The molecular biology and genetic engineering revolution catalyzed a new era of drug discovery. Academic labs and the new biotechnology industry could clone and express proteins to study their functions and to screen against collections of small molecules, peptide, antibodies, and proteins to look for new drugs. The earliest biotechnology companies strove to be fully integrated, housing biochemistry, screening, medicinal and analytical chemistry, in vitro and in vivo biology, informatics, and clinical operations. Over time, leaders appreciated that some activities were more cost efficient to outsource. Contract research organizations (CROs) emerged to run common types of assays that many of the new companies needed and first focused on relatively routine assays that could be readily run as a fee-for-service business model. These assays included profiling compounds for mutagenic or carcinogenetic properties, metabolic liabilities, off-target binding to predict safety and toxicity, and animal-based drug efficacy and toxicology studies. Other CROs also focused on drug discovery support with expertise in synthetic and medicinal chemistry and high throughput screening services.
For a particular biotechnology company, the ratio of in-house versus out-sourced R&D activities depends on the strategies being pursued. In fact, a popular model for biotechnology companies today is to be ‘fully virtual’, where all the R&D activities are outsourced! Implicit to the skilled use of CROs is that scientists within the company are expert in the methodologies and work closely with the CRO; these relationships can be directed solely by the biotech or based on partnerships where the CRO scientists contribute designs and ideas.
In parallel to the rise of CROs, two key driving forces led to the rise of academic drug discovery centers (ADDCs). The first was the industrialization of the drug discovery process. As assay miniaturization and robotic automation became more common, robotic systems were scaled to the needs of diverse academic groups, from a lab focused on automating a single assay to the comprehensive systems at the National Institutes of Health (NIH) Molecular Probes Production Center Networks (MLPCN). The MLPCN program, which ran from 2004-2014, introduced hundreds of academic labs to high-throughput screening and to the challenges of validating assays and hit compounds. The second driving force for the creation of academic drug discovery centers was the formulation of ‘chemical biology’ as a sub-discipline of chemistry. Chemical biology focuses on the use of chemical probes to dissect biological mechanisms and is now considered as a third fundamental strategy–together with genetics and biochemistry–to understanding biology. The acceptance of chemical biology as a field is manifest by the rebranding of chemistry departments, notably Harvard’s Department of Chemistry, which in 1995 changed its name to Chemistry and Chemical Biology. In the past 25 years, scholarly societies and journals focused on chemical biology have flourished.
Thus, ADDCs and chemical biology centers have emerged at universities to supply research faculty and student demand for access to chemical tool compounds. In addition to small-molecule drug-discovery efforts, academic centers can be focused on antibody discovery and state-of-the-art technologies in protein, nucleic acids, and cell therapies. Regardless of the drug modality, centers often focus on drug discovery for novel targets identified by academic labs. Typically, ADDCs are staffed with scientists with pharma and biotech experience who add drug-discovery professionalism and are interested in educating the next generation of drug hunters. Many high-value companies and novel therapeutics have spawned from the efforts of ADDCs.
Over 150 such ADDCs are members of the Academic Drug Discovery Consortium. Many of these centers also engage in partnerships and fee-for-service work with for-profit companies. For example, our team at the University of California San Francisco (UCSF) Small Molecule Discovery Center (SMDC) works with companies in diverse modalities of assay development and high-throughput screening, fragment-based drug discovery (FBDD), and medicinal chemistry. For-profit companies work with the SMDC under two types of agreements. Unlike CROs, we are not able to assign intellectual property, only to license it. Thus, like CROs, we can engage in fee-for-service for projects that will not generate intellectual property, such as running high-throughput or fragment-based screens or validating compounds’ mechanism of action using biophysical assays. These assays can be highly unusual, however, for instance drawing on our expertise in high-content imaging or fragment-based screening. For example, the SMDC maintains a unique library of mixed disulfides applied to the site-directed fragment approach called disulfide tethering. Typical clients for a CRO-type engagement are: (a) small companies without large compound libraries or automation; and (b) companies with novel targets/target classes that want help designing customized, bespoke, assay formats.
The other type of engagement is a true partnership, called “sponsored research.” We may engage in sponsored research when a higher level of intellectual engagement is desired and when intellectual property may be generated. For instance, the SMDC scientists have particular expertise in undruggable target classes like protein-protein interactions, proteases, and intrinsically disordered proteins. Typical collaborators for partnership are larger companies who have invested in a new target or technology and want to expand their project scope. To develop a successful sponsored research agreement, both sides must understand the balance between a focus on the critical path and the academic requirement to disseminate information to the public.
Thus, there are several considerations that come into play around deciding between a commercial CRO or an academic drug discovery center for a drug discovery project. One important consideration is the nature of the target and its uniqueness and complexity in the creation of the biological screen. Targets that have been extensively pursued, such as nuclear receptors, kinases, or GPCRs are usually in-scope for a commercial CRO. However, for a novel target, complex biology, or an unusual mechanism of action, the specific expertise required may be more readily found in the academic setting. In addition, universities with drug discovery centers often have core facilities in allied areas that could be brought to bear on the project; such technologies could include in vivo animal models of disease pathophysiology, systems biology-based platforms (e.g., genomics, proteomics, and metabolomics), structural biology (X-ray crystallography, NMR, and cryo-EM), and computational drug discovery.
Importantly, in an academic setting, the faculty may be the original discoverers of the disease biology or chemical technologies of interest. As just one example, the SMDC leadership were among the original developers and users of the disulfide tethering technology and UCSF faculty include key opinion leaders in KRAS cancer biology. Together, these investigators used the technology to develop the first published inhibitors of the oncogene KRAS G12C. Another consideration for deciding between commercial CROs and academic drug discovery centers can be geographic. An academic drug discovery center in your region allows for close interactions, sharing of reagents, and collaboration. This experience can be contrasted with commercial CROs that can be 12 times zones away. How the project is staffed and managed, and the nature of the information- and data-exchange are additional important considerations in both the commercial and academic spheres. It is prudent meet with the director of each prospective center and to talk with past customers to evaluate the specific technical capabilities, professionalism, and costs for a proposed project.
In conclusion, in addition to commercial CROs, one should consider ADDCs when exploring outsourcing phases of a drug discovery project. A very important consideration is the nature of the specific project, and its uniqueness and novelty. When it comes to bespoke assays and in-depth target biology, an academic drug discovery center could be the ideal partner for your project!
