Wednesday, October 18, 2006

Human Hybridomas and Biochips

Cesar Milstein's first hybridoma
When I think of William Gibson, I think of the interface between man and electronics; people who plug directly into the matrix, people who carry chips in their brain, and people with Zeiss-Ikon eyes that record all they see, not to mention self-aware artificial intelligence. I don't think so much about basic biology. It's clear though, that Gibson has kept an eye on biological developments.

In Count Zero, the second book in Gibson's "Sprawl trilogy", Turner, the corporate mercenary, orchestrates the defection of top scientist Christopher Mitchell from the fictional Maas Biolabs. Mitchell is described as their "head hybridoma man":
Somewhere near [Maas's] core [Mitchell] had perfected the hybridoma techniques that had eluded other researchers for almost a century; working with human cancer cells and a neglected, nearly forgotten model of DNA synthesis, he had produced the immortal hybrid cells that were the basic production tools of the new technology, minute biochemical factories endlessly reproducing the engineered molecules that were linked and built up into biochips.
I suspect it's no coincidence that Count Zero was first published in 1986, two short years after Jerne, Köhler and Milstein won the Nobel Prize for the development of hybridoma technology. If nothing else, it must have sounded cool to include.

So what are hybridomas? First a little background on B-cells. B-cells are a type of white blood cell, and are the antibody-producing component of the immune system. Antibodies are proteins composed of two heavy chains and two light chains. Segments of the genes that encode the heavy and light chains recombine during B-cell development, resulting in a population of B-cells that can produce many different antibodies. When a foreign molecules ("antigen") or foreign cell bearing an antigen finds its way into the blood stream, B-cells that produce antibodies capable of binding the antigen are stimulated to start dividing as part of the bodies defense system. This response is typically "polyclonal", meaning that several different B-cells, each producing a different antibody, respond. Of course it's more complicated than that, but I think that covers the key points (for more details, watch this flash movie of B-cell development).

Because of their ability to specifically bind bacteria, viruses and other antigens, antibodies were long considered to have promise as a "magic bullet" therapeutic and diagnostic agent. Because the immune response is polyclonal it wasn't possible to isolate a single type of antibody from the serum of immunized animals. B-cells don't survive very long outside the body, so it wasn't possible to simply grow clones in culture. In 1975, Kohler and Milstein figured out a way of culturing cells making a monoclonal, or a single type of antibody. They took B-cells from immunized mice, fused the cells with bone marrow tumor (myeloma) cells, and grew them under conditions in which only B-cell-myeloma fusions, or hybridomas, would proliferate (more details about monoclonal antibodies and hybridomas). Each hybridoma produces a unique mouse monoclonal antibody.

What about human hybridomas? There are, of course, ethical problems with injecting people with antigens to create human monoclonal antibody producing cell lines, limiting the availability of human antibody producing cells. Another problem is the limited number (and quality) of human myeloma cell lines to use as fusion partners. To get around these problems, early as the mid-1980s scientists had begun to develop methods to use recombinant DNA technology to engineer human and partially-"humanized" antibodies (some of the earliest experiments are mentioned in Kohler's 1984 Nobel lecture, for a recent review see Smith et al. (2004)). Successful human hybridomas equivalent to Milstein and Kohler's mouse hybridomas weren't reported until 2001 (Karpas et al.).

OK, so there are ways of generating monoclonal antibodies from human hybridomas. How would they be used in biochips? The term "biochip" as used today typically refers to miniaturized arrays of DNA, proteins, antibodies, or even cells. These are used for screening compounds, analyzing gene expression, and other, similar, assays. I think it's fair to say that hybridomas could be used to make the antibodies on antibody biochips. Similar cell fusion technology could be used to immortalize cells producing other proteins as well, even though recombinant DNA technology is likely a more practical method of creating cellular protein factories. That isn't the type of biochip that Gibson had in mind, however. His biochips form circuits that can interface with both electronics and the human brain.
The second table supported the cyberspace gear. The deck was identical with the one he'd seen on the oil rig, a Maas-Neotek prototype. The deck configuration was standard, but Conroy had said that it was built up from the new biochips.
"I don't know, man. I just don't know. What is it, some kind of cancer?
Turner followed him down the room, past a worktable where a micromanipulator waited beneath its dustcover, past the dusty rectangular eyes of a bank of aged monitors, one of them with a shattered screen.
"It's all through her head," Rudy said "Like long chains of it. It doesn't look like anything I've ever seen, ever. Nothing
"How much do you know about biochips, Rudy?"
Rudy grunted. He seemed very sober now, but tense, agitated. He kept running his hands back through his hair "That's what I thought. It's some kind of . . . Not an implant. Graft."
visible man brain sectionTheodore Barger at USC is working on chips that can actually replace the hippocampus, part of the brain involved in learning and memory. Just a few months ago, it was reported that brain implants can be used as a direct computer interface, both in monkeys and people. These experiments use traditional electronics and silcon chips.

A "chip" made purely of biological matter has not yet been achieved. Yael Hanein of Tel Aviv University and his colleagues have made progress in that direction, by figuring out a method to direct rat neurons to form regular patterns and make connections on a sheet of quartz. Getting those artificial neural networks to control electronics or interface with the neurons in the brain still lies within the realm of science fiction. In any case, it's unlikely that that the technical solution will lie within the field of hybridoma technology.

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