Members of the Weizmann Institute team clockwise from top left: Binyamin Gil, Prof Ehud Shapiro, Uri Ben-Dor, Yaakov Benenson and Rivka Adar.In the 1960s science fiction film Fantastic Voyage, a vessel is shrunk by military researchers and dispatched to destroy a blood clot threatening the life of a key scientist.
It sounded unbelievable then. But now, proving that science fact is quickly resembling science fiction, the world’s smallest computer – which was developed last year by Israeli scientists – has been successfully programmed to fight cancer.
The computer identifies changes in molecules that indicate the presence of certain cancers, diagnoses the type of cancer, and then produces a drug molecule to fight the cancer. Researchers from Israel’s Weizmann Institute have developed the prototype biological computer that identifies and diagnoses cancerous cells and then releases medication to destroy them. The results of the team’s research has been published in Nature and were presented last week by team leader Prof. Ehud Shapiro at a Brussels symposium ‘Life, a Nobel Story,’ in which Nobel Laureates and others addressed the future of the life sciences.
The Weizmann breakthrough offers the strongest indication yet that it will eventually be possible to build tiny medical ‘nanosubs’ that hunt down tumors and germs before delivering their drugs.
According to Shapiro, it will leads the way in years to come to create a “doctor in a cell” that will be able to operate inside a living body, identify disease, and apply the necessary treatment before external symptoms even appear.
“It is clear that the road to realizing our vision is a long one; it may take decades before such a system operating inside the human body becomes reality. Nevertheless, only two years ago we predicted that it would take another 10 years to reach the point we have reached today,” said Shapiro.
The original version of the biomolecular computer (also created in a test tube), capable of performing simple mathematical calculations, was introduced by Shapiro and colleagues in November 2001. An improved system, which uses its input DNA molecule as its sole source of energy, was patented, reported in 2003, and listed in the 2004 Guinness Book of World Records as the smallest biological computing device (approximately a trillion of these devices can fit in a drop of water)
As in the previous biological computers produced in Shapiro’s lab, input, output, and “software” are all composed of synthetic DNA, while DNA-manipulating enzymes are used as “hardware.” The team suggests that biological computers can have an enormous amount of brainpower because of DNA’s potential ability to store massive amounts of information: Less than a gram of DNA could store as much data as a trillion CD-ROMs.
The newest version’s input apparatus is designed to assess concentrations of specific RNA molecules, which may be overproduced or underproduced, depending on the type of cancer. Using pre-programmed medical knowledge, the computer then makes its diagnosis based on the detected RNA levels. In response to a cancer diagnosis, the output unit of the computer can initiate the controlled release of a single-stranded DNA molecule that is known to interfere with the cancer cell’s activities, causing it to self-destruct.
In one example, the computer determined that two particular genes were active and two others inactive, and therefore made the diagnosis of prostate cancer. A piece of DNA, designed to act as a drug by interfering with the action of a different gene, was then automatically released from the end of the computer.
“This work represents the first actual proof of concept and the first actual demonstration of a possible real-life application for this kind of computer. The molecular realization is rather intricate and it required a development of a number of molecular-manipulation techniques from scratch,” said Shapiro, an associate professor of computer science and applied mathematics who is also in the Weizmann Institute’s department of biological chemistry. “Our system is also quite complex. Tens of DNA strands can each react with any other strand. It turned out that our design was robust enough to cope with this complexity and function reliably despite imperfect function of its component.”
Some scientists have since concluded that it will be difficult to get DNA computers to outmuscle electronic computers. But Shapiro decided to focus on a DNA computer for use in the body, where silicon would have a hard time competing. The simple device has two states, “yes” and “no,” and changes from one to the other on the basis of a single variable, like the presence or absence of the RNA it is looking for. If at the end of a series of steps it is in the “yes” state, the diagnosis is positive.
“It’s really an ingenious concept,” said John Reif, a computer science professor at Duke University in the US who built his own molecular computer in 2000. “This could have a major significance in the medical world, if only they could get it in the cell,” he told AP, adding that until now no molecular computer has ever demonstrated much practical use.
Dr. Mauro Ferrari, a specialist in nanotechnology at the National Cancer Institute, was equally enthusiastic, telling The Washington Post: “The concept is to build something that does not require intervention by a doctor. … This is very exciting. … It could allow the killing of cancer at a very, very early stage.”
The computer works only in a finely balanced salt solution, and many hurdles have to be overcome before it has potential clinical application. The primary ones, Shapiro said, is a determination that the device will survive inside a biological setting, that it will not trigger an immune response and that it will be safe to use. Shapira added that the molecular computer could get “confused” when inserted in a medium filled with other types of molecules, thus triggering reactions harmful either to it or the cell in which it functions.
In addition to Shapiro, the other members of the research team were Dr. Rivka Adar and three graduate students: Yaakov Benenson, Binyamin Gil and Uri Ben-Dor. The team’s next assignment will be to package the microscopic computer so it functions within the complex chemical environment of the human body. “The problems are big,” Shapiro noted, “and we do not have a clear way to solve them… It is clear that the road to realizing our vision is a long one.”
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