The value of direct-to-consumer tests

 Direct-to-Consumer Tests on the Market Today. Identifying Valuable Tests from Those with Limited Utility

For health care professionals, the analytical validity of DTC tests is a primary concern. Analytical validity of DTC genetic testing can be defined by analytical sensitivity and specificity whereby analytical sensitivity is defined as how often a test is positive when the genetic variant of interest is present in the tested sample, and the analytical specificity is defined as how often a test result is negative when the tested sample does not contain the genetic variant of interest.18 A recent study by Tandy-Connor and colleagues19 “indicated that 40% of variants in a variety of genes reported in DTC raw data were false positives” when compared with clinical confirmatory testing. This study highlights the need to scrutinize the analytical validity of DTC genetic testing and consider confirmatory testing in a clinical diagnostic genetics laboratory. 

Per the American Society of Human Genetics, “companies offering DTC genetic testing should disclose the sensitivity, specificity and predictive value of the test, and the populations for the information is known, in a readily understandable and accessible fashion.”

Unfortunately, nobody cares about it, and the regulator is still on vacation.

World Press Photo BCN

Veure-les passar

El tema segueix sobre la taula. El debat sobre les proves genètiques i com regular-les preocupa a la FDA i encara que ja ha dit que cal aplicar els mateixos criteris que als subministraments mèdics (medical devices), hi ha molts dubtes sobre els detalls.

Els de Genomics Law Report expliquen el que ha passat a les compareixences recents. Si n'esteu interessats feu-hi una ullada.
Les preguntes clau:

Should the agency require proof of analytical validity, clinical validity and/or clinical utility prior to approving a particular test and, if so, what standards of proof should be required?
Should the agency regulate tests SNP-by-SNP, claim-by-claim or test-by-test, and what should be done to prepare for the inevitable arrival of tests based on whole-genome sequence data?
Should the agency oversee the labeling and advertising claims offered by companies in association with such tests?
Should the agency require companies to collect and submit data regarding the post-test benefits and harms and the actual (as compared to intended) uses of their tests?
Should the agency impose requirements on companies to prevent unauthorized testing, protect data privacy and limit companies’ ability to share genetic information without their customers’ consent?

While these questions, and countless more, will be critical to the development of sensible genetic testing regulation, one question clearly generates more and more emotional responses than any other:

Should regulators require some or all genetic tests to be routed through a clinician, or should tests be made available directly to consumers who desire them?

I mentrestant per aquí, les veiem passar...i ens costen una pasta...

PD. El gran Ferran Torrent representa una alenada d'aire fresc els diumenges, tant en directe a Rac1 com els comentaris a ARA. Cita Josep Renau: "Quan arribes a València i et menges una paella o una sípia t'oblides de la lluita de classes". I mentrestant els de FT ens recorden que "Valencia is burning"

The hype over genetic tests

Implementation of a companion diagnostic in the clinical laboratory:The BRAF example in melanoma

Analytical validity is one of the three steps for any assessment of genetic tests, combined with clinical validity and clinical utility. Understanding how this process affects specific tests is not that easy.Fortunately you can find a detailed explanation of one of them:the BRAF genotype analysis in tumor tissue samples for identification of melanoma patients that can benefit treatment with BRAF inhibitors.
Once you begin to read the article you'll understand the complexity of being precise in a test. This is the reason why if specificity and sensibility is uncertain, different methodologies are needed (check Figure 1).
But how to do it?. How to set up external controls of quality?. All these issues are covered in this article, that explains what's going on in practical terms. I'm concerned if due to such complexity, all "genetic test talent" is not concentrated in one site of the organization-hospital, and many departments and services -oncology or cardiology- are developing their own genetic tests. Somebody should block this option before it is too late.

El valor de les proves diagnòstiques genètiques

Economic evaluation of next-generation sequencing techniques in diagnosis of genetic disorders: A systematic review

Supporting Biomarker-Driven Therapies in Oncology: A Genomic Testing Cost Calculator 

Aquest és un tema amb moltes singularitats i cal estar atents als detalls. Entendre el cost-efectivitat de les proves diagnòstiques obliga a precisar molt què es pretén i com la prova diagnòstica modifica la decisió clínica. És per això que s'hauria d'aplicar el cost per persona identificada correctament com a punt de referència clau. Ara bé això no és senzill de calcular.

Ara tots els ulls estan posats en seqüenciar l'exoma, i un article recent arriba a aquesta conclusió:

On the basis of the available evidence and present findings, exome sequencing as a cost-effective option could have the potential to be used as a genomic test to diagnose suspected genetic disorders. However, there is still no consensus among studies on performing the exome sequencing test as a first- or second-line diagnostic test. While NGS methods are usually implemented as the last diagnostic test by reason of their relatively high cost, a number of recent studies have indicated that when exome sequencing is  implemented as a first-line test, extra examinations avoided for diagnosed patients may amply compensate for the cost of the test.

Per tant deixa oberta la qüestió i no respon a la pregunta.  Jo crec que és qüestió de dies, seqüenciar l'exoma es convertirà en l'estandard.

PS. Més material.

The time to stop recreational testing has come

 Direct-to-Consumer Genetic Testing: Value and Risk

Piecing together information from a variety of sources, one reporter concluded that by early 2019, more than 26 million people worldwide had been tested by the four leading companies, 23andMe, Ancestry, Gene By Gene, and MyHeritage (1). That volume was fueled by aggressive marketing, including discounts in the lead-up to major holidays to promote gifting of test kits. As of May 2020, the  undiscounted price of the basic test offered by the leading companies was $59–$99.

This is an example of what should not had happened. Recreative genomics doesn't add value and increases uncertainty and anxiety. 

Although many consumers of DTCgenetic testing express an intention to modify their lifestyle to address risk factors, studies typically show no changes at follow-up (15, 30). In the PGen Study, 59% of participants said that test results would influence their management of their health (31). However, an analysis of the 762 participants who had complete cancer-related data found that those who received elevated risk estimates were not significantly more likely to change lifestyle or engage in cancer screening than those who received average or below-average risk estimates (44). It may be relevant that no participants tested positive for pathogenic variants in highly penetrant cancer susceptibility genes. As for population health, the Centers for Disease Control and Prevention identify three conditions—hereditary breast and ovarian cancer syndrome,Lynch syndrome, and familial hypercholesterolemia—that are poorly ascertained despite the potential for early detection and intervention to significantly reduce morbidity and mortality (45). The hope is that DTC genetic testing could improve the situation (15). However,DTC genetic testing as currently carried out is likely to fill gaps in haphazard fashion, given the characteristics of purchasers, the scope of available products, and integration issues.

One message. Right now and until we don't know the implications of recreational genetic testing, direct to consumers testing should stop.

Banksy

 

The urgent need to define delivery models for genetic testing

Identification of Delivery Models for the Provision of Predictive Genetic testing in Europe: Protocol for a Multicentre Qualitative study and a systematic review of the literature

The increasing role of genomics in medical decision making requires a review on how services should be organised. Unless this effort is taken promptly, it will be much more difficult to adapt the messy organization to an efficient model for the delivery of services. This issues are explained in a recent article. The ten questions:

 The transfer of genomic technologies from research to clinical application is influenced not only by several factors inherent to research goals and delivery of healthcare but also by external and commercial interests that may cause the premature introduction of genetic tests in the public or private sector (i.e., introduction of a test despite insufficient evidence regarding its analytical validity, clinical validity, and utility). Furthermore, current genetic services are delivered without a standardized set of process and outcome measures, which are essential for the evaluation of healthcare services. It is important that only genetic/genomic applications with proven efficacy and effectiveness are delivered to populations, and particularly that technologies have favorable cost-effectiveness ratios

La capacitat predictiva de les proves genòmiques

Gene Maps Are No Cure-All

Les quatre característiques diferencials de les proves genòmiques es que són determinacions inespecífiques, d'alta validesa analítica, baixa validesa clínica i utilitat clínica problemàtica.  Això és el que ens explica un article a BMC Medical Ethics. I només a partir de la comprensió d'aquestes característiques es possible començar a parlar de les implicacions ètiques, legals i socials.
Doncs bé, avui llegia a WSJ la notícia sobre la baixa capacitat predictiva de les proves genòmiques completes (i per tant inespecífiques) a partir d'un estudi publicat a Science Translational Medicine, un contrast de la seva baixa validesa i utilitat clínica.
El resum diu:

New DNA sequencing methods will soon make it possible to identify all germline variants in any individual at a reasonable cost. However, the ability of whole-genome sequencing to predict predisposition to common diseases in the general population is unknown. To estimate this predictive capacity, we use the concept of a “genometype”. A specific genometype represents the genomes in the population conferring a specific level of genetic risk for a specified disease. Using this concept, we estimated the capacity of whole-genome sequencing to identify individuals at clinically significant risk for 24 different diseases. Our estimates were derived from the analysis of large numbers of monozygotic twin pairs; twins of a pair share the same genometype and therefore identical genetic risk factors. Our analyses indicate that: (i) for 23 of the 24 diseases, the majority of individuals will receive negative test results, (ii) these negative test results will, in general, not be very informative, as the risk of developing 19 of the 24 diseases in those who test negative will still be, at minimum, 50 - 80% of that in the general population, and (iii) on the positive side, in the best-case scenario more than 90% of tested individuals might be alerted to a clinically significant predisposition to at least one disease. These results have important implications for the valuation of genetic testing by industry, health insurance companies, public policy makers and consumers.

Està clar que només ens parla de la seqüenciació completa i la predisposició a 24 malalties. No es refereix a les proves dirigides a simptomes i malalties en concret. El tema és prou conegut, i n'he parlat en aquest blog. Encara no sé com pot ser notícia si no fos perquè això pot fer variar la valoració d'Illumina, que aquests dies vol ser comprada per 6.700 milions de dòlars i d'aquesta manera evitaria desembutxacar-se més doblers. Alguns inversors segurament pensen que aquesta tecnologia de seqüenciació completa del genoma individual l'encolomaran com predictiva malgrat no ho sigui i cal treure'n rendiment mentre el regulador segueixi de vacances. D'altres pensen que efectivament servirà per crear valor i millorar la salut.
De vegades penso que la dificultat resideix en el pànic que produeix un full en blanc a qui ha de posar-se a escriure. Aquest fet porta un dia a publicar una cosa i l'altre la contrària. Només el lector avesat en aquests afers sap comprendre quan l'estan engatussant. Ara bé, avui al WSJ han fet una cosa poc habitual que s'agraeix, mostren el finançament i conflictes d'interès dels autors de l'article a Science i diuen:

The new study was funded by the National Institutes of Health and a number of independent groups. Dr. Vogelstein and two co-authors are founders of Inostics and Personal Genome Diagnostics and own stock in the two gene-analysis companies.

Atès que la conclusió de l'article podria afectar negativament als drets residuals de propietat dels autors, ens trobem davant un cas singular de revelació de resultats negatius de recerca, fet altament inusual quan hi ha interessos pel mig.

Clinical utility of genomic sequencing

 Clinical utility of genomic sequencing: a measurement toolkit

From Genomic Medicine:

For a diagnostic test such as WGS (whole genome sequencing) to be accepted into practice, commissioned in a health system, or receive coverage and reimbursement through health insurance, evidence of clinical utility and cost-effectiveness is generally required. Unlike prospective clinical research where the ‘effectiveness’ of an intervention can be easily tied to a predefined health outcome, the concept of clinical utility in genetic medicine is rarely uniformly defined nor necessarily directly tied to a specific health outcome. As such, generating and evaluating evidence of clinical utility is complex. The challenge in defining clinical utility today is compounded by the extraordinary heterogeneity of rare diseases, as well as the polygenic nature of more common conditions for which WGS is expected to be relevant. In this paper, we aim to extend earlier conceptualizations of clinical utility as applied to the diagnostic use of WGS and suggest that this framework not only be used as a tool for evidence review

 The application of this model to WGS includes six levels of efficacy: technical efficacy, diagnostic accuracy efficacy, diagnostic thinking efficacy, therapeutic efficacy, patient outcome efficacy, and societal efficacy (Table 1, Fig. 1). The model is hierarchical; achieving a given level of efficacy is often but not always contingent upon a demonstration of efficacy at the preceding level. As described in Fig. 1, levels 1–3 are necessarily contingent but beyond level 3, a genetic test can achieve therapeutic, patient outcome, and/or societal impact in ways that are contingent upon one another or independent of one another. We retain the levels of technical and diagnostic accuracy efficacy (i.e., levels 1 and 2) as essential starting points in our guiding framework as they are fundamental precursors to achieving clinical utility. However, since these laboratory-based components of efficacy are well-debated and described in the WGS literature and in recent guidelines published by members of our group27, we focus here on four levels of the efficacy model (i.e., levels 3–6) that align most directly with a broad definition of clinical utility and extend beyond laboratory-based components of efficacy. In emphasizing these four levels of efficacy as components of clinical utility, our intent is to encourage the use of a broad set of health and non-health-related indicators of value to bolster the state of evidence in this area, rather than to convey that all aspects of clinical utility need to be achieved for WGS adoption and reimbursement.

 

 

Economics of genomics

The Economics of Genomic Medicine - Workshop Summary

Just imagine for a while that you are concerned about economic implications of genomics and you invite a distinguished professor of genetic medicine - James Evans- to the introduction of a workshop at IOM. Instead of more is better, he sends a cautious message to the audience. And beyond the potential and valuable applications for those that are already ill,  he openly critizises the current trend towards the use of genetic tests for the healthy:

Assessing the risk of common diseases through whole genome analysis of a healthy person has received the most attention, but this attention “is somewhat misplaced,” Evans said. Currently, assessment of genetic risk alleles has “rather feeble predictive power” because the increased risks tend to be small. “From a clinical standpoint I don’t know what to do with patients who are at a 1.3 relative risk for colon cancer,” said Evans. “Am I going to hurt them by doing more intensive screening, or am I going to help them?”

"I know what almost everybody in this room is going to die of,” said Evans. “We are going to die of heart disease or cancer. . . . We are all at high risk for these maladies regardless of our [genomically determined] risk. And many at decreased risk for heart disease will still die of heart disease. So we are all going to benefit from interventions that lower heart disease. We don’t really need to target people. It doesn’t do anyone much good to tweak our estimation of an individual’s relative risk for common diseases which we are all at high absolute risk of developing anyway."

 “The old adage that an elephant for a nickel is only a bargain if you have a nickel and you need an elephant applies here. I am not sure most of us need that elephant. Even if free, perceived low cost is an illusion, because the misapplication of medical tests—and make no mistake, whole genome sequencing is a medical test—is very expensive,”

A clear message for geneto-enthusiasts and marketeers. Cost-effectiveness of genetic testing starts with assessing if they are effective. If not, any economic analysis is useless . This is obvious, but we do need to repeat it, just in case.

PS. Must read, Reinhardt's blog.

PS. A report to understand the financial markets' mess and why recovery is far by now.

Opening the door to recreational genetics testing

On February 19th, the US Food and Drug Administration (FDA) authorized 23andMe to market a direct-to-consumer (DTC) carrier test for Bloom syndrome. Such test was classified as a medical device, and exempting it from premarket review. This may pave the way for DTC genetic testing in the US market.
The decision to open door for one test may represent the biggest move towards a recreational genetic testing market. You know that from this blog I have backed a ban on developing such markets and the need for an effective regulatory review different from the flawed medical device system.
The european regulator is still on holiday, I said that some months ago and it is still "out".

PS. Variations in health care in GCS Blog.

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.

The long and bumpy road to CRISPR (2)

 Editing Humanity. The CRISPR Revolution and the New Era of Genome Editing

In 2017 I wrote a post about the book by Jennifer Doudna, A Crack in Creation, now Kevin Davies, the editor of the CRISPR journal has published a new book on CRISPR. It is an effort to put all the information and details about CRISPR in one book. Therefore, if you want to now the whole story (or close to) this is the book to read. If you are interested in a general approach, then the Doudna book is better.

It is quite relevant the chapter that explains the role of Francis Mojica in CRISPR (chapter 3), and the chapter 18, on crossing the germline and what happened about the scandal of genome editing by JK.

“When science moves faster than moral understanding,” Harvard philosopher Michael Sandel wrote in 2004, “men and women struggle to articulate their own unease.” The genomic revolution has induced “a kind of moral vertigo.”49 That unease has been triggered numerous times before and after the genetic engineering revolution—the structure of the double helix, the solution of the genetic code, the recombinant DNA revolution, prenatal genetic diagnosis, embryonic stem cells, and the cloning of Dolly. “Test tube baby” was an epithet in many circles but five million IVF babies are an effective riposte to critics of assisted reproductive technology.

With CRISPR, history is repeating itself,

That's it, great book.

 

The uncertainty over genomics sequencing value in clinical decision making

Assessing Genomic Sequencing Information for Health Care Decision Making: Workshop Summary

"The value of genetic sequence information will depend on how it is used in the clinic", key statement that needs some elaboration. This is precisely what the IOM report does, you'll find in their pages the current situation about how genomics may impact in decision making. In chapter 5 you'll understand how an insurer decides about coverage of such tests according to 5 criteria:

1. The test or treatment must have final approval from appropriate governmental regulatory bodies, where required;
2. scientific evidence must permit conclusions about its effect on medical outcomes;
3. technology must improve net health outcomes;
4. the technology must provide as much health benefit as established alternatives; and
5. the improvement in health must be attainable outside investigational settings.

Unfortunately, if you start from the first one, you'll find a complete lack of references by governmental bodies on the approval of such tests. Therefore, I can't understand from the chapter how successful they are on such process.
While reading the book you'll increase your uncertainty about outcomes and value of genomic tests instead of reducing it. This was my impression. Let's wait for future good news, again.

PS. Summary of the report:
"Clinical use of DNA sequencing relies on identifying linkages between diseases and genetic variants or groups of variants. More than 140,000 germline mutations have been submitted to the Human Gene Mutation Database and almost 12,000 single nucleotide polymorphisms have currently been associated with various diseases, including Alzheimer’s and type 2 diabetes, but the majority of associations have not been rigorously confirmed and may play only a minor role in disease. Because of the lack of evidence available for assessing variants, evaluation bodies have made few recommendations for the use of genetic tests in health care."

False advertising

The concern over consumer protection is growing with new health technologies. This is not new, you may think. However the lawsuit by FTC against Genelink for misleading claims is the first case in a genetics testing company. Genelink said that they analyzed your DNA and afterwards send back nutritional supplements customized to your personal genome. The regimen, the company promised, was good for diabetes, heart disease, arthritis, insomnia and other ailments.On request by FTC, they were unable to confirm such promises.
Since you may find a similar test on the corner of the street, once again my question is: where is the regulator?

PS. Some months ago, was the FDA who asked 23and me to stop selling its genetics test kit.

PS. On DTC genetic tests, a good article.

Cost-effectiveness of genome sequencing (3)

Application of next-generation sequencing to improve cancer management: A review of the clinical effectiveness and cost-effectiveness

Once again, there is no need for cost-effectiveness if there is not a clear message on the analytical validity, clinical validity and utility of a diagnostic test.
A new article want to shed light on cancer and NGS, and says:

Our search for cost‐effectiveness studies on NGS in cancer care yielded 2037 articles. Only 6 articles included cost‐effectiveness studies of the application of NGS (targeted gene panel) in cancer

The 6 selected reports could be separated into 2 types. Three of the articles assessed the cost‐effectiveness of recommending patients receiving targeted therapy matching their genetic mutation identified via NGS; and the remaining 3 articles assessed the cost‐effectiveness of using NGS as part of the screening program to direct patients or high risk family members into prophylactic treatment

Two out of 3 articles in the “targeted therapy” group reported that NGS and targeted therapy was not cost-effective (Table 3A), using an ICER threshold of US$100 000 per Quality Adjusted Life
Year (QALY) gained. An ICER of less than US$100 000/QALYs gained is generally considered favourable for funding in the United States

Two out of the 3 articles in the “screening” group reported that the use of NGS was cost‐effective (Table 3B), that is, under US$100 000 per QALY gained.loser surveillance.

 In our evaluation of the effectiveness of NGS, we found that NGS is effective at identifying mutations in cancer patients, and we reported that 37% of the diagnosed patients proceeded to receive therapy matching their genetic profile. However, with only 6 articles available that assess the cost-effectiveness of NGS in various settings, it remains an area for future research to determine whether the technology is cost-effective in routine cancer management

Summary: the message is that there is no message with such a few observations!


Something is being missed...

Guillem Roma and Marta Roma

Organising genetic testing

Finally the government has decided to organise genetic counseling and testing. A recent instruction determines who does what. As you may remember I've said several times that government was on permanent holiday on this issue.
In this new instruction, at least two issues are forgotten: the tests that are covered, and the proliferation of sequencing instruments outside the lab. These are not minor issues.
Somebody should decide asap wether a test it is worth to be prescribed. Right now, there are no explicit constraints under the current instruction. And DNA sequencing instruments may be found in many departments under the consideration of research. If there is no clear split between research and care, I can imagine a close future with many messy labs within any hospital. Concentration of knowledge and specialisation provides wider guarantees for quality. Unless there is any mentorship program by clinical laboratories, things will go down the wrong path. Today I'm more worried than yesterday, unless these two issues are fixed.

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.

Courts as market makers

Recent decision invalidating Myriad patents has had immediate results. The market of genetic tests on breast and ovarian cancer has new entrants. The price of the test has decreased 40% (!) in just four months after the resolution. More entrants are expected in the next future for more tests.
The question is still the same, is there any clear cost-effectiveness analysis available for such tests? Why homebrew tests (LDT) are beyond any regulation? Does any regulator care about all this issues?. The answer is: up to now, we can't see any efforts. Patents create artificial monopolies, courts may create markets when invalidate patents,  but patients are concerned about health improvement and value. In an asymetric information environment, the regulator can't take permanent holidays. Overdiagnosed population doesn't necessarily mean healthier population.

 Forbes Healthcare Summit 2013

Insurance Companies Enter A New World

Bioethics for lab medicine

 Ethics for Laboratory Medicine

Key issues:

Table 1.Ethical Issues of particular importance in Laboratory medicine.

Informed consent 

Use of leftover specimens 

Biobanking 

Genetic testing 

Equity and access to laboratory testing 

Incidental findings and medically actionable results 

DTC testing 

Transfusion medicine and religious or ethical restrictions 

Disclosing medical error 

Emerging infectious diseases 

Test utilization 

The unique role of laboratorians, who care for patients but interact mainly with their samples rather than the person, creates distinct ethical dilemmas. In addition, laboratories function as critical parts of complex health systems, and the interaction of the laboratory with the greater healthcare system creates additional points of ethical friction (45). Clinical laboratory professionals are ethically bound to use our voices to advocate for excellence in patient care in the realms of respect for persons, beneficence, and justice, even in the face of technological, administrative, and, perhaps, clinical pressures to do otherwise.

Ethics represents moral principles based on cultural norms and values. Sometimes these moral values have been turned into federal or state laws or into local rules and regulations. However, laws and rules may be absent or difficult to apply to a given situation. When faced with ethical decisions, laboratorians should seek the input from other clinicians and laboratory colleagues. In addition, most hospitals have ethics boards comprising multidisciplinary teams of clinicians, lay people, and clergy to help guide decision-making.

 

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