The Medical Research Councils Laboratory of Molecular Biology (LMB) in Cambridge, UK, is a world leader in basic biology research. The labs list of breakthroughs is enviable, from the structure of DNA and proteins to genetic sequencing. Since its origins in the late 1940s, the institute currently with around 700 staff members has produced a dozen Nobel prizewinners, including DNA decipherers James Watson, Francis Crick and Fred Sanger. Four LMB scientists received their awards in the past 15 years: Venkatraman Ramakrishnan for determining the structure of ribosomes, Michael Levitt for computer models of chemical reactions, Richard Henderson for cryo-electron microscopy (cryo-EM) and Gregory Winter for work on the evolution of antibodies (see Figure S1 in Supplementary information; SI). Between 2015 and 2019, more than one-third (36%) of the LMBs output was in the top 10% of the worlds most-cited papers1.
What is the secret of the LMBs success? Many researchers and historians have pointed to its origins in the Cavendish Laboratory, the physics department of the University of Cambridge, UK, where researchers brought techniques such as X-ray crystallography to bear in the messy world of biology. Its pool of exceptional talent, coupled with generous and stable funding from the Medical Research Council (MRC), undoubtedly played a part. However, there is much more to it. None of these discoveries was serendipitous: the lab is organized in a way that increases the likelihood of discoveries (see New questions, new technologies).
To find out how, we conducted 12 interviews with senior LMB and external scientists to provide insights into the organization. We also analysed 60 years worth of archival documents from the lab, including research publications, meeting minutes, external assessments and internal management reports (see SI for methods).
The LMBs approach is to identify new and important scientific questions in uncrowded fields that require pioneering technologies to answer them. The lab develops that technology to open up the field; continual improvements bring more breakthroughs, which can be scaled up to enter markets. Here are three examples.
DNA sequencing. In the 1940s and 1950s, biochemists Max Perutz and John Kendrew sought a way to discriminate between normal and pathological haemoglobins and myoglobin. The LMB developed molecular fingerprinting and chromatography technologies11 that allowed various biological questions to be addressed, such as how genes are regulated or how molecular programming is involved in cell death. Protein and DNA sequencing also enabled the study of molecular mechanisms of viruses and organ development. Transferring these discoveries into clinical and industrial settings changed drug discovery from a process of screening compounds to one of active design.
Antibodies. At the LMB in 1975, biologist George Khler and biochemist Csar Milstein discovered a method to isolate and reproduce individual (monoclonal) antibodies from the many proteins that the immune system makes. This breakthrough enabled the characterization of antibodies, and sparked inquiries into gene regulation and programmed cell death. Monoclonal antibodies now account for one-third of new treatments that reach the clinic.
Cryogenic electron microscopy. The LMB has a long-standing history in the development of electron microscopy, with Aaron Klugs group using it in the 1960s to elucidate the structure of viruses. Cryo-EM visualizes atoms in biological molecules in 3D. It was developed on the back of three decades of the LMBs accumulated expertise in areas from optimizing cooling and vacuum technology to microscopy, computing-based imaging and electron detectors. The method has revolutionized protein research and many other areas.
We identify the LMBs management model as the key it sets a culture with incentives and provides oversight to optimize the interplay between science and technology. By integrating high-risk basic science with innovative technology, the LMB facilitates a knowledge feedback loop that helps the institute to identify promising questions and continuously push scientific boundaries (see SI, quote 1). In the context of economics and management theory, the LMB behaves as a complex adaptive system.
Here, we outline our findings and encourage research organizations, funding bodies and policymakers to consider adopting a similarly holistic and coherent approach to managing basic scientific research. In short, they should prioritize long-term scientific goals and effectively manage scarce resources; foster economies of scale and scope by promoting complementarities between different areas of scientific research; and create value by establishing synergies and feedback between scientific questions and engineering-based technology solutions.
The LMBs management strategy prioritizes three elements culture, incentives and management oversight that sustain a feedback loop between science and technology development (see SI, Figure S2).
Culture. The LMB sets a coherent culture by promoting scientific diversity among its staff, encouraging the exchange of knowledge and ideas and valuing scientific synergies between different areas of research. Senior managers view this culture as central to an evolutionary process in which a broad and diverse talent pool helps the organization to be flexible and to adapt and survive. Scientific discovery emerges from it in a sustainable but unpredictable way.
Csar Milstein analysing DNA.Credit: MRC Laboratory of Molecular Biology
The LMB recognizes the importance of having a defined, yet broad and open, institutional research direction. It encourages the recruitment of groups with diverse but aligned interests that are complementary (see SI quote 2). This approach has ensured that the LMB can achieve a critical mass of expertise in specific research areas. It enables economies of scale while retaining the flexibility to innovate by pioneering new avenues and emerging fields. It also recognizes that not every promising direction can be followed.
Scientific diversity has been a trait from the start. Although the lab was founded by physicists and chemists, its researchers today include mathematicians, engineers and zoologists (see SI quote 3). Yet too much variety is to be avoided in case it dilutes the culture. Minutes of an executive committee meeting from 1997 reveal the reticence of lab heads to appoint purely clinical researchers on the grounds that this might alter the labs culture and its focus (see SI quote 4).
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A diverse portfolio of related and aligned themes makes it easier to share techniques and methods between projects and inspires programmes to aim at bolder goals (see SI quote 5). For example, the development of cryo-EM to examine macromolecules benefited both the structural-studies division and the neurobiology division, and led to a better understanding of molecular pathways in neurodegeneration.
Incentives. The LMB uses an incentive structure to align the organizations culture with the goals of its people. Actively promoting shared values and common aims helps researchers to feel part of the LMB community and proud to belong to it, fostering long-term loyalty. The LMB has always had a non-hierarchical structure one in which emphasis lies in the quality of the argument, rather than in the status of the proponent, a 2001 external review of the LMB noted (see SI quote 6).
Unlike many labs, the LMB focuses on investing in and promoting junior members rather than bringing in external talent. This is reflected in the high standards of its junior scientific recruitment. Many of its Nobel prizewinners, including Richard Henderson and Gregory Winter, began their careers at the lab and were promoted internally.
Prioritizing small teams also optimizes the sharing of technologies and budgets and incentivizes scientists from different fields to converge on the same projects. Although the LMB is structured in divisions, almost all career scientists have independent but aligned scientific programmes. This connectivity often leads to rapid and creative combinations of ideas between teams. It also allows for the sharing of failure and resilience to it, which is inevitable in high-risk, high-stakes innovative research (see SI quote 7).
Structural biologist Daniela Rhodes studies chromatin structure and regulation at the LMB.Credit: MRC Laboratory of Molecular Biology
LMB resources are allocated in ways that encourage innovative collaboration between internal teams and divisions. For example, limits are set for research groups to bid for external grants, because these tend to have short-term, results-oriented requirements that might not align with the LMBs longer-term ambitions.
Furthermore, the LMBs director can flexibly allocate funds to promote innovative collaborations and initiatives. Recent examples include forays into synthetic biology (using engineering to develop or redesign biological systems) and connectomics (the study of the connections in the brain and nervous system).
Management oversight. The LMB uses a management oversight system that resolves tensions between technology and science priorities, which would otherwise affect productivity. Technologists aim to develop and improve tools to match the best specifications for as many potential users as possible. Scientists help to define technology specifications that are based on their aims and data, which are usually on the cutting edge of existing capabilities.
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Tensions are present in the differences between how technology developers and scientists speak, define problems, operate and organize their project milestones and risk assessments. Technologists often focus on developing solutions for relatively well-defined practical problems that are amenable to rigorous project-management techniques, whereas scientists tend to work on uncertain, ambiguous questions and problems that require flexibility in experimental processes and resource allocation2.
To address these issues, the LMB uses a mixture of interventions and a robust process for selecting which scientific questions it focuses on. For example, technology developers with distinct specialisms operate in a dedicated workshop unit to develop prototypes. Experienced principal investigators act as go-betweens, translating scientific terms into technical engineering requirements and vice versa. Decisions around scientific resources are delegated to the divisions; money for major technology development is allocated centrally through the labs executive committee. Thus, the feedback loop between science and technology that facilitates innovation is enhanced (see SI quote 8).
Because the LMBs strategy focuses on long-term, transformational goals rather than short-term incremental gains, its internal evaluation system for researchers is more concerned with the potential of the overall scientific programme3 than with standard individual performance metrics, such as the number of journal publications and citations, personal impact factors, grant funding, awards and collaborations. Scientists must openly assess which questions hold the highest value according to the LMBs focus areas, and balance that with the cost of technology development and risks of failure while sustaining diversity in their research portfolio.
To manage these competing demands, the LMB integrates internal expertise and external reviews. The quinquennial external review process by the MRC is a strategic approach to innovation that anticipates future trends and brings fairness to decision-making. In our interviews, managers articulated the importance of quinquennial reviews to inform and stress-test the scientific direction of the organization. These reviews include visits from a committee of reviewers who are aware of the labs culture and who score a group leaders scientific productivity and originality on the basis of reports, internal reviews and interviews.
Biochemist Max Perutz preparing a sample for examination using X-ray crystallography.Credit: MRC Laboratory of Molecular Biology
Individual labs are evaluated on the usual metrics, such as results from past research, but more emphasis is placed on the future outlook. As a result, a young investigators potential and the impact of their research might result in tenure, even if they have a limited number of publications. Marks below a certain point mean the research group will be closed within a year. But this remains an exception so that the long-term nature of programmes is not lost.
The review process also plays a crucial part in identifying emerging scientific trends and opportunities. For example, in 2005, the visiting review committee identified the need for a new animal facility that would highlight the potential of mammalian biology a concept that had not been prioritized previously (see SI quote 5).
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Indeed, the LMB generally declines projects that require scaling up technology and large physical spaces, in case they come to dominate the labs work and space requirements beyond the financial income that the project can generate. In 1996, for example, the lab decided to forgo projects that involved scaling up its profitable protein and antibody engineering successes (see SI quote 9).
The LMB could be seen as a high-quality incubator for early-stage innovative projects, with a high turnover of research projects. This turnover does not compromise the viability of the research, because the small group structure allows for flexibility of research projects and mobility of staff. The LMB focuses on projects until they become successful, fundable and scalable by having access to funding opportunities closer to later stages of scientific development and translational research.
Although these rules govern the LMB, the outcomes are more than the sum of their parts. The organizations management strategy gives rise to emergent behaviours and deliverables that align with its long-term research goals. The management model has emerged from a set of actions taken by management over time that collectively result in a coherent approach to achieving the overall aim of the LMB4. In management theory terms, the LMB is a complex adaptive system, similar to an ecosystem.
A complex adaptive system is a self-organizing system with distinctive behaviour that emerges from interactions between its components in a manner that is usually not easy to predict5. Components might include individuals and their activities; material parts, such as technologies; and the ideas generated from these interactions6.
Effective management of this complex adaptive system is fundamental to the LMBs success. Through continual adaptation and evolution, the LMB can generate new knowledge more effectively than most other institutions can.
For example, the LMB helped to develop cryo-EM for application in the biological sciences through collaborative efforts involving scientists and engineers and the integration of software and advanced cooling techniques. Rather than one individual orchestrating and coordinating all the steps, this multidisciplinary team exhibited self-organization and iterative adjustments, bound by its shared culture. This allowed the emergence of new solutions, mirroring the adaptability seen in ecosystems.
In our view, the LMB system should be considered a framework for how funding is allocated to basic science more widely. Looking to the future, however, we see three challenges that the LMB and the life-sciences community will need to overcome.
First, scientific questions in the basic biosciences are becoming more complex, requiring ever more sophisticated and expensive equipment7. Developing such tools might be beyond the capability of one lab, and wider institutional collaborations will be required.
The Medical Research Councils Laboratory of Molecular Biology in 2021.Credit: MRC Laboratory of Molecular Biology
Second, institutions dedicated to basic life sciences are increasingly urged by funders and society to transition quickly into clinical applications, which risks undermining the quality and competitive edge of their fundamental research8. The gap between fundamental bioscience and clinical translation is notoriously hard to bridge9 (see also Nature 453, 830831; 2008). It is also high risk.
In recent years, some funders have pulled out of basic bioscience. For example, more of the US National Institutes of Healths extramural funding over the past decade has gone to translational and applied research than to basic science (see Science 382, 863; 2023). Some highly reputable basic-science research institutions have suffered as a result and have even been dissolved, such as the Skirball Institute in New York City10. However, it is crucial to resist the temptation of dismantling basic science research, considering the complexity and difficulty of re-establishing it.
In response, a lab such as the LMB might enhance the translation of its discoveries by strengthening connections with the clinical academic sciences and private-sector industries. Leveraging strengths in the pharmaceutical industry in areas such as artificial intelligence and in silico modelling can bolster basic science without compromising a research labs focus. The LMBs Blue Sky collaboration with the biopharmaceutical firm AstraZeneca is a step in this direction (see go.nature.com/3rnsvyu).
Third, it is becoming increasingly challenging for basic science labs to recruit and retain the best scientific minds. Translational research institutes are proliferating globally. Biotechnology and pharma firms can pay higher salaries to leading researchers. And researchers might be put off by the large failure rates for high-risk projects in fundamental research, as well as by the difficulties of getting tenure in a competitive lab such as the LMB.
As a first step, governments must recognize these issues and continue to fund high-quality, high-impact fundamental science discoveries. The use of effective research-management strategies such as the LMBs will make such investments a better bet, de-risking discovery for the long-term benefit of society.
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The strategy behind one of the most successful labs in the world - Nature.com