Let’s get physical!

A healthy lifestyle is the cornerstone of cardiovascular health.

Lifestyle interventions are already a key component of primary prevention in low-risk cardiovascular disease groups, and serve as an important aide to pharmacotherapy in higher-risk groups. 

But according to the new guidelines by the American Heart Association (AHA) and the American College of Cardiology (ACC)1, a first line of therapy for mild to moderate–risk groups are lifestyle-only approaches for a proper blood pressure and blood cholesterol management.

As such, the next time you go to the doctor, you might get an exercise prescription instead of an order to visit the pharmacy. 

This is a major change in the idea of health, promoted by not taking a pill, but having a look at lifestyle in order to improve health – and avoid the numerous side-effects that certain medications can have. 

An exercise prescription is an individualized physical activity program designed using the Frequency (how often?), Intensity (how hard?), Time (how long?), and Type (what kind?), or the FITT principle developed by the American College of Sports Medicine (ACSM). 

Although most health care professionals and patients are aware that physical activity is recommended for good health, the abundance of scientific and lay recommendations for activity can be difficult to distil. As such, framing the exercise prescription by the FITT principle provides clinicians with more structured guidance on how to recommend exercise to their patients. 

The updated FITT exercise recommendations for adults with elevated blood pressure are the following: 

  • Frequency: in most, preferably all days of the week due to the transient Blood Pressure lowering effects that last for up to 24 hours after an exercise session; 
  • Intensity: Moderate, any intensity of exercise has been shown to lower Blood Pressure;
  • Time: >20 to 30 minutes per day to total >90 to >150 minutes per week of continuous or accumulated exercise of any duration;
  • Type: Emphasize aerobic or resistance exercise alone or combined, due to the recent evidence showing the Blood Pressure lowering effects of exercise do not vary by exercise modality2

The updated FITT exercise prescription recommendations propose more exercise options in less time, that hopefully will translate to better exercise adherence.

As a plus, we should be reminded of the advantageous effects of exercise on brain functions. Acute bouts of physical activity can stimulate transient Serotonin, Dopamine and Norepinephrine activity in the brain3

Furthermore, long-term exercise produces changes in the availability of receptors that can control the release of monoamines, like the Serotonin-1A receptor of the Raphe Nuclei4, and Dopamine-2 receptor in the Striatum5

Regular exercise has antidepressant/anxiolytic properties, and results in dramatic alterations in physiological stress responses. 

In addition to antidepressant and anxiolytic properties, the Serotonin system (5-HT) has also been linked to cognitive function; since, a distress of the 5-HT system is associated with cognitive syndromes, such as Alzheimer’s disease6

So, don’t shy away, and take at least a 20 min quick walk today. 

It’s free, and it’s good for you!

My boots were made for walking!

References:

1          Gibbs, B. B. et al. Physical Activity as a Critical Component of First-Line Treatment for Elevated Blood Pressure or Cholesterol: Who, What, and How?: A Scientific Statement From the American Heart Association. Hypertension 0, HYP.0000000000000196, doi:doi:10.1161/HYP.0000000000000196.

2          Pescatello, L. S. et al. Physical Activity to Prevent and Treat Hypertension: A Systematic Review. Med Sci Sports Exerc 51, 1314-1323, doi:10.1249/mss.0000000000001943 (2019).

3          Buhr, T. J. et al. The Influence of Moderate Physical Activity on Brain Monoaminergic Responses to Binge-Patterned Alcohol Ingestion in Female Mice. Front Behav Neurosci 15, 639790-639790, doi:10.3389/fnbeh.2021.639790 (2021).

4          Greenwood, B. N. et al. Freewheel running prevents learned helplessness/behavioral depression: role of dorsal raphe serotonergic neurons. J Neurosci 23, 2889-2898, doi:10.1523/jneurosci.23-07-02889.2003 (2003).

5          Clark, P. J. et al. Wheel running alters patterns of uncontrollable stress-induced cfos mRNA expression in rat dorsal striatum direct and indirect pathways: A possible role for plasticity in adenosine receptors. Behav Brain Res272, 252-263, doi:10.1016/j.bbr.2014.07.006 (2014).

6          Meltzer, C. C. et al. Serotonin in aging, late-life depression, and Alzheimer’s disease: the emerging role of functional imaging. Neuropsychopharmacology 18, 407-430, doi:10.1016/s0893-133x(97)00194-2 (1998).

N-of-1 patient: crafting personalised treatments for ultra-rare diseases with AntiSense Oligonucleotide (ASO) technology

The n-of-1 patient is that one person with a unique genetic mutation that causes an ultra-rare disease, designated as a disease with less than 30 patients in the whole world. The advent of affordable genomic sequencing has identified millions of n-of-1 patients, which is becoming a large and growing population with desperate needs.

Though a great progress is made in identifying n-of-1 patients, and ruling the genetic causes of their diseases; usually, drugs that work in patients with the common mutations, often do not work for these unique patients.

n-Lorem is a foundation created by Dr. Stanley Crooke, the founder, chairman and chief executive officer of Ionis Pharmaceuticals, a global leader in RNA-targeted therapy. This foundation was created to provide individualized treatments for patients with ultra-rare diseases using the technology developed at Ionis Pharmaceuticals.

The mission of n-Lorem is to use the versatility and specificity of antisense technology to kindly offer experimental antisense oligonucleotides (ASO) medicines to treat the n-of-1 patient. 

Antisense oligonucleotides (ASOs) are short, synthetic, single-stranded DNA-mimics that can alter the RNA, and consequently protein expression and function. Because they can manipulate the intermediate step between gene and protein translation – at the pre-mRNA level – ASOs can reduce, or restore, or modify protein expression by different mechanisms.

Very simply: DNA gets converted into mRNAASOs function in between the two. As such, if the DNA gene has a mutation and codes a dysfunctional mRNA, and consequentially a dysfunctional protein that causes a disease, an ASO can change that. The ASO has the correct complementary code to produce the precise mRNA, and automatically, the precise protein needed to perform the right function. By intervening in the step before protein gets translated, it makes sure that nothing goes wrong and that the mutated gene doesn’t go any further, preventing disease from happening.

Even though it only started one year ago, n-Lorem together with  Ionis Pharmaceuticals  have helped design and provide experimental ASOs for two unique patients: one with Batten’s disease and ataxia-telangiectasia (AT); the other one, with a FUS mutation in Amyotrophic Lateral Sclerosis (ALS). These have provided a tremendous opportunity to certify the n-Lorem concept and drive motivation forward.

Anyone can apply to n-Lorem for a potential treatment. The proposals are approved and prioritized based on certain criteria, such as the severity of the disease, feasibility of developing an ASO treatment for the genetic cause of the disease, degree of potential benefit vs. potential risks, practicality of treatment, availability of physician and institution to treat patient, and other intricacies of the condition. 

The unique patient needs to work with a physician that makes the connection to n-Lorem, who will then make an informed decision about whether a patient is appropriate to receive an experimental ASO treatment through a Commission.

It’s outstanding that the FDA reaction to n-Lorem has been very supportive; and, in fact, initial guidance has been put in place in January 2021 to reach more patients in need. 

Once regulatory permission has been given, an investigator-led clinical trial is initiated and the patient can receive their custom experimental ASO treatment at no personal cost and will all clinical support.

This cost-free individualized therapy is possible for Ionis Pharmaceuticals because of the inherent efficiency and versatility of the ASO technology. The knowledge of modern ASOs mechanisms and specific possible effectiveness in selected organs, with different possible routes of application, together with integrated safety databases, allows a dive for the treatment of unique patients. 

It’s honourable to use science to help the n-of-1 patient and their families. 

I hope for more Dr. Stanley Crooke’s…

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).

SARS-CoV-2 viral evolution

It’s funny that this pandemic can prove all anti-evolutionists wrong. 

Nothing like seeing Charles Darwin natural selection right in front of your eyes at the speed of light. Just look at the SARS-CoV-2 viral evolution…

In his book “On the origin of species” written in 1859, Charles Darwin defined natural selection as the “principle by which each slight variation of a trait, if useful, is preserved”. What does this mean (?), it means the individuals best adapted to their environments are more likely to survive and reproduce. 

What we are seeing now, is that the mutations of SARS-CoV-2 that better promote spreading, are the ones that are becoming more common among the population, even when derived in different locations. The virus is changing and evolving to spread more rapidly, because natural selection will optimize the level of virulence that maximizes pathogen fitness – expressed as the basic reproductive number (R0)1,2

On average, comparative data from previous studies tell us that, low-virulence infections have a greater chance of successfully establishing transmission cycles in humans than virus with higher mortality3. As such, as before, the virus actually just wants to spread and not kill.

But, since the environment also affects transmissibility, there are more factors on the equation “when will this madness end” than we would have wished for.

For example, in the evolutionary trade-off between virulence and transmissibility, because intra-host virus replication is needed to allow inter-host transmission, it is almost impossible for natural selection to optimize all traits simultaneously1 and give us some peace. 

For example, in the case of the Myxoma virus (MYXV) in rabbits, this evolutionary trade-off leads to an ‘intermediate’ virulence being more advantageous to the virus than a higher virulence1,4. This happens because the rabbit host dies before inter-host transmission, in the case of higher virulence; and, with lower virulence the virus goes absolutely nowhere, because it does not increase virus transmission rates. A similar trade-off model has been proposed to explain the evolution of HIV virulence1,5.

Unfortunately, experimental studies in some viruses have shown that high virulence can promote certain advantages, as in the case of malaria, where a higher virulence was shown to provide the Plasmodium parasites with a competitive advantage within hosts1,6. Or, in the case of the rabbit haemorrhagic disease virus (RHDV), where there is evidence that virulence has increased through time, probably because virus transmission often occurs through flies that feed on animal carcasses, making host death selectively favourable1,7.

Let’s thank the Gods that SARS-CoV-2 is NOT transmissible through flies.

So, current evolutionary theory tells us that it is possible to anticipate the direction of virulence evolution, if the key relationship between virulence and transmissibility, and hence viral fitness, is understood1. Crucial to this is the analysis of the intersection between genomics and evolutionary studies, what is called phylogenomics.

This field of science provides a way to understand virulence evolution, and creates a number of hypotheses that can be tested using appropriate experimental cell assays and bioinformatic tools8,9

The collaboration of public health and research teams worldwide has now allowed the publication of 620,338 SARS-CoV-2 genomes in GISAID (http://www.gisaid.org/) (as of February 25, 2020)9. At the same time, a dynamic nomenclature system for SARS-CoV-2 has been described to facilitate real-time epidemiology revealing links between global outbreaks that share similar viral genomes10. At the root of the phylogeny are two lineages, A and B; where, A is likely ancestral, as it shares two distinguishing variants with the closest known bat viruses. Further linage designations link new variants to geographically distinct populations, B.1 in the Italian outbreak, then other parts of Europe and the world; and, B.1.1 being the major European lineage which was spread throughout the world. However, many of the major lineages are now present in most countries, and recapitulate the global diversity of SARS-CoV-2, indicating that most local epidemics were seeded by a large number of independent introductions of the virus.

The current evolutionary tree of SARS-CoV-2 shows multiple introductions of different variants across the globe, with introductions from distant locations seeding local epidemics, where infections sometimes went unrecognized for several weeks and allowed wider spread11. The tree topology actually indicates that SARS-CoV-2 viruses have not diverged significantly since the beginning of the pandemic11. These results show that, so far, SARS-CoV-2 has evolved through a non-deterministic, noisy process; and, that random genetic drift has played the dominant role in disseminating unique mutations throughout the world11.

There remains an urgent need for a SARS-CoV-2 vaccine as a primary countermeasure to contain and mitigate the spread; and, the virus’s surface S (Spike) protein continues to be an attractive vaccine target,because it plays a key role in mediating virus entry into the cells, and is known to be immunogenic.

Of course, the virus was only recently identified in the human population with a short time frame relative to the adaptive processes that can take years to occur.

But, the most recent findings show us that the SARS-CoV-2 viruses that are currently circulating, constitute a homogeneous viral population, to which the current vaccines available will be sufficient to mitigate the spread. 

Soon, SARS-CoV-2 will become just another viral acquaintance during the winter, like a common cold

Tree

References:

1          Geoghegan, J. L. & Holmes, E. C. The phylogenomics of evolving virus virulence. Nature Reviews Genetics 19, 756-769, doi:10.1038/s41576-018-0055-5 (2018).

2          Bull, J. J. & Lauring, A. S. Theory and empiricism in virulence evolution. PLoS Pathog 10, e1004387, doi:10.1371/journal.ppat.1004387 (2014).

3          Geoghegan, J. L., Senior, A. M., Di Giallonardo, F. & Holmes, E. C. Virological factors that increase the transmissibility of emerging human viruses. Proc Natl Acad Sci U S A 113, 4170-4175, doi:10.1073/pnas.1521582113 (2016).

4          Kerr, P. J. et al. Next step in the ongoing arms race between myxoma virus and wild rabbits in Australia is a novel disease phenotype. Proceedings of the National Academy of Sciences 114, 9397-9402, doi:10.1073/pnas.1710336114 (2017).

5          Fraser, C., Hollingsworth, T. D., Chapman, R., de Wolf, F. & Hanage, W. P. Variation in HIV-1 set-point viral load: epidemiological analysis and an evolutionary hypothesis. Proc Natl Acad Sci U S A 104, 17441-17446, doi:10.1073/pnas.0708559104 (2007).

6          de Roode, J. C. et al. Virulence and competitive ability in genetically diverse malaria infections. Proc Natl Acad Sci U S A 102, 7624-7628, doi:10.1073/pnas.0500078102 (2005).

7          Di Giallonardo, F. & Holmes, E. C. Viral biocontrol: grand experiments in disease emergence and evolution. Trends Microbiol 23, 83-90, doi:10.1016/j.tim.2014.10.004 (2015).

8          Stern, A. et al. The Evolutionary Pathway to Virulence of an RNA Virus. Cell 169, 35-46.e19, doi:10.1016/j.cell.2017.03.013 (2017).

9          Sjaarda, C. P. et al. Phylogenomics reveals viral sources, transmission, and potential superinfection in early-stage COVID-19 patients in Ontario, Canada. Scientific Reports 11, 3697, doi:10.1038/s41598-021-83355-1 (2021).

10        da Silva Filipe, A. et al. Genomic epidemiology reveals multiple introductions of SARS-CoV-2 from mainland Europe into Scotland. Nat Microbiol 6, 112-122, doi:10.1038/s41564-020-00838-z (2021).

11        Dearlove, B. et al. A SARS-CoV-2 vaccine candidate would likely match all currently circulating strains. bioRxiv, 2020.2004.2027.064774, doi:10.1101/2020.04.27.064774 (2020).