June 25, 2000, scientist announced the completion of the initial mapping of the human genome at a press conference with Bill Clinton. That was several years than expected, thanks in part to DNA sequencer technology developed by industry pioneer Michael W. Hunkapiller and a multi-disciplinary team of employees.
Hunkapiller is president of Applied Biosystems, a leader in the development of instrument-based systems for the life sciences and research communities. One of the early developers of automated systems for the analysis of proteins, peptides, and nucleic acids, he joined Applied Biosystems in 1983. A key force behind the launch of the industry's first semi-automated technology for DNA sequencing in the mid-1980s, Hunkapillar has worked tirelessly to ensure Applied Biosystem's reputation as a company that constantly innovates and engineers high-quality products.
Innovate and automate. DNA or deoxyribonucleic acid is the blueprint of life. It is composed of four chemical subunits, called bases. The order of the bases provides coded instructions for everything a cell does. Sequencing determines the order of the bases along the DNA strand.
Researchers initially performed DNA sequencing by hand. They radioactively labeled each DNA strand, placed it on a gel, applied an electric current in order to separate the DNA into fragments, and laid the gel on film to be developed. Finally, after multiple rechecking of the sequence for errors, the scientist wrote the DNA code by hand. It was a tedious and labor-intensive process.
Under Hunkapiller's direction in the mid-1980s, Applied Biosystems developed the industry's first semi-automated DNA analyzer (the 370) that replaced gel electrophoresis with capillary electrophoresis. Modern versions of the sequencer work by taking a sample of DNA and cloning the strand. It then breaks the cloned DNA into its fragments, labels each component with a series of colored dyes, and records the order of these components into a computer program that writes the DNA sequence. It acts essentially as a large fluorescent microscope.
Although the original machine worked well, it was the first technology of its kind. "We had no idea what people were expecting from it," says Hunkapiller. "It was a research tool that worked well in the hands of someone who was an expert at running these analyses, but not so user-friendly for the novice."
Engineering marvel: An offspring of the
industry's first semi-automated DNA Sequencer, the 3700 DNA ABI Prism,
boasts ten times the throughput of the original design. According to
engineers, the design features a healthy mix of proven, off-the-shelf and
advanced technologies to meet accuracy and speed requirements.
As scientists began to find new applications for DNA analyses, the demand for faster and more efficient technology increased. In particular, when many of early adopters of the 370 analyzer became involved in the Human Genome Project, Applied Biosystems engineers realized they needed a machine that could process samples faster. To put things into perspective, 3 billion bases make up the human DNA instruction book. Applied Biosystems' first analyzer had the capacity to analyze just 5,600 bases per day. Today's analyzers can pump out nearly one-half million bases daily (see chart).
Balancing needs. In the world of DNA analysis, there are two types of scientists and researchers: Those who thrive on the cutting edge of technology and those who must make life and death decisions based on results that must be accurate.
Applied Biosystems balances these opposing quality demands through a two-tiered development program, dividing its 4,500 employees into two basic groups. "We have a team of people who are experts at innovating and getting things done quickly," says Hunkapiller. "They build a certain degree of robustness into the system right from the beginning, but release it before it is 'finished' in the manufacturing sense of the word."
Hunkapiller stresses that scientific customers are eager to try out new technology. "They want to play with the equipment themselves and suggest ways we can improve upon it. In a sense, we innovate with our customers."
The 10X improvement in ABI's machine
throughput was a key factor in helping sequence the human genome - which
consists of some 3 billion bases - faster than expected.
A customer who orders a second- or third-generation product has far different expectations. And rightly so. These machines are used for high-volume sequencing tasks or forensic analysis. "Quality here is paramount," says Hunkapiller. To address this requirement, a second Applied Bio-systems team specializes in fine-tuning existing systems.
Total teamwork. At the onset of the development of the company's latest innovation, the 3700 DNA ABI Prism® Analyzer, Hunkapiller put together a multi-disciplinary design team of more than 200 electrical, mechanical, optical, and computer engineers; chemists; biologists; field technicians; sales people; and accountants. "It takes a lot of different perspectives to figure out the quality issues and find the best ways to manage them," he says.
Even though the new model would be based in large part on existing technology, Hunkapiller called for monthly concept and feasibility reviews—a procedure that is an inherent part of all product development efforts. Experts from engineering, R&D, marketing, manufacturing, product test, and service development gather to discuss the results of their tests and analyses, review outstanding technical issues, and ensure that individual components meet specifications. Employees typically make formal presentations on topics ranging from customer feedback to component failure. A group discussion follows.
"This kind of process has all kinds of benefits," says Matthew Desmond, senior engineer, mechanical. "It forces you to take a step back and think about not only what you have done, but what you haven't done."
"We use these meetings as an opportunity to focus on the tough questions and get them resolved," says Project Manager Kevin Hennessy. "For example, if tests show that a component is frying after 100 hours, we need to find out why."
Senior technical heads also get together twice a week to discuss outstanding issues. Hunkapiller isn't shy about getting personally involved, either. He visits customers and vendors, and personally checks in with team members. "I can vividly recall looking up from my desk and seeing Michael there, asking to see a failed part that we were having a problem with," says Hennessy.
The result of this attention to the detail and commitment to quality? A totally automated system that is easy to use, yet speeds up and lowers the cost of research. In fact, technology developed by Applied Biosystems is widely credited for the initial mapping of the human genome. Sequencing of human DNA was completed in June 2000.
"The Human Genome Project heavily invested in developing technologies to
automate and accelerate the completion of the human genome sequence. The
development of these technologies by those in the private and academic sectors
has significantly increased the production of the human genome sequence," says a
spokesperson at the National Human Genome Research Institute.
"Because it is totally automated, we replaced 30 people with 8 or 9 who can produce about 75% more," says Tamara Feldblyum, Director of the DNA Sequencing Facility for the non-profit Institute for Genomic Research (Rockville, MD). "We run 96 samples every three hours, compared to the eight hours required to run the same number of samples before."
The new model is also more efficient and accurate. "It not only saves us time, but allows us to optimize our reactions, thereby cutting costs," Feldblyum continues. Her lab's cost per sequencing reaction is 80% less than five years ago.
To ensure accuracy, engineers incorporated a series of checks and balances so that the instrument will analyze a known sample in parallel with the sample being tested. "The application of different technologies allows us to perform validations from a number of different perspectives," says Hunkapiller. "For example, we often use chemistry or software checks to perform validations instead of a mechanical component."
Efforts to improve quality don't stop once a machine is on the market. Project Manager Kevin Hennessy relates a situation in which President Michael Hunkapiller was personally involved. "In the first two months of 1999, we were experiencing problems with a component. Not all systems were having this problem, and the component maker had been unresponsive, so it was not immediately clear what we were dealing with. During a meeting with the customer, Michael was asked about our efforts to correct the problem. Upon his return, Michael came over and inspected one of the failed parts. He asked for a written summary of the failure modes and history of issues, then contacted the component vendor and asked for their support in getting the problem resolved."
The vendor quickly formed a special design team and tasked it to solve the problem. Ultimately, engineers redesigned a complete new set of components that were tested and shown to increase lifetime. The component was approved for use on all instruments, leading to a reduction of failures in the field and an increase in machine reliability.
It's that kind of attention to detail and continuous improvement that has given Applied Biosystems its biggest vote of confidence—a leadership position in the marketplace. Product manager Michel Fox sums it up best: "Our customers have confidence that what they buy from us works, and that we can make it better over time."