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Chronobiome: Timing is Essential for Precision Medicine

Operations

09:00, April 25 2017

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Oliver Chao, Sanofi, reveals how chronobiome could be key to realizing the potential of precision medicine

Guess you won’t be too surprised if I tell you that precision medicine is actually an ancient concept. From prehistoric Ayurveda to Hua Tuo in the early era of the first millennium, as well as Hippocrates and his disciples of the Hippocratic School of Medicine (to this day), precision medicine has always been the ultimate goal of medical intervention. Certainly, it helps that former US President Barack Obama’s administration brought precision medicine to the national (and global) attention as a modern day health care platform in an era of patient centricity (fingers crossed for the next four years) [1].

If you are still entangled with the definitions of precision medicine, perhaps the concise motto of EFPIA (European Federation of Pharmaceutical Industries and Associations) can soothe your nerves: The Right Prevention and Treatment for the Right Patient at the Right Time. Evidently, the promise of precision medicine is still far from being fulfilled. Now in the third millennium, the advancement of relevant biotechnology has indeed contributed to rapid progress. That said the transition from targeting the average patient group (often a global market size) to a specific small population or individual requires conversely much more personalized data to achieve the precise treatment or prevention. What kind of data? Here’s my view of the personalized data that would be essential to live up to the promise of precision medicine.

The Fundamental Data

Naturally, nothing is more fundamental and personal than your own genome. The evolution of genome sequencing techniques over the last few decades has made it possible to document your very basic biological information rapidly and inexpensively. However, translating these data into manageable or feasible information for therapeutic treatment on diseases, derived from either genetic predisposition or environmental origins, is still a daunting task. Recently, James Watson (arguably the Godfather of genomic research) openly questioned the usefulness of genome sequencing for disease treatments: "You could sequence 150,000 people with cancer and it’s not going to cure anyone…” [2].  Although Dr. Watson’s critical comment might have originated from his personal experience with cancer, it reminded us that just knowing your ATGC composition may not be sufficient to find the right treatment. It is essential to elucidate the various identities of our genes in the biological, chemical soups, i.e. our bodies, at all possible stages of our lives.

The Variable Data

Our genes, the nucleotides DNA and RNA, are constantly going through various chemical interactions and modifications, which in turn are manifested in our proteomes. Thanks to recent progress in epigenetic research, the impacts of our lifestyles and environmental influence on our internal biochemical make-ups can be analyzed by various approaches. The revelation of the divergence of the epigenome provides us further insights into how subtle genetic variations may cascade into diseased phenotypes, as well as how distinctly one individual’s molecular/cellular matrix may react to exogenous stimuli. While there are permanent or longer lasting effects derived from epigenetic consequences, temporary or spontaneous adaptation of our biological systems occurs regularly. When an illness strikes at a specific point in our lives, these permanent or temporary variations can all constitute the disease manifestation. Therefore, extracting these variable bio-data will be critically important in our decision in disease treatment, if there is a treatment.

As the human body is a dynamic organism with constantly changing components, timing is vital for precision medicine. Traditional drug discovery targeting a large, average patient group might have conveniently overlooked ‘timing’ as a crucial factor. Recent advancement in circadian rhythm research, from identifying the molecular networks of clock genes to the rhythmic regulations of our physical and mental status, substantiates the critical role of correct timing for drug administration. But it is indeed easier said than done, as finding the right timing window for treatment comes down to a personal level.

Based on the progress of current omic studies, there’s reason to be optimistic that we have the means to document the expression time-courses and functional profiles of specific drug targets, together with their participated signaling systems in chronological patterns. In my view, the chronobiome would be a bona fide personalized database, as you will be your own control subject. Human chronobiome would be a collection of:

  • Your metabolomics on all relevant components (lipids, sugars, metabolites, etc.)
  • Your microbiota on the species living symbiotically or inauspiciously on and in you (skin, hair, mouth, guts)
  • Your immunoprofiles when you need to be ‘introspective’ on how your immune systems react to exogenous impacts (pathogens, vaccines, drugs, etc.)

Efforts to establish these personal data for individuals (both healthy and sick) have been the highlights of recent personalized data development. Nevertheless, if we only take measurements in single or minimal time points, we would have overlooked or mistaken many hidden information due to untimely samplings. In order to achieve the real precision details, all these omic data should be analyzed with multi-time points in a circadian or specific chronological period.

Addressing the Practical Issues

Notably, classical metabolomics, microbiota or immuno-sequencing/profiling experiments are still labor intensive and therefore incur high price tags. Multiple time-course studies for any such omic study would likely be unaffordable for most patients. To address these practical issues, single cell omic study represents a promising approach to improve efficiency and throughput, and would simultaneously reduce the cost to obtain these personalized data. From sequencing to immunoblotting, single cell technology should revolutionize and refine genomic and proteomic capabilities in providing fast and accurate personalized data. Integrating the overwhelming results on multiple key variable components would then require efficient big data mining and quick bioinformatic interpretation.

The progress in chronobiome would also depend on development of non – or moderately invasive tools to extract your biological fluids or to detect your metabolic changes reliably. We are entering an exciting era with rapid advancement of innovative biocompatible materials and nanotechnology that enable the development of a new generation of diagnostic devices. From external surface (artificial skin, contact lens) to internal organ membrane sensors, all exhibit good feasibility and adaptability within fixed time frames. With the collective efforts on all fronts of biotechnology development, the personalized chronobiome would hopefully become more practical and affordable as routine biometric recordings.

Actually, if you google ‘chronobiome’ now you will get no hits (perhaps you can start writing your version for Wikipedia). It is true that trying to continuously monitor the micro-organisms or nano-molecules roaming your body is a great challenge. But until time travel becomes a reality, the invisible fourth dimension will be the decisive factor for achieving the promise of precision medicine.

 

Oliver CHAO, PhD

Emerging Biomedical Sciences, External Innovation, Sanofi

 

References:

  1. Fact Sheet: President Obama’s Precision Medicine Initiative. https://www.whitehouse.gov/the-press-office/2015/01/30/fact-sheet-president-obama-s-precision-medicine-initiative
  2. James Watson, Provocateur. https://www.genomeweb.com/blog/james-watson-provocateur