Invertir en los logros del Premio Nobel – Autofagia

Historia del Premio Nobel

The Nobel Prize is the most prestigious award in the scientific world. It was created according to el testamento del Sr. Alfred Nobel to give a prize “a quienes, durante el año anterior, han conferido el mayor beneficio a la humanidad” 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.

Preocupaciones de Legado

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.

Premio Nobel

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.

Fuente: 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 radioactividad, antibióticos, rayos X, or PCR, as well as fundamental science like the fuente de energía del sol, the carga del electrón, estructura atómica, or superfluidez.

Reciclaje “Autocomido”

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 el Premio Nobel de Fisiología o Medicina en 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.

Fuente: 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.

Fuente: Premio Nobel

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 Premio Nobel de Medicina 2016, for his discovery of autophagy mechanisms.

Fuente: Premio Nobel

Detectando Autofagosomas

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.

Fuente: Premio Nobel

Caza de Genes de Autofagosomas

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.

Funciones de los Genes de Autofagosomas

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.

Fuente: Premio Nobel

Expandiendo de la Levadura a los Mamíferos

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.

Muchísimas Funciones de la Autofagia

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.

Fuente: Premio Nobel

Over time, autophagy became one of the most studied cellular mechanisms, with an explosion in the number of publications after the year 2000.

Fuente: Premio Nobel

Enfermedades Relacionadas con la Autofagia

With autophagy at the center of so many vital parts of cellular biochemistry and cell survival/maintenance, it is not surprising that problems in autophagy can be the cause of diseases. Alternatively, activation of autophagy could provide a cure for many other diseases.

Deregulation of autophagy has been linked to:

• Cáncer humano de mama y ovario, con mutación del gen BECN1 (homólogo al ATG6 de la levadura) en una gran parte de estos cánceres.
  • Muchas otras mutaciones o cambios en la expresión de los genes de autofagia se han vinculado al cáncer en el hígado, piel, riñón, pulmón, colon, etc.
• Mutaciones genéticas en humanos que alteran la autofagia pueden causar malformaciones cerebrales, retraso del desarrollo, discapacidad intelectual, epilepsia, trastornos del movimiento y neurodegeneración.
• En modelos animales, la pérdida de autofagia puede causar neurodegeneración, y la activación de la autofagia puede reducir la toxicidad de los agregados proteicos, considerados una causa raíz clave de las enfermedades de Parkinson y Alzheimer.
• Potenciar la autofagia podría ayudar a tratar la diabetes (la autofagia es inhibida por niveles altos de glucosa).
• La autofagia de mitocondrias se ha vinculado de manera compleja con el paro cardíaco, los riesgos de insuficiencia cardíaca y la progresión de la cardiomiopatía.

Una amplia variedad de enfermedades aparentemente no relacionadas comparten un problema: la acumulación de desechos celulares. Las agregaciones de proteínas amiloides, por ejemplo, están asociadas con la enfermedad de Alzheimer.

Una acumulación de lípidos en el hígado conduce a la enfermedad hepática grasa no alcohólica. Y las moléculas tóxicas se acumulan en una serie de deficiencias genéticas raras de enzimas.

Chemical & Engineering News

Fármacos de Autofagia

Activation of autophagy has become an entire field of medical research, considering how many diseases are linked to impaired autophagic functions.

However, the first tries did not really bear fruits, with a focus on inhibiting autophagy in cancer that appears to use autophagy to its benefit. Slow progress dampened investors’ enthusiasm.

A more promising option might be to stimulate autophagy to treat other diseases instead.

Pharmacological activation of autophagy is typically achieved by blocking the kinase activity of the mammalian target of rapamycin (mTOR) enzymatic complex 1 (mTORC1).

International Journal Of Molecular Sciences

Invertir en la Autofagia

Autophagy is a very promising field of biotech research thanks to its importance in maintaining proper cellular functions. However, it can also be a complex target for drugs, for the very reason that it is so complex and multifunctional.

It is nevertheless a method likely to bear fruits in solving so far incurable autophagy-linked diseases like Alzheimer’s or Parkinson’s.

You can invest in autophagy companies through many brokers, and you can find here, on securities.io, our recommendations for the best brokers in EE. UU., Canadá, Australia, Reino Unido, así como en muchos otros países.

If you are not interested in autophagy companies, you can also look into biotech ETFs like WisdomTree BioRevolution UCITS ETF (WBIO) (WT ), VanEck Biotech ETF (BBH), or  First Trust NYSE Arca Biotechnology Index Fund (FBT)  which will provide a more diversified exposure to capitalize on the growing biotech economy.

You can also look at our lists of the “5 Mejores ETFs de Salud para Invertir” and the “5 Mejores Acciones Biotecnológicas para Vigilar.”

Compañías de Autofagia

1. Cognition Therapeutics

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.

Fuente: Cognition Therapeutics

Found in brain and retinal cells, the sigma-2 receptor complex is believed to function as the “housekeeper” of the brain’s neuronal network, regulating key pathways in age-related diseases like Alzheimer’s disease, dementia with Lewy bodies, and dry AMD.

So the company uses sigma-2 modulators that can restore critical damage responses like protein trafficking and autophagy that are impaired in neurodegenerative diseases.

In vitro studies of experimental sigma-2 receptor modulators demonstrated an ability to prevent the binding of Aβ oligomers to neurons and also to displace bound Aβ oligomers from neuronal receptors.

The company is also investigating the potential of its main drug candidate for another form of dementia and an eye disease involving neurodegeneration.

Fuente: 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.

As 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.

Fuente: ImmuPharma

ImmuPharma has an exclusive license and development agreement and trademark agreement for Lupuzor with Avion Pharmaceuticals for its commercialization in the US.

This follows its business model of bringing far enough its candidate drugs, and then “enter into commercial deals with larger companies within the industry that then assume the responsibility to fund and complete the clinical development of each product through to registration and ultimately, market launch.”