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Overcoming barriers to early disease intervention

Nature Biotechnology volume 38, pages 669–673 (2020)Cite this article

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Although secondary prevention has been a longstanding healthcare imperative, in many cases, trials using this approach have not improved health outcomes2,3,4. One reason why these have failed is because the interventions often came too late in the disease process. For instance, even though a randomized trial of the small-molecule β-secretase 1 inhibitor verubecestat was targeted to prodromal Alzheimer’s disease patients at high risk for progression, it failed to meet its endpoints, likely because of mistimed (that is, late) intervention. In this trial, the participants already had cognitive symptoms of mild-to-moderate dementia due to the presence of pathological signs of elevated β-amyloid deposits in their brains; thus, the intervention was probably neither sufficiently effective nor early enough in the disease process to have a chance of therapeutic success. Notably, a worse clinical outcome was observed in the verubecestat group than in the placebo group.

As a general rule, as diseases advance progressively over time, the combined action of known and unknown causal factors damage the integrity of critical biological networks motifs (redundant feedback and feed-forward loops)5. Gradually, this disrupts the natural flow of essential cell signaling and leads to a loss of biological function, which ultimately manifests itself in overt disease phenotypes and symptoms. Over time, comorbidities and inefficient polypharmacy treatments take over, and organ systems of the human body undergo irreversible, progressive destruction of biological network motifs. Thus, patients lose their physiologic reserve and succumb to underlying conditions, without the ability to restore health. From a physiological standpoint, for individuals at a high risk of developing disease, it makes sense to act at a point sufficiently early in disease processes when biological network motifs still retain sufficient integrity and function to respond to interventions and prevent further decline — or even reverse it.

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Fig. 1: Differences in primary prevention, secondary prevention and early disease intervention, depicting target groups, goals and examples for each approach.
Fig. 2: Hypothetical illustrative example of integrated early disease intervention paradigm.

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Acknowledgements

Our perspective has benefited from a global network of colleagues. In particular, it has been challenged, informed and enriched by conversations with many people, including R. Hendricks, D. Blumenthal, B. Wiegand, K. Wildenhaus, J. Hedrick, S. Brady, G. Pigino, J. M. Peyrin, P. Prieto, J. Fleming and A. Zarur.

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Authors and Affiliations

  1. Connection Science, Massachusetts Institute of Technology, Cambridge, MA, USA

    H. Hugo Caicedo & Alex Pentland

  2. Corporate Sustainability and Innovation, Harvard University, Cambridge, MA, USA

    H. Hugo Caicedo

  3. Department of Surgery, Massachusetts General Hospital, Boston, MA, USA

    Daniel A. Hashimoto

  4. Harvard Medical School, Boston, MA, USA

    Daniel A. Hashimoto

  5. Materials Engineering, Universidad del Valle, Cali, Colombia

    Julio C. Caicedo

  6. Technology and Operations Management, Harvard Business School, Boston, MA, USA

    Gary P. Pisano

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Correspondence to H. Hugo Caicedo.

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Competing interests

D.A.H. consults for Johnson & Johnson, Verily Life Sciences, and Worrell. He has received research support from Olympus. A.P. is on the Advisory Boards of Pear Therapeutics. G.P.P. consults for Johnson & Johnson, Takeda, Bristol-Myers Squibb, Eli Lilly and Tolero, and serves on the Board of Directors of Axcella Health and Celixir.

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Caicedo, H.H., Hashimoto, D.A., Caicedo, J.C. et al. Overcoming barriers to early disease intervention. Nat Biotechnol 38, 669–673 (2020). https://doi.org/10.1038/s41587-020-0550-z

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