Let the viruses work for you

In the laboratories of the Massachusetts Institute of Technology, viruses are grown that coat themselves in selected materials and then organize themselves to create devices such as liquid crystals, nanowires and electrodes. The research is headed by Angela M. Belcher, Scientific American's Scientist of the Year

Philip Ross, Scientific American

The article was published in the February-March 2007 issue
For many years, materials science researchers wanted to know how the marine mollusk called "abalone" builds its spectacular and strong shell from simple minerals, so that they could imitate it and create similar materials themselves. Angela M. Belcher asked another question: Why not force the sea urchin to produce materials for us?
She inserted a thin plate of glass between the mollusk and its shell, then removed it. "We got a flat pearl," she says, "with which we could study the creation of the shell every hour, without having to kill the animal." It turned out that the abalone produces proteins that cause the ions that make up the calcium carbonate mineral to organize into two crystalline forms, which fit together perfectly - one strong form, and another form in which the crystals grow quickly. Her work earned her a doctorate from the University of California at Santa Barbara in 1997 and paved the way for consulting jobs in the pearl industry, a professorship at the Massachusetts Institute of Technology (MIT) and the position of founder of a start-up company called Cambrius in the town of Mountain View, California.
Belcher's goal was to develop biological "workers" that could move molecules from place to place, like bricks that would be used to build structures from the ground up, an approach known in the world of nanotechnology as self-organization. But first of all she had to find a creature more obedient than the sea abalone, which requires a lot of attention, grows slowly and to a certain extent is an expert in only one thing. Belcher was looking for something small, nimble and flexible - a cross between the elves from Maxwell's famous mini-molecules and the nimble elves of Santa Claus.
Belcher tried her luck with monoclonal antibodies because of the possibility of engineering them to stick to different objects, but she found them difficult to work with. Then, in the mid-90s, she heard about phage M13, a long, thin virus that infects bacteria but is harmless to humans. The virus, which is about 6 nanometers wide and one micron (1,000 nanometers) long, surrounds its single-stranded DNA with a protein coat. The sheath includes about 2,700 copies of a particular protein for lining the filamentous body, and a few single copies of several other types of protein for covering the ends. It is possible to engineer the different proteins and create different viruses in a billion possible combinations, each of which has unique properties of chemical attraction. A virus can stick to a certain material on the sides, to another material on one end and to a third material on the opposite end.
Biologists have exploited this chemical selectivity for a long time. They use M13 viruses that attach to certain organic materials to identify unknown samples. Belcher was the first to demonstrate how the virus can also mark inorganic materials, such as metals and semiconductors that underlie many useful products, and affect them. This was a rare example in which the physical sciences borrowed a method from the biological sciences: since the biologists had already done the dirty work, Belcher could simply go out and purchase a very wide and diverse collection of viruses, called by biologists a phage display library, at a price of about $300.
To get a virus that attaches to the appropriate molecule, Belcher uses a process called directed evolution. "We throw all our billion versions into a test tube, along with some substance, wash it and see what sticks to the substance," she says. "We then remove the infected viruses by changing their ability to react with the surface, for example by raising the acidity level, then collect the viruses and multiply them in a host bacterium."

Heroines of the virus

The reproduction in bacteria provides trillions of copies of a promising subset of viruses that undergo another phase of evolution. This time the conditions in the solution are changed to make it a little harder for the viruses to stick to the target material. And again, wash the less sticky versions and multiply the survivors. This cycle is repeated over and over again, under increasingly demanding conditions. At the end of the process, which may last three weeks, only one version of the phage remains - the one that infects most selectively.
Put a virus with a unique attraction to gold in a solution containing gold ions, and it will coat itself and produce a wire one micron long suitable for connecting adjacent components in a tiny electrical circuit. A slightly different virus could even chain itself to other viruses like it and form a gold wire several centimeters long. The threads can be woven into threads and woven into the fabric of a garment. Such a wire, if bound to chemically sensitive receptors, might serve as a detector of toxic substances or of threatening biological agents.
A year or two ago, Blecher caused yeast cells to fix gold, in an experiment that still has no practical application (although the coated cells, which are six microns wide, could be used in certain experiments as fluorescent markers that are very easy to see). Meanwhile, her students at MIT, who are learning how to use living things as a basis for creating materials, are performing the fixation of gold as an exercise in the laboratory.
Although Belcher continues to test the merits of several other organisms for experimental purposes, she is focusing on M13, in part because due to the viruses' enormous length-to-width ratio, they naturally organize themselves into more complex shapes. "Think of pencils in a box," Belcher says. "If you shake just a few of them, they land randomly. But if you increase their density, they tend to organize in a pack. She managed to make selected phages form a membrane with an area of ​​10 cmXNUMX and a thickness of less than one micron. She then fixed this structure into a stable sheet using chemical bonding.
Now Belcher, with her colleagues at MIT, Yit-Ming Chiang, Paula Hammond and K. T. Nam, and with funding from the US Army, is busy developing these surfaces for use as electrodes in ultra-lightweight lithium-ion batteries. "The weight of the batteries is very important to them. "The first planes that flew to Baghdad were loaded with batteries," says Belcher. "Our electrodes weigh 50-40 milligrams compared to the grams that normal electrodes weigh."
The negative electrode can be made from a sheet of viruses that have been enhanced to coat themselves in gold and cobalt oxide. The gold to improve electrical conductivity, and the cobalt oxide to exchange ions with the electrolyte in the battery. The ion exchange is what drives the charges from electrode to electrode. The electrode is arranged directly on top of a pre-formed polymer that serves as an electrolyte and creates a double layer. Now the team is busy convincing the viruses to grow the positive counter electrode, which will stick to the other side of the electrolyte.
The goal is to design the sheets so that they produce a solid whose surface will have alternating positive and negative electrodes. It will be possible to connect the electrodes in a column to get a higher electric voltage. The short distance between the electrodes allows fast charging and discharging and optimal use of the components. This battery will be able to be designed according to the space available to the planner. In this way, it will be able to save not only weight but also space, desirable features for both military electronics and ultra-thin MP3 players.
It seems that there are no elements and no compounds that viruses cannot differentiate between. One phage is specific for the semiconductor material gallium arsenic, but is indifferent to the very similar material gallium nitrogen. This ability to differentiate could perhaps be used as a means of detecting defects in the chips. Chipmakers sometimes grow crystals of one of these materials on top of another type of semiconductor. They do this so that the subtle differences in the spacing of the crystal lattices will cause a mechanical stress that will affect the electrical properties. When the crystals don't fit together properly, unnecessary atoms stick out where they shouldn't be. The viruses will be able to stick to precisely such defects. If the virus also carries a fluorescent label, it will become active under suitable conditions, and it will be possible to locate the defect using a microscope.

Big plans
But Belcher wants to go further with this technology. "We want to see if we can also find manufacturing defects in objects like an airplane wing," she says. Her research group also wants to harness the M13 phage to build entire transistors from semiconductor molecules and ions, then manufacture them in billions of copies. She admits that viral transistors won't be smaller or better, but their production won't require the use of harsh chemicals and should therefore emit less toxic waste.
Belcher also hopes to return to his duty to biochemistry. She wants to make M13 bind to both cancer cells and nanometer components, called "quantum dots", which can be seen in medical scans. The use of quantum dots has not yet been tried in humans, partly because of concerns about the toxicity of the heavy metals that make them up, especially cadmium. Belcher is trying to get her phages to stick to safer particles made of gallium nitrogen, indium nitrogen or other semiconductors. The US National Cancer Institute is funding this research.
Most of Belcher's projects at MIT are many years away from finding commercial applications, but Cambrios must work on applications that will reach the market in about two years before the company "burns" its capital. The company's CEO and president, Michael Knapp, says that in its three years of operation, the company raised 14 million dollars in two rounds of financing, opened a laboratory and hired 20 people, meaning that the rate of spending is 5 million dollars a year. He says that Cambrius strives to create a niche product that will generate high profits from small trading volumes: from flexible touch-sensitive plastic backgrounds.
The army is interested in flexible screens to stick on the windshield of vehicles so that it is possible to quickly install a computer interface in the driver's field of vision. Product designers are also interested in integrating the background with a computer monitor, so that it can be rolled up when not in use to save space. Today it is impossible to produce flexible textures because the high temperatures at which the conventional production technologies operate would melt their plastic backing.
"We intend to launch the product in mid-2007," says Knapp. "In any case, we will be involved in production, but the electronics industry prefers to buy from someone they know, so it is almost certain that we will also have partners."
Belcher continues to regularly advise Cambria on the company's various projects as well as conduct her own research. She says that while the company owns the rights to its viral production method, she and MIT retain the intellectual property of the current research. For example, her group at MIT was working on the electric battery while Cambria developed its own touch screen.
"I really enjoyed developing the basic science and transferring it to society," she says, adding that she is interested in doing it again. Belcher isn't giving away the purpose of her next company, except that like Cambrius, which combines viral components and inorganic building blocks, it will be about connecting things that don't normally go together.
Philip Ross is a science reporter from New York.