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Early computers could perform fairly complex calculations just by arranging a few analog circuits. By choosing appropriate resistor and capacitor values, arithmetic summers, integrators, and differentiators can be easily constructed using a single amplifier, so long as the answer is less than the supply voltage. Indeed this is, at least in part, how early computers were able to track and deploy countermeasures to incoming missiles. It is even possible to take a couple of transistors and turn them into a precision multiplier. Inspired by these simple circuits, researchers at MIT have created synthetic analog computers that run genetic machinery — in other words, living cell calculators. In addition to arithmetic, these computers are also able to also perform more complex functions like taking logarithms, square roots, and even do power law scaling (evaluate functions of x raised to a certain power). While these machines are not as convenient as any inexpensive calculator, they can process numbers up to four digits, and are a heck of a lot smaller.
Up until the mid-seventies, the old slipstick, or slide-rule, was the dominate calculating tool. In its most basic form, it uses two logarithmic scales to allow rapid multiplication and division. By exploiting feedback in gene circuits, the researchers could implement logarithmic-linear (think of old-fashioned log-linear graphing paper) computations over four orders of magnitude. To do this, a continuous range of input values are represented by things like the amount of certain kinds of sugars, or other molecules present in the cell.
For addition or multiplication, each of these inputs turns on a gene that manufactures an optically-detectable molecule called green fluorescent protein (GFP). For subtraction or division, one of the inputs instead suppresses the expression of GFP. Depending on how each input is rigged to behave in the genetic circuits, the different functions can be accurately encoded. The answer is read out by measuring the total fluorescence of the cell.
We recently reported on the creation of biological transistors inside cells at Stanford. These “transcriptors” were then used to build up various kinds of digital logic gates. Combining these kinds of digital circuits with the analog circuits described here, powerful sensing and control platforms can be created on the very small scales. Digital may reign supreme inside the neat little microcosm of a computer, but to interface to the real analog world, conversion elements for both directions will become essential.
One thing these machines could do would be to add a whole new level of precision to the regulation of genes. Biological clocks, as naturally implemented both at the cell and organism level, normally do things like control circadian rhythms, or cue the developmental programs that build the creature. These oscillators work fairly well, but lack the accuracy of the crystal timepieces used in computer chips. For the moment the researchers are hosting their biological computers in bacterial cells. They would like to develop analogous circuits that operate in mammalian cells, where these functions might be brought into better use.
If at some point we are to construct the “molecular ticker tapes” imagined by the creators of the new BRAIN Initiative to map neural activity, building these kinds of circuits into the readout devices would provide powerful methods of regulation and control. Having a complete brain activity map written into pieces of DNA inside each neuron is a nice idea, but to read that information out, and do something with it, we will need get the neurons to speak our language.
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