Medicine trends

The future of medicine

A new supplement in Nature explains the main trends in Medicine. It is really helpful to have a quick look focused on those approaches that are the more promising for the next future. From the issue, I would pick one article: A CRISPR edit for heart disease, A one-off injection to reduce the risk of cardiovascular disease is now a prospect thanks to advances in gene editing.This is amazing, it changes current perspectives on the first cause of death worldwide (18 million people per year).

 In 2014, Musunuru and his team showed that more than half of Pcsk9 genes in the mouse liver could be silenced with a single injection of an adenovirus containing a CRISPR–Cas9 system directed against Pcsk9. This led to a roughly 90% decrease in the level of Pcsk9 in the blood and a 35–40% fall in blood LDL cholesterol⁴. Next, they used a mouse engineered to contain human liver cells, and tuned the CRISPR–Cas9 payload to target human PCSK9⁵. The team succeeded in showing that the human gene can also be switched off.

This is changing the focus of drug research, and a recent article explains the new approach.  Let's see if finally delivers what they say.

How to change individual letters of your DNA?

Gene editing has made another step forward. And maybe a complementary to the former one, the CRISPR-Cas9,  that was proved viable by Jennifer Doudna and I explained some months ago in this post. No it is indeed more interesting. Two different approaches, base editing and CRISPR-Cas13, have been described in Science and Nature. Adenine base editing allows to correct mutations, it doesn't cut the gene to insert a new one. It is a sharp pencil rather than scisors. With CRISP-Cas13 it is possible to edit RNA, which converts genetic information into proteins. An exciting approach, you correct a book with temporary ink that disappears, rather than making a permanent mark (like in CRISPR-Cas9).
These are exciting times for genetic research, though we'll have to wait for specific clinical applications

Modigliani, now at Tate Gallery

Outperforming CRISPR?

 High-throughput functional variant screens via in vivo production of single-stranded DNA

A new technoique overcomes existing limitations of CRISPR: 

Unlike existing techniques depending on CRISPR-Cas–directed genomic breaks for genome editing, this strategy instead uses single-stranded DNA produced by a retron element for recombineering. This enables libraries of millions of elements to be constructed and offers relaxed design constraints which permit natural DNA or random variation to be used as inputs.

A group of researchers created what they call the "Retron Library Recombineering" (RLR) technique, which could allow scientists to run millions of genetic experiments at the same time. This tool, described in a recent paper in PNAS, employs retrons, which are bacterial DNA segments that undergo reverse transcription to generate single-stranded DNA fragments (ssDNA). RLR produces up to millions of mutations concurrently in bacterial cells and "barcodes" mutant cells, enabling the whole pool to be screened at once. This way large quantities of data can be quickly produced and analyzed.

Changing the production function of diagnostic tests

Next-generation diagnostics with CRISPR

Last week while reading Science I noticed a short and crucial article. Up to now CRISPR technology was focused on gene editing, now we can say that its usefulness is widening into diagnostics. It may change completely molecular diagnostics of "infectious diseases through detection of Zika virus (ZIKV), Dengue virus (DENV), and human papillomavirus (HPV) in human  samples, and noninfectious diseases, such as detection of gene mutations in circulating cell-free DNA from lung cancer patients." The production founction of lab testing would change completely.
Several articles explain details about it. The fight for patents is going to start again on CRISPR diagnostics. And this are unfortunately bad news.
Anyway, Science article reminds us:

These emerging diagnostic tools will by necessity be compared to standard diagnostics to ensure sensitivity and specificity and will need to be field-tested to guarantee performance in patient care settings, as environmental conditions and end-user application might affect performance. Proven assays, if affordable, promise to improve care in resource-limited settings where undifferentiated febrile illness is the norm and where gaps or delays in diagnosis, targeted care, and infection control contribute to infectious disease mortality and spread.

More details in The Verge.

Els nirvis de la indústria farmacèutica europea

 Assessment of main provisions and key EFPIA recommendations on the revision of the pharmaceutical package

La proposta de nova regulació farmacèutica europea ha desfermat la preocupació a una indústria que ja havia d'estar preocupada abans que això passés. I és que només veient els medicaments que s'han aprovat els darrers temps i la inversió en recerca recent, sabem que anem a empentes i rodolons.

En aquest context hi ha nirvis de la indústria sobretot per dues coses: per la protecció de dades regulatòries i per l'exclusivitat de mercat dels medicaments orfes. Diguem-ho clar, perquè la regulació de patents segueixi protegint d'igual forma el monopoli temporal. Aquest és el concepte. Després ve el detall de facilitar l'accés als medicaments per part dels pacients, però això ja són els serrells. 

Ahir UK ja va aprovar el Exa-cel, el medicament de CRISPR Therapeutics i ho va fer amb dues indicacions, anèmia de cèl·lules falciformes i beta-thalassemia. És la primera vegada al món que s'aprova definitivament una teràpia genètica ex-vivo basada en CRISPR. A la FDA un consell assessor va donar la seva aprovació que s'espera sigui definitiva el dia 8 de desembre. 

Curiosament CRISPR Therapeutics té la seu social a Europa ,no-UE , a Suïssa, a Zug. La va fundar Emmanuelle Charpentier fa 10 anys, guanyadora del Nobel amb Jennifer Doudna. Ara bé, només hi té la seu social. Tot, tot s'ha fet junt amb Vertex a Boston. Si mirem la vacuna de Pfizer va ser originada a Alemanya (Biontech), però va comercialitzar-se com nord-americana. Podríem repassar molts més exemples on la recerca europea és potent i la comercialització s'esvaeix. Però això no ho arreglarà la protecció mitjançant patents.

La indústria europea ens explica en un document quina serà la seva estratègia de lobby per als propers mesos i després d'explicar que la redacció actual provocarà el diluvi universal (menys accés als medicaments), diu el que cal fer (RDP vol dir protecció de dades regulatòries i OME vol dir exclusivitat de mercat de medicaments orfes):

• In line with the European Council Conclusions (March 2023), Europe needs to strengthen, rather than cut, the region’s RDP baseline and OME.
• Providing meaningful and predictable incentives, attainable fairly, that would encourage additional R&D investment compared to today.
• Jointly addressing barriers and delays to access based on a shared understanding of the evidence generated by the European Access Hurdles Portal.
• Limiting Bolar exemption for activities related to seeking regulatory approval.
• Developing a patient-centred, more inclusive definition of unmet medical need.
• By acknowledging the value of innovation and encouraging advancements in prevention, treatments and care, Europe can ensure that no patient is left behind.
• A robust framework for mechanism of action Paediatric Investigation Plans (PIPs) is essential to ensure that this new obligation is effective to achieve its purpose and is manageable for developers.
• Further optimising the regulatory framework and ensuring maximum use of expedited pathways in support of patient needs.
• Ensuring that supply chain and environmental requirements are proportionate and fit-for-purpose while not prohibiting or delaying patient access to medicinal products.

No entrarem en detall de cada qüestió ara. Convé repassar el document. Únicament caldria dir que anem molt endarrerits en el temps amb la regulació farmacèutica a Europa i això ens ha fet perdre pistonada. Que hi ha retards en l'accés, ho sabem, però aquest és sobretot un problema dels països i dels seus recursos financers. Convindria que la reflexió no fos tant en la protecció de patents i en canvi en els incentius a la recerca necessària per a millorar la salut poblacional. Per tant una reflexió conjunta, indústria i governs, de quines haurien de ser les prioritats i establir mecanismes per a dur-ho a terme (d'això no n'he vist res a la regulació proposada). Posar incentius sense assenyalar prioritats no ens menarà a una solució dels problemes actuals. Ho sabem també.

Albarrán Cabrera

Beyond CRISPR-Cas9

 Expanding the possibilities of CRISPR genome editing with Cas14 and CasΦ

SpCas9 comes from a bacterium called Streptococcus pyogenes (hence “Sp”). S. pyogenes is a human pathogen. There is some evidence that using SpCas9 for genome editing in humans may lead to dangerous immune reactions (Ferdosi et al 2019) although other reports have questioned the importance of this finding.

In addition SpCas9 is quite large. It is 1368 amino acids (aa) long and can be difficult to fit into standard delivery vehicles (learn about CRISPR delivery here). Thus it can be hard to get SpCas9 into target cells and tissues.

Finally, SpCas9 requires the presence of a specific DNA sequence known as a “PAM” to target an adjacent sequence for genome editing. SpCas9’s PAM is 5’-NGG-3’. The need for this sequence restricts the number of sites SpCas9 can edit. This limits SpCas9’s usefulness.

Are we prepared for CRISPR?

¿Estamos preparados para la edición genética?

The July-August issue of La Maleta de de Port-Bou publishes several articles on ethical and societal implications of CRISPR. It is specially helpful for those that have never read anything about it before. Tomàs Marquès provides an introductory text in accesible language. The conclusion after reading all the articles is that we are not prepared for CRISPR, but we are never prepared to understand all the uncertainties surrounding any innovation. The key question is to analyze concrete implications of outcomes and define what should be done.
My surprise was that you'll not find any reference to the word epigenetics. And most of the articles seem to focus on the genes as our fate. As you know, "We are not our DNA". Therefore, take care while reading it.

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.

CRISPR and the future of medicine

 130th Annual Shattuck Lecture (2020) - CRISPR: Rewriting DNA and the Future of Medicine

Great! A must watch!

Video with Jennifer A. Doudna, Ph.D., and Eric J. Rubin, M.D., Ph.D.

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.

Genome editing: understanding CRISPR-CAS9

Excellent speech by Salvador Macip at Grifols Foundation conference on CRISPR (in catalan):

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.

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

Genome editing: a potential weapon of mass destruction

The Patent Dispute Over Gene Editing Technologies: The Broad Institute, Inc. vs. The Regents of the University of California

Nobody could imagine two decades ago that a small part of wide range of bacteria's immune system could represent so much for genome editing. Known as CRISPR, clustered regularly interspaced short palindromic repeats, such mechanism can recognise and defend against viruses. The other part of the defense mechanism is a set of enzymes called Cas that can cut DNA and avoid the invasion of viruses. Mostly, these research was originated in Les Salines d'Alacant by Francisco Mojica a microbiologist.
As far as this is a natural process Dr. Mojica didn't show interest in patenting it. Now the row over patents is hot between UC Berkeley and the Broad Institute. I will skip details, you may find it in The Economist.
It seems that the fight is only to determine who was the first, and the Court will have to decide on March 9th. However, my question is: why is it still possible to file a patent over human nature?.
Meanwhile the public debate may be moved towards the use of such CRISPR technology for genome editing, and Science was publishing an article about the threat that misuse represents for human beings. Are we facing a new weapon of mass destruction?
Both issues, patents and bioethical implications are crucial at the moment. Former examples provide clear guidance of outcomes that should be avoided. Unfortunately, the race for the biggest size of the pie (billions of $) seems to be a priority over health and humanity.

The long and bumpy road to CRISPR (5)

 CRISPR: Genome Editing and Engineering And Related Issues

The constraints to genomic editing

CRISPR… ¿debemos poner límites a la edición genética?

A new publication by Fundació Grifols highlights the potential constraints to genomic editing. It is a good moment to have a look at it. Savador Macip says:

Los peligros, pues, son muchos, tantos como las cosas buenas que la edición genética nos puede aportar. De alguna forma, recuerda la energía nuclear. Descubrir los secretos del átomo nos ha permitido acceder a una cantidad inimaginable de energía, que usamos diariamente, pero que se debe regular de una forma muy precisa para evitar accidentes terribles y contaminaciones no deseadas. Y, lo que es más peligroso aún, la misma información sirve para fabricar una de las armas más mortíferas que conocemos, capaz incluso de destruir el planeta. A otra escala, CRISPR/Cas9 podría tener efectos parecidos.

La ciencia no se detiene, siempre continúa avanzando, y la sociedad corre el peligro de quedarse atrás. Por ello es importante que los debates sobre hacia dónde queremos ir empiecen cuanto antes mejor y que en ellos participe una muestra amplia de la población, no solo los científicos. Para conseguirlo es necesario que el máximo número posible de gente esté bien informada acerca de los avances más recientes, que entienda su alcance y sus implicaciones y que haga el esfuerzo de contribuir en los debates. A la vez, los científicos deben salir a explicar qué está pasando en sus laboratorios y los políticos deben proporcionar plataformas necesarias para estas discusiones. Solo así nos aseguraremos de que estos descubrimientos son usados

A must read.

Side effects, a good film to watch

The long and bumpy road to CRISPR (3)

 Cut-and-Paste Genetics. A CRISPR Revolution

Té múscul la indústria biotech?

Informe de la BioRegió 2022. El sector de les ciències de la vida i la salut a Catalunya

El dinamisme de la recerca en ciències de la vida a Catalunya és indubtable. Es mou però cap a on?. Avança realment o només crea expectatives?. 

He estat aquests dies a BioSpain2023, una trobada clau del sector, on el paper de les empreses catalanes també és notori. Hi havia 800 empreses en total, gairebé 2000 assistents. Però el més important és què es comprava i què es venia. 

Hi havia 744 actius per vendre, 323 productes i 1478 serveis. Les xifres impressionen, certament. I alguns poden preguntar-se quins són els actius en venda? Doncs fonamentalment patents i llicències. Per exemple, en miro una d'un institut públic (Sant Pau/UAB) "FANCONINIB – TARGETING DNA REPAIR IN CANCER THERAPEUTICS" (Fanconinib presents a new mechanism of action for cancer treatment that targets DNA repair and aims to "Fanconize" cancer cells and kill them by breaking their chromosomes through the inhibition of the FA/BRCA pathway. Currently there are no specific drugs in the market with inhibitory effect on this pathway). L'origen és una extensió d'indicació sobre un medicament existent.

I per què se'n diuen actius, si ningú sap com anotar-los com a tals en una comptabilitat? Doncs perquè és l'exemple més clar de financialització dels medicaments. Ho vaig explicar el mes de febrer passat comentant el gran llibre de Victor Roy, "Capitalizing a cure". Allà explica que el que es compra i es ven són expectatives financeres sobre teràpies més o menys elaborades que cotitzaran a borsa .

Miro quan és la inversió de 2022 en startups a Catalunya i em diu 455 milions, i algú treu pit com si fos molt. Miro què ha fet una sola empresa i Pfizer aquest any veig que ha comprat Seegene per 43 mil milions de dòlars, xifra record. Podem dir que Pfizer ha pagat cara l'externalització de la recerca d'un medicament oncològic (Conjugat Anticos-fàrmac ADC)? No ho sabem, ara bé el dia que el posi al mercat recordeu la xifra que li ha costat allunyar-se del risc de la R+D.

Les diferències en les xifres d'inversió entre noves empreses i gran indústria farmacèutica són abismals. Les notícies que es generen a premsa per les primeres són moltes però mai sabem on acaben. Les segones, són poques i acaben en un preu estratosfèric, que llavors si que és notícia.

Algú hauria de posar una mica de seny i realisme a tot plegat. Cal admetre que la musculatura de la traslació de la recerca a clínica és feble i que no tenim recursos per aplicar-hi, malgrat tenir talent, i molt. La funció de producció va més coixa per la K (de capital) en comparació de la L (de labour/talent). I sobretot per l'entorn/ecosistema que es necessita perquè la K i la L reixin. Més K i prou no es la solució.

Sempre recordaré el dia que jo estava a Berkeley i l'Ed Penhoet em va dir: "mira, els Estat Units ja no som líders mundials en cotxes, ni en molts sectors on la Xina ens ha passat pel davant, ara bé en ciències de la vida ens hi mantindrem. La gent pot parlar de recerca en xarxa i descentralitzada, però nosaltres la controlarem, controlarem la xarxa". És a dir el poder econòmic, la financialització es mantindria a les mans del USA. D'això en fa uns quinze anys. Mireu el CV de l'Ed Penhoet si no el coneixieu abans, i veureu el seu nivell.

I després de tot plegat i en relació a Catalunya, m'agradaria veure els resultats de la inversió en recerca pública, on són les patents? què han costat?  quants diners n'hem recuperat i qui és l'últim tenidor?. Fa molts anys que ho busco i no ho trobo. Potser perquè no existeix, o potser perquè no interessa que existeixi. Tant costaria un registre d'actius públics? Qüestió de transparència pendent, una vegada més.

PS. Aquest és un tema que no es pot ventilar amb un escrit curt. Per tant serveixin aquests paràgrafs com a punt de reflexió tant sols.

PS. He posat al buscador d'actius CRISPR i em trobo que només n'hi ha 8 (cap provinent de Catalunya). Increïble. Ningú podria imaginar als USA un congrés Biotech on 8 dels 744 actius, un 1% fos CRISPR a data d'avui (0% de Catalunya). No m'he mirat el detall però suposo que són olinucleòtids, allò que es pot patentar.

Rocio Madrid al KBR

An unprecedented discovery

Yesterday was World Crispr Day

 

Genome editing: the game of biology is about to change

Hacking the Code of Life: How gene editing will rewrite our futures

The foundations of gene editing came about because a scientist in Alacant, Dr. Mojica started to find weird DNA sequences in some bacteria he was studying. After that Profs. Doudna and Charpentier and later Prof. Zhang translated initial findings into practice. Therefore it all started when a microbiologist studied the arms race between bacteria and viruses.
You'll find all these details in a book by Nessa Carey. If you want to understand in plain words what CRISPR is and what may represent for biology, then you have to read it.

The gene editing revolution is creating a technological toolkit that almost any half-decent scientist can lean into and find something useful. On the one hand, that should make us very excited. We can both solve problems and simply indulge our curiosity. But should it also make us worried? Using chisels and a mallet, Michelangelo created some of the most exquisite sculptures we have ever seen. But give the same heavy, sharp tools to someone else, and we can get a very different and much bloodier outcome.

But the same technology can also be used to alleviate human suffering, and if we are smart enough, lessen the impact that our heavy-footed species has on the only planet we know of in the entire universe that supports complex life. We cannot un-invent this technology, we probably can’t even control its spread. So what choice do we really have but to embrace it and use it well, to create a safer, more equal world for all?