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Monster Sequencing Show


“Sequencing isn’t just for the US and UK anymore.” So observes Mark Sutherland, vice president of genomics at Amersham Pharmacia Biotech. Indeed, as the profiles on the following pages reveal, some of the biggest new customers of Amersham’s MegaBACE 1000 DNA Analyzer are not in Europe or North America. And although Amersham’s main rival in the high-throughput-sequencing business, Applied Biosystems, declined to name any recent big ABI Prism 3700 buyers, it’s a safe bet that many of the 2,000 of those instruments it has sold since January 1999 have been shipped overseas.

Here we portray the state-of-the-art in DNA analysis facilities — some of the largest genome sequencing and genotyping factories in the world. Their locations might surprise you, but their activities signal the emergence of a transnational genomics industry.

For instance, one of the current projects of Brazil’s São Paulo state genomics enterprise, a “virtual” sequencing operation that relies on instruments dispersed across some 60 laboratories, is a US Department of Agriculture contract to sequence and annotate a strain of the Xyllela fastidiosa pathogen that plagues grape crops in California. The São Paulo scientists claim they beat out the US’s own Joint Genome Institute for the contract.

The Beijing Genome Institute, whose Hangzhou branch elicited a government-ordered interstate-highway shutdown for the army-escorted delivery of its MegaBACE machines, has also extended its reach to the US, where it has established a bioinformatics company in San Mateo, Calif. This could be related to the fact that three of the five directors of the Chinese genomics operation are based in the US.

And one of Applied Biosystems’ more remote customers, DeCode Genetics in Reykjavik, is backed by a Swiss pharmaceutical company (Roche) and staffed by scientists from 25 nations.

Of course, “state-of-the-art” isn’t a crown anyone gets to wear for long in this market. Sutherland says that methods for souping up the MegaBACE as well as faster, cheaper, new sequencing techniques are under development at Amersham. And although ABI couldn’t be reached for comment, its investments in alternative sequencing technologies from companies such as Hyseq and SpectruMedix indicate parallel endeavors.

Competition for the high-throughput sequencing market is also emerging in the form of 384- and 96-capillary electrophoretic instruments with eight- and 10-color dyes and advanced robotics from Baylor College of Medicine and SpectruMedix. And rumor mills are rife with speculation about covert development of other non-capillary-based sequencing technologies.

DNA Sciences, whose fleet of MegaBACEs pictured on p. 42 is not even one year old, is already readying to upgrade to the microchannel-chip sequencing device that it is codeveloping with Amersham. That technology, says CEO Hugh Rienhoff, should enhance throughput by a factor of five.

It’s only a matter of time before the monsters here are considered dinosaurs.

— Adrienne Burke

Genome Carnaval

The São Paulo Genome Project began humbly with Xylella fastidiosa, a plant pathogen. Two years and 61 labs later, the project has $270 million in funding and a number of sequences under its belt. It’s considered the brainchild of José Fernando Perez, scientific director of the São Paulo State Research Funding Agency.

The labs are scattered throughout 13 cities in the state of São Paulo — a logistics challenge to the massive effort to get Brazil up to speed in genomics. Unlike other groups that divvy up projects by facility, the Organization for Nucleotide Sequencing and Analysis defies the distance between its dozens of labs and works as one entity. It’s a unique model, and one that they hope will continue successfully as it expands. Andrew Simpson of the Ludwig Cancer Institute in São Paulo (a group that works closely with ONSA on its human cancer sequencing effort, looking at expressed genes in tumor cells) heads up the initiative to involve all of Brazil in the genome center. The plan is to wind up with 100 sequencing labs across the country, from Amazon to Uruguay, Simpson says.

So far, though, São Paulo is going it alone. “Funding in the state of São Paulo is robust, unlike the rest of the country,” says Sergio Verjovski-Almeida, professor of biochemistry at the University of São Paulo, the network lab pictured here. So when Perez came up with the idea, it was obvious where to begin.

Originally, Perez just wanted to prove that Brazil could get in on the sequencing action. When the Xylella sequence showed he was right, he turned to a new goal: establishing Brazil’s presence as a leader in the field. “We are trying to become more focused toward efficiency,” he says, referring mainly to finances. “In the first Xylella project, the cost was around $13 million” — primarily because minimizing cost wasn’t an issue when he was getting the effort up and running. Now, he says, they’re “trying to bring down the price to an international standard.”

ONSA has its fingers in plenty of pies: human cancer, plant pathogens, sugarcane, and bacteria, with plans to broaden its horizons even more. But its niche, Perez feels, will be in plant pathogens. In fact, when the Joint Genome Institute stopped after a rough draft of Xylella, the USDA enlisted Brazil’s virtual center to finish sequencing this pathogen, a different strain than the original Xylella ONSA had already completed. Perez also plans to branch out from sequencing to structural and functional genomics.

These new plans may be driven by the realization of past ones. Two years ago, there was a measles epidemic in Brazil; in order to identify the virus responsible, scientists had to send it to the CDC in Atlanta. “Now,” Perez says proudly, “we can do these things in Brazil.”

— Meredith Salisbury


São Paulo Genome Project, Sao Paulo, Brazil

• 11 MegaBACEs, 8 ABI Prism 3700s, 41 ABI 377s

• Total staff: estimated 350

• 61 labs in virtual sequence center

• Value of instruments: $16 million

• Current sequencing studies include Xylella, Leifsonia xyli; plans to begin at least 10 bacterial genomes this year


Great Spiral Forward

Mayor Baoxing Qiu of Hangzhou, China, knew exactly what he wanted, and he wanted it fast. The Beijing Genome Institute (pictured here) had been receiving lots of attention for sequencing a chunk of chromosome 3 for the international human genome project and he wanted a piece of the action.

Flashing 300 million Chinese yuan, or $35 million, he lured BGI to set up a branch in his city 1,200 miles away. There was one catch: he wanted 38 MegaBACE 1000 sequencers up and running within 18 days — in time for the Chinese New Year on January 24, 2001.

“It seemed impossible,” says Mathew Huang, a BGI co-director who also works full time at PPD Discovery in Menlo Park, Calif. “You can’t even process the paperwork fast enough for the import-export control.”

Nevertheless, the mayor was determined. To make room for the state-of-the-art sequencing center he ordered the evacuation of a local government building within 48 hours. Never mind that the city didn’t have enough juice to get the machines going: he simply squeezed it out of the neighboring residential area, cutting their power by 40 percent. Locals didn’t seem to mind eating in the dark. “Because there was this wow effect,” says Huang. “They had an open house and everybody came in to take a look and they were fascinated.”

Together the 70 MegaBACE and 11 ABI 377 sequencers at the two locations churn out 10 megabases of sequence a day. Aside from finishing chromosome 3, the BGI has taken on three new major projects: finding all the SNPs common in the Chinese population; shotgun-sequencing the pig in collaboration with a Danish consortium; and sequencing the Indica strain of rice. (The international rice genome project is sequencing the Japonica strain.) Future plans include identifying the active proteins in traditional Chinese herbal medicine.

“Because in China labor is cheap and machines expensive, we use less automation than you typically see and more people,” says Huang. The two branches employ a staff of 400.

BGI is not just expanding across China. It has spun off a bioinformatics company in San Mateo, Calif., and is planning a sequencing service center in San Diego. “If you want to set up a collaboration with any US concern, it’s much easier for your customer to talk to you if you have a US office,” says Huang. “The mere fact that you can be in the same time zone is a big plus.”

— Aaron J. Sender

Beijing Genome Institute, Beijing and Hangzhou, China

• 70 MegaBACE and 11 ABI Prism 377 sequencing machines

• Total staff: 400

• Capacity for 10 megabases of sequence, or 50,000 reactions, per day

• Sequencing rice, pig, and human chromosome 3

• Genome-wide SNP discovery project in Chinese population

• Plans for high-throughput proteomics project focused on traditional Chinese medicinal herbs



Genotyping Lagoon

Regardless the proximity to the Arctic Circle, 56 ABI Prism 3700 sequencing machines can generate enough heat to cause a meltdown.

DeCode’s operations — currently dispersed over five locations in a suburban industrial neighborhood on the 64th parallel — will soon be consolidated into a state-of-the-art facility near the Reykjavik airport that is better equipped to power and ventilate its genotyping factory. According to Bjorgvin Richardsson, genotyping director, its arsenal of instruments makes DeCode not just the only owner of a 3700 in Iceland, but the largest commercial genotyping facility on the planet.

To be sure, DeCode had a rough start when it began acquiring Prisms two years ago. The first 3700 that Applied Biosystems delivered in June 1999 was a lemon. “It never worked, so we sent it back,” says Richardsson.

But after trying out several more of the machines that the backlogged vendor delivered six months later, the Prism became DeCode’s instrument of choice. Richardsson, who says he likes everything in his lab to be “as automated as possible,” found the 3700 to be superior in that regard.

Last September a small army of ABI engineers installed another 20 of the instruments at DeCode, followed by 20 more in October, and 10 in November.

Six of the machines are dedicated to good old-fashioned sequencing, in search of mutations in the Icelandic population. But the bulk are employed around-the-clock conducting genome-wide scans for microsatellite markers, which Richardsson says are cheaper to analyze and more informative for DeCode’s purposes than SNPs.

Richardsson notes that DeCode gets even faster throughput by preparing PCRs in a 384-well format with six Cyberlab C-400 instruments.

To manage such ultra-high throughput, Richardsson says DeCode’s in-house software development has been paramount. All PCR trays, equipment, blood samples, and even employees are bar-coded so that each step of a process can be scanned and logged into a database. Richardsson says, “We can always follow what’s going on where and, if something fails, trace it back.”

To date, a staff of 67 people, working 16-hour shifts on weekdays and 12 hours on weekends, has scanned 30,000 individual samples for 1,000 disease markers. DeCode’s goal is to genotype as many of Iceland’s 300,000 citizens within the next two years as will consent. Ultimately, the company’s genotype database will be set up to enable users, under government supervision, to cross-reference the Icelandic Health Sector Database of anonymous, encrypted medical records, as well as a national genealogy database.

Now that the equipment is running smoothly, Richardsson says the only bottleneck to achieving those goals is collecting donors’ blood samples fast enough.

— Adrienne Burke

DeCode Genetics, Reykjavik, Iceland

• 56 ABI Prism 3700 sequencing machines

• 50 dedicated to microsatellite detection; six dedicated to sequencing

• Total staff: 450

• Intends to genotype entire 300,000-person Icelandic population within two years

• Can produce 500,000 to 600,000 genotypes per day

• Studying 40 common diseases in seven areas: cancer, autoimmune, cardiopulmonary, CNS, eye, metabolic, women’s health


Razor Sharp RIKEN

When Japan’s publicly funded RIKEN Genomic Sciences Center opened its doors in October 1998, 16 years had already passed since Tokyo University biophysics professor Akiyoshi Wada began widely promoting his idea that the future of biology lay in sequencing supercenters. Wada envisioned machines concentrated in factories around the globe processing large volumes of data and reading information hidden within DNA.

In a classic case of gaiatsu, or outside pressure, it was only after the idea took hold overseas that researchers in Japan were convinced to back the project.

Now director of the GSC in Yokohama, about 30 km south of Tokyo, Wada oversees six groups including one that contributes to Japan’s Human Genome Project and an NMR facility dedicated to developing an encyclopedia of protein folds.

Sequencing, which accounts for about a quarter of the center’s activities, is being conducted by two groups. One aims to finish sequencing the center’s library of 128,000 mouse cDNA clones this year. The other, having completed human chromosome 21 last May, is now chipping away at 11 and 18.

Wada (pictured at right) has his eye on the cutting edge. Of selecting new research projects he says, “Our sole criterion is if by doing it we will be accomplishing something being done nowhere else in the world.”

Already, his various groups have achieved what Wada claims are “firsts” in Japan. They have built the RISA 384-capillary sequencer in collaboration with Shimadzu, developed an original method for synthesizing full-length DNA, created the multimagnet NMR system, and established a cell-free protein synthesis system.

Among the center’s future plans are to explore protein-protein and protein-DNA interaction and to research links between genes and behavior.

To ferret out the secrets of brain function and human intelligence, GSC scientists will also begin comparing human and mouse genes to data generated by a new chimpanzee genome-sequencing project.

Wada says his strategy is “to advance the main research while we are already moving ahead on the future possibilities it presents.” The central research and pilot projects overlap and parallel each other, and leaders of each project coordinate their efforts and meet for monthly progress reports.

With additional projects creating mutant mouse and plant stock and developing bioinformatics, the work at the center aims to integrate knowledge about genes from the molecular level to that of the living organism.

“While the 20th century science was all about creating islands of knowledge,” Wada says, “the 21st will be about connecting them.”

—Sara Harris

Genomic Sciences Center, Yokohama, Japan

• Sequencing machines: 31 RISA; 6 ABI 377; 13 ABI 3700; 10 LiCor; 18 MegaBACE

• Total value of instruments: $21.6 million

• Total staff: 90

• Sequencing capacity: 42.6 megabases per 20-hour day

• Current project goals include: completing mouse cDNA sequence within the year and establishing encyclopedia for study of multiple gene-caused adult diseases (cancer, diabetes, hypertension, arteriosclerosis); sequencing human chromosomes 11 and 18


Going Deep

Just because DNA Sciences spent $6.6 million on its fleet of MegaBACEs, has sunk untold resources into development of a “next-generation” sequencing device, and relies on six separate staffs of software programmers to keep its data in order doesn’t mean technology is king around here.

Instead, the firm’s success will depend largely on the designs of its studies, says CEO Hugh Rienhoff. “The secret to genetics is not technology. The secret to genetics is having really good design and going specifically for the kinds of things you’re interested in,” he says.

In DNA Sciences’ case, that would be low-frequency genetic variations. Among DNA samples collected through its Gene Trust donor program, academic collaborations, and the recently acquired PPGx/Sequana database, the company aims to identify common genetic causes to common diseases — in other words, moderately penetrant genes. “We’re not interested necessarily in high-penetrance genes … that have those clear Mendelian patterns in families,” Rienhoff explains, “because they’re rare.”

Rienhoff credits genetics veteran Ray White, DNA Sciences’ CSO, with developing the approach that will differentiate this company from others in the field. “Everybody else is still doing the family-based, high-penetrance, rare kinds of diseases,” Rienhoff contends.

Each DNA Sciences study employs the MegaBACEs differently. For instance, Rienhoff explains, “If you know that a particular region or nucleotide is variant, we use sequencing there rather than genotyping because sometimes there is more than one change in a given stretch of DNA. And we’re interested in identifying the extent of what you might call allelic variation in a particular region. You couldn’t do that if you simply genotyped at a single site.”

He adds that the capillary electrophoresis instruments are flexible enough to suit all of the company’s “interrogation needs.” Whether a study demands finding STR markers, genotyping SNPs, or “deep sequencing” — the method DNA Sciences uses to determine sequences of specific genes or regions in a large number of people — the processes are the same up until the last step. So, Rienhoff says, using the MegaBACEs for all three methods is more effective than sequencing with one device and genotyping with another.

But while the MegaBACEs churn away at samples, prototypes of the company’s microchannel chip sequencing device wait in the wings. Rienhoff says the new instrument, which DNA Sciences licensed to Amersham Pharmacia Biotech, could reduce costs and increase throughput for sequencing and genotyping by a factor of about five. Although he predicts that Amersham won’t opt to cannibalize its MegaBACE market by commercializing the newer instrument before two years’ time, it should be online at DNA Sciences by late 2001.

What will DNA Sciences do with all those MegaBACEs then? “Make coffee tables out of them,” Rienhoff jokes.

DNA Sciences, Fremont, Calif.

• 48 MegaBACE sequencing machines

• Total staff: 152

• Examining genes and gene variants where link to disease has been established

• STR and SNP genotyping and sequencing of human DNA

• Capacity to genotype 40,000 SNPs or 50,000 STRs per day

• Current studies in sudden infant death syndrome, cancer, asthma, inflammatory bowel disease, osteoporosis, type 2 diabetes

The Scan

LINE-1 Linked to Premature Aging Conditions

Researchers report in Science Translational Medicine that the accumulation of LINE-1 RNA contributes to premature aging conditions and that symptoms can be improved by targeting them.

Team Presents Cattle Genotype-Tissue Expression Atlas

Using RNA sequences representing thousands of cattle samples, researchers looked at relationships between cattle genotype and tissue expression in Nature Genetics.

Researchers Map Recombination in Khoe-San Population

With whole-genome sequences for dozens of individuals from the Nama population, researchers saw in Genome Biology fine-scale recombination patterns that clustered outside of other populations.

Myotonic Dystrophy Repeat Detected in Family Genome Sequencing Analysis

While sequencing individuals from a multi-generation family, researchers identified a myotonic dystrophy type 2-related short tandem repeat in the European Journal of Human Genetics.