Although many scientists point to the Human Genome Project as the leading milestone of recent years, many other advances'such
as array technology and RNA interference±also push ahead basic and applied research. The experts interviewed here explore
recent developments in knowledge and techniques.
|by Mike May and Gary Heebner
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Life science moves ahead rapidly, and has for the past couple decades. In fact, life science advances so fast that telling a milestone from just another incremental achievement can take some thinking. Fortunately, Donald Kennedy, editor-in-chief of Science, provides two guidelines. He says, "One feature of a milestone is the development of really new technology that lets scientists do things that they never could before that advance." Such advances include fluorescent microscopy and high throughput genomic sequencing. "The second feature worth pointing out about milestones," says Kennedy, "is a discovery that brings into play a whole assembly of new technology to do something that we would very much like to do." For example, it would surely be a milestone in life science to combine genomics, drug discovery, and other approaches to fight human disease or aging (for more on aging see the accompanying Updates on Aging).
In the past five years, though, selecting the key milestone in life science seemed easy enough for the experts interviewed here. They all pointed out the sequencing of the human genome. Many also added sequencing model organisms as equally important. Other milestones emerged, as well. For example, Kennedy indicates the value of small interfering RNAs. He says, "They provide the capacity to knock down rather than knock out gene function, and that lets us explore all the ways that RNAs may influence control over transcription." The experts interviewed here also mentioned the value of automation, microarrays, microfluidics, and other technological advances that drive life science.
The advances, however, go beyond molecular-based science. Improvements also push ahead behavioral sciences and ecology. For example, a combination of electronic tags and satellites recently helped a team of scientists from the Hopkins Marine Station track Atlantic bluefin tuna. Other behavioral scientists now use robots to tease out details behind displays of aggression and communication.
As the experts interviewed here reveal, life science quickly moves to levels never imagined. Read on to hear about some exciting recent advances and possible advances that lie ahead.
Some of the major milestones in recent years for the life sciences come from processing more samples of smaller size, which can be done, for example, with microarrays. Steve Lombardi, senior vice president, product marketing and development at Affymetrix, ranks microarrays among the top five milestones of the past five years. He says, "The world of life science used to think of a genome as a list of genes. Microarrays enable whole genome science by showing us that there is a molecular biology of the genome." The devices can be made in a laboratory or purchased ready to use from companies such as Affymetrix. Companies specializing in the fabrication of microarrays include GE Healthcare, Hitachi Genetic Systems/MiraiBio, and Thermo Electron.
These devices also provide new ways to study disease. Lombardi explains that high density arrays let scientists look at disease-related sequence variation, see what genes get turned on with a disease, and understand the transcription factors that bind to DNA and turn on the genes in the first place. He adds, "The amount of information we can now put on one Affymetrix chip±over 6 million probes±means that you can do all of this on one chip on one platform." Moreover, this approach is unbiased and hypothesis-free. That is, a scientist lets the experiments reveal how the genome works.
Microarrays can also be aimed specifically at signal transduction research, especially with products from EMD Biosciences and SuperArray Bioscience. Li Shen, president of SuperArray, says, "The microarray is a revolutionary concept. It changes how we can get information from a cell."
For example, SuperArray's GEArrays can be used to validate and confirm a hypothesis, especially one related to a disease. Shen says, "We have quite good coverage for different applications. We have about 50 arrays for pathways of diseases, including cancer, immunology, neuroscience, toxicology, stem cells, and developmental biology."
In addition to making microarrays for many applications, SuperArray also aims to make this technology simpler to use. She says, "Another technical focus for us is making microarrays reliable and easy to use. We want microarrays used in every lab as a routine tool, like the polymerase chain reaction [PCR] is used today."
Fine Tuning the Fluid Flow
Microfluidics handles very small volumes of fluids, including nano- and picoliter volumes, for DNA analysis, the separation of human blood cells, and other applications. This field includes lab-on-a-chip technology, which comes from several companies, including Agilent Technologies, Caliper Life Sciences, Cepheid, and Gyros.
According to Kevin Hrusovsky, president and chief executive officer of Caliper, "Lab-on-a-chip technology might not have been a milestone in the past five years, but it will be in the next five." He adds that as many as 70 percent of the top-tier big pharmaceutical companies use this technology.
For example, Caliper's LabChip 3000 drug discovery system miniaturizes, integrates, and automates enzymatic and cell based assays. Hrusovsky says that this instrument is being used by Johnson & Johnson, Merck, Pfizer, sanofi-aventis, and other big pharmaceutical companies that need higher quality screening and profiling data. He says, "The LabChip 3000 is very robust, much less expensive, and we have not had a chip-quality return in over a year."
Advances in drug discovery will also come from new approaches to protein identification and quantification. For example, the disposable Prespotted AnchorChip±a matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) target±from Bruker Daltonics can help researchers find new lead compounds or biomarkers. According to Detlev Suckau, head of application development for MALDI-TOF instruments and proteomics at Bruker, "This chip provides a 10-fold to 100-fold increase in sensitivity." It consists of a plastic substrate±developed by Eppendorf and Bruker Daltonics±with prespotted MALDI matrix and calibrant spots. Suckau says, "Eppendorf has the technical expertise to produce injection molded plastic chips of the required quality for this product. So it was an excellent choice to work with them."
A Gene Take Down
When scientists first learned about genes, they surely thought of finding ways to block them. A variety of systems±including genetically engineered lines of mice, altered tissue culture cells, and molecules like short interfering (si) RNA'suppress or knock down genes. Among the experts asked here, and probably many life scientists, RNA interference (RNAi) ranks as an important milestone.
To cause RNAi, a scientist puts double stranded RNA into a cell. The double stranded RNA matches up with complementary mRNA and destroys it, which stops it from making proteins. So far, scientists know that RNAi takes place in cells from many organisms, including mammals, and it apparently participates in antiviral defense and the regulation of gene expression. A number of companies±including Ambion, Dharmacon, and New England Biolabs±offer RNAi kits.
David Brown, research and development senior scientist and head of the siRNA project group at Ambion, believes that RNAi filled a research void. He says, "Genome projects verified the blueprint of life±all the genes±but the key is to understand how they interact and function. RNAi provides the opportunity to link gene identity with gene function. You can eliminate a gene's expression and see what happens."
This technique can be used in basic and applied research. For example, RNAi can be used to fight disease. A researcher can knock down individual genes and see how it affects the phenotype of different cells. For instance, says Brown, "Cancer researchers can look for gene-specific siRNAs that affect proliferation or apoptosis or angiogenesis or telomerase activity." In addition, these techniques can be applied to high throughput assays. Brown says, "We now have delivery techniques for cell lines and primary cells that provide highly reproducible knock down in every well of a 96- or 384-well plate."
In many experiments, scientists would prefer to focus on primary cells. According to Pat Dillon, president and chief executive officer at ArtisOptimus, "People have always known the importance of primary cells." Still, researchers often used immortalized cells instead, mostly out of convenience. "But immortalized cells are not normal," says Dillon. "Some are a lot farther from normal physiology than you would like for studies." For example, immortalized cell lines can grow differently than cancer cells in the body.
To give researchers access to primary cells, ArtisOptimus grows primary mouse embryo fibroblasts (MEFs) from normal and knockout mouse models that retain their initial growth and genetic properties. The company offers knockout MEFs for several areas related to cancer research: cell cycle, apoptosis, and signaling studies.
Moreover, providing primary cells with known gene knockouts will open new approaches to studying disease. For instance, Dillon says, "Certain MEFs have been used in studies of growth, which can be applied to cancer biology." In addition, primary cells can be used for drug development. As Dillon says, "We have generated some knockout MEFs that include genes involved in drug transport. With these, a researcher can look at a drug's metabolic effects."
Updates on AgingSAGE KE±the Science of Aging Knowledge Environment—offers one-stop shopping for investigators interested in the science of aging. This site features scientist-written reviews, perspectives, as well as case studies on neurodegenerative diseases. In addition, it delivers new stories on the latest discoveries and orientation articles on hot topics in the field. This website also provides meeting information and a variety of other useful sections.
Screening and Simulation
In the world of biotechnology and pharmaceutical companies, researchers remain on full-time alert for improved throughput in drug screening. Although that process keeps picking up speed, Jeff Mooney, commercial technology director in the Life Sciences Division at Corning, says, "You can now run through the targets quickly, but you still have a bottleneck of both false positive and negative ±hits," and the inability to screen intractable or orphan targets."
To enhance the accuracy of screening, Corning developed its Epic platform. Mooney says, "We surveyed bottlenecks from identifying viable targets to validating leads, and then designed the Epic system to solve some of these problems." That produced a label-free, high throughput system that detects biomolecular interactions. For instance, this platform identifies interactions between proteins, proteins and small molecules, and chemicals±all on a 384-well plate.
After releasing this product, Mooney started receiving positive feedback from customers. He says, "We have people telling us that an assay which took six months to develop for conventional screening systems can be done in just a week with our system." In addition, Mooney says, "We are currently working with customers on assays for intractable targets as well as on assays to validate a reduction in both false positive and negative hits. Better lead generation will reduce costs and hopefully enable better drugs."
Some of today's experimental research can take place in silico. That is, interactions, biologic processes, and system behaviors can be modeled on a computer. Mikhail Gishizky, chief scientific officer at Entelos, says, "Use of computer biosimulation is in its infancy for life sciences." He adds, "Computer simulation will play a greater role in understanding qualitative and quantitative differences in biologic processes between, for instance, mouse and man, and help scientists make better decisions." At Entelos, scientists build quantitative models that predict human biological behavior. Specifically, this company's PhysioLab technology enables the development of large-scale, whole-system models of dynamic biological behavior. In fact, this modeling system is being used in many projects with pharmaceutical companies, including finding druggable targets and designing clinical trials.
The greatest advances of the recent past required combinations of technologies. Even more integration might lie ahead, especially in fields like systems biology. Kennedy says, "it's very hard to predict what new technologies will be possible even in the near future." As an example, though, he says, "Applications of lab automation are going to outstrip our capacity to even envision what they might be." Although he worked in neurobiology for many years, he adds, "When I walk into a neurophysiology lab today, I see people using computers to manage experiments in ways that I would not have dreamed possible." Perhaps a scientist's dreams are the very things that lead to milestones.
Mike May () is a publishing consultant for science and technology based in Madison, Indiana, U.S.A. Gary Heebner ( ) is a marketing consultant with Cell Associates in St. Louis, Missouri, U.S.A.
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