Precision medicine

 Precision Medicine for Investigators, Practitioners and Providers

Many topics under the same umbrella:

Table of Contents

Introduction

2. Role of genomics in precision medicine

3. High throughput omics in the precision medicine ecosystem

4. Infant gut microbiome

5. Paraprebiotics

6. Fecal transplantation in autoimmune disease

7. Drug pharmacomicrobiomics

8. CRISPR technology for genome editing

9. Engineering microbial living therapeutics

10. Organ on a chip

11. Multicellular in-vitro organ systems

12. The role of biobanks in biomarker development

13. Translational interest of immune profiling

14. Organoid pharmacotyping

15. Large datasets for genomic investigation

16. Modern applications of neurogenetics

17. Genomic profiling in cancer

18. Genomics in pediatrics

19. Genomics of gastric cancer

20.  Genomics of prostate cancer

21. MicroRNAs and inflammation markers in obesity

22. MiRNA sequencing for myocardial infarction screening

23. Cell free DNA in hepatocellular carcinoma

24. Non coding RNA in cancer

25. Germline variants and childhood cancer

26. Pharmacogenomics in cancer

27. Proteomic biomarkers in vireoretinal disease

28. Proteomics in respiratory diseases

29. Cardiovascular proteomics

30. Host genetics, microbiome, and inflammatory bowel disease

31. Sampling, Analyzing, and Integrating Microbiome ‘omics Data in a Translational Clinical Setting

32. Omics and microbiome in sepsis

33. Molecular and omics methods for invasive candidiasis

34. Lipid metabolism in colorectal cancer

35. Salivary volatolome in breast cancer

36. immunodiagnosis in leprosy

37. decision support systems in breast cancer

38. Electronic medical records and diabetes phenotyping

39. Clinical signature of suicide risk

40. Machine learning and cluster analysis in critical care

41. Artificial intelligence in gastroenterology

42. Algorithms for epileptic seizure prediction

43. Precision medicine in ophthalmology

44. Phenotyping COPD

45. Lifestyle medicine

46. Precision medicine for a healthier world

47. Aging and clustering of functional brain networks

48. Nutrigenetics

49. Genome editing in reproductive medicine

50. MRI guided prostate biopsy

51. Precision Nutrition

52. Theranostics in precision oncology

53. Precision medicine in daily practice

54. Imaging in precision medicine

55. Organoid for drug screening

56. Printing of personalized medication using binder jetting 3D printer

57. 3 D printing in orthopedic trauma

58. Consumer genetic testing tools in depression

59. The future of wearables

60. Tumor heterogeneity and drug development

61. Smartphone based clinical diagnosis

62. Smartphone biosensing for point of care use

63. Data security and patient protection

64. Blockchain solutions for healthcare

65. Ethical questions in gene therapy

66. Pitfalls of organ on a chip technologies

67. Regulatory issues of artificial intelligence in radiology

68. Academic industrial alliance

69. The future of precision medicine

70. Precision Medicine Glossary

71. Useful internet sites

Editing human genome

 MODERN PROMETHEUS. Editing the Human Genome with Crispr-Cas9

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.

 

Improving CRISPR, a crowd of proteins

Improving CRISPR from Mammoth Biosciences; 

 Genome editing is the process researchers use to make targeted changes to an organism’s DNA (its genome). Scientists have used a variety of technologies for genome editing (see the history of genome editing here). However, since ~2012, CRISPR has made the genome editing processes much easier. CRISPR associated or “Cas” proteins drive this process. They are relatively easy to target to specific DNA sequences. They also work in many organisms.

Yet, the main Cas protein currently used for CRISPR genome editing, SpCas9, has limitations. In this post, we cover SpCas9’s limitations and how newly discovered Cas protein families, Cas14 and CasΦ, potentially overcome these limitations. We hope Cas14 and CasΦ will enable more efficient genome editing in diverse organisms and tissues.

 

An unprecedented discovery

Yesterday was World Crispr Day

 

CRISPR Nobel prize

 Genetic scissors: a tool for rewriting the code of life

GREAT NEWS! 

The Royal Swedish Academy of Sciences has decided to award the Nobel Prize in Chemistry 2020 to

Emmanuelle Charpentier, Max Planck Unit for the Science of Pathogens, Berlin, Germany

Jennifer A. Doudna, University of California, Berkeley, USA

“for the development of a method for genome editing”

Popular information: Genetic scissors: a tool for rewriting the code of life (pdf)

Scientific Background: A tool for genome editing (pdf)

Unfortunately, the Royal Swedish Academy of Sciences has shown its ignorance about the real discovery of CRISPR. It happened in the '90s in Salines de Santa Pola by Dr. Martinez Mojica.

Stop Covid with CRISPR Diagnostics (3)

 Detection of SARS-CoV-2 with SHERLOCK One-Pot Testing

Former posts have highlighted the potential of CRISPR for molecular  diagnostics, specially in case of Covid. Now NEJM provides details of Sherlock test.

Protocol here

Why CRISPR is a breakthrough

Programming life: An interview with Jennifer Doudna

‘The Joy of the Discovery’: An Interview with Jennifer Doudna

Covid-19 testing landscape

COVID-19 diagnostics in context

This is the best summary of current supply of diagnostic tests for Covid-19:

COVID-19 tests can be grouped as nucleic acid, serological, antigen, and ancillary tests, all of which play distinct roles in hospital, point-of-care, or large-scale population testing.
Table 1 summarizes the existing and emerging tests, current at the time of writing (May 2020). A continuously updated version of this table is available at https://csb.mgh.harvard.edu/covid

Eric Topol says:

There are now *88* @US_FDA  cleared (by EUA) #COVID19 tests so far. Their false negative rates range from 10-48% (by post-release reports).
Might be better to have less tests, more accuracy, with faster turnaround

I agree.

Table 1 Performance comparison of different test types.
Throughput is determined by process type and assay time. In general, automated plate-based assays have higher daily throughputs. Hashtag (#) indicates example systems that have received FDA emergency use authorization (FDA-EUA). See https://csb.mgh.harvard.edu/covid to access continuously updated information. PCR, polymerase chain reaction; PCR-POC, PCR–point-of-care; ddPCR, digital droplet PCR; NEAR, nicking endonuclease amplification reaction; RCA, rolling circle amplification; SHERLOCK, specific high-sensitivity enzymatic reporter; DETECTR, DNA endonuclease-targeted CRISPR transreporter; NGS, next-generation sequencing; μNMR, micro–nuclear magnetic resonance; LFA, lateral flow assay; ELISA, enzyme-linked immunosorbent assay; CLIA, chemiluminescence immunoassay; EIA, enzyme immunoassay; ECLIA, electrochemiluminescence immunoassay; ECS, electrochemical sensing; VAT, viral antigen assay; IFM, immunofluorescence microscopy; WB, Western blot.

Type	Target	Virus	Assay time	Process type	FDA-EUA	Examples
PCR	Viral RNA	SARS-CoV-2	2–8 hours; >12 hours	Plate	56	#Roche, #LabCorp, #BioMerieux, #Qiagen, #Perkin-Elmer, #Becton Dickinson, #Luminex, #Thermo Fisher, others
PCR-POC	Viral RNA	SARS-CoV-2	<1 hour="" td="">	Cartridge	2	#Cepheid, #Mesa, Credo
ddPCR	Viral RNA	SARS-CoV-2	2–4 hours	Manual	1	#BioRAD
NEAR	Viral RNA	SARS-CoV-2	15 min	Cartridge	1	#Abbott
OMEGA	Viral RNA	SARS-CoV-2	1 hour	Plate	1	#Atila BioSystems
RCA	Viral RNA	SARS-CoV	2 hours		0
SHERLOCK	Viral RNA	SARS-CoV-2	1.5 hours	Kit	1	#Sherlock Biosciences (CAS13a)
DETECTR	Viral RNA	SARS-CoV-2	1 hour	Kit	0	Mammoth Biosciences (CAS12a)
NGS	Viral RNA	SARS-CoV-2	Days		1	#IDbyDNA, Vision, Illumina
μNMR	Viral RNA	SARS-CoV-2	2 hours	Cartridge	0	T2 Biosystems
LFA	IgG, IgM	SARS-CoV-2	15 min	Cartridge	3	#Cellex, #Sugentech, #ChemBio, Innovita
ELISA	IgG, IgM	SARS-CoV-2	2–4 hours	Plate	4	#Mount Sinai, #Ortho-Clinical (2), #EUROIMMUN US Inc., BioRAD, Snibe, Zhejiang orient, Creative Dx
CLIA	IgG, IgM	SARS-CoV-2	30 min	Cartridge	2	#Abbott, #DiaSorin
EIA	IgG, IgM	SARS-CoV-2	2 hours	Plate	1	#BioRAD
MIA	IgG, IgM	SARS-CoV-2		Plate	1	#Wadsworth Center
ECLIA	IgG, IgM	SARS-CoV-2	20 min	Plate	1	#Roche
ECS	IgG, cytokine	SARS-CoV-2	1 hour	Cartridge	0	Accure Health
VAT	Viral antigen	SARS-CoV-2	20 min	Cartridge	1	#Quidel, Sona NT, RayBiotech, SD Biosensors, Bioeasy
Microarrays	Ig epitopes	SARS-CoV-2	1.5 hours	Plate	0	RayBiotech, PEPperPRINT
IFM	Viral protein	SARS-CoV	3 hours	Manual	0
WB	IgG, IgM; viral protein	SARS-CoV	4 hours	Manual	0

How advances in biological science are transforming economies and societies

The Bio Revolution: Innovations transforming economies, societies, and our lives

McKinsey Global Institute is well known by their excellent papers and analysis. Forget consultancy for a while, if you are interested in the disruptive knowledge, go to MGI. Recently they have released an excellent report on the Bio Revolution. This is a timely contribution for an issue that those that read this blog already know: we are within a huge change on how life has been considered. CRISPR technology, among others, are changing quickly the landscape.

The potential scope and scale of the (direct and indirect) impact of biological innovations appear very substantial. As much as 60 percent of the physical inputs to the global economy could be produced biologically. Around one-third of these inputs are biological materials (such as wood). The remaining two-thirds are not biological materials, but could, in principle, be produced using innovative biological processes (for instance, bioplastics).

A pipeline of about 400 use cases, almost all scientifically feasible today, is already visible. These applications alone could have direct economic impact of up to $4 trillion a year over the next ten to 20 years. More than half of this direct impact could be outside human health in domains such as agriculture and food, consumer products and services, and materials and energy production. Taking into account potential knock-on effects, new applications yet to emerge, and additional scientific breakthroughs, the full potential could be far larger.

A must read.

Stop Covid with CRISPR Diagnostics (2)

CRISPR–Cas12-based detection of SARS-CoV-2

Mammoth Biosciences (a firm founded by Jennifer Doudna) has partenered with GSK to commercialise a CRISPR Covid test. Therefore, there are right now two firms in the race: Sherlock and Mammoth.
The paper in Nature explains the details:

Here we report the development and initial validation of a CRISPR–Cas12-based assay9 for detection of SARS-CoV-2 from extracted patient sample RNA, called SARS-CoV-2 DNA Endonuclease-Targeted CRISPR Trans Reporter (DETECTR). This assay performs simultaneous reverse transcription and isothermal amplification using loop-mediated amplification (RT–LAMP)14 for RNA extracted from nasopharyngeal or oropharyngeal swabs in universal transport medium (UTM), followed by Cas12 detection of predefined coronavirus sequences, after which cleavage of a reporter molecule confirms detection of the virus. We first designed primers targeting the E (envelope) and N (nucleoprotein) genes of SARS-CoV-2 (Fig. 1a). The primers amplify regions that overlap the World Health Organization (WHO) assay (E gene region) and US CDC assay (N2 region in the N gene)6,15, but are modified to meet design requirements for LAMP. We did not target the N1 and N3 regions used by the US CDC assay, as these regions lacked suitable protospacer adjacent motif sites for the Cas12 guide RNAs (gRNAs). Next, we designed Cas12 gRNAs to detect three SARS-like coronaviruses (SARS-CoV-2 (accession NC_045512), bat SARS-like coronavirus (bat-SL-CoVZC45, accession MG772933) and SARS-CoV (accession NC_004718)) in the E gene and specifically detect only SARS-CoV-2 in the N gene (Supplementary Fig. 1). This design is similar to those used by the WHO and US CDC assays, which use multiple amplicons with probes that are either specific to SARS-CoV-2 or are capable of identifying related SARS-like coronaviruses.

Edward Hopper 

CRISPR, a big leap for mankind

Human Nature



You may find it now on Netflix

CRISPR Technology explained by Dr. Martínez Mojica

El impacto de la tecnología CRISPR en biomedicina.

Sesión científica celebrada en la sede de la Reial Acadèmia de Medicina de les Illes Balears el 9 de julio de 2019 a cargo del profesor Francisco Juan Martínez Mojica, microbiólogo, investigador y profesor español titular del Departamento de Fisiología, Genética y Microbiología de la Universidad de Alicante.

Stop covid with CRISPR Diagnostics

With Crispr, a Possible Quick Test for the Coronavirus

Sherlock's quick, CRISPR-based coronavirus test gets emergency nod

STOP COVID

Point-of-care testing for COVID-19 using SHERLOCK diagnostics

Great!

The FDA granted its first emergency authorization for a CRISPR-based test for COVID-19, developed by Sherlock Biosciences, designed to turn results around in about an hour compared to the four to six hours needed for other molecular diagnostics.
The test is based on the company’s namesake technology, SHERLOCK, short for Specific High-sensitivity Enzymatic Reporter unLOCKing, a Cas13a-based CRISPR system that targets RNA rather than DNA. It looks for an RNA sequence specific to SARS-CoV-2, the virus that causes COVID-19, in patient samples taken from the upper airways with a swab or from airways in the lungs known as bronchoalveolar washing.
“If it’s there, it attaches to the Cas13 enzyme and activates it, which leads to the chewing up and cleaving of RNA probes,” Sherlock CEO Rahul Dhanda told FierceMedTech. When cleaved, those RNA molecules release a fluorescent signal to show the virus is present.

CRISPR Diagnostics (for COVID-19)

CRISPR–Cas12-based detection of SARS-CoV-2

Applied technologies for detection of COVID are basically PCR molecular assays and immunoassays. However, CRISPR developments are entering into diagnostics and you may find the first example in Nature.

We report development of a rapid (<40 accurate="" and="" as12-based="" assay="" br="" crispr="" detection="" easy-to-implement="" extracts.="" flow="" for="" from="" lateral="" min="" of="" respiratory="" rna="" sars-cov-2="" swab="">We validated our method using contrived reference samples and clinical samples from patients in the United States, including 36 patients with COVID-19 infection and 42 patients with other viral respiratory infections. Our CRISPR-based DETECTR assay provides a visual and faster alternative to the US Centers for Disease Control and Prevention SARS-CoV-2 real-time RT–PCR assay, with 95% positive predictive agreement and 100% negative predictive agreement.

The role of CRISPR in diagnostics tests is going to increase.

Daido Moriyama 

Repairing DNA: a review

The promise and challenge of therapeutic genome editing

Jenifer Doudna publishes a must read review article on genome editing in Nature this week. 

Current clinical trials using the CRISPR platform aim to improve chimeric antigen receptor (CAR) T cell effectiveness, treat sickle cell disease and other inherited blood disorders, and stop or reverse eye disease. In addition, clinical trials to use genome editing for degenerative diseases including for patients with muscular dystrophy are on the horizon.

 Notably, all of the genome-editing therapeutics under development aim to treat patients through somatic cell modification. These treatments are designed to affect only the individual who receives the treatment, reflecting the traditional approach to disease mitigation. However, genome editing offers the potential to correct disease causing mutations in the germline, which would introduce genetic changes that would be passed on to future generations.

 At the time of writing, international commissions convened by the World Health Organization (WHO) and by the US National Academy of Sciences and National Academy of Medicine, together with the Royal Society, are drafting detailed requirements for any potential future clinical use.

Meanwhile, CRISPR is closer than you think.

Fig. 1: Ex vivo and in vivo genome editing to treat human disease.

Fig. 2: The genome editing toolbox.

Fig. 3: Emerging tools.

Fig. 4: Editing the human germline.

Germline genome editing under scrutiny

Societal and Ethical Impacts of Germline Genome Editing: How Can We Secure Human Rights?

Geneva Statement on Heritable Human Genome Editing: The Need for Course Correction

A CRISPR Moratorium Isn't Enough: We Need a Boycott

The Human Right to Science and the Regulation of Human Germline Engineering

The last frontier in genome editing (if it exists) is germline. The special issue of The Crispr journal on bioethics contains an article of special interest and proposes a third process for evaluating individual and societal harms: a Human Rights Impact Assessment.

Human germline alteration is possible, due in part to democratization of genetic tools required for genome editing, and international scientific and legislative bodies are developing frameworks to manage the ramifications of this technology. Common among these frameworks are two pillars: public engagement and foundational principles. These components are necessary for respecting the autonomy of individuals and for fair processes and respecting diverse values.

However, they are not sufficient for protecting the most vulnerable members of society who may not even be in a position to participate in democratic processes. We propose implementing a HRIA, which captures concerns of public health and offers an opportunity to evaluate and anticipate the societal impact of GGE iteratively as the technology advances, public sentiments evolve, and cultural contexts shift. We recognize that this will raise new challenges of how such assessments are shared and implemented and how they can be enforced. We urge regulatory bodies and policy makers to consider this assessment approach in helping to establish robust regulatory frameworks necessary for the global protection of human rights.

And the Geneva Statement on Heritable Human Genome Editing says:

No decision about whether to pursue heritable human genome modification can be legitimate without broadly inclusive and substantively meaningful public engagement and empowerment. Such deliberations may be challenging and messy. They will take time and organizing them will necessitate creativity, hard work, and significant human and financial resources. The course correction proposed here is essential to these efforts.
We must in the meantime respect the predominant policy position against pursuing heritable human genome modification, if we are to prevent individual scientists or small committees from making this momentous decision for us all. This will preserve time to cultivate an informed and engaged public that can consider and discuss the societal consequences of altering the genes of future generations and make wise, democratic decisions about the shared future we aspire to build. 

I agree.

PS. CRISPR in 2020  Two major reports on germline editing, from the National Academies/Royal Society and the World Health Organization, will be released in 2020. We hope the reports will coordinate, with all the voices of CRISPR being heard, so we can build consensual and broadly acceptable frameworks to ensure we use CRISPR responsibly, especially regarding usage in human embryos for germline editing. The public has asked for it, and the community has been working on it. The science versus society gap will be bridged.

Fighting against techno-eugenics

A Chinese scientist who shocked the medical community last year when he said he had illegally created the world's first gene-edited babies has been sentenced to three years in prison by a court in southern China.
He Jiankui announced in November 2018 that he had used a powerful technique called CRISPR on a human embryo to edit the genes of twin girls. He said he modified a gene with the intention of protecting the girls against HIV, the virus that causes AIDS. Many scientists expressed concerns about possible unintended side effects of the genetic changes that could be passed down to future generations.
Last fall, He also indicated there might be another pregnancy involving a gene-edited embryo. The court indicated that three genetically edited babies have been born.
The closed court in Shenzhen found He and two colleagues guilty of illegal medical practice by knowingly violating the country's regulations and ethical principles with their experiments, Xinhua news agency reported. It also ordered He to pay a fine of about $430,000.

Such unethical medical behavior is the worst news of 2019. And this article explained last June the reasons:

The link between CCR5 and HIV is fairly well studied. Disabling CCR5 removes the doorway HIV uses to enter and infect cells, but it does so only for some strains of HIV; there are others that don’t need CCR5. Further, the genetic sequence He’s edits produced does not match this well-studied variant of CCR5; in fact, it has never been observed in humans or animals. In other words, no one has any idea whether the variant with which Lulu and Nana are now living will affect HIV immunity or anything else.
That’s a key issue: Genes don’t do just one thing. Most illnesses and traits are influenced by dozens, hundreds, even thousands of DNA variations. Each of our roughly 20,000 genes is linked to many different aspects of our physiology and health. So what else does CCR5 do? A variant that provides protection against HIV also seems to increase susceptibility to a number of more common diseases, like flu and West Nile virus.
CCR5 has also been linked to brain function, which led to some sensational headlines and media speculation that the gene-edited babies might have enhanced brains. There are likely myriad other processes to which CCR5 contributes that we don’t know about yet. To that point: before the recent study, no one had researched whether the CCR5 mutation resulted in better or worse health over a person’s lifetime.
The CCR5 story illustrates a flaw in the logic that underlies gene editing. Efforts to change one gene to affect one illness in a future person ignore the fact that health is the result of infinitely complex interactions within and outside a person’s body. In most cases, the presence or absence of a particular genetic variant is not the sole determinant of a disease or condition.

And this article reminds us that, despite the appearance of agreement, ethical questions that have surrounded human germline editing for years have yet to be properly addressed.

Unnatural Selection: Season 1 | Main Trailer | Netflix

Gen-ethics (2)

Special Issue: The Ethics Of Human Genome Editing

The CRISPR journal has released a special issue on ethics. You'll find an article with the title "Heritable Genome Editing and the Downsides of a Global Moratorium". This is exactly the opposite argument that Françoise Baylis provides in her book. I think that it is unacceptable a recommendation that nations should "regulate HGE for safety and efficacy only and without distinguishing between therapeutic and enhancing modifications". We can't leave such decisions to scientists and practitioners. I'm really concerned about it.

Gauguin Portraits

Gen-ethics

Altered Inheritance
CRISPR and the Ethics of Human Genome Editing

Our future belongs to all of us. Or maybe not? Maybe somebody could decide for us without noticing it?. The "decisions about the use of genetic technologies in humans are too important to be left to scientists", society has to achieve a broad consensus. Françoise Baylis in her new book sheds light on this issue. She explained his position in an article last spring and now she has published a remarkable book on ethics and genome editing. Her calls for an open and comprehensive international process to reach political, scientific, and social/ethical consensus on regulation of human genome editing have been  unattended up to now. Her ultimate goal:

I want to live in a world that promotes equity and justice and celebrates difference, a world where everyone matters. I want to live in a world where we embrace neighborliness, reciprocity, social solidarity, and community in pursuit of human flourishing and the common good. I want to live in a world where we value collegial as opposed to competitive relations. I don’t want to live in a world where a select, privileged few are able to inscribe their privilege in their DNA and thereby exacerbate unfair class divisions and other social injustices. For these reasons, I want for all of us to reflect on whether heritable human genome editing is a boon or a threat.

I agree. An essential reading highly recommended.