The Theranos contretemps as a serious scandal

Last Thursday WSJ released a long article on Theranos clinical lab. In this blog you may check my February and July posts on this firm under the title: A closely guarded secret. As you may imagine, such a title was not coincidental. There were some clues that justified it, something unusual was happening. And WSJ has contributed to shed light on the issue. All the details in it. Basically, the summary is that analytic validity and clinical validity is under compromise. This is an exemple:



If you want to read a first person account, you'll find it here and here. Some additional articles: Wired, New Yorker, Clinical Chemistry and Laboratory Medicine (CCLM), Forbes, NYT, WP,...
This is not only a contretemps, it is a serious scandal and a huge problem to credibility for this start-up.
From Wired:

Theranos got a lot of traction by tapping into the frustration—both from consumers and the medical community—that diagnostic testing is too painful, too slow, and too expensive. “Their problem is they tried to do it with existing diagnostic instrumentation, instead of innovating new diagnostic instrumentation,”

Theranos is a black box that has touted results rather than process. “The ability of the lab medicine community to police and correct itself depends on that flow of information,” says Master. Instead, Theranos’ research was internal, and rather than submit their work to peer review the company cited their FDA approvals as evidence that the technology worked.

At least in the USA there is a regulator, the FDA, lab regulation in Europe was enacted in 1998, completely outdated under a third party scheme, not a direct public regulator. Therefore, there is a pressing motive to speed up new and different rules in Europe. Microfluidics and nanotechnologies are calling for and urgent overhaul.


 PS. An statement from WSJ:

In 2005, Ms. Holmes hired Ian Gibbons, a British biochemist who had researched systems to handle and process tiny quantities of fluids. His collaboration with other Theranos scientists produced 23 patents, according to records filed with the U.S. Patent and Trademark Office. Ms. Holmes is listed as a co-inventor on 19 of the patents.

The patents show how Ms. Holmes’s original idea morphed into the company’s business model. But progress was slow. Dr. Gibbons “told me nothing was working,” says his widow, Rochelle. In May 2013, Dr. Gibbons committed suicide. Theranos’s Ms. King says the scientist “was frequently absent from work in the last years of his life, due to health and other problems.” Theranos disputes the claim that its technology was failing.

The media and the Theranos incredible deception

On Theranos failure, highly recommended for journalists.
From CBSNEWS, a basic piece to understand the power of the media in creating and destroying (false) value:

Was the media duped by Elizabeth Holmes?
A conversation with 60 Minutes about media coverage of the rise and fall of Elizabeth Holmes and her hot startup, Theranos

Theranos on trial

 Podcast: 'The Dropout: Elizabeth Holmes on Trial'

ABC News' #1 podcast is back with new episodes, available on Tuesdays.

Money. Romance. Tragedy. Deception. The story of Elizabeth Holmes and Theranos is an unbelievable tale of ambition and fame gone terribly wrong.

You'll find it in Spotify every week

 

Economia de la llibertat d'expressió

En Foss pensa que la llibertat d'expressió no hauria de ser regulada, ho va dir al blog fa dies (amb alguns límits afegeix, i aquí s'atura). Ara hi torna tot referint-se a un article sobre Mill i Holmes. El resum:

Mill believes that individuals are free in the sense that they have the ability to choose their beliefs, even if they frequently opt for the easier alternative of uncritically following the mainstream. At the same time, he believes that a society can create conditions that are conducive to individual flourishing. Mill's free speech defense is based not only on the argument that individuals are more likely to pick true beliefs if presented with several alternatives, but also on the notion that a society that prizes dissent promotes the development of character traits in its citizens that will in turn allow that society to prosper. Holmes, on the other hand, views individuals as constrained by firmly rooted preferences shaped by accidental circumstances, but regards society as constantly evolving and adjusting and, to a large extent, free to determine its future course. His defense is staked on a constitutional commitment to safeguarding the conditions for collective self-determination in an uncertain and perpetually changing world.

Les circumstàncies accidentals cal tenir-les en compte, la llibrtat d'expressió acaba essent contingent del moment. Tema complicat que no impedeix que es reguli el dret d'expressió per tal de garantir el bé comú que aquests dies cal preservar per sobre de tot.

PS. Ara ja s'han destapat definitivament. El lema "La calle es nuestra" el trobo proper a "La calle es mía". Aquesta és la relació que hi trobo i que mostra coincidències, no us confongueu. Definitivament, pensar que uns pocs poden apropiar-se de tot o que tant sols un ho pot fer, ho trobo indignant. A la radio cal vigilar les expressions d'apologia de la violència i inducció al delicte, ho dic per l'entrevista d'aquest matí (a la mateixa radio que Arcadi Oliveres parlava fa uns dies). Observo suposats demòcrates amb comportament antidemòcrata quan la democràcia no afavoreix els seus interessos. Els fiscals poden haver-ho sentit tal com ho he sentit jo i està tipificat al codi penal. La ignoràcia de les lleis no és excusa pel seu incompliment.

PS El gran Barbeta ho explica bé:

Los presuntos indignados han recibido el apoyo de intelectuales que ya no saben a quién servir, de cantautores septuagenarios dispuestos a galopar de nuevo con las teenagers del siglo XXI, de nacionalistas españoles que como antes la Falange no son de derechas ni de izquierdas... y hasta del más ilustre de los procuradores franquistas felizmente reconvertido al pacifismo.

I l'Enric Juliana alerta de que les coses poden anar a pitjor, molt pitjor, i cal prevenir mals majors.
Bona referència de Màrius Carol a Saint-Exupéry.. Potser els acampats no la llegiran, malauradament.
A la p.80 de LV us trobareu amb un indocumentat, us ho podeu estalviar.Es va colar l'article que va proposar el becari del cap de setmana.

Els venedors de fum i la regulació de pa-sucat-amb-oli

 En Joan Font de Comediants va decidir celebrar els 50 anys del grup fent una obra amb el títol "El venedor de fum", una història personal reflectint tot el que ha estat la trajectòria. És evident que en Joan Font és un venedor d'històries magnífiques que ens han omplert moltes hores de joia i distracció. Unes històries on l'audiència gaudia d'allò més bé. I si hagués de triar una obra de les moltes que van fer, jo diria "El llibre de les bèsties", l'obra magna de Ramon Llull posada en escena muda. Impressionant. Voldria tornar a veure-la.

Doncs bé, de venedors de fum amb altres consequències més preocupants en tenim molts. Ahir entrava a la presó per 11 anys Elizabeth Holmes pel cas Theranos, un gran frau diagnòstic basat a Silicon Valley. N'hem parlat molt aquí. Però hi ha altres venedors de fum que sota una aureola de certesa,  seguretat i eficàcia, ofereixen una profunda incertesa que sovint no acaba qualificada pels tribunals com a frau. Això succeeix quan el regulador no ha fet bé la seva feina (i els tribunals tampoc) i ja ho vaig explicar pel cas dels diagnòstics in vitro fa 6 anys. Doncs bé ara que ja és efectiva la regulació ja podem veure el desgavell que es produeix. En temps de pandèmia es va fer evident. Resulta que de les noves proves per detecció de Sars-COV-2 no en sabíem a Europa la sensibilitat i especificitat, arribaven amb una marca CE que fan uns organismes i que no serveix per saber la magnitud dels falsos positius i negatius. La solució era esperar que la FDA digués quina era la sensibilitat i especificitat d'una prova per tal de comprar-la. Tot això, en general, la gent del carrer ho desconeixia i ho desconeix, només intuïa que hi havia resultats que no eren certs i que si els feien dues vegades no sortia el mateix.

Ara que ja ha passat la pandèmia, tenim el mateix problema però agreujat. Les empreses han après que la regulació de pa sucat amb oli europea és una oportunitat a explotar. I dic això perquè veig una febre de comercialització de noves proves diagnòstiques sense cap avaluació independent i que quan hi ha una dada de sensibilitat i especificitat resulta que només és publicada principalment pels empleats o accionistes de l'empresa que les fabrica. I ara volen que els mateixos que han subvencionat la recerca siguin els seus clients. I ja hem tancat el cercle. I si voleu hi podem afegir la caixa negra de les patents i ja ho tenim tot. Just avui que hi ha tres països que passen de llarg de la nova regulació europea de patents, sabeu quins són? Democràcies plenes i modernes: Polònia, Croàcia i Espanya. I si voleu podem afegir que han patentat privadament les proves diagnòstiques quan han disposat de finançament públic. I aquí m'aturo. L'últim que tanqui el llum i la porta.

'Pseudomnesia

Fake lab tests

Bad blood

We all know that we live in a post-truth society. But this may have strong effect in your health. The case of Theranos, a US lab is explained in an excellent book by John Carreryrou is a precise example. You create an expectation that with a blood drop all tests can be done, you develop the narrative, the social and entrepreneurial support, and...while the regulator is on vacation (as usual) you perform fake test that can endanger your health. Imagine that your coefficient of variation is 34-48%, while it should be less than 10%!. The results may hurt you directly.
The book provides a lot of details:

As for the lab itself, it was a mess: the company had allowed unqualified personnel to handle patient samples, it had stored blood at the wrong temperatures, it had let reagents expire, and it had failed to inform patients of flawed test results, among many other lapses

And strong messages for start-up investors:

By positioning Theranos as a tech company in the heart of the Valley, Holmes channeled this fake-it-until-you-make-it culture, and she went to extreme lengths to hide the fakery. Many companies in Silicon Valley make their employees sign nondisclosure agreements, but at Theranos the obsession with secrecy reached a whole different level.

FT recommends this book for this summer, and I agree that it will help you to understand and avoid similar fake business that we can detect around us. It should never happen again.

The Theranos scam whistleblower

 Thicker Than Water

From the hero whistleblower of the infamous Theranos scam, Thicker than Water is a look at never-before-revealed details behind closed doors at the company, revealing a cautionary tale of corporate bullying, gaslighting, ego, and wealth run amok in Silicon Valley.

Tyler Shultz had been in the workforce for less than a year when he emailed Elizabeth Holmes, his employer and the CEO and founder of Theranos, with concerns that the company’s lab practices were faulty, ignored quality control, and were potentially dangerous to patients. The COO fired back with a dismissive and insulting email, to which Tyler replied: "Consider this my two weeks’ notice."

From there, his life spun out of control at the hand of Elizabeth, her team of high-powered lawyers, and the patriarch of Tyler’s own family, George Shultz—one of America’s most prominent statesmen, who sat among the top of the Theranos Board of Directors. And yet, Tyler forged on. To protect his own conscience, the honor and reputation of his grandfather, and the health of patients worldwide.

Thicker than Water is Tyler’s as-told-to story—a harrowing and heartbreaking roller coaster of biomedical drama, family intrigue, and redemption—that will ultimately make you feel as though you are at a dinner party, seated next to a brilliant friend with one hell of a story. 

Les hores baixes de la indústria farmacèutica catalana

La nova queixalada a la teranyina: el cas Esteve

 Què cal fer quan les dades no ajuden a un bon titular? Doncs maquillar-les. Fa uns mesos va sortir en portada per exemple com Catalunya acumula el major nombre de plantes de producció farmacèutica, 79 de 173. El que no deien és la producció, i per tant que les fàbriques més grans i de les empreses capdavanteres no es troben aquí. 

Ara a Via Empresa podeu trobar un detall de què ha passat amb la indústria farmacèutica catalana, una davallada constant i paulatina. Una informació que no trobareu als mitjans de comunicació convencional, perquè no interessa. El missatge és clar, la pèrdua continuada de posicions en termes de propietat i de mercat. El motiu? Molts, però està clar que algú va decidir i està decidint fer caixa abans de fer els deures.

Marcelo Brodsky

PS. Elizabeth Holmes, Theranos, va entrar ahir a la presó per complir sentència de frau durant 11 anys.

The smart money in tech would not have made this mistake

It's about Theranos. You may find my previous posts in this link. Now SEC has confirmed that was a "massive fraud". That's it. If you want a good analysis check FT.
Microfluidics is not an easy prêt-à-porter technology. Many people knew it but Mrs Holmes has been selling it as snake-oil. And as usual in these cases, the end of the film is already written. She can't go to the lab for the next 10 years, a fine, and the company may be closed. All started with and article by Mathew Herper in WSJ. An innocent article with an innocent question that she couldn't answer. That's all. Silicon valley smart money would not have made this mistake.

Modigliani exhibition in Tate Gallery now

Canviant la funció de producció de les proves diagnòstiques

 Real-Time, Multiplexed SHERLOCK for in Vitro Diagnostics

Durant la pandèmia es va produir una innovació notable a la tecnologia de proves diagnòstiques. Va passar desapercebuda per alguns, però no pels que llegiu aquest blog. Es tracta d'utilitzar CRISPR que inicialment s'ha desenvolupat per a edició genètica, per a la detecció d'àcids nucleïcs en un sol pas, i per tant també de Sars-COV-2. La dificultat d'aplicació que tenia aquella prova, que va rebre el vist-i-plau de la FDA era que el procés no es podia automatitzar, i per tant calia amplificació prèvia. Ara acaba de publicar-se la prova definitiva que pot capgirar moltes coses, i que per tant pot canviar la funció de producció dels laboratoris. La troballa d'enzims termoestables ha estat la qüestió clau per a l'èxit de l'equip de Feng Zhang.

Cal dir que la companyia rival, Mammoth Biosciences, de Jennifer Doudna,  també té en marxa una prova similar: DETECTR BOOST.

I ara ja ha començat el procés de patentar enzims. Tant per una empresa com per l'altre. I això esdevé inadmisible si el que es pretén patentar la natura o variacions sobre la natura. Però ningú se n'està adonant , als USA ja s'ha fet tard, però a Europa encara hi som a temps.

N'estic segur que les patents, una vegada més, limitaran l'accés a aquesta gran innovació.

Cartier-Bresson

PS. Per si voleu saber com funciona DETECTR BOOST

PS. Per tal de comprendre l'abast del que signifiquen les proves diagnòstiques basades en CRISPR el millor és consultar un article de revisió com aquest. I la taula següent conté les dades bàsiques:

Characteristics of reported CRISPR-based diagnostics

From: CRISPR-based diagnostics

Name	Enzyme	Preamplification	Assay timea (min)	Sample preparation	Readout	Applications	LODc (mol l−1)	LODc (copies per ml)3	References
CRISPR type II
NASBACCb	Cas9	NASBA	120–360 (one pot)	Column-based or crude extraction	Colometry	Discrimination between African and American ZIKV	1.0 × 10–15	6.0 × 105	25
CRISPR–Chip	Cas9	–	15	Column-based	Electrochemical	Detection of gDNA from cell lines and DMD patients	2.3 × 10–15	1.4 × 106	45
CRISDA	Cas9 nickase	SDA	90	Column-based	Fluorescence	Detection of gDNA; breast-cancer-associated SNPs in cell lines	2.5 × 10–19	1.5 × 102	27
FLASH	Cas9	PCR	NS	Column-based	NGS	Detection of gDNA; antimicrobial resistance genes in clinical samples	1.9 × 10–18	1.1 × 103	71
CAS-EXPAR	Cas9	EXPAR	60	Chemical (phase separation)	Fluorescence	Sensing of methylated DNA; L. monocytogenes mRNA	8.2 × 10–19	4.9 × 102	91
Cas9nAR	Cas9 nickase	Strand-displacing DNA polymerase	60	Column-based	Fluorescence	Detection of bacteria (S. typhimurium, E. coli, M. smegmatis, S. erythraea); detection of KRAS SNPs in cell lines	1.7 × 10–19	1.0 × 102	111
CRISPR type V
DETECTR	Cas12a	RPA	10 (RPA) and 60–120 (CRISPR)	Crude extraction	Fluorescence	Detection of HPV16 and HPV18 in human samples	1.0 × 10–18	6.0 × 102	36
Cas14-DETECTR	Cas14 (Cas12f)	PCR	NS (PCR) and 120 (CRISPR)	Crude extraction	Fluorescence	Detection of HERC2 SNPs in human samples	n.s.	6.0 × 103	41
HOLMES	Cas12a	PCR	88 (PCR) and 15 (CRISPR)	Column-based	Fluorescence	SNP discrimination in cell lines and human samples; detection of viruses (PRV, JEV); virus-strain discrimination	1.0 × 10–17	6.6 × 103	37,38
CRISPR-materials	Cas12a	RPA	40 (RPA) and 240 (CRISPR)	Synthetic targets	Fluorescence or μPAD (visual and electronic)	Detection of EBOV synthetic RNA	1.0 × 10–17	6.6 × 103	79,80
CDetection	Cas12b	RPA	10 (RPA) and 60–180 (CRISPR)	Synthetic targets or crude extraction	Fluorescence	Detection of HPV16; human ABO blood genotyping; BRCA1 and TP53 SNPs	1.0 × 10–18	6.0 × 102	112
HOLMESv2	Cas12b	LAMP	40 (LAMP) and 35 (CRISPR) or 120 (one pot)	NS	Fluorescence	SNP discrimination in cell lines; RNA virus detection (JEV); human mRNA and circular RNA detection; DNA methylation	1.0 × 10–17	6.0 × 103	39
E-CRISPR	Cas12a	–	30–180	Synthetic targets (nucleic acids)	Electrochemical	Detection of viruses (HPV16, PB19) and protein (TGF-ß1)	5.0 × 10–11	3.0 × 1010	77
CRISPR type VI
–	Cas13	–	NS	NS	Fluorescence	Detection of human mRNA; detection of bacteriophage λ-RNA	1.0 × 10–12	6.0 × 108	30,31
SHERLOCK	Cas13	NASBA or RPA	132 (NASBA) or 120 (RPA) and 60–180 (CRISPR)	Column-based or crude extraction	Fluorescence	Detection of viruses (ZIKV, DENV) and bacteria (E. coli, K. pneumoniae, P. aeruginosa, M. tuberculosis, S. aureus); discrimination between virus strains; detection of SNPs	2.0 × 10–18	1.2 × 103	32
SHERLOCKv2b	Cas13	RPA	60 (RPA) and 60–180 (CRISPR) or 60–180 (one pot)	Column-based or crude extraction	Fluorescence or lateral flow	Detection of viruses (ZIKV, DENV) and bacteria (P. aeruginosa, S. aureus); discrimination between virus strains; detection of SNPs	8.0 × 10–21	4.8	22,34
SHINEb	Cas13	RPA	50 (one pot)	Crude extraction	Fluorescence or lateral flow	Detection of SARS-CoV-2	8.3 × 10–18	5.0 × 103	62
STOPCovidb	Cas12b	LAMP	60 (one pot)	Crude extraction	Fluorescence or lateral flow	Detection of SARS-CoV-2	3.3 × 10–18	2.0 × 103	63
CARMEN	Cas13	PCR or RPA	20 (RPA) and 180 (CRISPR)	Column-based	Fluorescence	Detection of 169 viruses; subtyping of influenza A strains; detection of HIV drug-resistant mutations	9 × 10–19	5.4 × 102	67
APC-Cas	Cas13	Allosteric-probe-initiated amplification with DNA polymerase	110 (APC) and 30 (CRISPR)	None	Fluorescence	Detection of S. enteritidis	One colony-forming unit	–	92
	Cas13	–	<240	Column-based	Electrochemical	Detection of microRNAs (miR-19b and miR-20a)	1 × 10–11	6.0 × 109	46
PECL-CRISPR	Cas13	EXPAR	30 (CRISPR), 30 (phosphorylation of pre-trigger), 30 (EXPAR)	Column-based	Electrochemiluminescence	Detection of microRNAs (miR-17, let‐7 family miRNAs)	1.0 × 10–15	6.0 × 105	78

1. NS, not specified; APC-Cas, allosteric probe-initiated catalysis and CRISPR-Cas13a system; BRCA1, breast cancer 1 gene; circRNA, circular RNA; Cas9nAR, Cas9 nickase-based amplification reaction; CRISDA, CRISPR–Cas9-triggered nicking endonuclease-mediated strand-displacement amplification; DENV, dengue virus; DMD, Duchenne muscular dystrophy; EBOV, Ebola virus; E. coli, Escherichia coli; HERC2, HECT and RLD domain containing E3 ubiquitin protein ligase 2 gene; HPV, human papillomavirus; JEV, Japanese encephalitis virus; K. pneumoniae, Klebsiella pneumoniae; KRAS, KRAS proto-oncogene GTPase; M. smegmatis, Mycobacterium smegmatis; M. tuberculosis, Mycobacterium tuberculosis; PECL, portable electrochemiluminescence chip; P. aeruginosa, Pseudomonas aeruginosa; PB19, parvovirus B19; PRV, pseudorabies virus; S. erythraea, Saccharopolyspora erythraea; S. aureus, Staphylococcus aureus; S. enteritidis, Salmonella enteritidis; S. typhimurium, Salmonella typhimurium; TP53, tumour protein P53 gene.
2. aAssay time indicates the approximate incubation time most frequently used in the referred study (different assay times can be reported, depending on the intended sensitivity and the readout).
3. bPOC compatibility indicates whether the entire assay as reported—including sample preparation (that is, crude extraction) and readout—can be performed at POC or in the field with minimal equipment.
4. cLimits of detection cannot always be directly compared across studies, in particular because some studies did not report how the LOD was determined, or reported the target concentration either in the transport media of the sample or in the final reaction. The LODs shown here reflect the optimal LODs reported. In general, LODs depend on the type of input material (raw or synthetic), type of readout and incubation time.