Nobel-palkinnot
Sijoittaminen Nobel-palkinnon saavutuksiin – Autofagia
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Nobel-palkinnon historia
The Nobel Prize is the most prestigious award in the scientific world. It was created according to Mr. Alfred Nobel’s will to give a prize “to those who, during the preceding year, have conferred the greatest benefit to humankind” in physics, chemistry, physiology or medicine, literature, and peace.
A sixth prize would be later on created for economic sciences by the Swedish central bank, officially called the Prize in Economic Sciences, often better known as the Nobel Prize in Economics.
The decision of who to attribute the prize to belongs to multiple Swedish academic institutions.
Perintöhuolenaiheet
The decision to create the Nobel Prize came to Alfred Nobel after he read his own obituary, following a mistake by a French newspaper that misunderstood the news of his brother’s death. Titled “The Merchant of Death Is Dead”, the French article hammered Nobel for his invention of smokeless explosives, of which dynamite was the most famous one.
His inventions were very influential in shaping modern warfare, and Nobel purchased a massive iron and steel mill to turn it into a major armaments manufacturer. As he was first a chemist, engineer, and inventor, Nobel realized that he did not want his legacy to be one of a man remembered to have made a fortune over war and the death of others.
Nobel-palkinto
These days, Nobel’s Fortune is stored in a fund invested to generate income to finance the Nobel Foundation and the gold-plated green gold medal, diploma, and monetary award of 11 million SEK (around $1M) attributed to the winners.
Lähde: Britannica
Often, the Nobel Prize money is divided between several winners, especially in scientific fields where it is common for 2 or 3 leading figures to contribute together or in parallel to a groundbreaking discovery.
Over the years, the Nobel Prize became THE scientific prize, trying to strike a balance between theoretical and very practical discoveries. It has rewarded achievements that built the foundations of the modern world, like radioactivity, antibiotics, X-rays, or PCR, as well as fundamental science like the power source of the sun, the electron charge, atomic structure, or superfluidity.
“Itse syövä” kierrätys
When progress in microscopy allowed us to learn about the inner workings of complex cells, scientists discovered that they contained many sub-units, each performing a special function.
This discovery was rewarded by the Nobel Prize in Physiology or Medicine in 1974, in part to the Belgian scientist Christian de Duve for the discovery of the lysosome.
Lysosomes are specific structures dedicated to digest/recycle components of the cells. This way, a no-longer-wanted or damaged part of the cell can be destroyed safely and its components reused.
It can also be a reaction to a lack of resources, with the cell consuming some of its components to keep working.
Lähde: Frontiers
Progressively, they discovered that lysosomes can absorb and recycle not only smaller components but entire parts of the cell like whole organelles (ribosome, mitochondria, etc.).
De Duve investigated this process and discovered a dedicated type of vesicle existed to transport what was to be recycled into the lysosome.
De Duve calls this process autophagy, which comes from the Greek words auto-, meaning “self,” and phagein, meaning “to eat.” And the vesicles involved would be called autophagosomes.
Lähde: Nobel Prize
Autophagy was clearly a very important cellular mechanism, preserved among a wide range of organisms throughout evolution, from amoebas to insects, frogs, and mammals.
However, how this process actually worked stayed a mystery. At least until clever analytical methods were invented by Yoshinori Ohsumi, the winner of the 2016 Nobel Prize in Medicine, for his discovery of autophagy mechanisms.
Lähde: Nobel Prize
Autofagosomin havaitseminen
Yoshinori Ohsumi, when starting to direct his own lab in 1988, went on to focus on vacuole, the cellular organ equivalent to the human lysosome in microorganisms and plant cells.
His primary model was yeast, mostly because it was easier to grow and study yeast than more complex cells. The yeast genome would also be elucidated much sooner than the human genome and was easier to modify genetically.
However, yeasts’ internal structures are difficult to distinguish on a microscope, and it was not clear at the time if autophagy was a mechanism present in yeast.
To elucidate it, Ohsumi created mutant yeast that lacked the genes for the degradation enzyme in the vacuole. The idea was that if the vacuole could not degrade absorbed components, the still theoretical yeast’s autophagosomes would pile up in the cell.
To make the results more clear, Ohsumi also starved the yeasts, forcing them into an intense autophagy activity. The results were almost instantaneous, with a massive accumulation of autophagosomes in the yeast cells easy to spot using simple microscopy.
Lähde: Nobel Prize
Autofagosomin geenien metsästys
Now armed with an easy-to-analyze model to create abundant autophagosomes, Ohsumi would go hunting for the genes responsible for these structures.
To do so, he exposed his yeast to a chemical that created mutations and then induced autophagy. So when one gene responsible for autophagosome was damaged, the process would break, and he could find the mutation and the gene in question.
While somewhat simple in theory, this was a complex affair in practice, and took a lot of work to identify 15 different genes responsible for autophagosome in yeasts.
These genes would be first named APGI-1 to APGI-15, and later on, renamed ATG genes for all autophagy-related genes.
Autofagosomin geenien toiminnot
Ohsumi would also look at these genes and the corresponding proteins and elucidate their biochemical functions.
He would find a complex regulation process: First initiated by a stress signal (TOR), which activates a regulatory complex, activating another protein complex, which then forms the autophagosome vesicles.
Lähde: Nobel Prize
Laajentuminen hiivasta nisäkkäisiin
Now knowing the genes responsible for autophagy, Ohsumi’s team could go find the equivalent in mammals. Interestingly, they found that in mice, deficiency in the Atg5 gene would cause the mice to be unable to cope with the starvation that precedes feeding and die.
This would be the first indication of how important autophagy and autophagosomes are in all organisms and not just in yeast.
Autofagian monia, monia toimintoja
Further research by Ohsumi and many other scientists would demonstrate that autophagy plays a vital role in response to starvation and other types of stress, as it provides the cell quickly with the energy and building blocks it needs.
It is also responsible for protection against infections, with autophagy able to eliminate invading intracellular bacteria and viruses (xenophagy).
Autophagy would later be proven to contribute to embryo development and cell differentiation.
Cells also use autophagy to eliminate damaged proteins and organelles, a quality control mechanism critical for counteracting the negative consequences of aging. Autophagy is also a key factor in the origin of cancer, with many cancer cells mutating due to damaged mitochondria or other subcellular components.
Lähde: Nobel Prize
Over time, autophagy became one of the most studied cellular mechanisms, with an explosion in the number of publications after the year 2000.
Lähde: Nobel Prize
Autofagiaan liittyvät sairaudet
Kun autofagia on keskeinen monissa solubiokemian ja solujen eloonjäämisen/ylläpidon tärkeissä osissa, ei ole yllättävää, että autofagian häiriöt voivat aiheuttaa sairauksia. Toisaalta autofagian aktivointi voisi tarjota parannuskeinoa moniin muihin sairauksiin.
Deregulation of autophagy has been linked to:
- Human breast and ovarian cancer, with mutation to the BECN1 gene (homolog to yeasts’ ATG6) in a large portion of these cancers.
- Many other mutations or changes in the expression of autophagy genes have been linked to cancer in the liver, skin, kidney, lung, colon, etc.
- Genetic mutations in humans that impair autophagy can cause brain malformations, developmental delay, intellectual disability, epilepsy, movement disorders, and neurodegeneration.
- In animal models, loss of autophagy can cause neurodegeneration, and activation of autophagy can reduce the toxicity of protein aggregates, believed to be a key root cause of Parkinson’s and Alzheimer’s diseases.
- Enhancing autophagy could help treat diabetes (autophagy is inhibited by high glucose levels).
- Autophagy of mitochondria has been linked in complex ways to cardiac arrest, heart failure risks, and progression of cardiomyopathy.
Laaja kirjo näennäisesti epäyhtenäisiä sairauksia jakaa yhteinen perusongelma: solujätteiden kertymä. Esimerkiksi amyloidiproteiinien aggregaatiot liittyvät Alzheimerin tautiin.
Rasvojen kertymä maksassa johtaa ei-alkoholiseen rasvamaksatautiin. Ja myrkylliset molekyylit kasaantuvat harvinaisten geneettisten entsyymivajavajojen yhteydessä.
Autofagia-lääkkeet
Autofagian aktivointi on kehittynyt koko lääketieteelliseksi tutkimusalaksi, kun otetaan huomioon, kuinka moniin sairauksiin on yhteys heikentyneisiin autofagia-toimintoihin.
Kuitenkin ensimmäiset yritykset eivät tuottaneet tuloksia, kun keskityttiin autofagian estämiseen syövässä, jossa syöpä hyödyntää autofagiaa omaksi edukseen. Hidas edistyminen laski sijoittajien innostusta.
Lupavampi vaihtoehto voi olla autofagian stimuloiminen muiden sairauksien hoitoon sen sijaan.
Farmakologinen autofagian aktivointi saavutetaan tyypillisesti estämällä mammalian target of rapamycin (mTOR) -entsyymikompleksin 1 (mTORC1) -kinaasitoimintaa.
Sijoittaminen autofagiaan
Autofagia on erittäin lupaava bioteknologian tutkimusalue sen merkityksen vuoksi solujen oikean toiminnan ylläpitämisessä. Kuitenkin se voi olla myös monimutkainen kohde lääkkeille juuri siksi, että se on niin monimutkainen ja monitoiminen.
Se on kuitenkin todennäköisesti menetelmä, joka tuo tuloksia ratkaistaessa tähän mennessä parantumattomia autofagiaan liittyviä sairauksia, kuten Alzheimerin tai Parkinsonin tautia.
Voit sijoittaa autofagia-yrityksiin monien välittäjien kautta, ja löydät täältä, securities.io, suosituksemme parhaista välittäjistä Yhdysvalloissa, Kanadassa, Australiassa, Ison-Britannian, sekä monissa muissa maissa.
Jos et ole kiinnostunut autofagia-yrityksistä, voit tarkastella myös bioteknologian ETF:iä, kuten WisdomTree BioRevolution UCITS ETF (WBIO) (WT ), VanEck Biotech ETF (BBH), tai First Trust NYSE Arca Biotechnology Index Fund (FBT), jotka tarjoavat monipuolisemman altistuksen kasvavan bioteknologian talouden hyödyntämiseen.
Voit myös tarkastella listojamme “5 parasta terveydenhuollon ETF:ä sijoitettavaksi” ja “5 parasta biotekniikkaosaketta seurattavaksi.”
Autofagia-yritykset
1. Cognition Therapeutics
CGTX Hintakaavio
Cognition is a biotech company focused on neurodegenerative diseases.
The company is notably targeting amyloid beta oligomers, agglomerates made of proteins that are linked to Alzheimer’s disease.
The amyloid proteins have proven very resistant to treatment, with only one approved treatment (Aducanumab) despite 35 years of research. Its manufacturer Biogen is going to discontinue the drug in 2024, after its approval in 2021.
Cognition Therapeutics (CGTX ) is attacking amyloid beta oligomers instead of amyloid plaque, thanks to recent evidence that the oligomers are the actually most neurotoxic form of amyloid beta protein.
This provides the company with a new target untested by previous experimental therapies.
Lähde: Cognition Therapeutics
Löytyy aivo- ja verkkokalvosoluista, sigma-2-reseptorikompleksin uskotaan toimivan aivojen hermoverkon “talonhoitajana”, säädellen keskeisiä polkuja ikään liittyvissä sairauksissa, kuten Alzheimerin tauti, Lewyn kappaleita sisältävä dementia ja kuiva AMD.
Yritys käyttää siis sigma-2-modulaattoreita, jotka voivat palauttaa kriittiset vauriovastaukset, kuten proteiinien kuljetuksen ja autofagian, jotka ovat heikentyneet neurodegeneratiivisissa sairauksissa.
In vitro -tutkimukset kokeellisista sigma-2-reseptorimodulaattoreista osoittivat kyvyn estää Aβ-oligomeerien sitoutuminen neuroneihin ja myös irrottaa sitoutuneet Aβ-oligomeerit neuronireseptoreista.
Yritys tutkii myös pääasiallisen lääkekandidaattinsa potentiaalia toisen dementian muodon ja silmäsairauden, joka liittyy neurodegeneraatioon, hoitoon.
Lähde: Cognition Therapeutics
Research in curing Alzheimer’s disease has been an arduous process. At the same time, the aging of the population and the already 6.9 million affected patients in the US alone means that any breakthrough would turn into an instantaneous blockbuster drug.
Because Alzheimer’s disease seems intimately linked to protein accumulation that would normally be solved through autophagy, this is a promising prospect for further R&D.
2. ImmuPharma (IMM.L)
ImmuPharma is another biotech company exploring the potential of autophagy in treating diseases.
Its main drug candidate, LP140, is a first-in-class autophagy immunomodulator for the treatment of Lupus.
The drug is already in phase 3 of clinical trials, and pre-clinical data indicate it could be useful for other autophagy-linked diseases.
It is also investigating the antibacterial & antifungal potential of BioAMB, an amphotericin-B variant, a known antifungal molecule.
BioAMB is expected to display much lower kidney toxicity than amphotericin-B and can be administrated with a simple injection instead of an IV.
Lähde: ImmuPharma
ImmuPharma has an exclusive license and development agreement and trademark agreement for Lupuzor with Avion Pharmaceuticals for its commercialization in the US.
Tämä noudattaa sen liiketoimintamallia, jossa se kehittää kandidaattilääkkeensä riittävän pitkälle, ja sitten “solmii kaupallisia sopimuksia suurempien alan yritysten kanssa, jotka ottavat vastuulleen rahoittaa ja viimeistellä kunkin tuotteen kliinisen kehityksen rekisteröintiin asti ja lopulta markkinoille tuomiseen.”
