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Quenching Your Thirst for Knowledge

Quenching Your Thirst for Knowledge

Today marks the beginning of a new program to bring you, the Laboratory Automation community, the best in news and information about our field.  This month sees the introduction of the first initiative, a live news feed from Meltwater Inc.  The Lab Man talked with ALA president Jim Sterling, about Meltwater and the overall ALA information program. 

Jim indicates that if you go to ALA's website today, you'll see a scrolling feed of laboratory automation related news items.  This is brought to you via collaboration with Meltwater, Inc., a Norwegian-based company that uses a proprietary state-of-the-art search platform which sifts through more than 14 billion matches daily.  The company developed one of the first electronic news agents in 1996. Experiences from a two-year research program in cooperation with the Norwegian Computing Centre and funded by the Norwegian Science Foundation are integrated into the current Meltwater News solution. 

According to Jim, the sophisticated keyword searches behind the news feed have been designed in collaboration with a team of ALA member experts.  But even sophisticated searching still gathers a considerable amount of extraneous material, so the same team of ALA experts (including The Lab Man) do a daily selection of the literature "hits" before they are placed into the news feed.  This way we can assure the information you see is either directly related to laboratory automation or an interesting similar technology.  For instance, in today's feed is an article telling us that "Scientists at Tufts University have received a $3.3 million contract from the U.S. Defense Advanced Research Projects Agency (DARPA) to develop chemical robots that will be so soft that they will be able to squeeze into spaces as tiny as 1 centimeter, then morph back into something 10 times larger, and ultimately biodegrade."  Perhaps someday we'll see those used for process chemistry assays?  Who knows? 

Since ALA is a technology focused organization, one would expect this newsfeed to take advantage of the latest in information-sharing technology!  Jim relates that one can subscribe to The ALA Global LabAutomation Newsfeed as an RSS feed.  This is available to anyone, not just members.  The Lab Man has the RSS feed going right to the top of his My Yahoo home page, ahead of his finance, sports and even Netflix feed!  ALA can also insert its own news items, to keep you up-to-date on association happenings.  We can also insert news items that you submit, so feel free to email a link or a note to The Lab Man if you think something should be in the feed! 

Why is ALA doing this?   Jim says it's all part of the latest version of the ALA strategic plan, the cornerstone of which remains offering education and information to the laboratory automation community.  The latest ALA member benefit survey indicated that the #1 perceived benefit of ALA membership is being connected to the latest and best information about our field, through a variety of means such as the LabAutomation conference, JALA, short courses, Spotlight Series, and of course (Ahem!) The Lab Man blog & podcast.  This new service is part of a new initiative to take this to mission to new heights using web-based technology. 

You'll see more developments from this new program over the coming months, so watch the newsfeed carefully.  We'll let you know when something new is about to happen!  Give us some feedback - please!  We value your opinion. 

Until next time,

Domo Arigato, Mr. Roboto   

 

 

Inside Biopharma Lab Automation

Inside Biopharma Lab Automation Imagine an industry that is highly technology dependent

The Lab Man knows of several large companies that have successful centralized internal laboratory automation groups, such as Amgen, Bristol-Myers Squibb, Eli Lilly and Pioneer Hi-Bred to name a few.  Other companies have taken a decentralized approach, with automation resources scattered throughout various functional groups of the organization.  Regardless of the organization, anyone involved with implementing lab automation in a corporate environment faces some of the same issues and questions.  What technology can I use "off-the-shelf"?  What can be customized to fit my workflow and who does the customization?  What do I need to create or customize myself?  How does the customized technology get supported long-term?  The Lab Man talked with Peter Grandsard, an Executive Director of Research with Amgen Inc. in Thousand Oaks, CA about his Research and Automation Technologies group with regard to these same questions. 

Peter indicates the mission of the R&AT department (yes, they call themselves rat!) is to acquire and implement effective laboratory automation technologies to expedite the discovery and development of therapeutics.  They are an eclectic group of 16 employees, consisting of chemists, biologists, engineers and physicists, plus four full-time outside contractors (three system integrators and one machinist).  They are responsible for four Amgen research sites in the United States. 

The Lab Man asked Peter what their philosophy is toward "build or buy" given the strong resources in the group.  He replied that they would always like to "buy" and implement technology "off-the-shelf", but Amgen believes that automation and informatics should fit the internal workflow, rather than vice-versa, so often modification of existing technology is necessary.  In approximately one in five cases, some degree of create-from-scratch is necessary - either a component of the system or the entire system itself.  In these cases, they prefer to work with a collaborator, such as a national laboratory, academic group or a commercial technology provider. 

Peter says this philosophy really hasn't changed over the past 10 years, but several factors involved in the decision making have indeed changed.  They find the commercially available lab automation technology has improved and become more robust and reliable, thus requiring less tinkering just to simply make it work.  Commercial sources of customized solutions have matured as well.  Peter also finds that his internal resources have matured, becoming more knowledgeable and capable, so they have greater internal capacity to create from scratch.  Interestingly, he says that 10 years ago his (then) less experienced staff was quite eager to "build" but project urgency and some lack of experience often forced them to "buy".  Now, with more experience and capability, these same people are still eager to "build", but better appreciate the business tradeoffs, and so tend to make more balanced build or buy decisions. 

When working with outside collaborators to achieve custom solutions, Peter feels that it's key to match the Amgen goals and motivations with that of their collaborator.  For instance, if the Amgen goal involves developing really novel, one-off technology, then they choose a collaborator with a matching mission, an organization with instrumentation research as a focus, such as a national laboratory.  If the goal requires doing extensive biology or chemistry application development, then they may choose an academic laboratory that has "wet science" capability.  If the goal is to create custom technology that then can be replicated and supported across multiple sites, then the collaboration will likely involve a commercial entity.  Peter finds that commercial entities are eager to collaborate today on new development, to share the risk of new product development and test the market. 

And what is the philosophy for staffing his group today?  As with many companies, Amgen is watching headcount carefully.  So the R&AT group has created a capacity and capability model, which delineates the type and amount of skills necessary to fulfill their mission.   Certain roles are defined as "core" to their mission and will be accomplished via full-time employees.  Other roles, such as support, maintenance, training, system replication and fabrication are not considered "core" and will be fulfilled via contractors.  Some roles, like system integration, fall into both categories.  When headcount is tight, they lean more toward fulfilling that role via outside resources.

So, that's the inside story from one company.  Why don't you share some of the philosophy from your organization?  Leave a comment!  Please!  

Until next time,

Domo Arigato, Mr. Roboto   

 

 

An Automated Crystal Ball?

An Automated Crystal Ball? Imagine an industry that is highly technology dependent

X-ray crystallography has been used as a tool for studying the structure of proteins since the Nobel Prize (1962) winning work of Max Perutz and Sir John Chowdry. The technique has been especially useful in studying the three dimensional interaction of potential drug molecules with target molecules. X-rays bounce off the crystal (diffraction) and the intensity of the diffracted beams are measured using film, X-ray sensitive plates, CCD cameras, or the latest innovation, pixel-array detectors. The diffraction data is transformed into an electron density map which the skilled crystallographer uses to build a three-dimensional model of the atomic structure It has been a methodology incorporating as much art as science, based on the experience of the experimenter, and has involved a great deal of tedious and laborious experimental design and execution. As soon as automated robotic manipulation and microliter scale liquid handling entered the laboratory realm, crystallographers became keenly interested in the possibilities such technology offered to their discipline. The Lab Man asked Eric Baldwin, Director of Protein Crystallography at Bristol-Myers Squibb (BMS) in Princeton N.J. to give us an update on automation in this interesting field.

Eric indicates that the X-ray method requires the production of a crystal. Protein samples need to be prepared and those protein samples combined with the drug molecule to be studied. The complex of protein and drug has to be induced to form a crystal. This is a largely empirical art. The crystallizer will often try many hundreds of different experiments to cause the protein-drug complex to crystallize. In the late 1970?s it was common for crystallizers to exchange lists of recipes for growing protein crystals that had worked for them in the past. By the early 1980?s many were experimenting with the application of experimental design methods that produced novel combinations of reagents that might produce crystals. These new recipe lists were adopted by a commercial enterprise which began to sell crystal screening kits. These kits were very popular and now 1000?s of solutions are available for sale. Traditionally all crystallization experiments were set up by hand. A few micro-liters of the protein solution and an equal amount of one crystal screening solution would be mixed together and the experiment observed for several days to see if crystals would grow. This would be repeated for 100?s or 1000?s of different solutions, trying to find a combination of reagents that would grow useful crystals. This was obviously very labor intensive and an excellent opportunity for automation to improve efficiency and eliminate errors caused by human fatigue.

In the mid-1990?s the first commercial crystallization robots appeared. These were widely purchased in pharmaceutical crystallography labs and were successfully used to screen the many hundreds to thousands of crystallization conditions needed to find those that grew crystals. Many of the early attempts tried to directly replicate the manual process, the hanging drop method for growing protein crystals. This was quite slow and introduced less-reliable steps that the researcher ?had to watch? or would do by hand to avoid a robot error. The most error prone event was the final step when the crystallization experiment was sealed for vapor equilibration. The hanging drop method mixes the protein solution and the crystallization screening solution on a surface. The surface which could hold only one crystallization drop or as many as 96 drops needs to be flipped over and suspended above a reservoir to create the crystallization environment. Automated cover slip flippers were generally not reliable enough for routine un-supervised operation.

Other automation difficulties included the large range in reagent viscosity and volumes that the robot needed to be able to dispense during the typical experiment. Protein crystallization experiments often use polymers of polyethylene glycol (PEG) to facilitate the crystallization process. When these polymers are mixed with proteins they compete with the protein for water of solvation. This action promotes the assembly of proteins into aggregates that might cause crystal nucleation. PEG solutions are quite viscous. Hence, the automation application would need to be able to accurately dispense low viscosity solutions like water and high viscosity solutions like PEG. The dispensed volumes are also quite variable. Crystallization drops may be a combination of 1 microliter of protein solution and 1 microliter of crystallization screening solution. This 2 microliter drop is suspended over a 100-500 microliter well solution. Hence, a 100- to 500-fold range in volume dispensing needs to be done accurately with the same apparatus. A robotic system that performs well with these requirements is difficult to implement by merely automating the manual process. New robotic systems requiring new workflows have been designed to work in an unsupervised mode, account for viscosity changes, and dispense low or high volumes with task specific hardware.

According to Eric, at BMS the ability to prepare 1000?s of crystallization experiments using automation has been very useful for quickly finding the conditions that produce crystals for many proteins. But the ability to set up these experiments created new bottlenecks that needed to be addressed. Each crystallization experiment needs to be visually examined under a microscope and repeatedly checked over the course of a week or more to determine if the experiment produced crystals or a result that might be close to conditions that would give crystals. To address this bottleneck, automation experts at BMS built and deployed a crystal imaging system that takes high-magnification digital pictures of crystallization experiments. This has dramatically reduced the need for scientists to examine experiments under the microscope and provides a time-lapsed series of images to help understand how the experiment evolved over time.

A camera with a motor driven zoom lens is mounted over a controllable X/Y stage. A robotic arm moves crystallization experimental trays to/from storage and the imaging stage. Crystallization experiments evolve over many days and so multiple images are captured over the course of each experiment on a user-defined schedule. A database allows association of protein information and crystallization conditions with images. An extension of this custom software, Image Viewer, is used for displaying and scoring crystallization images. This tool is used externally by the BMS outsourcing partner in India to manually annotate all crystallization experiments, and is used internally by BMS crystallizers to rapidly visualize crystallization ?hits? and follow up with new experiments. During the night-time crystallization images are scored overseas and all of the interesting results are emailed to the crystallizers a report that they receive at 8 AM in the morning. "We have set up 100?s or 1000?s of crystallization experiments on a Friday afternoon, and the crystallization scientist has had an email on Monday morning when he returned to work, indicating that a big crystal was ready for data collection", says Eric. The scientist could go right to the correct drop and harvest the crystal and data collection could begin immediately. The team has also integrated RockMaker, a key third-party software package, to design crystallization experiments and dispense them on Tecan liquid handlers. Scientists can drag the conditions from Image Viewer back to RockMaker to initiate the design of a focused experiment, allowing for very efficient experiment design flow. Finally, a fully integrated robot-ready inventory of bar-coded solutions for rapid custom crystallization experimentation has been created.

When asked to speculate on future directions for automation, Eric noted that one obvious extension would be to replace manual scoring of crystallization experiment images with a computational scoring process. As far back as 25 years ago scientists at the Naval Research Labs in Washington experimented with using defense image analysis technology to accurately score the crystalline and non-crystalline results of crystallization experiments. Because crystals have edges, detecting them is relatively easy with modern algorithms. However, non-crystalline material in the experiment, precipitate, looks like snow and can hide crystals. More difficult is the fact that snowy precipitate can be ?good? or ?bad?. The experienced human eye can tell the difference between ?good shiny precipitate? that might lead to crystals from the bad brown precipitate that is just denatured proteins. Distinguishing these different precipitates with image analysis tools will be a challenge for many years ahead, but because we have millions of images that have been manually annotated we may now have a superior basis set for a machine learning experiments.

Another area of developing technology is the field of data collection automation. Robots have been available for the past 5-7 years that will automatically mount crystals for X-ray data collection. However, the latest generation of detectors threatens to make these robots obsolete. The new pixel-array detectors are so fast that the rate-limiting step in data collection is not exposure of the crystals to the X-rays but movement of the sample to and from the liquid nitrogen storage Dewar to the X-ray beam. New robots will be needed to rapidly select the crystals and place them in the X-ray beam every few seconds.

Keeping track of all of these samples is also becoming a problem. One instrument company has introduced RFID technology that works at liquid nitrogen temperature. The crystals are mounted on RFID encoded pins and stored in a liquid nitrogen bath until they can be exposed to the X-ray beam. Sample information is loaded onto the RFID. When the pin is selected for data collection and moved into position, the RFID reader in the robot arm downloads the pin information to connect the sample information with the resulting diffraction data set.

In The Lab Man's opinion, the automation of X-ray crystallography is fascinating microcosm of how laboratory automation evolves. First we attempt to directly automate the manual procedure, only to discover that it doesn't always translate well. We re-engineer the process to better take advantage of automation, and then realize we have created new bottlenecks, some manipulative in nature, others perhaps data related. As those eventually get addressed, the bottlenecks shift. Mix in globalization developments and what we have is a complex evolution that has a lot of potential blind alleys, which can consume both funds and time. To gain the best productivity from such evolutions, long-term vision and guidance is essential, which at BMS is readily available from an excellent team of internal automation experts.

Until next time,

Domo Arigato, Mr. Roboto

Designing Experiments the Automated Way

Designing Experiments the Automated Way Imagine an industry that is highly technology dependent

Thanks to everyone who provided feedback after our previous blog regarding the future location for the LabAutomation conference. Stay tuned - a decision will be coming this summer!

Today we're discussing Design of Experiments, or DOE, and the combination of that technique with laboratory automation. The LabMan reached out to a long-time expert in the field, Paul Taylor, Principal Scientist at Boehringer Ingleheim, to discuss the topic. Paul indicates that DOE as an experimental approach was developed by Sir Ronald Fisher beginning in 1919 during his work at the Rothamsted Experimental Station located at Harpenden, Hertfordshire, England. In his role there as a statistician he developed the concept of ANOVA, or Analysis of Variants, which is still used today to determine which factors in an experiment produce significant effects and whether the response is linear or non-linear. In 1925 he published Statistical Methods for Research Workers, followed in 1935 by The Design of Experiments.

DOE is an approach to optimizing a given experimental operation in an iterative, efficient and statistically-driven way, by systematically evaluating the impact of individual experimental variables on the final, measured outcome of the experiment. The approach can be relatively simple for experiments involving just a few variables, or quite complex for multi-variant experiments. In all cases, the idea is to rigorously explore the impact of variables in a well-organized, highly systematic way that minimizes the number of tests to be run and maximizes the statistical relevance of the results.

The rub has always been that it can be a lot of work to do DOE on even a moderately complex problem. It can take significant time to design the array, or table of experiments to sufficiently evaluate all the variables inherent to the problem. This requires knowledge of both the science involved and experimental statistics - usually not resident in the same person. It can then be very tedious and time consuming to run all these experiments. In some cases, there may not be enough supply of experimental components (such as reagents) to run all the desired experiments. In other cases, experimental components may not be sufficiently stable across the span of time necessary for a human to complete the entire planned table of experiments. Many, even most scientists will take intuitive shortcuts rather than go through the DOE tedium. Sometimes this works and other times experimental blind alleys end up taking as much or more time than a carefully planned DOE approach would have.

So, we have a powerful experimental approach that has the disadvantage of being tedious, computationally intensive, involving laborious setup, and consuming both time and supplies. It sounds like the ideal situation for the application of computerized design with automated execution! Specifically, for chemical/biochemical experiments, there are now many choices of automated liquid handling systems that can assume the tedium and complexity of executing a DOE array of experiments, and can do so in a fast and miniaturized way. Computerized power for designing a DOE array of experiments and analyzing the results certainly exists. As Paul points out, the key is then in linking the two into a package that intuitively appeals to the scientist.

Several technology providers have taken a stab at this. Paul has spent a good deal of time working with and helping to develop the Automated Assay Optimization (AAO) package sold by Beckman Coulter for their Biomek FX. Symyx has developed Lab Execution software for chemical process optimization using their Benchtop System. Others have developed "home-grown" versions of similar approaches. Paul feels that for such systems to be successful, they must be capable of translating experimental inquiry in the way a scientist would think to the physical and practical reality of automated system execution. This would basically involve an automated system capable of reading a scientist-generated table of experimental parameters together with a range for each parameter, and translating that into a series of automated methods for exploring the response range for each parameter.

If you want a deeper introduction to DOE, sign up for the ALA short course on the topic at the next LabAutomation conference!

Until next time,

Domo Arigato, Mr. Roboto

New location for LabAutomation?

New location for LabAutomation? Imagine an industry that is highly technology dependent

Let me begin this blog by saying that we want your feedback! You may not know it, but you can post comments to this or any LabMan blog by clicking on "add comment" at the bottom of each post. In this case, we're discussing future locations for the LabAutomation conference, so if you have an opinion, please post a comment! Don't wait and grouse when the conference ends up in a place you don't like!

For those not involved with conference planning, it may be surprising to learn that conference venues are planned 3 to 5 years out. To get a specific place at a specific time of year, you have to get into the que early. So, the ALA is now going through that planning process for the LabAutomation 2011 and beyond dates. To demystify this process, The Lab Man talked to Brenda Dreier, the ALA Director of Event Management and to Dr. Jim Sterling, the current ALA president. Brenda related the history of LabAutomation venues. The conference began in 1998 in San Diego, at the Sheraton Harbor Island Hotel. By 2000 the conference had outgrown that facility, and moved to the Palm Springs Convention Center. Growth and pending construction caused the conference to move to the San Jose Convention Center in 2004 and 2005, and then back to Palm Springs in the years since. The conference continues to grow, so what venue will be appropriate by 2011?

Jim pointed out several factors in the pending choice. The end of January time slot is both traditional and beneficial. It's the beginning of the budget year for many attendees, so travel funds may be more available. It's also the beginning of the fiscal year for many of the conference exhibitors, so they are eager to get the year started with a bang, including new product announcements. The ALA has always had a tradition of inviting attendees to take a break from the winter, come to a warm, inviting climate and experience an excellent conference along with mingling with colleagues while enjoying some good food and beverage. All of these factors have helped the conference achieve the current level of success, and it's not wise to mess with winning formulas. That means choosing among cities with warm climates and available facilities in January. Brenda indicates those cities under consideration include Palm Springs, San Diego, Anaheim, Long Beach, Phoenix and Los Angeles.

Unlike some conferences, the ALA tends to stay in a location for multiple years. Multi-year agreements lower the cost and those savings that can be passed on to attendees and exhibitors. The ALA has been able to keep room cost below $200/night during peak demand time in Palm Springs. This practice also lets attendees become familiar with both the convention center and the surrounding locale, so time can be spent more productively. Keeping with this practice, the venue chosen for 2011 will also be the conference site for 2012 and 2013.

What specific factors influence the choice? Obviously, your feedback counts (hint!). From a physical standpoint, the conference requires a convention center large enough to accommodate anticipated growth, but also not so large as to dwarf the event. Attendees like to shuttle back and forth between talks and the exhibit floor, so that needs to be a convenient walk. Exhibitors need sufficient space and pre-conference time for setup. There must be adequate numbers of right-sized rooms for both podium sessions and the extensive short course program. Enough hotel rooms should be available within reasonable walking or shuttle distance. The city itself must be easily accessible by air, given that conference attendees come from all around the country and world. Ideally, there would be a local scientific presence to encourage walk-in attendance. And, naturally, the finances have to be right.

The timeframe for this decision is June of this year. So, if you have an opinion, please post a comment!

Until next time,

Domo Arigato, Mr. Roboto

Innovation and Change at LabAutomation2008

Innovation and Change at LabAutomation2008 Imagine an industry that is highly technology dependent

Once again the LabAutomation conference has provided many of us with a welcome respite from winter and a chance to feel young again amidst the populace of Palm Springs! Our technical field and the conference continue to grow and thrive! This year saw a record attendance of 4670 from some 40 countries. The event continued the tradition of presenting the top 100 podium presentations on laboratory automation, as well as 189 posters, 18 short courses and 21 industry-sponsored workshops. It has truly become an event with more to offer than one can absorb, so a return visit is almost mandatory to stay abreast of new developments.

Speaking of new developments, the acquisition of Velocity 11 by Agilent was announced at the opening evening (sponsored by V11). Thus continues the recent trend previously noted by The Lab Man of consolidation among the vendor community. The Agilent spokesman indicated that his company was very glad to be entering the laboratory automation market and I'm sure that feeling is shared among the user community. Those who have been around as long as The Lab Man will remember, however, that Agilent in its former incarnation as Hewlett Packard was for a while a laboratory automation player with its Automated Chemical Systems line of products, including the ORCA robot. What comes around goes around! Change is often circular.

Even though the prevailing trend in the vendor community is one of consolidation, there are still many new providers entering the market. The ALA continued its program to support and highlight new companies via Innovation AveNEW, which provided booth space to eight startup companies. It should be noted that Velocity 11 got their jumpstart years ago when the conference provided them such a booth, so this program does pay dividends to our community. Innovation is what these young companies are all about, as clearly shown by the fact that two of the three New Product Awards (NPA) went to very young companies. The NPA winners were:

Qiagen, for their QIAsymphony, a highly integrated and user friendly bench top workstation aimed at the DNA and RNA purification and amplification market. The device is highly modular to allow ease of reconfiguration for a broad application range.

Viaflow, for their Vision Pipetting System, a handheld pipette system that finally brings these devices into the wireless and iPod age. It has a very familiar scroll-wheel type control, a full color display for menus and images, and an optional Bluetooth interface for data transfer.

Formulatrix, for The Formulator, a next-generation automated liquid handler using a microfluidic chip to measure and dispense discrete volumes of liquid. The chip has 96 outputs and two metering chambers of 0.2 and 3.0 microliters volume.

The ALA's recognition of innovation is not limited to the exhibit floor. The $10,000 Innovation Award is given each year to the presenter best demonstrating vision, originality, seminal technology, applications and strategies. That award went to James Landers, Ph.D., University of Virginia, for his podium presentation, "A Simplified Microfluidic Device for Ultrafast Genetic Analysis With Sample-In/Answer-Out Capability: Application to T-cell Lymphoma Diagnosis." The ALA offers full travel support awards to students presenting posters and a $1000 award is given to the top student poster. This year the winner was Nicole Tolan, Michigan State University, for her poster titled, "Development of a High-Throughput Microfluidic Array for Detecting Multiple Metabolites From Blood Components to Determine Drug Efficacy and Mechanisms of Action".

Other quick impressions:

The Lab Man found it fascinating to watch the mind of a Nobel Laureate, Dr. K. Barry Sharpless, at work during his plenary address.

Dr. Henry Chesbrough, University of California, Berkley, spoke about changes in the path to innovation and praised the efforts in that regard of Stanford University as the "2nd most prestigious academic institution in California".

Riding a Segway is not only fun, but a real education in how original thinking can lead to devices that are engineered in new and amazingly simple and intuitive ways.

The visiting FIRST students (see previous blog) were an amazingly enthusiastic and bright bunch. We read much about the demise of high-technology education in our country, but you certainly wouldn't know it talking to these kids!

Please check out the podcasts recorded "live" on the exhibit floor at the conference! And PLEASE enter some comments to let The Lab Man know how he's doing!

Until next time,

Domo Arigato, Mr. Roboto

Teaching Microplates New Tricks

Teaching Microplates New Tricks Imagine an industry that is highly technology dependent

The microplate has been around as a 96 well molded tray of "test tubes" since the 1950's, when John Liner at the Linbro Company produced a vacuum formed version. The format concept was originally developed in early 1951 by Dr. G. Takatsky of the N.P.H. in Hungary, where he machined multi-well plates in acrylic for use in Virolgy and Serology testing, which involved multiple serial dilutions. By the early 1960's the NIH was getting heavily involved in Rubella vaccine testing, and an NIH investigator, Dr. John Sever, recognized the microplate concept as a way to mechanize this testing. He and Frank Cooke, of Cooke Engineering, set about to refine the concept, eventually leading to an injection-molded, polystyrene 96-well plate - the style essentially still with us today. Production began in 1965 and Cooke was granted a patent for the microplate and trademark for the name Microtiter by 1968. Shortly thereafter, Dynatech acquired Cooke Labs. Dynatech and Data Packaging Corp. formed a joint venture called CoStar, which was acquired by Corning in 1993. If you'd like to read a detailed history, visit this website assembled by Roy Manns, or read the paper by Tom Astel in JALA Vol 5, Issue 6.

So, other than a bit of nostalgia, what is The Lab Man getting at? Well, the fact that most of the microplates being used today are still made of injected molded polystyrene. Certainly the process is much better controlled and standardized than in 1965. Plates are available in higher density formats, and different colors and opacities. You can even buy very sophisticated plates from Corning with an optical biosensor imbedded in the bottom of each well. But the basic building material is still polypropylene! This is an era of exotic plastics! We build airplanes out of carbon fibers. Nanotubes are all the rage. Surely there are now interesting options available to improve on Cooke's original (and apparently good) choice of polystyrene over 40 years ago? To ask this question, we talked to Lane Niels, a guru and consultant in the field of Assay Biophysics, about new developments in microplate material science.

Lane points out that polystyrene was initially chosen for its clarity, hardness, rigidity and ability to be injected molded. It was also considered to present a largely inert surface, but it was able to be derivatized in a relatively controlled way. While polystyrene still proves to be an excellent material, we now understand a lot more about surfaces and biochemical interactions. No plastic is truly inert in all situations. Conversely, true inertness would be a disadvantage in promoting some biochemical interactions. So we can look at the characteristics of various new plastics and make educated choices.

In Lane's opinion, a material likely to become more popular is Cyclo-Olefin Copolymer (COC). You can read about the plastics technical specifications here. What makes it interesting for microplate use? COC appears to be more inert and is more hydrophobic than polystyrene. Inertness is influenced not only by the chemical structure of the polymer, but also by the process used to initiate the polymerization process. Polystyrene polymerization is activated using strong oxidizing agents, such as stannous ion. Industrial grade oxidizing reagents can often leave behind a minute trace residue of heavy metals, which can affect certain binding assays (i.e. Ca+ binding), especially when working in very low volumes. Lane has reviewed published studies where such binding assays worked fine in typical 96-well volumes, but didn't perform well at lower volumes. The polymerization process for COC is activated thermally, which is much less likely to result in any unwanted chemical residue. COC can be radicalized using gas plasma to facilitate surface derivatization. It has similar rigidity to polystyrene, so COC microplates can be made to be very flat, with very flat well bottoms if desired.

If you want to experiment, ask your local med (not mad) chemist to cook up some COC for you! Or, if you'd rather avoid interacting with synthetic chemists, COC plates are available from various vendors, such as the Beckman Chemlib microplates or those from Aurora Biotechnologies.

Until next time,

Domo Arigato, Mr. Roboto

Microsoft a player in Bioinformatics?

There are always rumors floating around about what next market segment Microsoft will explore

There are always rumors floating around about what next market segment Microsoft will explore.  Will Microsoft take on Google?  Will Microsoft develop an iPhone-like device?  Will Microsoft become a dominant force in bioinformatics?  Wait a minute, bioinformatics?  That’s hardly the same realm as search engines or consumer communications, but it does appear to be a field that Microsoft is interested in.  Take a look at the web site for their Cambridge, U.K. research lab, and you’ll see Computational Biology listed as one of the areas of interest.  A check of their job openings shows that they are hiring people with bioinformatics backgrounds.  So, can we expect someday for a release of “MS Bioinformatics Suite” or have the annoying Clippy animation ask if we need help processing DNA sequence data?  Probably not, but there is no doubt that Microsoft has noticed that life sciences related computation is a growing field and doesn’t want to be left out.  To that end, they were key in forming the BioIT Alliance, a collaborative group consisting of Microsoft and various life science technology providers. 

To learn more about the BioIT alliance, The LabMan spoke to Rudy Potenzone, Industry Technology Strategist for Microsoft.  Rudy indicates that the BioIT alliance was formed in the middle of 2006 to promote a greater level of partnership among providers of bioinformatics tools and to inform them about new technology developments at Microsoft.  Member companies include those focused solely on bioinformatics software as well as laboratory equipment companies whose products include control or data processing software.  The common link is the development of software-containing products aimed at the life sciences market.  Microsoft feels that its core Office products, such as Excel and Word, have long been intertwined with many bioinformatics software applications.  New developments involving and following Vista and Office 2007 will transform those products significantly, so Microsoft felt it was essential to educate bioinformatics providers about their new technology directions. 

There is no cost for a company to become a member of the BioIT Alliance.  The relationship is essentially a co-marketing agreement between a member company and Microsoft.  There are opportunities for members to attend various workshops, seminars and discussion groups focused on the use of various tools or future developments.  Sharing of ideas and applications among members is encouraged.  Rudy says that members often see the use of Microsoft tools in ways they haven’t previous envisioned, such as integrating the Vista workflow foundation with the control of robotic devices.  One recent project with Alliance member Scripps Research Institute involved building a collaborative molecular environment (CME) client-based tool that lets researchers share 3-D information via Microsoft Office SharePoint Server 2007 and Vista.

Rudy expects that soon we’ll begin to see bioinformatics products emerge that take advantage new Microsoft capabilities, and ideally this will provide the structure for many more products to be linked in ways that were not possible or just too difficult in the past.  He mentioned that Thermo-Fisher has recently announced that it has established a working relationship with Microsoft aimed at developing next-generation laboratory knowledge management, based on open guided by NIST and the SAFE consortium for electronic signatures.  The ultimate goal is better information flow among scientists to accelerate the rate of scientific discovery and development.

The LabMan knows from experience that standards and interoperability don’t happen overnight or by chance, but only as the result of a lot of dedicated effort.  The constructive support of an industry heavyweight such as Microsoft may help encourage wider adoption and move efforts ahead faster.  That can’t be a bad thing, if done well. 

Thanks to Velocity 11 for sponsoring this months blog! 

 

Until next time,

Domo Arigato, Mr. Roboto  

Dean Kamen talks about technology education and FIRST

Dean Kamen talks about technology education and FIRST According to a recent note in the EETimes, Americans have been losing interest in EE

According to a recent note in the EETimes, some are theorizing that American students have been losing interest in electrical engineering because the dramatic technological advances in electronics have had the unintended consequence of making electronics less accessible to curious young minds. How many of you became interested in technology via various tinkering opportunities as a youngster. One person who has been actively trying to address this situation is Dean Kamen, the inventor of the Segway Human Transport Device. Dean has established an organization called FIRST (For Inspiration and Recognition of Science and Technology). The mission of FIRST is to inspire young people to be science and technology leaders, by engaging them in exciting mentor-based programs that build science, engineering and technology skills, that inspire innovation, and that foster well-rounded life capabilities including self-confidence, communication and leadership.

Although Kamen may be best known among the general public for his work on the Segway, his background is as an entrepreneur and inventor of numerous biomedical devices, including the first portable insulin pump for diabetics. He holds over 440 U.S. patents and his accomplishments were recognized in 2000 when he was awarded the National Medal of Technology by President Clinton. In 1989 he founded FIRST as a way to get high school age students interested in and excited about science and technology. The approach is to give teams of students the task of creating robotic devices and placing those teams with their creations into competitions that Kamen seeks to make as exciting for the students as a high school football or basketball game. From the first competition involving 28 teams in a New Hampshire high school gym, the program has grown to involve over 100,000 students from all around the world, and will host it's 2008 championship competition in 2008 in the Georgia Dome.

FIRST promotes the ethos of Gracious Professionalism, a way of doing things that encourages high-quality work, emphasizes the value of others, and respects individuals and the community. Gracious professionals learn and compete like crazy, but treat one another with respect and kindness in the process. Key to making this happen is mentoring from volunteers from the field of science and engineering, as well as financial support from industry and technical organizations. To this end, the ALA has agreed to become a financial sponsor of FIRST. To contribute to the mentoring process, the ALA has invited two of the elite FIRST teams of students to attend LabAutomation 2008, where they will display their robotic creations and have the opportunity to mingle with professionals from our field of endeavor.

We come from a profession where "proof is in the data", and there is some real data available to show the impact of FIRST. Recently, Brandeis University's Center for Youth and Communities conducted an independent, retrospective survey of FIRST Robotics Competition participants and compared results to a group of non-FIRST students with similar backgrounds and academic experiences, including math and science. They found among other things, that FIRST students were more than twice as likely to expect to pursue a career in science and technology, and nearly 4 times as likely to expect to pursue a career specifically in engineering.

Paul Gudonis, the president of FIRST will be a closing plenary speaker at LabAutomation 2008, and will talk about the organization and the concept of Gracious Professionalism. The Lab Man will certainly be there to listen with interest, and hopes that many of you will be there as well. Take the opportunity to chat with the high school teams and consider for yourself whether FIRST is something that you and/or your organization should be involved with.

Post a comment and let us know if you're supportive of this ALA initiative!

Until next time,

Domo Arigato, Mr. Roboto

Vision Systems Evaluate Behavior

Vision Systems Evaluate Behavior Imagine an industry that is highly technology dependent

Vision systems have been around a long time in laboratory automation, and before that in industrial automation. The Lab Man remembers in the late 80's watching a video made by Gary Kramer (NIST) where he attached a then-small camera to the bottom of a Zymate robot arm to film the robots-eye view of an automated process. The video nearly induced motion sickness among the audience! The purpose wasn't just fun, but to develop visual error-checking mechanisms in the robot interface to a Hewlett-Packard autosampler. Since then, robot-guiding machine vision has been used in a number of colony-picking robot applications, such as the Genetix QPIX, but has never really become a common component for guiding or checking movements in laboratory robotic systems.

With the growth of PC-based computing power and the decrease in the cost and size of CCD or CMOS imaging devices, image-based detection has become common in High Content Screening and molecular pathology. Some of these applications track visual events over the course of time rather than just one static image, capturing up to 30 images per second, which equates to immense amounts of data. Recently The Lab Man came across an application of vision systems and innovative software that is facilitating a completely new way to log and analyze something that has been of interest for a long time - animal behavior. To learn more, we talked to Dr. Lucas Noldus, founder and CEO of Noldus Information Technology in the Netherlands. They're involved in a number of efforts to analyze animal or human behavior using vision systems and novel software, including the evaluation of human expression and body language, and the analysis of animal gait patterns to identify locomotor defects.

The application that caught the "vision" of The Lab Man was the analysis of mouse or rat behavior as the phenotypic expression of the animals genotype, and subsequently evaluating how that behavior varies as the result of disease, surgical treatment, drug treatment or genetic variation. Dr. Noldus points out that pharmacologists and neuroscientists have a long history of devising mechanisms to stimulate and log mouse behavior, usually based on fixed sensors in a special enclosure designed to evaluate activity or locomotion. This has provided a rather single-dimension insight into very complex behavior and it was often hard to separate behavior as a response to the unique and stressful test surroundings vs. behavior due to drug or disease. Noldus supposed that it would be much better to evaluate changes in animal behavior as they occurred in their regular "home" without the overt intrusion of sensors or devices. Home for a laboratory mouse means their home cage, complete with familiar water, food and bedding.

To accomplish this "low intrusion" behavioral analysis, one must be able to observe and log very subtle changes in animal behavior that may occur in the home cage environment, such as types of body postures, body motions, interactions with other animals and interactions with their environment. Vision systems allow the capture of raw data with enough resolution and detail to observe such subtle behaviors. Noldus has designed home animal cages that unobtrusively incorporate a wide field video camera to capture this data. He and his colleagues then needed to develop software that was capable of isolating and logging subtle behaviors. This required two breakthroughs. In the past, image analysis has required relatively static environments, with stationary test objects and clean, simple, high contrast and reproducible backgrounds to ensure reliable isolation of the test subject image. However, home cage environments present a very dynamic image situation, with bedding, substrate and perhaps food scattered around in ever-changing patterns. The animal itself moves around and may appear differently at various times or angles due to spots or fur texture. So Noldus developed dynamic subtraction algorithms to allow their image analysis software to isolate and monitor the test animals image over long periods of time in the midst of a dynamic environment. Secondly, they developed software tools to track multiple points on the contour of the animal to get a more accurate analysis of various behaviors beyond just simple locomotion and position in space.

This software all runs easily on a typical, high-end PC. In fact, Noldus has designed a high-throughput version where one CPU is used to acquire data from four cage modules. Dozens of these can be networked together to automate an entire animal facility.

For those of you who like to visualize, go to this web page to view some interesting video clips of this technology in action. And be aware, as you sit at your desk doing this, that a vision system may be evaluating your behavior pattern!

Until next time,

Domo Arigato, Mr. Roboto

Is Your Industry Going Hollywood?

Is Your Industry Going Hollywood? Imagine an industry that is highly technology dependent

Imagine an industry that is highly technology dependent. In fact, the creative use of new technology gave birth to this industry and the ongoing evolution of technology continues to have a profound impact. This industry is also totally dependent on a constant stream of creativity, new ideas and intellectual property. As this industry matured, it realized that effective marketing and sales efforts could significantly increase the success of its products. So this industry became dominated by large companies that were vertically integrated all the way from the beginning of the IP creative process through marketing, distribution and final point-of-sales. As these megaliths matured, they needed increasingly larger revenue streams to keep their growth rate high, and so they became more and more dependent on "blockbuster" products and the associated marketing to maintain that growth. The creative process suffered, as only products with perceived "blockbuster" potential got advanced, even though everyone acknowledged that it was very hard to predict what products would be a "blockbuster". So those involved in the creative process grew frustrated, and some left to work for younger, smaller companies that were focused only on the creative process, and which typically contracted with the large, megalithic companies for marketing and sales of their products. Eventually, the large megalithic companies became so ineffective at the creative process that they got out of that business, ceding that portion of the business to the small, creative companies, and focusing on what they were good at - marketing, sales and distribution. And to accompany the many small, IP-creating companies an equal number of small, young technology companies sprung up, for after all, the industry was and is still very technology driven.

Sound a bit like your industry? Well, I'm describing the motion picture industry, but the same scenario at various stages of evolution can be seen across many industries. This was the subject of a recent article by Liam Bernal in The Scientist, entitled "Why Pharma Must go Hollywood". In short, Bernal proposes that the pharma industry is going and must go through this same evolution. It's a fascinating read and in light of that premise, I thought it would be interesting to ponder the evolution of laboratory automation should this scenario come to pass. To assist in this pondering, I enlisted Charles R. Powell, Chief Commercial Officer of Aurora Biotechnologies. Charles has a well rounded past, having spent many years in the lab automation product division of Beckman Coulter as well as the investment banking industry with CIBC Oppenheimer where he focused on the biotech and pharma industry.

Charles points out that the current pharma model of automated drug discovery is based on the need to generate a large number of leads, to feed multiple therapeutic programs, hopefully eventually resulting in multiple new chemical entities hitting the market each year. The automation and informatics infrastructure needed to support and sustain such an approach is considerable, taking a good amount of money and time to develop and support. If, on the other hand, drug discovery were all done via many small biotechs, Charles feels that such companies would not likely be willing to make a similar financial investment in large infrastructure, nor would their program even require an infrastructure of that size. Perhaps more importantly, though, they would not be able to afford the time required to develop and implement a complicated infrastructure. Their corporate time frames are short and they have to be focused on generating science and IP rather than on building an infrastructure that may not pay off for many years.

Charles notes that you can already see examples of the pharma "Hollywood" model today, it's just not gone 100% that direction. Today, over a quarter of the products of the top 20 pharma companies are the result of in-licensed compounds. He refers to this movement as the "democratization" of drug discovery. Naturally, small drug discovery companies still need to do sophisticated science and still value technology that offered productivity improvements, although perhaps on a more personal scale. In this model, Charles thinks it'll be increasingly important to provide scientists with tools and consumables which allow them to "ask and answer" the same types of scientific questions that are explored in big pharma, but without the presence of large, expensive infrastructure. You could envision this being addressed via more pre-packaging of experimental tools. For instance, microplates sold already spotted with appropriate amounts of test compounds together with homogenous assay reagents provided at the proper concentration. A basic liquid handling device and plate reader would be all that was needed to support a moderate throughput screening effort.

The Lab Man would also point out that such a distributed R&D model would only increase the challenge of sharing data. This will heighten the need for products like ELN's that adhere to common standards of data interchange and offer organizations templates for data and terminology that multiple parties can agree upon.

How would this model affect the development of laboratory automation products? Charles speculates there would probably more outsourcing of areas of product development because with the de-emphasis on "big infrastructure" products, it'll be harder to sustain the need for continuous internal presence of certain types of expertise. Even large technology providers like Beckman-Coulter already practice this. In a way, this is just like Hollywood, where a small creative studio outsources special effects work to another company, who may in turn outsource work to model makers or computer graphics specialists. They all come together as a team for a specific project, but then go their separate ways when the project is done. If the "buying" players, i.e. pharma/biotech, are smaller and more decentralized, then the technology providing players also have to minimize their infrastructure investment and become more nimble.

If this sounds like a more uncertain and less stable environment all around, you're right. Ask people in the movie industry, or even those who work now for very young biotech companies. Innovation is driven by the need of all the small players to differentiate themselves, to stand out of the pack. Presumably in the "Hollywood" model, innovative companies would find each other and team up on a project basis, resulting in the periodic sensational product like occasionally comes out of Hollywood - something like the Lion King. Where would R&D money come from? The large Pharma's would still be out there doing marketing, sales and distribution, just like the current large Hollywood studios. They would probably be the primary source of funding for projects out amongst the collection of small R&D biotech's, along with private and public investment money.

So, is your industry "going Hollywood"? Are you ready?

As you read this, The Lab Man is in the Kashmir Himalaya, seeking enlightenment for yet more future blogs. Namaste! Keep reading! Please comment!

Domo Arigato, Mr. Roboto


ALA Spotlight in Your Neighborhood!

ALA Spotlight in Your Neighborhood! The recent ALA industrial automation survey indicated that the speed, reliability and function of laboratory automation tools

The recent ALA industrial automation survey indicated that the speed, reliability and function of laboratory automation tools are no longer the most limiting factor in the use of such automation. The current limiting factors have to do with the challenge of doing science with such tools, such as developing and validating new automated protocols. In response to this information, the ALA has worked together with two leading providers of laboratory automation to put together a series of workshops that focus specifically on the practical matters and challenges of putting automation to work to do good science. This is the new ALA Spotlight Series.

The Lab Man talked to ALA President Professor Doktor Reinhold Schaefer about these events. He indicates that this is a series of 4 FREE workshops to be held this fall in San Diego, San Francisco, Princeton and Boston. Exact dates, locations and program details can be found on the ALA website. The ALA has partnered with Symyx Technologies and Thermo-Fisher to provide a full day of presentations specifically focused on "how-to" aspects of putting automation to work to do science. This will be an interactive, tutorial-type workshop environment to discuss the successes and challenges of transferring and deploying automation and related technologies in the laboratory, in essence, putting automation to work in a real-world bio-pharma laboratory. As with JALA a