from SBS' president
LET'S GIVE HTS A CHANCE!By G. Sitta Sittampalam
Timing is critical in many aspects of life. Just as I was describing some of the challenges faced by the pharmaceutical industry in the February issue of SBS News, and the opportunities that exist for SBS members to educate the general public, someone at the Wall Street Journal (WSJ) was also looking into pharmaceutical industry woes.
The major thrust of an article by Peter Landers in the February 24 issue of WSJ (Drug Industry's Big Push Into Technology Falls Short) is that the investment in early drug-discovery technologies-namely combinatorial chemistry and high-throughput screening (HTS)-has not paid off. The implication is that the current lack of productivity in the industry may be attributed to this huge investment in the 1990s that has not yet yielded demonstrable savings.
This analysis in WSJ is akin to attributing the failure of the "dot.com" ventures in the last few years to the Internet.
Let me be specific. The advent of HTS and combinatorial chemistry technologies in the early '90s enabled parallel testing of thousands of new chemical entities for biological and pharmacological activity. This advance, along with the development of new assay technologies and liquid handling instrumentation, marked the birth of a new economy around HTS and drug discovery. The pharmaceutical industry, which was already plagued by productivity issues and competitive pressures, quickly adopted the new technologies as part of a repertoire of approaches to addressing the dwindling pipelines.
As usual, the advent of new technologies tends to generate considerable hype regarding capabilities and potential before such technologies are adequately field-tested. Some turn out to be great successes; others do not. In retrospect, even a comment that appeared in the news section of The Lancet in 1995 stating that "medicinal chemistry has undergone a revolution" (Seeking potential drugs in chemical libraries, pages 1167-1168) was clearly an overstatement made without an understanding of the trials and tribulations of drug discovery.
Not Panacea, But Progress
After almost 10 years of activity, it is now clear among drug-discovery scientists that HTS is not the panacea that many in the medical community and pharmaceutical industry predicted, nor is it the answer to productivity problems in the industry. However, this does not invalidate the technologies themselves; they have contributed significantly to the early testing paradigms that continue to evolve.
In fact, the automation and information technology tools developed for HTS are beginning to make an impact in later stages of drug development as well as early stages. High-throughput ADMET and target profiling are starting to generate data that could improve the quality of drug candidates significantly. Improved sample-handling systems and data-analysis tools are also becoming available, as added benefits in response to the HTS demands of high-content screening and imaging technologies. Integration of this information would ultimately lead to better understanding of disease pathology and treatment modalities. High-throughput approaches are also being adopted in fields outside the pharmaceutical industries, such as in screening for catalysts, fragrances, and food additives.
Education is Key
So what is the answer to the lack of productivity in the drug industry? Again, we need to educate the public, as well as some of our colleagues in the health care industry, and the media. A "hit" or "lead" in early discovery is not the medicine that is finally successful in the clinic. Refining a lead molecule to have appropriate biochemical, biophysical, and pharmacological properties is inherently challenging and time-consuming. Complex tests in cells, tissues, organs, and animals should not only define the pharmacology, but also measure efficacy, toxicity, and side-effect profiles.
Candidate molecules that make it through this rigorous testing phase have to be effective and safe in humans. The probability of technical success in the clinic is critically dependent on the quality of the molecules identified in the early phase, and this is precisely where the combinatorial chemistry, HTS, and related technologies are beginning to make the difference.
This approach is not necessarily incompatible with good science and serendipity-which was the sole method of discovering drugs 20 years ago. The concepts of efficient screening and the ability to observe and understand complex biology in real time are needed to make serendipitous discoveries.
As Martin Mackay points out in the WSJ article, we have learned a lot about the benefits and shortcomings of HTS and related technologies in the last 10 years. More and more compounds are successfully making it through early-phase testing. It will take another 5-10 years before the contributions of HTS come to the market. The Internet took that long to become the useful tool we see today. Therefore, to link the lack of productivity in the pharmaceutical industry to early-phase discovery technologies is not appropriate.
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educational outreach
"Nano World" Opens the Door to Science & Technology
By David Roman and Marilynn Larkin
 How can we share nanobiotechnology with the public in a meaningful way? That's the question that Anna Waldron, director of education for the Nanobiotechnology Center at Cornell University in Ithaca, New York, and colleagues asked three years ago. The answer: It's a Nano World, an extraordinary, 3,000-square-foot traveling exhibit that is currently on tour at Innoventions at Epcot® in Lake Buena Vista, Florida (www.itsananoworld.org). Funded largely by the US National Science Foundation, the exhibition's mission, explains Waldron, is to foster a lifelong interest in science and technology among children and adults alike. "Nanotech and nanobiotech are hot topics right now, and interest is wide-spread among the general public. The original idea for the exhibit came right before the nanobiotech craze hit, and therefore the timing couldn't have been better."
Gearing Up
Scientists, educators, museum staff, and artists worked together to develop It's a Nano World, which is the first-ever non-commercial exhibit at Innoventions at Epcot®, notes Carl Batt, co-director of the Nanobiotechnology Center. To get a sense of how young children perceived the "nano world," the team conducted interviews with children in Ithaca and surrounding areas. They discovered that most children had little understanding of things that were too small to see.
"Young children are fine with something that is one meter in size, but not so fine with millimeters, which are still visible to the naked eye," adds Waldron. "So, when we are talking about nanoscale, it's a challenge to get them beyond that millimeter size range."
Therefore, Batt, Waldron, and colleagues at Ithaca's Sciencenter museum held brainstorming sessions, after which more than 200 concepts were evaluated, and 20 prototypes that seemed workable on a museum floor were created. Eventually, the team settled on six exhibit clusters:
Entrance to Nano World provides an introduction to the nano world universe, with photos, films, and interactive exhibits demonstrating a range of sizes.
Cell sorters is a place where visitors can stick their hands into a glove box and use tools to separate out different cells based on their physical properties.
Magnification features a giant magnifying glass, a magnification station with magnifying glasses and microscopes of various strengths and sizes.
Cells in action is a video theatre environment where visitors are immersed in a world of moving cells.
Adventures of tiny things contains, among other hands-on exhibits, a pollen pinball game and germ launcher.
Giant blood drop invites young visitors to jump into a pit of thousands of small red plastic balls. The pit represents a single drop of blood, whereas each red ball represents a red blood cell. Also included are a small number of white sponges representing white blood cells.
The exhibits had to be interactive and fun, but also provide a learning experience or outcome, rather than just being a "toy" or "game," says Waldron. Therefore, the Sciencenter was a key player in the exhibit-selection process, because its staff understood how to develop exhibits that are informal, enjoyable, short term, and educational. The selection process was challenging, but also rewarding and exciting when the team saw in the eyes and faces of the children that they "got it"—for example, that they grasped the concept of nanoscale. The design firm, Painted Universe, was brought on board to make everything inviting and child- and adult-friendly. "The exhibition contains lots of playful colors, and an invigorating atmosphere, which we scientists at Cornell wouldn't necessarily have thought of doing."
Moving to Epcot
Once Cornell's educational and scientific goals were met, Waldron then had to work with Innoventions at Epcot® to ensure that the discovery park's criteria were met. Clearly, both wanted to get visitors excited about technology. But, says Waldron, "they're a commercial entity and we're not, so the language we were speaking was somewhat different. In the end, though, we understood what had to be accomplished to make It's a Nano World a success. We both made a few concessions, ended up with what we wanted, and were pleased with the outcome." The National Science Foundation provided supplemental funds to enable Cornell to set up the exhibit at the discovery park.
Originally scheduled to run through March, It's a Nano World is being held over through the beginning of May. Meanwhile, the Cornell team is learning how such exhibits can serve as an educational experience for the whole family. One example, says Batt, is the cell sorter cluster. "A cell sorter is one of the more routine analytical tools scientists use to study populations of cells, and people in our center are also looking to produce them on a micro scale. But the question was, how would we create something visitors would care about, that didn't look like it belonged in some dusty museum?"
The result, "is a scaled-up, very kinetic cell sorter exhibit that looks at fluorescence and magnetic properties—something kids can have a lot of fun with. And alongside these things are signs explaining how the cell sorter works in real life. We found that kids playing at the stations didn't read the signs. But when their parents saw how engaged their children were, the parents read the signs and told them what was going on. So, here you have something that's fun, children get engaged, parents have a chance to enjoy themselves and read what it's all about—and it becomes a collective learning experience."
The bottom line, Batt observes, is that "raising the level of scientific literacy among the general public is a good idea. The backlash against genetically modified organisms, for example, tells us that we can't just sit up here in our company or university environment and expect people to accept what we're doing because we're convinced we're doing it for the greater good. You have to get out there and explain what you're doing, and this gives us a rewarding opportunity to dialogue with the general public."
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Advancing The Science of Drug Discovery
Stories in This Issue:
