Inducing methylation

Nutrition, Exercise and Epigenetics: Ageing Interventions

Epigenetics refers to an inheritable but reversible phenomenon that changes gene expression without altering the underlying DNA sequence. Thus, it is a change in phenotype without a change in genotype. The field of epigenetics is quickly growing especially because environmental and lifestyle factors can epigenetically interact with genes and determine an individual’s susceptibility to disease. Interestingly, aging is associated with substantial changes in epigenetic phenomena. Aging induces global DNA hypomethylation and gene-specific DNA hypermethylation due to the altered expression of DNA methyltransferases (DNMTs).

The evidence of the impact of epigenetics on aging is growing. And nutrition plays a key role on epigenetics through the life course. Thus, there are crucial reasons to focus on nutrition early in life.

It is clear that epigenetic alterations caused by aging may provide a milieu that can develop age-associated diseases such as cancer, cardiovascular diseases, neurocognitive diseases and metabolic diseases. Nutrition is one of the most important environmental factors that can modify epigenetic phenomena. Therefore, one might speculate that nutrition may delay the age-associated epigenetic change and possibly reverse the aberrant epigenetic phenomena that can cause age-associated diseases. Indeed, many nutrients and bioactive food components, which can affect one-carbon metabolism that can regulate methylation of DNA and histone or directly inhibit epigenetic modifying enzymes, are showing promising results in delaying the aging process and preventing age-associated diseases through epigenetic mechanisms.

And beyond nutrition, there is exercise. This is what this book explains and it shows the foundations for better health. If it's "only" an issue of regulating methylation...where are the incentives?

Brandant com un saltamartí

Epigenetic protein families: a new frontier for drug discovery

Si ja sabem que al costat de la genòmica hi tenim la proteòmica i la metabolòmica, i que per sobre encara hi tenim l'epigenètica (que literalment vol dir més enllà de la genètica), ara a Nature ens expliquen les diferent famílies i el que representen per al futur de la recerca en nous medicaments.
L'article de revisió és d'aquells que em guardaré perquè si fins ara s'explicava la importància de l'epigènetica i com el paradigma genòmic de la predestinació brandava com un saltamartí, calia posar ordre a les idees. Però també perquè explica amb tot detall com:

Epigenetic regulation of gene expression is a dynamic and reversible process that establishes normal cellular phenotypes but also contributes to human diseases. At the molecular level, epigenetic regulation involves hierarchical covalent modification of DNA and the proteins that package DNA, such as histones. Here, we review the key protein families that mediate epigenetic signalling through the acetylation and methylation of histones, including histone deacetylases, protein methyltransferases, lysine demethylases, bromodomain-containing proteins and proteins that bind to methylated histones. These protein families are emerging as druggable classes of enzymes and druggable classes of protein–protein interaction domains.

L'explicació inicial m'ha semblat un resum útil:

 Although all cells in an organism inherit the same genetic material, the ability of cells to maintain the unique physical characteristics and biological functions of specific tissues and organs is due to heritable differences in the packaging of DNA and chromatin. These differences dictate distinct cellular gene expression programmes but do not involve changes in the underlying DNA sequence of the organism. Thus, epigenetics (which literally means ‘above genetics’) underpins the fundamental basis of human physiology. Importantly, the epigenetic state of a cell is malleable; it evolves in an ordered manner during the cellular differentiation and development of an organism, and epigenetic changes are responsible for cellular plasticity that enables cellular reprogramming and response to the environment. Because epigenetic mechanisms are responsible for the integration of environmental cues at the cellular level, they have an important role in diseases related to diet, lifestyle, early life experience and environmental exposure to toxins1. Thus, epigenetics is of therapeutic relevance in multiple diseases such as cancer, inflammation, metabolic disease and neuropsychiatric disorders, as well as in  regenerative medicine

Així doncs, ens trobem davant un horitzó de noves descobertes que es va configurant i que explica en bona part perquè s'ha tardat més d'una dècada en traslladar el projecte genoma humà  cap a aplicacions terapèutiques àmplies. Però també s'obre un nou interrogant sobre a seguretat dels modificadors epigenètics dels medicaments. La forma com caldrà avaluar-ho suposarà més exigència al regulador i una necessitat de transparència de la caixa negra encara més gran. Seguirem atents,  perquè per ara ja se li ha girat feina amb els inhibidors HDAC, per al limfoma cutani de cèl.lules T, el primer d'aquests medicaments.

PS. I si voleu una perspectiva diferent, consulteu aquest article.

PS. Millor no saber-ho. Ja ho vaig explicar fa temps i ara ho trobareu al WSJ. Cal conèixer la teva predisposició a l'Alzheimer mitjançant un test genètic? de què et servirà. Podeu llegir aquí una història real que em confirma el que deia.

PS. I si l'altre dia teníem una galleda d'aigua freda, ara en tenim una altra de calenta. 23andMe acaba d'obtenir una patent genòmica als USA. I precisament ho fa utilitzant arsenal de dades epigenètiques. Després de cinc anys sense beneficis i sense haver apostat per les patents, han trobat un forat i el podrien fer més gran. Cal estar atents.

In “Round Hill” (1977), the light is a harsh glare, enveloping five languid bathers in the Caribbean in a self-contained, enclosed moment of time and place. The figure in the foreground turns away from us, so we see only the back of his head; the others are self-absorbed, expressions hidden behind sunglasses.

Alex Katz: Give Me Tomorrow’, Tate St Ives to September 23, www.tate.org.uk 

A controversial view of epigenetic inheritance

A critical view on transgenerational epigenetic inheritance in humans

A new article in Nature suggest that more evidence is needed to ascertain the role of epigenetic inheritance.

Even if the molecular mechanisms exist to transmit epigenetic information across generations in humans, it is very likely that the transgenerational transmission of culture by communication, imitation, teaching and learning surpasses the effects of epigenetic inheritance and our ability to detect this phenomenon. Cultural inheritance has certainly had an adaptive role in the evolution of our species, but the evidence for transgenerational epigenetic inheritance, as laid out above, is not (yet) conclusive. 

Let's wait for new evidence...

DNA methylation assays as epigenetic biomarkers

Quantitative comparison of DNA methylation assays for biomarker development and clinical applications

A new milestone has been achieved in Medicine. Tracking epigenetic alterations is crucial to understand a disease. However, epigenetic biomarkers are needed to assess such changes. Its precision (sensitivity-specifity) is  paramount for its clinical application. Now a group of international researchers has certified its performance (partially). Have a look at this Nature article:

Genome-wide mapping and analysis of DNA methylation has become feasible for patient cohorts with thousands of samples, and epigenome-wide association studies have been conducted for numerous biomedically relevant phenotypes. To translate relevant epigenome associations into clinically useful biomarkers, it is necessary to select a manageable set of highly informative genomic regions, to target these loci with DNA methylation assays that are sufficiently fast, cheap, robust and widely available to be useful for routine clinical diagnostics, and to confirm their predictive value in large validation cohorts.

Among its conclusions I would like to highlight three of them:

(i) Absolute DNA methylation assays are the method of choice when validating DNA methylation differences in large cohorts, and they are also an excellent technology for developing epigenetic biomarkers.

(ii) Relative DNA methylation assays are not a good replacement for absolute assays. However, experiences of scientists in the contributing laboratories suggest that carefully selected, designed and validated relative assays can cost-effectively detect minimal  races of methylated DNA against an excess of unmethylated DNA.

(iii) Global DNA methylation assays suffer from noisy data and divergent results between technologies. Locus-specific assays (possibly combined with prediction) provide a more robust alternative

That's it. Very soon will see the epigenetic biomarkers in routine clinical use. And afterwards,  epigenetic drugs and treatments. Then, we'll confirm that the promise of precision medicine is a reality. The implications for medicine as a scientific discipline and clinical decision making are huge, and specifically, healthcare organizations will need to adapt to new knowledge and technologies.

PS. Neuroepigenetics: DNA methylation and memory

Epigenetics contribution to clarify disease mechanisms

Epigenetics at the Crossroads of Genes and the Environment

You may find an updated definition of epigenetics in this JAMA article:

 Epigenetics refers to information transmitted during cell division other than the DNA sequence per se, and it is the language that distinguishes stem cells from
somatic cells, one organ from another, and even identical twins from each other. Examples include (1) DNA methylation, a covalent modification of the nucleotide cytosine, that is copied during cell division at CpG dinucleotides by the maintenance enzyme DNA methyltransferase I; (2) posttranslational modifications of nucleosome proteins about which the DNA double helix is wrapped; and (3) the density of  nucleosomes and higher-order packaging of chromatin within the nucleus, including its relationship to the nuclear lamina.

If this is so, why is the message of predictive genetics so widespread?. I've insisted on this issue before.

 The field of epigenetics and epigenetic epidemiology have much to do to improve measurement of epigenetic marks, inform natural variation in such marks, and the biological and population level relationships between genes, environment, and epigenetics. This is an important emerging area as it holds promise for better risk prediction in precision medicine as well as for clarification of disease mechanisms among the existing opaque landscape only partially informed by traditional genetic and environmental studies to date.

 A short and relevant article that provides hints for further reading.

PS. Epigenetic phenomena, from Nature.

Approaching the golden age of epigenomics and epitranscriptomics

A new twist on epigenetics

If epigenomics is crucial to discard the genetic predestination paradigm, now we can add a new 'omics to the paradigm: epitranscriptomics. Last February, Nature published interesting news related to recent scientific developments:

The epigenome helps to explain how cells with identical DNA can develop into the multitude of specialized types that make up different tissues. The marks help cells in the heart, for example, maintain their identity and not turn into neurons or fat cells. Misplaced epigenetic marks are often found in cancerous cells.

 Chuan He and Tao Pan are two researchers that have been working on new ways of controlling gene expression

He and others have shown that a methyl group attached to adenine, one of the four bases in RNA, has crucial roles in cell differentiation, and may contribute to cancer, obesity and more. In 2015, He’s lab and two other teams uncovered the same chemical mark on adenine bases in DNA (methyl marks had previously been found only on cytosine), suggesting that the epigenome may be even richer than previously imagined.

The team had shown for the first time that RNA methylation was reversible, just like the marks found on DNA and histones.

Methylated adenine bases are the focus of research on gene expression.

The meta-informational challenge of molecular data

The future of DNA sequencing

Where does DNA sequencing goes from here?. Nowadays, this is an appropriate question to pose.  The answer appears in an article in an interesting article in Nature.

Now, geneticists would like to have DNA sequences for everyone on Earth, and from every cell in every tissue at every developmental stage (including epigenetic modifications), in health and in disease. They would also like to get comprehensive gene-expression patterns by sequencing the complementary DNA copies of messenger RNA molecules.

In a mere 40 years, the central goal of putting molecular data about cells to practical use has changed from an informational challenge to a meta-informational one. Take clinical applications of genome-sequence data. It may soon be possible to use DNA sequencing routinely to analyse body fluids obtained for any clinical purpose. But only a vast amount of well-organized data about the multi-year medical histories of millions of people will provide the meta-information needed to establish when to ignore such data and when to act on them.

IA pertot arreu

Multimodal biomedical AI

En aquest blog he anat explicant darrerament els avenços en la intel·ligència artificial i els podeu trobar en aquestes entrades. La innovació és tan ràpida que costa molt estar atent al que està passant. Per aquest motiu us suggereixo una ullada a l'article que parla de la intel·ligència artificial multimodal en biomedicina, recullo una frase:

The development of multimodal AI models that incorporate data across modalities—including biosensors, genetic, epigenetic, proteomic, microbiome, metabolomic, imaging, text, clinical, social determinants and environmental data—is poised to partially bridge this gap and enable broad applications that include individualized medicine, integrated, real-time pandemic surveillance, digital clinical trials and virtual health coaches (Fig. 1). In this Review, we explore the opportunities for such multimodal datasets in healthcare; we then discuss the key challenges and promising strategies for overcoming these. 

I un gràfic: 

 

i el que són els foundation models:

Bommasani R et al, arXiv, July 2022

i si voleu saber l'última informació sobre "multimodal ai", la trobareu aquí.

I jo em pregunto, hi ha algú aquí aprop que estigui a l'aguaït de tot això? Es tant important que convindria no perdre passada i em temo que fem tard.

PD. Avui  a WSJ i al NYT 

"This is going to change everything about how we do everything. I think that it represents mankind’s greatest invention to date"

Clinical utility of genomic sequencing

The Path to Routine Genomic Screening in Health Care

Now that whole genome sequencing is knocking at the door of the clinician, it is the time to ask for clinical utility. The understanding of how such information will change diagnostic and therapy is paramount. There is still no need for cost-effectiveness, clinical utility comes first.
And the editorial at Annals explains exactly this issue, highly recommended:

There should be little doubt that individually tailored health care management plans based on DNA analysis are coming, but the timing of their introduction into routine clinical care is contingent on further demonstrations of clinical utility and proven implementation models.

My impression: let's wait for epigenetic biomarkers, beyond whole genome sequencing that provides less than 100 actionable genes out of 20.000. Though,

 The fact that only a small percentage of people would benefit from GS today is counterbalanced by growing evidence that the benefit could be significant, and perhaps even life saving

 

Pepe Castellanos at Barnadas Gallery

Cost-effectiveness with uncertain effectiveness

Cost-effectiveness of a gene expression score and myocardial perfusion imaging for diagnosis of coronary artery disease

Gene expression testing is quite different from genetic testing. Gene expression refers to epigenetic regulation of genes that occur without alteration of DNA. I've covered such topics several times in this blog. Today, I would like to focus on a recent published work on a new test  that assesses whether or not a patient's chest discomfort or other symptoms are due to obstructive coronary artery disease. Sounds interesting, since angiography is a costly technology.
A quick look at this recent article will raise new doubts. As you know, there is no need for cost-effectiveness analysis when effectiveness is uncertain. When talking about testing effectiveness means, sensitivity and specificity, AUC and so on. But what happens when the seller (or the model) decides about the threshold and afterwards focuses on negative predictive value of 96% and provides the desired value?. The threshold is only an option in the model. Why not change it?. There is a circular reasoning on that.
My concern is that health economics should look in detail at such issues. It is not an issue of conflicts of interest. In this case any health economist should avoid entering such territory.

Lamarck returns

Lamarck's Revenge: How Epigenetics Is Revolutionizing Our Understanding of Evolution's Past and Present

I've just started to read this amazing book. Chapter 1 says:

Charles Darwin espoused evolution as driven by natural selection. However, an earlier theory, proposed more than a half century before the first publication of Darwin’s greatest work, came from a naturalist whose life and work were limned by the flames of the French Revolution.

Lamarck arrived at a three-step process in what was to be the first really rational explanation for what we now call “organic evolution.” First, an animal experienced a radical change of the environment around it. Second, the initial response to the environmental change was some new kind of behavior by that animal (or whole species). Third, the behavioral change was followed by morphological changes that were heritable in subsequent generations. This proposed process came to be named after its author. Today, a variant on what Lamarck proposed is sometimes called “neo-Lamarckism,” but more often “epigenetics,” or “heritable epigenetics.”

Jean-Baptiste-Pierre-Antoine de Monet, Chevalier de Lamarck, had a different view about heredity and why animals changed through time. His scientific beliefs were that things that happen to us during our lives can change what we pass on to our next generation, and perhaps into even further generations. Darwin knew well what Lamarck theorized. Darwin believed that his own theories about evolution could not coexist with any aspect of what Lamarck postulated. We now know this is no longer the case.
Lamarck’s Revenge looks anew at what are, perhaps, humanity’s most basic questions: the “where,” “when,” and “why” of getting to the present-day biota on this planet. But the vehicle to do this is by asking specifically about the “how.” What were the evolutionary mechanisms, the balance between Darwinian and neo-Lamarckian (aka heritable epigenetics), that produced not only our physical biology but some aspects of our heritable behavior as well?

Here are some possibilities. First, that the process known as epigenetics combined with periods of extraordinary environmental change has played a far greater role in what is called the “history of life” than is accepted by all but a small cadre of revolutionary biologists. This is perhaps most decisively shown through the epigenetic process of “lateral gene transfer,” where on a given day, in a given minute, some organism is invaded by another and a product of that invasion is the incorporation of vast numbers of new genes, making the invaded creature something else again, neither the invader nor the invaded. This is known.
Second, new evidence points to a probable role of epigenetics in producing rapid species transitions by mechanisms other than lateral gene transfer. Science has discovered that major evolutionary change of a species can happen a thousand times faster by epigenetics than by the process demanded by the Darwinian theory of single, random mutations along a creature’s genome or DNA (or, in some cases, RNA). This is most likely to occur during and immediately after rare, major environmental perturbations (such as mass extinctions and their aftermath).

Integrating genome and epigenome studies

The Key Role of Epigenetics in Human Disease Prevention and Mitigation

I've said it many times: beware of snake-oil sellers. Nowadays you may find it everywhere, specially on internet. You may get a genetic test for a disease that creates a false illusion of safety, or another that provides an unnecessary and avoidable concern. Only evidence based prescribed tests can be considered appropriate.
Therefore, if you want to confirm that genome is not enough, you have to check the review at NEJM on epigenetics. At the end of the article you'll find the explanation on why we do need integrated genome and epigenome association studies. You'll understand that cancer is fundamentally an epigenetic disease.
The current knowledge is changing quickly some conventional truths and "known unknowns" that we've had for years. This is good news for citizens, and bad news for snake-oil sellers if detected. Governments should help citizens on this screening effort, and protect citizens from fake medical information.

La motxilla epigenètica

Tots aquells entusiasmats amb el paradigma de la predestinació, és a dir que si coneixem el genoma personal podrem predir les malalties, han de saber que ja fa anys que ha fet aigües. Ho he dit altres vegades, les òmiques s'obren pas, i en especial l'epigenòmica. Fa uns dies vaig fer una conferència sobre l'estat actual de la medicina estratificada, i vaig fer referència al mercat dels "companion diagnostics", les proves diagnòstiques d'acompanyament sense les quals no seria possible l'estratificació. La medicina estratificada era un primer estadi en la medicina individualitzada, ara les coses han esdevingut més complexes. Tot i el temps que ha passat,  el nombre de proves diagnòstiques aprovat encara és limitat. tant sols 15. Ara bé, aquest és un entorn en ebullició i veurem noves aportacions, si els recursos disponibles ens ho permeten. La qüestió oberta segueix essent recurrent: després de 7 anys de medicina estratificada, encara no disposem de cap avaluació seriosa del que aporta.
La nova medicina combinarà disciplines òmiques, i això és va fer palès al curs d'epigenètica al que vaig assistir. Les dues aportacions de la Maria Berdasco van ser d'elevada qualitat, la introducció i la d'epigenètica i càncer. Vaig tenir la impressió que s'ha avançat molt en recerca i hi ha molt més del que imaginem per traslladar a la pràctica ( per exemple a la p.31  trobareu quatre medicaments ja disponibles).
Avui topo amb una mostra més de que l'epigenètica és el tema del moment al The Economist d'aquesta setmana. La troballa de Rehan et al. assenyala que l'herència epigenètica es podria traspassar dues generacions. Ho fan amb ratolins. En concret si l'àvia era fumadora, els nets mostren les alteracions epigenètiques provocades per la nicotina.
Si tot plegat va per aquí, ja cal que ens ho fem mirar. El genoma és el que és i la metilació i acetilació regulen l'expressió dels gens (epigenoma). Tenint en compte que podem ser hereus dels hàbits més o menys saludables dels progenitors,  i si alhora hi afegim l'status social que ens aporten -recordeu el que vaig explicar dels macacos-, tot plegat faria un motxilla epigenètica més feixuga per uns que per altres.

PS. Encara que de genoma en tenim un, i diuen que aviat el preu baixarà a 1.000 dòlars, penseu que d'epigenomes en tenim uns 450 (!!!),- un per cada tipus de cel.lula-  per tant això es complica i molt.
PS. Potser aviat veurem alguns economistes fent models d'epigenetic overlapping generations....per tal de predir la despesa...
PS. Presentacions d'interès d'Oliver Rivero i Vicente Ortún al mateix congrés Llàstima que al pdf hi han posat una marca d'aigua inoportuna, podria ser menys invalidant...
PS. Per cert, sobre els recursos públics disponibles per la ciència. Observo nirvis entre alguns científics, poden ser fonamentats. Ara bé, no he vist encara cap descripció dels resultats en termes de patents i llicències i el que ha suposat de retorn per al sector públic. Ni tant sols la més mínima preocupació per la transparència. Sovint em pregunto si ens trobem davant una altra privatització dels beneficis i una socialització del cost. Per ara tinc només evidència anecdòtica.
PS. La malaltia del cost, de Baumol, explicada per l'Incidental Economist en una sèrie.
PS. Comparteixo el que diu en Garicano a FT. Preocupant.

Monet (1905)

Avui a Christie's

Searching for a healthy ageing

The Biology of Inequalities in Health

The Lifepath research consortium aimed to investigate the effects of socioeconomic inequalities on the biology of healthy aging. The main research questions included the impact of inequalities on health, the role of behavioral and other risk factors, the underlying biological mechanisms, the efficacy of selected policies, and the general implications of our findings for theories and policies. 

 The impact of socioeconomic condition on premature aging is mediated by known behavioral and clinical factors and intermediate molecular pathways that Lifepath studies have revealed, including epigenetic clocks (age acceleration), inflammation, allostatic load, and metabolic pathways—highlighting the biological imprint (embodiment) of social variables and strengthening causal attribution.

 There is still a wide gap between social and natural sciences, both on methodological and conceptual grounds. Natural sciences focus in particular on biological mechanisms and outcomes, i.e., they address “zoe” (biological life), while social sciences address “bios” (biographical life), if we refer to the terminology used by Ronald Dworkin. In fact, epidemiologists aim to connect zoe and bios in meaningful ways, though this attempt has rarely become explicit. An exception is the work of Nancy Krieger who proposed the concept of “embodiment.” Biology and biography (124) meet in the health status of an individual, depending on social position at a given age. These concepts start to be incorporated into epidemiological research, via the integration of social contexts and biomarkers in a life-course approach. The results from analyses carried out within Lifepath suggest that the socioeconomic environment, from early life and across the life-course, is an important risk factor for health and exerts its effects via intermediate biological mechanisms.

Great research!

PS. Austin Frakt in NYT Putting a Dollar Value on Life? Governments Already Do

Edward Hopper

Genome editing, closer than you think

Human Genome Editing Science, Ethics, and Governance

Last week the US patent office ruled that hotly disputed patents on the CRISPR revolutionary genome-editing technology belong to the Broad Institute of Harvard and MIT. In a former post I explained the dispute. Genome editing in my opinion shouldn't be patented and will see exactly the impact of such ruling in US and elsewhere in the next future.
If you want to know in detail what does genome editing means for the future of life sciences, have a look at NASEM book.

It is now possible to insert or delete single nucleotides,interrupt a gene or genetic element, make a single-stranded break in DNA, modify a nucleotide, or make epigenetic changes to gene expression. In the realm of biomedicine, genome editing could be used for three broad purposes: for basic research, for somatic interventions, and for germline interventions.

CRISPR (which stands for clustered regularly interspaced short palindromic repeats) refers to short, repeated segments of DNA originally discovered in bacteria. These segments provided the foundation for the development of a system that combines short RNA sequences paired with Cas9 (CRISPR associated protein 9, an RNA-directed nuclease), or with similar nucleases, and can readily be programmed to edit specific segments of DNA. The CRISPR/Cas9 genome-editing system offers several advantages over previous strategies for making changes to the genome and has been at the center of much discussion concerning how genome editing could be applied to promote human health.

I would just want to say that these patents destroy the soul of science, since access should be available with no barriers for the development of  innovation. Patents are not the incentive for discovery in this case, as I explained in my post, natural processes should'nt be patented. And this is why today is a really sad day.

PS. My posts against patents

Michael Kiwanuka. Home again