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from SBS’ president
SBS: What our Members need to know
By Dejan Bojanic
One of my New Year’s resolutions is to enhance communications between the SBS governing body and the membership. Therefore, I am taking this opportunity to tell you a bit more about our Society—in particular, who we are and what we do.
SBS is about 2,000 members strong, covering a wide range of disciplines and interests in government, academic, industrial and vendor community sectors. It was created 10 years ago principally to bring together the various parties involved with high- throughput screening (HTS), an emerging discipline at the time, and was the catalyst for our first HTS conference in Philadelphia. The annual conference established SBS, and from those modest beginnings the society has grown to be a wide ranging resource very much focused on supporting its membership and advancing the science of drug discovery.
SBS is a not-for-profit organization. What this means is that our business model is very simple: to maintain the organization so that it can support the SBS community and to be as cash neutral as economic circumstances allow. Apart from supporting the members as our number-one priority, our only other business is not to go out of business.
Bearing in mind the uncertainties and risks associated with running expensive conferences (recall that we were in Baltimore on Sept 11, 2001, and that Hurricane Ivan affected conference attendance in 2004), our financial reserves provide a modest buffer to ensure solvency. Thus, we balance our fiscal responsibilities to keep the membership benefits high, membership costs low, and to keep the society there for you in the future.
Governance
The governing body is the Board of Directors (BOD). The BOD comprises nine members in good standing who are elected by you, the membership. To maintain continuity, each Board member’s tenure is for three years, and each year we have three members who leave and are replaced.
The vote in 2004 resulted in Richard Eglen, Tina Garyantes, and Lisa Minor joining the team, replacing Bob Campbell, Marc Feiglin, and Jim Marks. The remaining incumbents are Alan Fletcher, John Westerfeld, Dave Burns, Emilio Diez, Kelvin Lam, and Neil Benson. Board members take time out of their very busy schedules to support SBS in this important role. Board meetings are held four times a year at a venue in the New Jersey to Massachusetts corridor, and generally last a whole day, covering topics such as the conferences, finances, strategy, etc.
Complementing the BOD are the Officers, who include Christine Giordano, Executive Director of the SBS office; Sitta Sittampalam, Past President; Al Kolb, President Elect; and myself (President). The Officers, together with Chairman of the BOD, Alan Fletcher, comprise the Executive Committee. The Executive Committee helps to set agendas for Board meetings, etc., and often discusses business requiring rapid resolution.
Since the BOD are elected by the membership, they have voting rights and are responsible for decision making. In contrast, the Executive Committee, with the exception of the Chairman of the BOD, are not elected by SBS members and thus have no voting rights. Christine Giordano is the chief staff executive of SBS, whereas the President is elected by the BOD.
There is a three-year life cycle to the presidency. The President-Elect is in training for one year. He or she then becomes President, and eventually moves on to become the Past President. It seems complex, but having this structure gives us a contingency in the event that the President is unable to fulfill SBS obligations because of work commitments. The President helps to provide leadership and strategy and is a liaison between the board and the membership as well as being the official voice of the SBS. Though the President provides guidance, the BOD, through voting, ensures that SBS is truly a democratic organization.
SBS Office
The nerve center of SBS is in Danbury, Connecticut. Under Christine Giordano’s leadership, the office staff are involved in all aspects of running the society, covering administrative, governance, legal and financial management; member services; program/product development; strategic development and alliances. The annual conference takes a lot of effort to organize and the objective is to continually improve the event. Multiple activities have to be coordinated, and each year the office takes on greater responsibilities.
This year the whole conference, except the program itself, will be handled by the office, and they are also taking on the organization of regional conferences, the next one being in San Francisco in April.
Publications
As well as the conference, which is a very visible asset of the society, we have another jewel in the crown, the Journal of Biomolecular Screening. The journal has built an excellent reputation as the premier publication in the field. Larry Walker is the Editor-in-Chief, and it is a testament to his leadership that the journal has achieved its prominent position in such a short period of time.
SBS News is another vehicle to support the community, and provides an excellent opportunity to keep members briefed of news and views. I certainly couldn’t communicate better without it, and it gives the members the chance to express themselves in unique ways and to show their more human sides!
Committees
SBS also has several standing committees. We encourage at least one Board member to be part of each committee to maintain effective communication, and it is expected that each committee present to the Board at least once each year. The various committees are: Academic Outreach, Awards, Conference, Education, Endowments, Microplate Standards Development, Partners in Commerce, Program, and Publications. Each committee has a varying number of participants and the only requirements are society membership and the willingness to contribute.
Moreover, we have several ad-hoc Special Interest Groups (SIGs) that address a wide range of topics such as Screen Design and Assay Technology, Sample Management, ADMET, Automation Quality Control. Further information on the committees and SIGs can be found on our web site at www.sbsonline.org.
So that’s it—a summary of SBS in a nutshell. It is a tribute to you, the members, that SBS has grown to be the organization it is today. We are now in an excellent position to reach out to you and the wider community to help with networking, educational programs, and to support the science of drug discovery.
If you wish to contribute and help SBS achieve our aims, please consider joining a committee, SIG, or the BOD in 2005. You may even want to consider this as one of your New Year resolutions.
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new technology
Automated Microscopy & Image Analysis Holds Promise for Early Drug Discovery
By Marilynn Larkin
Harvard scientists have developed a new, high-throughput method of visualizing the multifaceted impact of drugs on human cells in culture. The technique, which uses automated microscopy and cell image analysis to provide quantitative measures of how individual cells are affected by a wide range of perturbations, will be especially useful for discovering the mechanism and predicting the toxicity of new drugs, according to the researchers, who report their findings in a recent issue of Science (2004; 306; 1194-1198).
The work represents a collaboration among investigators at Harvard’s Bauer Center for Genomics Research and Harvard Medical School’s Institute of Chemistry and Cell Biology (ICCB) and Department of Systems Biology. It “illustrates the potential of microscopy to go beyond a description of what something looks like to being a detailed quantitation of what’s going on in the cell,” said Timothy Mitchison, PhD, co-director of the ICCB and head of the team’s efforts to automate the collection of thousands of cell images.
“Most drug-discovery professionals won’t use a microscope for primary HTS. But I think automated microscopy will be particularly useful in target identification and target validation in tissue culture,” Mitchison told SBS News. “For example, there’s a huge interest now in screening RNAi libraries, which tend not to be very big. The druggable genome set is less than 10,000 clones and you want a lot of information. That’s when the technology becomes really helpful. It’s also relevant to lead stratification—when you have a bunch of hits and want to evaluate them, and you’re dealing with no more than 1000 or so molecules that need to be compared and contrasted.”
How it Works
The technique, which is also referred to as high-throughput cytological profiling, lets researchers test numerous variables at once, wringing innumerable discrete cellular measurements from a single experiment. For the Science study, the team placed unengineered human cancer cells in 384-well microplates and different concentrations of drugs—both medicinal and toxic—were added to the wells. They then probed cell physiology using fluorescent stains for DNA and 10 proteins involved in replication, cell structure, or signaling pathways.
After 20 hours of cell growth, the team used automated microscopy to collect about 500,000 images of the treated cells, followed by approximately 5 billion individual measurements of each cell’s size, shape, proteins, DNA, and organelles. Specially designed computer software allowed the researchers to convert the copious data into profiles of the effects of each drug, yielding distinctive red and green fluorescent “fingerprints” for each—not unlike the color-coded data from a DNA chip.
However, unlike DNA chips that blend data into an “average” denoted by dots of color on a grid, cytological profiling preserves the individual data points, so the investigators can go back and analyze detailed information. “By allowing quantitative measurement of many proteins and structures in cells over many samples, as well as systematic comparison among samples, our method brings microscopy into the ‘-omics’ era, similar to genomics and proteomics,” said Mitchison.
“It’s a cheap and technically simple strategy for profiling the effects of drugs,” added Zachary Perlman, lead author of the Science paper. “If drugs that have similar effects have similar profiles, then this might offer a way to select or exclude compounds earlier in the screening process.”
The method, said Mitchison, “is comparable to two existing technologies. One is reporter gene assays, where you engineer in a luciferase construct that responds to specific substances. The advantage we have over that technique is that we don’t need to engineer the cell line. Researchers can use primary cells and don’t have to make a new cell line for each new project. The disadvantage is that the readout is a little more complicated than luciferase readouts.
“The other technology I’d compare our method to is Western blotting. Our approach has several advantages: we use much smaller quantities of material; we get subset localization, which in many cases gives us a lot of additional information; and it’s less laborious, so you can do far more data points more cheaply than with Western blots. The disadvantages are that you don’t get the molecular weight information; you have to be pretty sure of the specificity of your antibody; and it’s not clear that the sensitivity is similar. Our method might not be as sensitive for rare proteins.”
However, Mitchison continued, “if you think of what we did as the equivalent of many, many immunoassays, the comparison I’d make is with expression (mRNA) profiling, which is a very expensive technology that is still fairly difficult to interpret. The beauty of expression profiling is that you can do the whole genome and get broad information. With our profiling technique, we measured 10 different parameters, so we didn’t have the same depth of information—but, on the other hand, we needed far less material and we could get a lot more information from those 10 points.”
The Potential
The study published in Science was non-hypothesis-based, noted Mitchison. “We simply took drugs and let them tell us whatever they wanted; as a result, we got broad comparisons across a lot of drugs, but we didn’t get new mechanistic information. We were able to say some drugs would like each other and some wouldn’t, but since I am particularly involved in the cancer arena, I would like, for example, to input genetic variation as one of my variables, and compare a smaller number of drugs with some mechanism-based endpoints.”
Mitchison is also interested in the concept of phenotypic structural activity relationship (SAR). For most drug-discovery professionals, he said, SAR involves biochemical assays and toxicology outputs. Phenotypic SAR, by contrast, “is where you look at how changing a methyl group here or a hydroxy group there quantitatively affects the small molecule at the level of phenotype—that is, the biological effect on the cell.” For that, “you have to be able to precisely quantitate phenotype, with similar accuracy as for an enzyme assay.”
For example, the 100-drug panel used in the Science study included five kinase inhibitors purchased from the same company. “It turned out that three of them clustered right next to each other, and two of them were far away,” said Mitchison. “We would have expected all of them to cluster together, and wondered why they didn’t. We looked, and saw that the three that had clustered were very closely related structurally, and the two that were far away had very different structures. So, in this case, we saw a fairly close relationship between chemical structure and phenotypic effect.”
This means that in a kinase program, for example, “while the biochemistry team is busy measuring biochemical inhibition constants on a panel of kinases, you could have an automated microscope clicking away, outputting quantitative measures of biological effect. Then, as you systematically varied structure in your optimization program, you could at the same time quantitate the effect on the biology. Thus, I see a particular use in medicinal chemistry where multiple targets are expected.”
Does the Harvard team plan to commercialize the new technology? “For it to be of value,” said Mitchison, “one would have to standardize procedures, test reagents, input human cells—all this is not easy to do in an academic lab. So while we’re not planning to commercialize it, I do think it’s a good idea, and I would like to see it happen.”
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Advancing The Science of Drug Discovery
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