A roadmap for achieving self-sustainability of academic high throughput screening core facilities
Many academic HTS centres, faced with the high costs of drug discovery and decreasing federal funding, are struggling to survive. Just as with any small business, a sound business plan is critical for achieving and maintaining self sustainability.
High throughput screening for hit identification has now taken a strong foot-hold in academia. The academic high throughput screening (HTS) core facility caters, depending on the institutional mandate, to the drug discovery needs of its clients.
The academic HTS laboratory is not just a fee-for-service facility, but a strong, critical, collaborative partner in elevating academic drug discovery research efforts to unheralded heights. However, the HTS staff is neither tenured faculty, nor fully supported by a defined budget or cost centre.
The self-sustainability of an academic High Throughput Screening Laboratory is in part dependent on its state-of the art infrastructure, ability to meet the needs of incoming projects, tiered rate structure, and institutional support.
As such, self-sustainability is kinetic in nature, and maintaining a steady stream of projects is essential to the fiscal health and the business plan of a screening core.
Based on our experience at the University of Kansas, we present a roadmap for successfully transitioning academic high throughput screening laboratories to become self-sustainable in a short period. The academic screening centres are better served, in the long run, by merging forces with each other to endure the current, difficult environment of reduced federal funding and competition.
Regional consortia would fill this need, allowing sharing of compound libraries and the other gap-filling screening resources between academic screening labs in areas where institutional support for core HTS functions is sparse. By fostering collaborative partnerships between the institutional faculty and other core facilities on university campus, the academic screening centres are in a unique position to strengthen and transform screening projects to bona fide and robust drug discovery projects.
In recent years, drug discovery has gained a new home in academia. Though smaller in scale than in pharma, academic and non-profit drug discovery operations have taken root by way of new high throughput screening (HTS) laboratories and increasing resources in academic medicinal chemistry. HTS laboratories enable screening of large compound libraries against target of choice using validated biochemical, biophysical or cell-based assays.
A number of recently FDAapproved drugs originated from HTS campaigns, validating HTS as a reliable starting point for drug lead identification (1). With the fiscal and patent cliff issues surmounting pharmaceutical drug discovery, the pharmaceutical industry has adopted open innovation strategies with academia to maximise their research capabilities at low cost and to feed their drug discovery pipeline.
The new goals of academic research now encompass the full spectrum of chemical genomics and chemical biology, ranging from target identification and validation to compound library screening, probe development and in vivo efficacy assessment using small animal models. The academic need for a drug discovery infrastructure has led to establishment of HTS centres on many academic campuses over the past decade.
The HTS laboratories range from moderately equipped academic screening centres to well-endowed Molecular Libraries Probe Centers Network (MLPCN) centres funded by the NIH Roadmap initiative (2). These centres provide expertise and support to investigators in areas of probe/drug discovery in academia and execute primary, secondary and tertiary screening campaigns.
Extensive resources are invested in funding purchase and maintenance of equipment-heavy HTS labs. Since screening campaigns are labour- and cost-intensive, the overall cost to maintain and run HTS facilities on academic campuses has become a challenging issue. Many newly-minted academic HTS centres are struggling to survive, just as with any small business, when faced with decreasing federal funding and the high costs of drug discovery.
How can they survive, and indeed prosper, in this funding economy?
This past year, the University of Kansas High Throughput Screening Laboratory achieved self-sustainability, and herein presents principles for achieving and maintaining self-sustainability for academic HTS cores. Though much of this discussion is focused on academic drug discovery service providers, it is applicable to any academic research support core. And this battle for self-sustainability is a kinetic struggle, and must be constantly fought to maintain core facility financial stability through excellence in its service and logic in its business model.
Academic service cores support the institutional investigators who have the funding, but not necessarily the technical expertise or instrumentation to fulfill their research needs, through unique and critical services, such as proteomics, imaging, NMR/Mass spectroscopy and HTS. Traditionally, most universities share the same types of cores, such as animal facilities, nuclear magnetic resonance (NMR), mass spectrometry, and the like, but the need for HTS cores is rapidly increasing in priority.
These cores provide screening services and assist researchers in bridging the drug discovery gap between their basic research and preclinical drug development (3). This is a difficult and sometimes risky gap, and can be very difficult for academic researchers to fund, often being described as too applied for NIH, or too early for pharma interest. Academic HTS cores step in at this point and take the biological target or assay of the investigator and screen for novel modulators against the target, which can result in novel probe tools for further research, or for potential leads for drug development.
Academic HTS cores often start off with strong backing and interest, which sometimes can dwindle if the needs of the greater academic community are not met adequately and in a time-efficient manner. Alternatively, many academic HTS cores originated in the National Institutes of Health (NIH) Roadmap for Medical Research (4).
These HTS labs were started or supported by the pioneering work of the Molecular Libraries Screening Centers Network (MLSCN) and the subsequent Molecular Libraries Probe Production Centers Network, initiated and supported by the NIH Roadmap. But with the end of the MLSCN, and soon the concluding of the MLPCN programme, several HTS cores lost, or will lose, much of their support and business.
Likewise, all non-MLPCN HTS cores eventually lose their fundamental founding financial support, the start-up funds that supported the establishment of the core facility. Thus starts one of two fates: either continued strong support through supplementation from the university, or the new struggle for financial stability, a battle for self sustainability.
The University of Kansas High Throughput Screening core was started in 2007 as a university core lab, and was not part of the MLSCN or MLPCN screening labs. KU-HTSL has achieved self sustainability through a combination of federal funding and support from its collaborators and clients, including academic researchers, biotechs, pharma and disease foundations. We would like to offer what we have learned from the past few years as helpful principles for achieving and maintaining self sustainability, to other academic screening labs (5) (Table 1).
This advice should serve useful to other types of service cores as well, as many of these are generally applicable advice, such as the familiar SWOT analysis, for identifying and addressing the Strengths, Weaknesses, Opportunities, and Threats to the function and survival of the laboratory (Table 2).
Core Laboratories at the University of Kansas
There are 15 core service laboratories at the University of Kansas (6) (Table 3).
Five of these cores originated prior to the 1990s and have stood the test of time. Not surprisingly, these early cores serve critical needs, such as animal care, mass spectrometry and nuclear magnetic resonance (NMR) services. No currently existing cores originated in the 1990s, but since 2000, 10 new cores have originated at the University of Kansas and remain today, along with the pioneer core service laboratories. Newer technologies from the past 10 years have brought about the rise of these new service labs, such as cores for high throughput screening, bioinformatics and proteomics.
Academic High Throughput Screening Core Facility (AHTSCF) budgets rely primarily on institutional support and fees charged to collaborating investigators in exchange for screening services. AHTSCFs, like most service core labs, require varying degrees of internal, institutional financial assistance to keep their service costs competitive.
This is a win-win scenario for the service lab and the university, as the AHTSCF offers discounts for university investigators, and higher rates for external and for-profit collaborators. Since competitive pricing structures do not pull in enough revenue to maintain self-sustainability, the AHTSCF is continually dependent on funding from grants or direct support from the presiding department at the academic institution.
The degree to which an AHTSCF relies on institutional support depends on the funding the core is receiving from the government, collaborators, foundations and other sources. During the first five to 10 years of its operation, a typical AHTSCF should expect to receive half of its operating costs from these sources or from the parent institution. This gives the core screening lab flexibility to focus on establishing and executing a self-sufficiency action plan. This plan may include tasks such as developing its customer base, establishing its core services, training staff, gaining experience in core operations, and developing a realistic business model.
The remainder of the operating budget is derived from service fees, which are not intended to garner profits, but rather to recover costs and maintain operations. With time and prudent business decisions, the AHTSCF should slowly wean off of the institutional support, replacing it with income from the ever-increasing customer base and higher operating efficiency.
Even if and when self-sufficiency is met, support from the parent department should still be available in situations of unexpected costs, such as a dip in clients, loss of funding, or to smooth out budget bumps from replacement and upgrade of expensive screening platforms. In this way, institutional support can provide security to the screening core in the face of competition, to maintain the integrity and service function of the lab.
Funding and Governance
The KU-HTSL, now starting its fifth year, is supported by a variety of mechanisms (Table 4).
KU HTSL is supported, in part, by the Centers of Biomedical Research Excellence (COBRE), Center For Cancer Experimental Therapeutics (CCET), the Kansas Technology Enterprise Corporation (KTEC), the Kansas Bioscience Authority (KBA) and the KUMC Cancer Center. In addition, funding is derived from NIH grants and private funding. Collaborations with federally funded researchers provide crucial support to the screening lab. This grant funding is often derived in the form of supporting aims in large grants, where HTS is a critical component of a major funded project.
The KU HTSL is a shared resource of the University of Kansas Medical Center (KUMC) Cancer Center and the University of Kansas Department of Research and Graduate Studies (KU RGS). Administration and organisation is provided both by external and internal advisory boards. Individual projects are managed by the collaborating principal investigator alongside the HTS director and HTS project managers.
In addition to its work with researchers and clients, the KU HTSL core synergises with other service cores at the University of Kansas to provide a greater range of capabilities for research and drug discovery. The broad clientele of the KU HTSL, to internal and external, non-profit and for-profit entities, provides much needed financial support. However, these extracurricular services need to be balanced with services to the supporting institution, to ensure proper service to local university researchers’ needs, and to bring value to the investment made by the supporting groups at the university.
One advantage in work with for-profits and external institutions is the implementation of the higher market rate for the services rendered. This translates into higher fees for services, but too much external work proves to be a disincentive to funding support and subsidisation by the home university. Otherwise the university will essentially be subsidising the work of external researchers.
HTS rate structure and pricing variables
The ATSCFs are established, for the most part, by funding received from the state or federal agencies. As such, the rate structure that the ATSCFs are mandated to follow are governed, in the United States, by the Office of Management and Budget (OMB) Circular A-21: Cost Principles for Educational Institutions. OMB Circular A-21 is a government circular that sets forth the rules governing the eligibility, accounting principles and calculation of costs in support of sponsored research.
Every service in each core laboratory has three distinct rates: Internal federal rates, external federal rates, which is about 5% more than the internal rates, and external market rates. The latter may be established on a case-by-case basis. The rates are set through a rigorous evaluation of costs of labour, materials and lab administration costs. Sadly, the rates are also influenced by inertia; decisions about programme funding that were made many years ago. Further, the rates need to be regularly subjected to a reasonability test.
The academic HTS core relies on a three-tier rate structure for collecting fees for its services:
1. Institutional investigators comprise researchers from within the parent institution, and within state, and receive the best possible, lowest rate for services thanks to subsidies from the department hosting the HTS lab.
2. External academia and non-profit organisations, either from within or outside of state bounds, also provide valuable collaborations but are not subsidised to the degree of internal researchers. The fees they do pay are well below CRO prices, however.
3. Industry or forprofit organisations, regardless of location in/out of state, have the highest rate structure.
HTS service cores recoup money from internal department support and fees to cover salaries, consumables and other costs. The fees charged for HTS services range very broadly, dependent on several pricing variables, based on the type of assay, consumables, equipment and labour hours required. Variables include assay development time requirements, the type of HTS screen needed, the type of assay desired, the plate format, and other variables (Table 5).
Unique costs associated with AHTSC facilities
HTS service labs require steady funding, as with all service core facilities, but there are several unique costs found in screening cores. Unique to HTS cores are the screening platforms and liquid handling workstations, which can cost anywhere from $50,000 to $500,000 per instrument, and many instruments can be integrated to make a seamless, automated screening workstation. Alternatively, these instruments can be left non-integrated, for use in a modular setting.
Every few years, newer, better HTS instruments outdate older models, such as 384-tip based robots making 8-tip liquid handlers practically obsolete. As newer instruments with more capabilities arise, however, prior models become more affordable for academic labs. HTS cores face ever changing assays, with needs for new types of instruments, as is currently being seen with the increasing demand for label-free instrumentation.
Progressively smaller volume bulk dispensers and compound dispensers with smaller volume capacity (nanolitres and picolitres) are being developed, along with more sensitive detectors, smaller wells in microplates (384, 1536 and 3456), and plate readers that can read these smaller wells. For HTS service cores to compete with pharma or with CROs, they need to occasionally and strategically upgrade their instruments.
Similar to HTS cores, non-HTS service core facilities also need to upgrade instrumentation when new technology is developed. Any service core with such expensive, large and complicated instrumentation faces steep prices on service contracts. Particularly complex screening instruments, such as acoustic-based or label-free, may have service contracts costing more than 10% of the purchase price of the instrument, per year.
HTS service cores are typically staffed with specialists in their respective fields, with wide knowledge of different types of assay systems and sciences, which is necessary to offer expert consultation for their core services to the diverse array of collaborators needing assay services. However, automation engineers are practically non-existent in academic HTS labs, and the core facility’s staff members, depending on their interest, take on the task of trouble shooting and maintaining their instruments.
Product pricing: striking a balance
AHTSCFs may have an easier time staying self-sustained if they increase the rates they use to charge for services. But increasing the rate structure can cause its own problems, driving away investigators to cheaper solutions, or competing service labs or vendors. Affordability and price competition are key factors to maintaining this balance. If the charge for services is too high, potential collaborators will spend their project funding elsewhere.
A principal investigator may be tempted to divert $45,000 away from a planned high throughput screening campaign, choosing instead to spend it on one year of a post-doc’s salary. Both options carry inherent risks and benefits. A post-doc may be funded for a full year, but the work will generally be less, and possibly lower quality, than focused efforts of a full HTS team, project manager, director consultation, and the array of provided HTS services. We compare the pros and cons of this predicament in Table 6.
This fine balance of price in the rate structure is critical to achievement of self-sustainability. It is no small task to set up this delicate structure, and requires a stringent evaluation of the costs of consumables, reagents, labour and administration costs. Further, the established rates must be regularly compared to the rates of other academic screening cores to evaluate the reasonability of prices.
Screening core service labs, like any business, depend on steady, strong throughput of product to provide a steady stream of income, while providing the promised services to the client in a timely manner. Compared to pharma screening facilities, most academic HTS cores are small, underfunded, understaffed, with considerably smaller compound libraries and lack medicinal chemists needed to verify hits identified through screening campaigns. But like a small family-owned shop, these relatively small academic screening facilities have several unique strengths.
The affordability of instruments and microplates and screening reagents has improved, allowing AHTSCFs to offer the same types of screening as pharma, but on a smaller scale of 2,000-50,000 small molecules. These smaller screens are still more than enough for pilot data for grants (2,000 compounds), or screening for novel probes for academic research (50,000 compounds).
Table 7 presents an updated list of screening centres, according to the Society for Laboratory Automation and Screening (7).
Interestingly, the number of academic HTS labs in the US has doubled in the past three years, growing from roughly 22 academic HTS labs in 2008 to at least 44 in 2011 (2).
The ever growing number of academic HTS cores brings these services in closer proximity to the academic researcher, fostering collaboration through alliances within their own state or even within their own university. It is likely that this trend will continue, as more universities jump on the bandwagon, seeking their own cores for screening. The layoff of drug discovery scientists from pharma may continue to supply personnel, redistributing top scientists into smaller biotechs, startups and academia.
Bottlenecks threaten throughput
Throughput in a AHTSCF varies depending on the type of project, whether it is amenable to HTS, and how developed the assay is prior to delivery to the HTS service core. The automated nature of HTS allows for a faster completion of assays that are robust, with minimal variability, and miniaturised to a 384-well or other microplate format suitable for screening.
Assay development and optimisation toward this end are the predominant rate limiting steps to an efficient screening project. Many assays from non-HTS basic research labs are initially not robust enough (or sufficiently miniaturised) to be run on automated screening platforms and workstations. Assay development and optimisation take many times longer than actually running the high throughput screen, but are critical to generating viable data. If development time is extensive, project completion takes longer and costs more in labour hours.
This in turn discourages new clients, while reducing the total number of projects that can be completed per year. An assay that is too complicated or sensitive to be miniaturised into a 384-well format needs to be identified and before it can cause a throughput-crippling bottleneck. These scenarios highlight the value of consultation with expert HTS staff, who can advise alternative assays, orthogonal methodologies, or more suitable reagents and experimental systems.
Networking extramural clients
Maintaining a steady stream of viable projects and collaborators is essential to the business plan of a screening core. Reaching out to potential clients can be arduous and time-consuming, and even costly. Similarly, for basic research labs seeking help in areas outside of their expertise, it can be very frustrating to navigate the maze of paperwork associated with setting up a contractual agreement with a fee for service lab or contract research organisation (CRO).
To alleviate this burden, new web-based services such as ScienceExchange (www.scienceexchange.com) have been formed to help link researchers to service labs. Academic screening labs should participate in these online marketplaces to bring in new projects and broaden their collaboration network.
Networking by online services and networking sites have their value, but should not fully replace classical scientific networking methods such as conferences, seminars, scientific society exhibitions, advertising in publications and trade journals, writing publications and the like. For self-sustainability to become a reality for AHTSCFs, we need to be open to not just internal funding and projects, but also other universities, disease foundations, biotechs, industries and pharma; any relevant science group that is either looking to outsource or needing probes.
Over the past several years, KU HTSL has had healthy, productive collaborations with each of these extramural clients, and has been pleasantly surprised by the large interest of disease foundations for HTS and probe discovery. Networking, seeking collaborators and projects, and seeking funding all shares a common thread – to keep enough good projects in the pipeline, swing a wide net. Appealing to not just federal grants, but also private foundations and business entrepreneurs, and provides unexpected collaborations and projects.
Targeted campaigns to disease foundations and academic departments that lack HTS or medicinal chemistry support is a good way to bring in new projects. It is highly beneficial when the university’s upper management gets actively involved in high profile negotiations. A full-time business development person is needed to identify prospective clients. The university should have a competent technology transfer office to mediate MTAs/CDAs.
Self-sustainability of an academic HTS lab is also positively influenced by presence of a project management function which ensures momentum in the flow of project direction and funding. KU-HTSL has adopted an industry-based model of project management to maintain a continuous flow of information between the principal investigator and HTS facility.
The faculty and staff in academia generally make all the key decisions in project direction either alone or sometimes with a collaborator. Due to the diverse interests and commitments of the university faculty, organising a co-ordinated effort in academia is extremely challenging and requires fostering of a commitment from all personnel involved in team-based projects.
The KUHTSL is part of a much larger drug-discovery institute which brings all elements essential to maintain project momentum, budgets, time-lines and transitions from early to late phase drug discovery. The KU drug discovery has hired industry-trained, highly-experienced project managers who help maintain communication, funds and data flow for all projects starting from high throughput screening laboratory.
In KU drug discovery management, each drug discovery project team comprises team members who are multi-disciplinary, and an industry trained project manager, who works with the principal investigator to provide project stewardship, and is responsible for developing and implementing project plans.
The principal investigator is generally a university faculty researcher, who discovers interesting biology and conceptualises the target-based drug discovery project. The project manager coordinates meetings with the principal investigator and the high throughput screening facility to discuss and develop assay development and optimisation plans for early screening phase based on available funds and overall goals. The principal investigator generally drives the project and is responsible for setting project scientific direction and with the help of the HTS director, in resolving technical issues facing the project and the team.
The actives identified from the assay are further characterised in secondary screens and the data is used at this stage to procure more grant funding. The results from screening are often utilised for filing an early stage patent application, in which case the project manager establishes communication with the principal investigator, the HTS director and the technology transfer office to establish co-inventors and time-lines on the created intellectual property. The team may also include students and/or HTS staff who work under the direction of the Principal Investigator and HTS director.
The project manager, in discussion with the researchers, helps decide on the appropriate timing of publication of drug screening data and disclosure of the results of publicly funded research. Depending on how far the project progresses, the project manager also brings in other available expertise at different stages of drug discovery to expand the team’s capabilities. If the academic screening project results in valuable hits, chemo-informaticians, analytical biochemists and medicinal chemists join the core group in mapping out the hit to lead optimisation strategies.
The management team also contacts database managers, pharmacologists and formulation experts at later stages of the project. The university clinical scientists also join the teams during more advanced stages of the project, providing clinical validation and direction in setting the clinical proof of concept strategy, and maybe a co-inventor on intellectual property.
At all stages of drug discovery collaboration, the project manager identifies projects, contributes to organising project teams, designing timelines, and co-ordinating efforts of strategic university researchers, relevant university service cores, and their external collaborators from industry, disease foundations, regulatory and technology transfer resources. Regularly scheduled team meetings with preset agendas and formal minutes are held to focus teams on time-lines, discuss issues, make decisions, prepare status reports, maintain project 66 Drug communication and manage critical path, timelines and budget.
Since project management is a new skill in the academic sector, the management practices are very flexible and project managers are constantly learning and adapting, based on individual projects and their varied objectives. The project manager also provides flowchart schematics for project timeline with go/no go decision points and deliverables, and also provides grant submission support on translating drug target to clinical proof of concept.
Based on their pharmaceutical development experience, the project manager, in collaboration with the HTS director and the principal investigator, defines key decision points from drug target identification and validation through clinical proof of concept, and identifies data sets from experiments and studies to support each of the decision points.
Achieving self-sustainable AHTSC facilities: the path forward
Academic screening consortia. Academic service cores must compete with CROs to maintain viability. In order to survive in this competitive atmosphere, academic screening centres need to merge forces to endure in this difficult environment of reduced federal funding and competition. Regional consortia would fill this need, allowing sharing of compound libraries and other screening resources between academic screening labs in areas where institutional support for core HTS functions is sparse.
Compound libraries and management
First, compound storage and management could be organised and shared between AHTSCFs. Compound libraries could be purchased by a group of AHTSCFs, divided and shared equally. In addition, this could entail sharing the tasks of organising the libraries and compound collections, and avoid duplicate efforts and libraries between screening cores. This type of library compound sharing is currently being practised by Melvin Reichman at the Lankenau Institute for Medical Research (LIMR) Chemical Genomics Center (LCGC), a screening facility in Wynnewood, PA.
The KU HTSL has already collaborated with the LCGC for compound sharing, and KU HTSL has carried out several small screening campaigns with compounds from the LCGC library. Most academic HTSLs often do not have sufficient funding to support the purchase and maintenance of a large compound library and an expensive compound storage system, but could afford this type of sharing scheme, ordering assay-ready plates or small sample compound libraries or subsets from larger academic screening facilities.
Unique instrument and technology sharing
While all screening cores have basic liquid handlers, bulk dispensers and plate readers in stock, the limited budget of academic service cores limits their ability to purchase, maintain and operate the wide range of specialty instruments and platforms available to HTS. As different screening labs focus on different specialties, a consortium would enable academic screening cores to share their talents with other cores, screening and non-screening. For instance, KU HTSL has several unique platforms utilising novel label-free technology, but had (until this past year) lacked instrumentation for ion channel research.
David Weaver’s Vanderbilt Screening Center, however, specialises in ion channel research, and is equipped with multiple Hamamatsu FDSS systems (Function Drug Screening System), and is well experienced in screening assays dealing with GPCRs, ion channels and transporters. A team of KU HTSL researchers and the director recently travelled to Vanderbilt to seek advice and input relating to this type of instrumentation. These types of communication between academic screening cores can unite and strengthen our edge against competition from industry, while adding value to services provided to the HTS core’s clients.
Data analysis and information management
All screening labs need adequate data analysis capacity, but more advanced data sets, such as high content screening data sets, can be more readily and quickly analysed by those academic centres that specialise in those areas. The prevalence of internetbased cloud storage and data sharing provide the means for shared assay data management, also. Small academic screening cores without sufficient funds for a laboratory information management system (LIMS) can collaborate with a secure, webbased LIMS of another screening core. Expertise sharing between academic cores can lead to new solutions for data management and storage.
The chief bioinformatician at KU HTSL, Jianwen Fang, developed his own LIMS, called K-Screen, in part thanks to the help of the creators of MScreen from the University of Michigan. KU HTSL’s K-Screen is a database management system designed for high throughput screening data management, analysis, mining and visualisation, and was developed using open source Linux/Apache/MySQL/PHP platform (9).
By using open source software programs, and the inception of the homemade LIMS thanks to collaboration with the University of Michigan, Jianwen was able to make an affordable solution to meet the database management needs of KU HTSL, without the steep price of a commercial LIMS. KU HTSL freely offers the KScreen algorithms to other AHTSCFs at no cost, and advises in setting up their own database management system.
Medicinal chemistry plus HTS
High throughput screening cores need to stay competitive for federal grants to maintain their funding levels. The Molecular Libraries Probe Production Centers Network (MLPCN) demonstrated the strength of comprehensive screening centres and the aid of medicinal chemists to provide the expertise and technology needed to improve the specificity and strength of screening hits.
Academic screening cores need the assistance of medicinal chemists, but very few universities have both a high throughput screening lab and a medicinal chemistry department, such as the one at the University of Kansas and the University of Pittsburgh (9). Medicinal chemistry departments are very rare, and are even rarer at medical schools, where drug discovery efforts are needed the most, due to the cutting edge targets being pursued.
Institutional seed funding
The AHTSC facilities play a critical role in enhancing academia’s mission in drug discovery. We have witnessed many drug discovery-related grant applications that did not originally get funded succeed in subsequent submissions when a HTS component is included with strong pilot data.
Many academic investigators with potentially fundable drug discovery project ideas have been unable to develop strong grant applications due to a lack of pilot data, a critical component to show the granting agencies that the target has been validated, a robust HTS-amenable assay exists, and pilot screening data is encouraging. We challenge the upper management in academia to provide seed funding in the range of $25,000 to $50,000 to investigators to develop competitive grant applications.
If successful, this modest investment could result in a 10- to 30-fold return on investment, bringing $250,000 to $1.5 million, depending on the type of grant, to support the investigator’s drug discovery research. Not to forget, a sizeable percentage of the funds received go to the institution towards supporting its Facilities and Administration costs. It’s a win-win scenario for both the investigator as well as the institution!
Intellectual property, technology transfer and royalties
The AHTSCFs are keenly aware of the intellectual property that might be associated with all aspects pertaining to the therapeutic target, including assay novelty, med chem-optimised screen hits, therapeutic relevance of the probes/leads developed. At KU-HTSL we work very closely with the Technology Transfer and Commercialization office in filing provisional patent applications, and navigating communications with the interested pharmaceutical industry or disease foundation partners.
Occasionally, entrepreneurial investigators embark on setting up incubator companies either on campus or in close proximity to the campus and maintain close collaborations with the institution. It is well recognised in recent years that the AHTSCFs are not just ‘fee-for-service’ providers, but are indeed true partners with substantial intellectual input in transforming the investigators’ projects into bona fide drug discovery projects. As such, the HTS staff members are often named as co-inventors in patent applications, and the AHTSCFs are the beneficiaries of any royalties that come out of the marketable discoveries.
While this scenario is not just quite the case with most AHTSCFs, it is indeed becoming the norm and plays heavily into the self-sustainability of the AHTSCFs. To those AHTSCFs that strictly maintain a ‘service’ mindset, we caution to look beyond the service fees and publications and glean into patent filings and the potential for royalties for their contributions.
Rather than work independently, in isolation and against each other, academic screening labs need to recognise the importance and advantages of helping each other, buffering weaknesses and uniting. This is not just for the embitterment of the landscape of drug discovery and patients, but also for our very survival as we each fight for selfsubsistence as federal research dollars are waning or shifting to more translational directions.
By forming a consortium of allies, academic screening labs will be better able to meet the needs of academic investigators who carry cutting edge research, and apply the ready availability of technology and expertise, as the MLPCN stage of the NIH Roadmap Initiative comes to a conclusion. The proposed steps would eliminate waste, cut costs and improve efficiency, all-important drivers of self-sufficiency. The participating AHTSCFs would maintain their autonomy, in the proposed consortia, as long as there is a memorandum of understanding that has clearly addressed not just publications and revenue sharing, but also the stake in intellectual property, technology transfer and any royalties that will be realised.
We also implore the management in academia not to treat the AHTSCF staff as secondclass citizens, as is the case now, but to make the senior AHTSCF staff tenured or tenure-track faculty. The AHTSCF staff’s salaries would then not come from the AHTSCF service revenue, but from the university’s operational budget itself. This is easily defendable because the Facilities and Administrative component of a funded grant, especially with a HTS component, hitherto has not been reflected in the AHTSCF revenue stream or budget.
With the salaries covered, the AHTSCF can now offer its screening services at a somewhat reduced cost. This would enable the institutional investigators to easily afford AHTSCFs services which would in turn increase the number of incoming projects, the associated revenues, and thus make self-sustainability of AHTSCFs a reality rather than a dream. DDW
The authors would like to thank Drs Joseph Heppert, Roy Jensen, Barbara Timmermann and Scott Weir for their continued support of the KU HTSL and drug discovery research at KU, and their dedication to the HTS laboratory’s continued mission of excellent service and self sustainability. KU-HTSL is a KU Cancer Center Shared Resource, and is funded in part by NIH Grant (P20 RR015563, Timmermann, PI) (COBRE Program of the NCRR).
Dr Peter McDonald holds a doctorate in molecular pharmacology from the University of Pittsburgh School of Medicine, Department of Pharmacology. Peter joined the University of Kansas High Throughput Screening laboratory in 2008. He provides project consultation and screening services, including high throughput screening (HTS) and high content screening (HCS), and develops cost estimates for incoming projects.
Dr Anuradha Roy is interim director of the KU HTSL. Prior to joining KU, she led various aspects of drug discovery at PTC Therapeutics Inc after her postdoctoral work at Cleveland Clinic Foundation. She holds a doctorate in Biochemistry/Molecular Biology from Jawaharlal Nehru University (India). Anu leads enzyme- and cell-based screens at KU-HTSL.
Dr Rathnam Chaguturu was the previous director of KU-HTSL. He is currently the Senior Director- Exploratory Research, Center for Advanced Drug Research, SRI International in Harrisonburg, Virginia. Rathnam has more than 30 years of experience in new lead discovery and development, executing high throughput screens and managing hit to lead projects. He has authored more than 50 research publications including reviews and book chapters, and holds 11 US patents. He is the founding president of the International Chemical Biology Society, and the Editor-in-Chief of the journal Combinatorial Chemistry and High Throughput Screening, published by Bentham. He is currently editing a book, tentatively titled, Collaborative Drug Discovery: Strategies for Academic, Industry and Government Partnerships, to be published later this year by Wiley & Sons.
1 Macarron, R, Banks, MN, Bojanic, D, Burns, DJ, Cirovic, DA, Garyantes, T, Green, DV, Hertzberg, RP, Janzen, WP, Paslay, JW, Schopfer, U, Sittampalam, GS. Impact of high-throughput screening in biomedical research. Nat Rev Drug Discov. 2011 Mar;10(3):188-95.
2 McDonald, PR, Roy, A, Taylor, BJ, Price, AR, Sittampalam, S, Weir, S, Chaguturu, R. High throughput screening in academia. Drug Discovery World 2008; Fall: 59-74.
3 Roy, A, Taylor, BJ, McDonald, PR, Price, AR. Hit-to-probe-tolead optimization strategies: a biological perspective to conquer the valley of death. In Seethala R & Zhang L (Editors), Handbook of Drug Screening, Second Edition, 2009: Informa Healthcare: 21-55.
4 Website: http://nihroadmap.nih.gov/grants/fundedresearch.asp. Accessed December 2011.
5 McDonald, PR, Roy, A, Chaguturu, R. The University of Kansas High-Throughput Screening Laboratory part II, enabling collaborative drugdiscovery partnerships through cutting-edge screening technology. Future Med Chem 3(9): 1101-1110, 2011.
6 Website: http://www.rgs.ku.edu/org/rgs_centers.pdf. Accessed December 2011.
7 Website: http://www.slas.org/screeningFacilities/facilityList.cfm. Accessed December 2011.
8 Tai, D, Chaguturu, R, Fang, J. K-Screen: A free application for high throughput screening data analysis, visualization, and laboratory information management. Comb. Chem. High Throughput Screen. 2011 Nov 1;14(9):757-65.).
9 McDonald, PR, Roy, A, Chaguturu, R. The University of Kansas High-Throughput Screening Laboratory part I, meeting drug-discovery needs in the heartland of America. Future Med Chem 3(7): 789- 795, 2011.
10 Website: http://www.slas.org/screeningFacilities/facilityList.cfm. Accessed December 2011.