new proteins. His team has built a database of known protein folds that is used by software to calculate how likely an enzyme will form a certain shape. But Jaramillo says the software can only get you so far: to get the full function you need to use directed evolution, a technique already used in the second-generation biofuel industry.

In 2003, researchers in Homme Hellinga's lab claimed to have designed on a computer proteins that could bind trinitrotoluene, another component of bombs and landmines, and the neurochemical serotonin. Other researchers tried to repeat the experiment but found the designed proteins did not work as expected. Almost five years after publishing the work, Hellinga retracted the papers.

To make his dinitrotoulene-sensing protein, de Lorenzo used a technique called directed evolution. The term is a bit of a misnomer as it's not possible to direct evolution as such - the technique works by having selection favour particular outcomes.

He started with a strain of the bacterium pseudomonas putida that grows in toluene, a near relation to the dinitrotoluene target, and mutated its toluene-sensing protein to try to make it specific to the landmine chemical. Many bacteria that convert a chemical such as toluene have associated proteins that act as sensors - they play a key role in regulating the production of enzymes that perform the actual conversion and stop the cell from wasting energy on making too many of them.

"We go to the protein and look at what sort of variants there are," explains de Lorenzo. In doing so, the team found one reason why rational protein is so hard.

"We found that amino acids not in the pocket could change the specificity of the pocket. So it may be a good idea to not concentrate on the design of the pocket," says de Lorenzo. In the case of the toluene sensor, the pocket hardly changed at all.

The initial mutations made the protein less fussy about the types of toluene it would detect. This happened quite quickly. A much slower process then adapted the protein so that it would only attach to dinitrotoluene. "I think this tells us something about how proteins evolve in nature to acquire new specificities," says de Lorenzo.

"You can't avoid evolution. Darwinian selection exists at every level. But it is something that synthetic biologists who come from engineering don't want to hear," concludes de Lorenzo.

This feature was written for a special issue of Engineering & Technology on biotechnology. You can read more here.

Synthetic biology aims to solve energy conundrum

2008-06-18T23:19:00Z

You can power laptops - and, potentially cars - using hydrogen extracted from water. The trouble is that it takes a lot of electricity. A simpler way would be to do it naturally, using enzymes - proteins which catalyse reactions - and bacteria. These do exist: certain green algae and "cyanobacteria" can split water using photosynthesis to produce molecular hydrogen.

But to create a generation of cars that would run on water with some sludge in the back, we need to learn how to design our own bacteria and enzymes that can co-opt natural processes for our ends.

Natural hydrogen-producing enzymes are complex, often using metal atoms to help them work. "For many of the enzymes related to energy production, people have no idea how they are actually organised," says Giovanna Ghirlanda, a protein-design researcher at the University of Arizona. In some cases, no one knows where the metal atoms lie within the protein, she says.

Natural enzymes won't work too well in future fuel cells; they need to be modified, as the best hydrogen producers are poisoned by oxygen. "But oxygen is one of the main products of photosynthesis," says Professor Alfonso Jaramillo of the Ecole Polytechnic, near Paris.

Some researchers are trying to tweak the enzymes to make them less sensitive to oxygen, but with limited success. As a part of the EU-funded BioModularH2 project, Jaramillo's team is using a different approach: stick with the natural enzyme and engineer another set of proteins that take oxygen out of the cell before it can do any harm. These hydrogen producers are longer-term options: it may take 10 years to get to a prototype, says Jaramillo.

You can read the rest at the Guardian.

Drivers not required

2005-12-10T21:56:55Z

A bunch of off-road cars and trucks are lined up as dawn breaks over the Nevada desert. There are no drivers at the wheel: these cars have computerised minds of their own. Their engines running, they are just waiting for the command from their electronic overlord to start driving. As the first one gets the signal, it lurches out of the starting gate and, instead of driving straight out into the desert, it suddenly turns left towards a grandstand crowded with spectators. But, just as suddenly it changes its mind and it is off on a 200km course across the desert in the second race of its kind: a race that involves no human drivers, except for those in the safety cars.
]]> The people looking on as each car heads off in this robo-rally include teams of engineers who stand to collect a $2m prize if one of these vehicles makes it to the finish in one piece. For close to two years, these teams have completed qualifiers that test the cars' ability to dodge cones and concrete slabs. Now, each car would have ten hours to pick its way round a course that crossed dry lake beds, ran along rutted dirt tracks and through narrow underpasses. Finally, the course wound through a high pass with cliffs on one side and a steep, metal-bashing drop on the other. On the way, the vehicles would have to deal with obstacles as tricky as tank traps. Some of them looked like they could drive over most of the obstacles. The biggest was a monster truck from Oshkosh, with its cab sawn off so that it could get through the low tunnels on the route.

This combination of Robot Wars and Wacky Races had a purpose. In ten years, US military, which put up the $2m prize for the race, wants to have a third of all military vehicles - whether planes, trucks or tanks - to be able to drive themselves with no help from soldiers. And robo-vehicles will not be restricted to tanks and trucks. It did not make it to the final race, but one team has successfully made a robotic motorbike that can stay upright without a rider.

Maybe 20 years on from now, you won't need a driving licence because the car will be doing all the driving itself. And even when you take over and try to point it in one direction, computers under the bonnet will be working out whether that is a good idea or not.

Some of this technology is already in cars. Some posh cars have radar systems similar to those used by aircraft. They look out for other cars, and let you know loudly if you are likely to hit one. Cameras in some cars look at the white lines on the motorway and use them to make sure you cannot drift out of one lane, and end up decorating the front of a truck piling along in the next lane. Soon, there will even be smart headlights that follow the road around at night, making sure you don't miss any sharp corners and discover off-roading the hard way.

In 2004, it looked as though technology had a long way to go. The first race saw even the best-designed car that year - Carnegie-Mellon University's Sandstorm - forced to stop after just 12km. The others did not even get that far. Some ended up in ditches, most had to stop because their computers became confused. One managed to get itself stuck in a barbed-wire fence.

This year and almost 18 months on, five vehicles finished a different course, including OshKosh's massive truck TerraMax and the two cars entered by Carnegie-Mellon. The difference? According to the veteran robocar designer at Carnegie-Mellon, William "Red" Whittaker, who came up with the concept behind Sandstorm and its successor H1ghlander, the cars could "see" a lot better.

Robocar makers are careful people, which is handy. No-one wants to be run over by a tractor driven by Silicon Sam just because its cameras were playing up. The engineers don't just rely on one set of eyes to guide a vehicle. They use lots of them. And, because these cars have a digital map, they see how their car is doing by asking orbiting satellites where they are.

Every competitor had a Global Positioning System (GPS) receiver that it could use to check its position on the map. But that was not enough on its own. The sudden left turn by the car at the start that went to be the winner - Stanford Racing's Stanley - was because the GPS told it to go that way. Later on in the race, several teams noticed that the GPS was telling the vehicles to head straight over the cliffs on the treacherous Beer Bottle Pass. Plus, GPS will not tell you about rocks, tank traps or animals in the way.

Sitting on top of each vehicle was a forest of cameras and sensors. Stanley alone has four laser rangefinders, radar and two cameras for stereo vision, with yet another camera for getting close-ups of objects in the road. The laser rangefinders paint the landscape with light - invisible to the human eye - and see what gets reflected back to work out what is in the way. The vehicles back that information with images from cameras.

Gary Schmiedel, in charge of the TerraMax project at Oshkosh, explained why his team also used stereo cameras: "Stereo vision finds things like fences or objects like cones that are very different in colour to the rest of the scene. But you need to be careful with the information you pay attention to. These sensors report a lot of things that are not of interest, things that are not in your way."

Whittaker's Sandstorm and H1ghlander have laser scanners and cameras sitting in a dome on top of the vehicle that swings from side to side. "Driving with your head in a neck brace gives you an idea of what these sensors give to you without this," said Whittaker. "If you're coming up to a T-junction and want to see what is, the sensor can turn and look directly out the passenger side."

Although the cameras on TerraMax do not move around as much as Whittaker?s vehicles, they do have a trick up their sleeve that goes way beyond what people or animals are able to do. "For stereo vision, you need two cameras with overlapping fields of vision. We have three cameras," said Schmiedel. Two are close together, like human eyes, one is further away from those two. "At slow speeds, we use the two cameras that are close together. As speed picks up, we switch to use two cameras that are space further apart."

The advantage of TerraMax's approach is that by moving its eyes further apart, it gets a much more accurate range for obstacles that a long way away. Switching back to the cameras that are close together, it can get a better look at things that the vehicle is near. For Schiedel, that ability translates into an ability to drive faster safely than human drivers. "Where you have a known area and the path is pretty well-defined, you could run the truck a lot faster," said Schiedel. For roads with tight turns and big hazards, the truck could slow right down. "We negotiated Beer Bottle Pass very gingerly."

Whittaker said he sees robocars taking part in races alongside vehicles with human drivers to demonstrate what they can do. Robot cars running in the Paris-Dakkar rally is just one possibility. "We are looking for another race. There are so many classic races out there." He likens the situation to the early days of flight: "Then, no-one knew what planes could do, so they went around barnstorming to show the machines off. Today, most people haven?t seen driverless vehicles and even fewer have ridden in them." Having cars compete would let the public see how the robotic versions can perform.

Unlike the early pilots, the robo-vehicle designers have some ideas about what their creations will be able to do. Whittaker wants vehicles for his ranch that will fix fences and harvest crops. Others will drive around airports, plouging snow out of the way. And Schiedel forecasts we will see convoys of trucks following nose to tail along motorways, perhaps with a human driver at the head to let the robots know where to go. But not necessarily at the front. Whittaker sees the situation where the robots will be out in front: the driver will just decide which road they take. Soon we will all be back-seat drivers.

Written for the December 2005 issue of Flipside.

The digital human

2005-08-23T20:41:30Z

What should have been the scientific advance of the new millennium - and put forward as the key to human life - turned up more mysteries than it solved. In 2003, the Human Genome Project delivered a long list of amino acid sequences and the genes that those sequences comprised. In principle, molecular biologists had everything they needed to tie genes to functions in the body.
]]> The workhorses of the body are proteins. They are long chains of atoms that fold up in unusual ways to expose tiny chemically reactive areas. The active ingredient of the blood cell, haemoglobin, is a protein that lets four molecules of oxygen bind to it on the way out of the lungs. Once it has carried the oxygen to a muscle to be used, it takes molecules of carbon dioxide back to be exhaled.

Body functions are almost all handled in some way by at least one protein, and genes provide the basic blueprints for those proteins. Cells are made out of a combination of complex molecules from basic chemicals and it falls to proteins building most of those molecules. Before the human genome was sequenced, what biologists knew was that genes tell some of these builder proteins what to make. By unlocking the secrets of the genome, biologists could surely work out how the body works.

Life is nowhere near that simple, it seems. Scientists found there was a problem with the genome that had been sequenced: there were fewer genes in the human DNA sequence than expected. Estimates had put the figure at 100,000 at the start of the project in 1990. By October last year, researchers concluded there could be fewer than 25,000. This figure is ten times lower than the types of protein in each person's body. Other projects, such as one to uncover the way that the malaria parasite operates, have turned up similar results.

The sequenced human genome also contained large chunks of 'junk' DNA: these were bits of the genome that did not seem to have any function at all. They just filled in between the 'real genes'. Yet, some experiments indicated that this apparently useless DNA does get involved in processes in the body.

As they tried to work out what the genome project revealed about the body, biologists began to understand that more complex processes needed to be invoked explain to determine how each of the active genes produces the proteins that appear in each different type of cell that makes up the human body.

Prof Denis Noble of the University of Oxford physiology department, said relying on the genome alone "is like looking at a telephone directory and thinking you have the secrets of the city".

Biologists use the term 'gene expression' to describe the conversion of genetic information into proteins and ultimately into cell building blocks. This is a complex process that involves a number of steps and many different proteins. Gene expression is not just down to the structure of the DNA, but the makeup of the cell and what it is doing at the time. Proteins will interfere with the process as well as taking part in it.

Noble said a bottom-up view, working up from the genome, is not the way forward because it is higher-level processes that determine the behaviour of the cell and how the genetic material gets involved. "I liken it to an organ keyboard: the music comes from player not the keyboard," he said. And gene expression is far from being static. "I tell my students, if you go to the theatre and have a good laugh or a cry, your gene expression will have changed for the week."

Following the initial sequencing of a representative human genome, researchers are turning to those of known individuals. One company, 454 Life Sciences has said it could sequence the genes of one of the scientists who uncovered the structure of the DNA molecule, James Watson, in one year. That is a huge reduction on the 15 years it took for the first attempt. In the future, researchers believe it will be a routine exercise to sequence DNA as costs fall way below $1m to $200, about the same as the cost of a magnetic resonance imaging (MRI) scan.

The question is what can be done with this genetic information if it does define what biologists need to know about the body? So, the research is moving up to the level of proteins, cells, organs and the body overall. The key for a loose collaboration of researchers around the world is a model to tie the various representations of biological processes together. The aim of the Physiome Project, initiated by the International Union of Physiological Sciences (IUPS), is to build a computer model of the human body. The models will extend from the genetic level through protein reactions, cell functions, tissue behaviour through to the way that organs behave. Using such an extensive model, doctors could, in principle, work out how badly a patient might react to a new drug simply by providing their DNA sequence and simulating with it. It might even reveal whether patients are lying about taking their medication or what they are eating as such a model would show what effects different drugs or foods have on gene expression, and on their ability to recover from a disease.

The Physiome Project is not the only one of its type. The US defence research agency DARPA has kicked off a set of projects that go under the banner of Virtual Soldier. If the project is successful, soldiers of the future will wear electronic dog tags that contain genetic and physiological information about themselves. Field doctors will put the tags of injured soldiers into a computer and use full-body models, which DARPA has called 'holomers', to guide them on the best course of treatment. However, the ability to simulate the body processes of a human is years away. Even the most optimistic predictions put this ability 20 to 30 years into the future.

There are some apparent similarities between the Physiome Project and the Human Genome Project. The main one is the scale of the new project. It is potentially a massive undertaking that will involve many teams from around the world. The systems that are being built today are taking into the account the fact that researchers will need to share each others' models and even compute resources.

But the workers do not expect the same level of attention that surrounded the Human Genome Project as the worldwide team neared the completion of its task. "There is no instant win with the physiome, although the work has yielded tangible results already," said Noble. "But few have realised the scale of what needs to be done. In the way they recognised the scale of the Human Genome Project. And I don't expect that to happen with the Physiome Project. With the human genome project they could at least declare they were 98per cent there. You can't do that with the processes of the body because we will always be filling in the detail."

The quest to build a computer model of the human body from genes up is one that researchers know to be impossible. "It is easy to show that, to build up from the genome that there is not enough material in the solar system to do that on a computer," said Prof Denis Noble of the University of Oxford physiology department and one of the pioneers of the Physiome Project. "To compute exhaustively is beyond anything we could ever build. I did a calculation that showed you would require 1027 Blue Gene supercomputers to simulate all of the molecular interactions in a single cell. And there are a billion such cells just in the human heart.

"We will never have that much computing power. But that is mindless simulation. You need simulation with insight. You need to determine which part of simulated reality is the explanatory bit. It is a restriction that forces us to think. Computing will always be a bottleneck but a good disciplinary bottleneck."

Noble began devising mathematical models the way that the heart works some 40 years ago and has developed over the years progressively more advanced representations of the vital organ using differential equations to model much of the behaviour of tissues and cells. The heart models run on supercomputers attached to the UK's computing grid, simulating seconds of real time in the space of hours of compute time.

Scale is a big problem for modelling biological systems. "The physical scales vary by four orders of magnitude. A signal between cells may start at the protein level and the response may be at the full cell level. You also have reactions that take fractions of a second for a protein but the results of that reaction may take days or months to have an effect," said Henry Kelly, president of the Federation of American Scientists (FAS), a group that kicked off a number of projects to model body functions under the banner Digital Human in 2001.

The key to developing the models further is to find alternative representations that are easier for computers to work with. "I have worked with some people who have done a brilliant job of seeing the same equations that don't require so much heavy computing. You need mathematical insight to see how complex differential equations behave," said Noble. "It is possible that we will find how to reduce models at one level to faster, more computable representations as we move up to the higher-level models."

Kay Howell, vice-president of IT at the Federation of American Scientists (FAS), said it is unclear how far mathematical transformations will get researchers: "Computational biology is very new. We don't have a mature set of computational methods and algorithms for tackling the problems as yet. But it will be a huge growth area. The complexity of what researchers are looking at means it is too hard to do any other way."

Heart target

The Physiome Project and similar efforts may be years away from delivering a digital model of the human body, but benefits from the work could be realised much sooner.

"Some goals are immediately in view. My audiences are sometimes surprised when I say it is already being used in pharmaceutical research and in regulatory bodies," said Prof Denis Noble of the University of Oxford. "For people designing and screening drugs, the problem for them is working out which drugs will cause cardiac arrhythmia and which don't."

"Nearly 40 per cent of compounds researched by the pharmaceutical industry hit the heart. They react with one of the transporters, called hERG, and cause arrhythmia in the heart."

This problem has helped the cost of drug research soar. The Tufts Center for the Study of Drug Development reported a couple of years ago that the average cost to develop a new drug is $802m. Withdrawals are much more expensive. Merck's withdrawal of the painkiller Vioxx because of its effect on the hearts of some patients saw more than $25bn wiped off the company's share price in one day and consumers lined up a series of class-action suits.

Today, the methods for determining the effect of a drug on the heart during trials is based on analysis of one feature found in electrocardiogram (ECG) traces. "People look at the T-wave of the ECG for prolongation. There is almost an industry in measuring that interval. But a very poor marker for what you want to know: will the drug kill someone?" said Noble.

Modelling on its own would not solve the problem but, in combination with experiments to determine the behaviour of drugs on cells in the heart, Noble said the process of screening out potentially lethal drugs could be made more efficient. "It would have one of the biggest impacts on healthcare costs. If we moved from 98per cent attrition to 95per cent, we would more than double the output of the pharmaceutical industry," argued Noble. "I discuss this quite frequently with the pharmaceutical industry to see if we can get round the problem. If it works something will happen that will be of immediate benefit and we would find computing becomes used in the same way it is used in the automotive or aerospace industries."

In the US, another shorter-term project is to use modelling to improve the training of medical and biology students. The Federation of American Scientists (FAS) is building software that will ultimately run on games machines such as the Playstation 3 that will run interactive simulations of biological processes. "These new games devices are supercomputers. You can have spectacularly impressive visualisations," said Henry Kelly, president of the FAS. "The question is: do you want to? Cellular processes are visually boggling. In engineering, things do simple things like twist along one axis. They don?t fall apart, reassemble and then turn inside out. It is the mother of all visualisation challenges. Everything is in motion.

"You can show the full detail but you might want a more cartoon-like view. This is an interesting research issue."

This feature is an excerpt from an eight-page special report published in the August/September 2005 issue of Information Professional on the Physiome Project.

Blood, water, oil, tobacco

2003-11-01T22:15:04Z

As stock market prices soared in the late 1990s on the back of the technology boom, an unexpected beneficiary of the massive rise in mobile phone sales was a group of Rwandan and Ugandan soldiers fighting the troops of the Democratic Republic of Congo. It was a link that underlined the growing connection between risks and dangers in the developed and the developing world.
]]> In the late 1990s, as cellphone sales soared, supplies of tantalum - a metal needed to make parts of their circuitry - became severely limited. Congo is rich in coltan, a tantalum-rich ore, and the troops were only too happy to supply Western companies with it.

In a two-year period to the end of 2000, Michael Renner, senior researcher at the Worldwatch Institute estimates the troops made some $250 million from mining coltan in Congo. As the technology bubble burst, the price of tantalum fell from historic highs to sub-1980s prices almost overnight. For a while, it seemed that the soldiers would be starved of the funds they needed to continue the war.

The tragedy for Congo was that it is not just rich in coltan. Diamonds and other precious minerals are readily available. "Unfortunately, because Congo is resource rich, those forces said they would move onto something else," said Renner, perpetuating the conflict.

Although a number of resource-driven conflicts have petered out in sub-Saharan Africa recently, thanks to increased co-operation between African nations, resource conflicts are not necessarily over.

"The international trade in raw materials keeps increasing phenomenally. With increased globalisation, there is so much more opportunity for forces in developing world to say: 'If we have control over this resource we will find ways to get these into play'," said Renner. "It would not be surprised if similar patterns were to replay in other countries."

Renewed interest in Africa's oil deposits, already the cause of internal strife in Cameroon, Chad and Nigeria, could fuel conflicts elsewhere on the resource-rich continent where tensions have already been raised. Renner pointed to oil exploration in Chad and pipeline projects in Cameroon: "A lot has gone wrong. The social disruption has been immense and local communities bear the brunt."

If lessons are not learned from those experiences, there will be other flashpoints: "The tension does not necessarily come down to one group controlling a resource. It is the feeling within a community that something terrible has been wrought upon them," said Renner.

Such tensions could lead to terrorists taking control of unstable states, or key parts of them, with resources providing ready access to funds. Bruce Hoffman, vice-president for external affairs at the US thinktank RAND Corporation, said: "Terrorist groups could take over leadership of a country, on a covert basis. With a failed state, terrorists with access to money could take over and clandestinely turn it into a terrorist nation. It could be in areas that have not been associated with terrorism: such as West Africa."

James Kirkhope, research director of the US-based Terrorism Research Center, said he is more optimistic about the situation in Africa because of international co-operation, such as Nigeria's role in convincing President Charles Taylor to leave Liberia.

"In Angola and Nigeria, civil society has been building, so progress has been made," said Kirkhope. Although the US campaign in Afghanistan highlighted the danger of an entire failed state, there are areas within countries that represent potentially more serious problems. Their lawlessness attracts terrorists and other forces so they become areas of global instability. The Tri-Border zone between Argentina, Brazil and Paraguay is a prime example, although there are areas of Somalia and Sudan equally at risk.

"The cracks between nations represent the biggest threat," agreed Hoffman.

Interpol has warned that terrorists can now gain access to large amounts of cash through counterfeiting networks. Those factories lie in areas such as the Tri-Border zone. "Middle Eastern groups are funding themselves through bootleg goods [in these regions], and sending the funds back to the Middle East," said Kirkhope.

Access to money and a base will provide terrorists with a base to potentially scale up their attacks, an aspect made more disturbing by the rise in large-scale suicide terrorism. Hoffman said suicide attacks are, on average, four times more lethal than traditional terrorist bombings and that modern terrorists "see themselves engaged in a total war. That brings about much higher levels of lethality".

Kirkhope said: "If they have a message, they want an attack of mass destruction, of mass disruption. That is the reason why major attacks will bubble up in the kitchens of the terrorists."

As parts of the developing world move beyond legitimate control, there are aspects of Western culture that will prove to take a disproportionate toll on life in the developing world. The Global Burden of Disease report prepared by the Harvard Disease Burden Unit and the World Health Organisation (WHO) claimed that, by 2020, tobacco will cause for just under 9% of the total disease suffered by people around the world, compared with just under 6% for heart disease caused by blocked or hardened arteries, the leading single disease. Despite its rapid rise in infection rates, deaths from acquired immunodeficiency syndrome (AIDS) are still expected to be lower than those from tobacco.

Even as Western countries build more effective crumple zones and other safety systems in their cars, motor vehicle accidents continue to increase rapidly in the developing world. By 2020, according to the Harvard and WHO study, disability and death from motor vehicle accidents will be more prevalent than from tuberculosis and, at 5% of the total disease burden, not far behind heart disease.

Dr David Maunder, principal researcher at the UK Transport Research Laboratory, said there is work to reduce road accidents in developing countries. "But it is a long slow process, as we have seen in the developed world."

This feature was part of an eight-page dossier feature published in the November 2003 issue of Geographical on the dangers in the world.