Tag: precision medicine

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Precision: the new Tinder Belle of the Heart

Precision medicine is an emerging approach to medical care.  It takes into account individual variations in genetic make-up, metabolism and other biological and environmental factors, to better determine which treatment and prevention strategies for a particular disease may work better for which groups of people1.

Today, precision medicine is routinely integrated into the care of cancer patients, and has provided substantial increases in cancer free survival2. For example, translational studies investigating signatures within the tumour that promote disease progression, can predict individual responses to standard and targeted chemotherapy regimens2,3.

In the cardiovascular field, even though the prognosis for people with heart failure has improved in recent decades as research studies demonstrate the effectiveness of various medications, precision medicine is still in its infancy.

Some aspects of precision medicine are routinely used by healthcare providers, like the blood level of the biomarker called B-type natriuretic peptide, which is a sensitive indicator of whether heart failure is worsening or if treatments are helping1,4. This biomarker can also help the doctor determine whether shortness of breath symptoms in an individual are due to heart failure, or another medical problem1.

But as it is now, patients diagnosed with heart failure are still offered essentially identical treatments, regardless of whether their disease was caused by coronary artery disease, genetic mutations, or an autoinflammatory processes2. 

Also, historically, clinical trial participants have been predominantly white people with particular genetic variants; but, individuals with different racial and ethnic ancestry have different genetic variants, and therefore, may not have the same response to a certain medication or treatment1.

While this “one-size-fits-all’ approach has led to improvements in clinical outcomes in large populations, the individual response rates continue to vary tremendously; and, it is often difficult to distinguish patients who will achieve a favourable response, from those who will experience disease progression, and ultimately succumb to their illness2.  

As such, in the cardiovascular field, it is urgent to personalize heart failure care by identifying groups of patients more likely to develop heart failure, and tailoring which medications and other therapies could be most effective for them1. Currently, many individuals are left poorly treated, and there is substantial room for improvement2.

Key studies demonstrating selective efficacy of certain drugs in patients harbouring specific genetic variants, indicate a direction where treatment responses can be predicted using individual genetic information. 

Given the recent cost reductions in exome sequencing, for example, this can now be used routinely to identify genetic variants that predict heart failure prognosis, and specific responses to medical and device-based therapies. Such information can further provide critical insights into new disease mechanisms, like Lamin A mutations that display a molecular phenotype that is dramatically distinct from other forms of dilated cardiomyopathy5. 

More and more we come to realize that despite a common surface phenotype or symptomology, certain mutations may actually give rise to distinct diseases that need to be appropriately treated.

As such, researchers need to increase clinical trial diversity, so that optimal treatment approaches can be found for each population group. Also, the power of supercomputing should be used to rapidly predict the outcomes of possible new treatments. And, processes for sharing information across large databases shouldbe put in place with guarantees of patient privacy (e.g., cloud-based platforms), so that clinicians/scientists can quickly collaborate and share data internationally.

Moreover, updated health-wearable devices, artificial intelligence and other deep learning technologies strategies will ultimately be employed to develop testable hypotheses from large datasets, and provide precision-personalized approaches to cardiovascular health care.

Let’s hope Precision will be more than a one night stand on Heart’s Tinder list….

Yayoi Kusama art installation, Berlin Modern Art Museum

References:

1          AHA. Emerging practice of precision medicine could one day improve care for many heart failure patients. Heart.org https://newsroom.heart.org/news/emerging-practice-of-precision-medicine-could-one-day-improve-care-for-many-heart-failure-patients?utm_campaign=sciencenews19-20&utm_source=science-news&utm_medium=phd-link&utm_content=phd09-12-19 (2019).

2          Kory J. Lavine, C. E. C. Precision Medicine for Heart Failure: using “omics” technologies to find the road to personalized care. Heart.org https://professional.heart.org/en/science-news/heart-failure-in-the-era-of-precision-medicine/Commentary (2021).

3          Prasad, V., Fojo, T. & Brada, M. Precision oncology: origins, optimism, and potential. Lancet Oncol. https://linkinghub.elsevier.com/retrieve/pii/S1470-2045(15)00620-8 17, e81-e86, doi:10.1016/s1470-2045(15)00620-8 (2016).

4          Maisel, A. B-Type Natriuretic Peptide Levels: Diagnostic and Prognostic in Congestive Heart Failure. Circulation. https://www.ahajournals.org/doi/10.1161/01.CIR.0000019121.91548.C2 105, 2328-2331, doi:doi:10.1161/01.CIR.0000019121.91548.C2 (2002).

5          Cheedipudi, S. M. et al. Genomic Reorganization of Lamin-Associated Domains in Cardiac Myocytes Is Associated With Differential Gene Expression and DNA Methylation in Human Dilated Cardiomyopathy. Circ Res. https://pubmed.ncbi.nlm.nih.gov/30739589/ 124, 1198-1213, doi:10.1161/circresaha.118.314177 (2019).

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Yogurt as precision medicine, or how your gut might be undermining your health

The gut microbiome is a community of microorganisms that lives in our gastrointestinal tract. It is so far, the most studied microbial community in healthy humans, because of its known role in a range of functions and diseases, like Inflammatory Bowel Disease (IBD)1,2.

To gain perspective on the magnitude of the bacterial presence inside of us, and potential effects on our bodies, the human body expresses 20,000 eukaryotic genes while the gut microbiome expresses 3.3 million prokaryotic genes. This suggests that the genetic contribution of the microbiome to humans may be many hundreds of times greater than the genetic contribution from the human genome.

Most of the microbes in the microbiome do not cause disease. In fact, we need them to perform many important functions that we cannot do ourselves. Microbes digest food to generate nutrients for host cells, synthesize vitamins, help to absorb nutrients and minerals, produce short-chain fatty acids, metabolize drugs, detoxify carcinogens, stimulate renewal of cells in the gut lining, and activate and support the immune system1. 

The fermentation by-products acetate, propionate, and butyrate are important for gut health; and, provide energy for epithelial cells, enhance the integrity of the epithelial barrier, and provide immunomodulation and protection against pathogens1. 

Current investigations explore resident bacterial gene function, and the potential role it might have in human health and metabolism. Each individual has its own microbiome, and no one common microbe is present in all body sites or all individuals. 

Researchers identified the composition of different individual microbiomes, but they also identified the metabolic pathways of the microbial communities found in different body sites (e.g., skin, colon, liver…).  What is interesting is that microbial membership diverges greatly between healthy individuals; but, the metabolic pathways of our own microbiomes is very similar, with common ‘housekeeping’ properties that maintain cell function and a functional body site ecosystem3,4.

The interactions between the gut microbiota and our bodies immune system begins at birth4. The microbiota shapes the development of the immune system; and, in turn, the immune system shapes the composition of the microbiota. This cross-talk between the microbes and our bodies is transmitted through a vast array of signaling pathways that involve many different classes of molecules, and extend upon multiple organs such as the gut, liver, muscle, and the brain. This creates axes of metabolic pathways, or highways of chemical communication, between the gut and the different organs in our bodies.

Because the gut microbiome is highly malleable, it can be altered throughout our lifespan by environmental factors, such as diet, stress and medication. What we have seen during the last 60 years, is an increaseincidence of gut dysbiosis, which is an imbalance in the intestinal bacteria that leads to disease.

As such, there is much interest in developing new therapeutic tools for manipulating the composition of the gut microbiota to benefit our health. A better understanding of how variations in this symbiotic relation within us, supraorganisms, will contribute to disease risk and health sustainability; and, will point the way to new therapeutic interventions and disease prevention strategies.

Danone, a leading yogurt multinational food corporation, is developing “precision probiotics”, for example. Researchers at Danone aim to tailor probiotics to an individual’s diet, phenotype, lifestyle, age, gender, genetics and microbiome. The intention it’s to bring to the gut activities or functions that are not provided by our own gut microbiome, or our own genes.

It’s funny that around 1920’s, Isaac Carasso, the creator of Danone, first started selling yogurt in pharmacies, using ferments isolated from the Institute Pasteur, and label it as health-food. It’s like going full circle.

References:

1          Bordigoni, A., Halary, S. & Desnues, C. in Encyclopedia of Virology (Fourth Edition) Vol. https://www.sciencedirect.com/topics/medicine-and-dentistry/gut-microbiome  (eds Dennis H. Bamford & Mark Zuckerman)  552-558 (Academic Press, 2021).

2          Lloyd-Price, J. et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature 569, 655-662, doi:10.1038/s41586-019-1237-9 (2019).

3          Visconti, A. et al. Interplay between the human gut microbiome and host metabolism. Nature Communications10, 4505, doi:10.1038/s41467-019-12476-z (2019).

4          Nicholson, J. K. et al. Host-Gut Microbiota Metabolic Interactions. Science 336, 1262-1267, doi:10.1126/science.1223813 (2012).