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A chip off the old block?
Electronics giants attempt to apply their skills in the burgeoning market for collecting and processing genetic data
By Tam Harbert -- Electronic Business, 4/1/2000
"The Human Genome Project is basically transcribing the text of a very big book," says Nicholas Naclerio, vice president and general manager of the BioChip Systems Unit of Motorola Inc., Schaumburg, IL. "But we'll have all this text without having any real understanding of what it means." It's like knowing the alphabet, but not yet being able to read anything. There's still a long way to go before it will make much sense.
The race has actually been going on behind the scenes for about a year, as several electronics companies have quietly joined the ranks of public biotech companies and privately-funded start-ups that were secretively developing biochips. Motorola was one of the first, launching its BioChip Systems Unit in late 1998. Agilent Laboratories (a unit of Agilent Technologies Inc., the Hewlett-Packard Co. spin-off) has been researching biochips for several years, according to Darlene Solomon, R&D manager and senior laboratory scientist for the chemical and biological systems department at Agilent Labs in Palo Alto, CA. Agilent's Chemical Analysis Group last fall introduced the first commercially available "lab-on-a-chip," which prepares biological samples, handles fluids and performs biochemical analysis all on one microchip. And a new start-up in Wisconsin is developing a way of manufacturing biochips using a Texas Instruments Inc. technology called digital light processing (DLP).
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| "The Human Genome Project is basically transcribing the text of a very big book. But we'll have all this text without having any real understanding of what it means." --Nicholas Naclerio, vice president and general manager of the BioChip Systems Unit of Motorola Inc. |
Indeed, there could be huge markets around the corner not only for biochips, but also for the equipment to manufacture them. "We are looking at the biochip business as if we were looking 25 years ago at the semiconductor business," says Fred Schiele, president and CEO of JMAR Technologies Inc., San Diego, which makes specialty semiconductor manufacturing equipment.
"This area of genomics is going to take off like a rocket," says Bob Palay, CEO of NimbleGen Systems LLC, the private company founded last fall in Madison, WI, to commercialize a biochip manufacturing method that uses TI's DLP technology. "What's really going on here is the collaboration between world-class physics/engineering and world-class genomics," he says. "The rate of speed of [gene] sequencing has doubled every six months. That's Moore's law on steroids." The application of engineering and physics will allow biologists to study organisms at the biomolecular level. Not only will biochips allow them to collect many points of data quickly, but they'll also have the processing power available to crunch that data, he notes (see sidebar on IBM.)
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Groups race to decode the book of life While the Human Genome Project has been grinding away for 10 years to map the human gene, it's a commercial company that's likely to break the code the soonest. The goal of the Human Genome Project, sponsored by the National Institutes of Health and the U.S. Department of Energy, is to determine the precise arrangement of the units of DNA in human genes, a process called sequencing. Its original goal was to have the job completed by about 2005. But the commercial value of that genetic information has prompted a number of companies to do it faster and lock it up with patents. In particular, J. Craig Venter, president of Celera Genomics Group, Rockville, MD, has been speeding up the race. In May 1998, he announced that his company would sequence the human genome by 2001. More recently, he has predicted that Celera will complete the work by this summer. What's more, some companies such as Incyte Pharmaceuticals Inc., Palo Alto, CA, and Hyseq Inc., Sunnyvale, CA, are working on deciphering and patenting only the parts of the genome believed to be the most commercially valuable. Incyte, for example, is mapping only 10% of the human genome -- the 10% that contains single-nucleotide polymorphisms (SNPs) that are thought to contain the human body's most active codes. And these companies will, of course, expect compensation for their work. They are busy filing patents on the new genes they are decoding. Incyte, Hyseq and Celera all plan to charge multi-million-dollar fees for access to their databases. The Human Genome Project publishes all of its data on the Web. Nevertheless these commercial companies have put pressure on the government project to produce results sooner. The HGP now plans to have a rough draft of the genetic data available in 2001, and will follow with a more complete version by 2003. -- T.H. |
That kind of talk has Wall Street salivating over anything related to biochips. As projections of how soon the human genome project would be completed have shortened (see sidebar), the market caps of biotechnology companies -- many of which have positioned themselves as the tool vendors for the genomics age -- have gone through the roof. Affymetrix Inc., the current biochip market leader, saw its stock soar from $31 in March 1999 to more than $250 in early March 2000. The company has never made money and doesn't expect to break even until the fourth quarter of this year, says Anne Bowdidge, associate director of investor relations at the Santa Clara, CA-based company. But biotech investors are twitchy. They got spooked in mid-March when leaders in United States and Britain said scientists around the world should have free access to research on the mapping of human genes. Affymetrix stock, and the shares of other biochip companies, took a beating. Affymetrix shares fell more than 34 points on March 14 to close at roughly $203.
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| "We are looking at the biochip business as if we were looking 25 years ago at the semiconductor business."--Fred Schiele, president and CEO of JMAR Technologies Inc. | |
Chipping away at definitions
The term biochip gets tossed around loosely, and actually encompasses a range of devices, some of which have little in common with semiconductor technology. And predictions for how big the market will be may have very little in common with reality. While some forecasters predict that the market for biochips could amount to billions of dollars within the next five years, BioInsights, a market research firm in Redwood City, CA, takes a more conservative view, putting today's worldwide market at $226 million, reaching almost $1 billion by 2005 (see table).
BioInsights splits the market into three categories: DNA chips, lab chips and protein chips. DNA chips are small flat surfaces on which strands of one-half of the DNA double-helix -- called probes -- are placed. Because one half of the DNA double-helix naturally bonds with its complementary other half -- a process called hybridization -- this type of chip can be used to identify the presence of particular genes in a biological sample. These chips, also called microarrays, can be manufactured using a variety of techniques, including semiconductor processing technology, on a variety of surfaces, including glass and plastic.
Lab chips, the product Agilent is marketing, allow researchers to perform a sequence of experiments on a chip. The most common type of lab-on-a-chip uses microfluidics, a technique in which fluid samples move through tiny channels from one experiment site to another on the chip. The primary application for these devices is high-throughput screening, in which they are used to test biological samples more quickly at lower cost than current lab techniques.
Protein chips are similar to DNA chips, except that they sample individual proteins, which make up the DNA. The market for these devices is less immediate because medical science is further from identifying and mapping all the 100,000 proteins that make up DNA.
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The most significant and biggest application for biochips is the use of DNA microarrays for expression profiling, according to Felicia Gentile, president of BioInsights. In expression profiling, the chip is used to examine messenger RNA, which controls how different parts of the genes are turned on or off to create certain types of cells. If the gene is expressed in one way, it may result in a normal muscle cell, for example. If it is expressed in another way, it may result in a tumor. By comparing these different expressions, researchers hope to discover ways to predict and perhaps prevent disease.
Another promising application, now in the research phase, is pharmacogenomics. In pharmacogenomics, scientists try to correlate minute variations in a person's DNA with responses to drugs. These variations -- called single nucleotide polymorphisms (SNPs) -- affect a patient's ability to metabolize a drug and can have a major impact on the correct dosage.
A thorough understanding of SNPs could lead to personalized drugs, targeted to patients' specific genetic profiles. Last year, 10 international drug makers and a London-based charitable foundation established a $50-million, non-profit effort, called the SNP Consortium, which is working to identify and map SNPs and put that information in the public domain. In a research effort that will complement that of the Human Genome Project, the group intends to identify at least 300,000 and map at least 150,000 SNPs by April 2001. Both Motorola and IBM Corp. have joined the consortium within the last few months.
A twist on "Digital DNA"
Motorola's interest in the SNP Consortium is a natural extension of its efforts to connect with the world of genetics research. In fact, Motorola's biochip focus grew out of a group within Motorola that constantly scans the horizon for new enterprises for the company, says Naclerio. The company saw the dramatic revolution going on in life sciences due to progress in genetic research. "We are just at the cusp of a whole new science," Naclerio exclaims.
Motorola figured that it could play a role by bringing its engineering and manufacturing skills to bear on biochips. The chip giant has experience in a wealth of areas, including semiconductor technology, micro-electromechanical systems (MEMS), high-density interconnect and flat-panel display manufacturing. "So we're able to draw from all these different technologies," he says. It also knows how to make products in high volume with high quality and has extensive knowledge in electronics and software, Naclerio points out.
Naclerio thinks the company can take advantage of some parallels between electronics and biology. "Think of the human genome as a big computer program, and each gene is a subroutine that describes how to make a particular protein in the body," says Naclerio. DNA microarrays act like associative memory chips, comparing samples of a patient's DNA against known, stored patterns of DNA. "It's massively parallel biochemistry."
The lab-on-a-chip device functions somewhat like a microprocessor, in that it carries out complicated multi-step processes, notes Naclerio. And then there's the input-output interface. Many of today's DNA chips use a chemical that causes the DNA to fluoresce when a match occurs. This requires expensive scanning equipment, costing $50,000 to $100,000, to detect the fluorescence. Motorola aims to incorporate electronic circuitry to detect the various states of DNA on a chip, says Naclerio. DNA carries an electrical charge, and that charge can be read on a chip just like cells on a memory array, he explains.
In fact, Motorola has taken an equity investment in a private company in Pasadena, CA, called Clinical Micro Sensors Inc., that is developing just such a technology. And Motorola has forged a number of other alliances to gain access to some key biochip technologies. In late 1998, Motorola invested in Orchid Biocomputer Inc., Princeton, NJ, obtaining an exclusive license to the company's lab-on-a-chip technology. Motorola also holds an exclusive license to a DNA chip technology developed at Argonne National Labs, Argonne, IL.
Ultimately, says Naclerio, Motorola seeks to develop a small device that would fit in the palm of a doctor's hand. In fact, the BioChip Systems Unit is part of a team of researchers awarded a three-year, $9-million contract in October by the National Institute of Standards and Technology to develop a biochip-based disposable device for doctor's offices that would enable the rapid diagnosis of life-threatening bacterial infections. Motorola Lab's Physical Science Research Laboratories in Tempe, AZ, is heading the project and will be responsible for designing and manufacturing the device.
The BioChip Systems Unit is already producing thousands of biochips each month, but most of them are used by its internal research organization, says Naclerio. The company plans to introduce a DNA chip for the research market later this year, he says.
While Agilent has its own research program in biochips and associated instrumentation, it also has forged a strategic alliance with a biochip company to get into the market early. The lab-on-a-chip introduced last fall relies on technology licensed from Caliper Technologies Corp., Mountain View, CA.
Each chip can process 12 samples, performing some basic handling and sample separation steps, but it's still a far cry from a completely automated microscale laboratory. "We're basically at the transistor stage now," says Kevin Meldrum, product marketing manager in Agilent's Chemical Analysis Group. "Nobody's there yet with these devices. That's something that's going to take time."
Building biochips
What will also take time is determining which manufacturing process makes sense for biochips. The methods for making these devices are about as varied as DNA itself, and companies are still casting about to find the right manufacturing method to suit their chips, Meldrum notes.
The choice of manufacturing method may depend on the complexity and the longevity required by the devices, says Meldrum. If one chip can be used to process many samples, then it may justify a more expensive manufacturing process, such as silicon wafer techniques. However, if the device will be built in high volume and needs to be disposable, cheaper methods, such as plastic injection molding, will be pursued, he says.
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| "Our chips are basically microscope slides with pieces of DNA printed on them."--Lewis Gruber, CEO of Hyseq Inc. | |
Hyseq Inc.'s DNA microarrays, for example, use a low-cost manufacturing technique. "Our chips are basically microscope slides with pieces of DNA printed on them," says Lewis Gruber, CEO of the Sunnyvale, CA-based company. The company uses a micro-spotting technique, whereby a robotic arm simply dips an array of pins into DNA material and then presses it onto the glass.
Affymetrix and others use a photolithographic process to pattern the DNA sequences onto the chips, an expensive process that can take many masks. At Affymetrix, masks are used to expose parts of a glass wafer, on which certain chemical processes take place, to construct single-strand DNA probes. The wafers are then diced, and individual arrays are packaged in injection-molded plastic cartridges.
A third method, sometimes used by microfluidics device makers, is laser micromachining. In this technique, a software-controlled laser cuts a pattern into a substrate. This patterned substrate is used to make a mold. The chips are then mass-produced using plastic injection molding techniques.
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Motorola manufactures its lab-on-a-chip devices at a Tempe, AZ, process development line for its semiconductor and MEMS business, says Naclerio. The manufacturing process is "kind of like a MEMS technology," he says. Motorola uses semiconductor processes such as photolithography and etching to make the chips. But because the feature sizes of these chips are much larger than typical ICs, "we are more likely to get our equipment from the flat-panel industry or a high-density circuit board facility" than a chip fab, he says.
Inexpensive testing
Beyond the manufacturing costs, companies also are working to lower the cost of using biochips. In many of the DNA chips, a match is flagged by some sort of fluorescent material. An expensive reader costing $50,000 to $100,000 is required to scan the chip and detect these levels of fluorescence.
Companies aiming at the very low-cost market are developing ways to avoid this. In Clinical Micro Sensors' technology (one of Motorola's partners), for example, DNA matches are detected bioelectronically. The company deposits anywhere from 10 to 50 DNA probes on a printed circuit board that measures roughly one square inch. Rather than using fluorescence, the company uses an organic atom that has iron in it and can generate an electronic signal when the DNA matches, according to Randy Levine, vice president for business development at CMS. While the device has far fewer probes than biochips from such companies as Affymetrix, which markets to researchers, the CMS chip should be much less expensive to manufacture and read. That should make it appropriate for a mass medical market, he says.
"They are in the business of discovering DNA, and we are in the business of diagnosing it," he says.
He envisions a device that allows a doctor to not only detect strep, but also identify the strain of strep so that she can prescribe the correct antibiotic on the spot. Such a device need not have thousands of probes, only a handful that would test for the known strains of strep, he notes. He expects that CMS will introduce its first product, for early adopters, later this year.
The path that various companies take to manufacture biochips may hinge on whether they are targeting a mass market, like Motorola and CMS, which requires high volume and low cost, or the research market, which may require a more custom process tailored to specific applications. Indeed, Agilent's Meldrum thinks that the ASIC manufacturing model may best suit the biochip market. Under that model, specific chips are built to meet specific needs. "It's unlikely that there will be a canned answer that meets everybody's needs," he says.
Desktop biochip publishing
But the manufacturing technique being developed by NimbleGen Systems, a Madison, WI-based company using TI's digital light processor technology, may actually enable researchers to churn out their own custom biochips quickly and inexpensively. The method resulted from an unusual collaboration among University of Wisconsin researchers at the school's Center for Nanotechnology and the Center for Biotechnology. Biotech researchers trying to figure out how to make their own DNA microarrays approached Dr. Franco Cerrina, director of the Center for Nanotechnology. "Michael Sussman from the biotechnology center came to me and said, `Do you know how to make photolithographic masks? I need 80 of them,'" says Cerrina. The photolithographic process used by Affymetrix uses as many as 80 masks, says Cerrina. As the researchers realized that producing these masks would cost anywhere from $40,000 to $80,000, they began to discuss other possible solutions.
Cerrina -- who had been thinking about possible photolithographic applications for TI's DLP technology ever since he heard a paper presented on it in 1993 -- suggested they try it. The digital light processor uses an array of micro mirrors, each mirror measuring 16 microns, to direct light. The size and layout of these mirrors just happened to fit very closely the dimensions of the DNA chip the researchers wanted to make.
Because the mirrors can be redirected by software control to shine lights in different patterns, NimbleGen's method allows you to create "virtual masks" rather than having to actually build a sequence of physical masks. Not only is it less expensive, says Cerrina, but because it's controlled by a software program it's quick and easy to make changes. He claims the system can manufacture a biochip in 12 hours. Glass masks, in contrast, take weeks or months to make, he says. It's like the difference between mainframe computing and PCs. He likens it to "a desktop publishing system for DNA chips."
Tam Harbert is Electronic Business' national editor in Washington, DC. She can be reached by e-mail at tharbert@reporters.net.
