Month: August 2020

Herramientas

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Trimero

English version

Varios lectores han escrito comentarios sobre la entrada anterior del blog. ¡Gracias! La lectura siempre es bien recibida. Para los interesados en recomendaciones de verano, ahora estoy leyendo “Mindset“. Creo que es un clásico de psicología. De especial interés para mí son las comparaciones deportivas. La descripción de John McEnroe no tiene desperdicio. Carol Dweck, la autora de “Mindset”, publicó en Nature una versión para nerds de sus investigaciones aplicadas al ambiente educativo.

Está semana quiero cubrir la base de algunas estrategias de inmunoterapia en diferentes enfermedades humanas. Los anticuerpos monoclonales son proteínas que tienen la función de bloquear la acción de microorganismos y defendernos de infecciones. Están conformados por dos cadenas ligeras y dos cadenas pesadas organizadas en región variable y región constante. Dentro de la región variable existe un segmento conocido como región hipervariable donde está localizado el sitio de unión del anticuerpo a su antígeno particular. La región constante esta implicada en algunas acciones efectoras como la activación de macrófagos y la iniciación de la cascada del complemento. Los anticuerpos, por su alta especificidad, son una de las herramientas más versátiles con la que cuentan los médicos en la actualidad para tratar enfermedades autoinmunes y cáncer.

La técnica original para producir anticuerpos monoclonales (abs) basada en hibridomas (fusión de linfocitos y células de mieloma) fue diseñada en la década de los setenta por Cesar Milstein y George Kohler. Sir Gregory Winter y su grupo de investigación establecieron procesos modernos para generar abs mediante tecnología de ADN recombinante.

De acuerdo con su origen los abs pueden ser:

  1. Ratón: Toda la proteína es de ratón. Una forma de identificarlos es por el sufijo mo. Ejemplo muromonab, anti-CD3 utilizado en el tratamiento del rechazo de algunos tipos de trasplante refractario a corticoides.
  2. Quimérico: La región variable es humana y el resto es de ratón. Se identifican por el sufijo  xi como rituximab, anti-CD20 base de la terapia en varios tipos de linfoma.
  3. Humanizado. La región hipervariable donde esta el sitio de unión al antígeno es humana y el resto es de ratón. Tienen el sufijo zu como trastuzumab, anti-HER2 fundamental para el manejo de algunos tumores de mama y estómago.
  4. Humanos: Toda la secuencia del anticuerpo es de origen humano. Cuentan con el sufijo u como adalimumab, anti-TNF indicado en varias enfermedades autoinmunes como artritis reumatoide, psoriasis, etc.

En otra entrada del blog voy a comentar sobre algunas modificaciones a la estructura básica de un anticuerpo con potencial terapéutico (BITEs, nanobody, etc).

Para terminar, otro libro recomendado. Es una historia sobre una reunión para tomar una cerveza. Hacía 1975 un empresario y un biólogo quedaron en un bar en San Francisco para hablar de negocios. El biólogo no estaba muy motivado en asistir porque estaba decepcionado de sus anteriores experiencias en tratar de comercializar una idea originada en su laboratorio. El empresario era insistente y planteaba buenas ideas. La reunión agendada para 30 minutos duró casi toda la tarde. Varias cervezas después Robert A Swanson y Herbert Boyer acordaron las bases para fundar Genentech. La historia completa puede leerse en este buen libro. ¡Tomar una cerveza puede cambiar la vida! ¡Hasta la próxima!

Tools

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Trimero

Several readers have written comments on the previous blog entry. Thank you! For those interested in summer recommendations, I am currently reading “Mindset.” I think it’s a psychology classic. Of particular interest to me are the sports comparisons. John McEnroe’s description is remarkable. Carol Dweck, the author of “Mindset,” published in Nature, a nerdy version of her research applied to the educational environment.

This week I want to cover the basics of some immunotherapy strategies in different human diseases. Monoclonal antibodies are proteins that have the function of blocking the action of microorganisms and defending us from infection. They have two light chains and two heavy chains organized in a variable region and a constant region. Within the variable area, there is a segment known as the hypervariable region where the antibody binds to its particular antigen. The constant part is involved in some effector actions such as macrophage activation and initiation of the complement cascade. Due to their high specificity, antibodies are one of the most versatile tools available to physicians today to treat autoimmune diseases and cancer.

The original technique to produce monoclonal antibodies (abs) based on hybridomas (fusion of lymphocytes and myeloma cells) was designed in the seventies by Cesar Milstein and George Kohler. Sir Gregory Winter and his research group established modern processes for generating abs using recombinant DNA technology.

According to their origin abs can be:

  1. Murine: All the protein is from a mouse. One way to identify them is by the mo suffix. For example, muromonab, anti-CD3 used in the treatment of rejection of some types of corticoid-refractory transplants.
  2. Chimeric antibodies: The variable region is human, and the rest comes from a mouse sequence. The suffix xi identifies chimeric antibodies. An excellent example is rituximab, anti-CD20, the basis of therapy in several types of lymphoma.
  3. Humanized antibodies: The hypervariable region with the antigen-binding site contains a human sequence, and the rest is of mouse origin. They have the suffix zu as trastuzumab, anti-HER2 fundamental for the management of some breast and stomach tumors.
  4. Human antibodies: All the sequence of the antibody is of human origin. They have the suffix u as adalimumab, anti-TNF indicated in several autoimmune diseases such as rheumatoid arthritis, psoriasis, etc.

In the next blog entry, I will comment on some modifications to the basic structure of an antibody with therapeutic potential (BITEs, nanobodies, etc.).

To finish, another recommended book. It is a story about a meeting over a beer. About 1975, a finance wizard and a biologist met in a bar in San Francisco to talk about business. The biologist was not very motivated to attend because he was disappointed with his previous experiences trying to market an idea originating in his laboratory. The entrepreneur was persistent and came up with good proposals. The meeting, scheduled for 30 minutes, lasted most of the afternoon. Several beers later, Robert Swanson and Herbert Boyer agreed on the basis for founding Genentech. The full story is beautifully described in this enjoyable book. One beer can change a life! See you next time!

Readings

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Trimero

I like to read. A lot. A little bit of everything. Science, novels, essays, biographies. During the first months of 2020, I have read 30 books (here the complete list until now). For this summer-time blog entry, I will recommend three readings. An original article, a review article, and a book. Excellent material for those who can go to the beach!

  • An article: A few weeks ago in Nature, researchers from Yale University published a paper on the pro-inflammatory protein interleukin 18 (IL-18). Tumor-infiltrating lymphocytes overexpress components of the IL-8 signaling pathway. At the same time, high amounts of IL-18BP, an IL-18 “decoy” receptor that inhibits its activity, can be found in several mouse and human tumor types. The group also developed a modified form of IL-18 that does not bind to IL-18BP and has impressive anti-tumor potency. One of the authors of the article is Miguel Fernandez de Sanmamed, who is now back in Pamplona. Excellent Golden Boy!
  • A review article: anti-PD1 antibodies are considered a revolution in the treatment of cancer patients. The results in overall survival, quality of life, and response rate are very encouraging. Unfortunately, some patients do not benefit from immunotherapy, or the disease progresses quickly after being under control for a while. Antoni Ribas published a comprehensive review of the causes of primary and secondary resistance to checkpoint inhibitor therapy earlier this year. In the text, he describes different molecular pathways such as beta-catenin or JAK-STAT and their impact on immunostimulant antibodies’ action.
  • A book. The best book that has passed through my hands this year is “El infinito en un junco” by Irene Vallejo. It’s a book about books, a meta book. It describes the origin of writing beautifully and the transition from papyrus, parchment, and paper through time. Vallejo’s masterpiece is a highly recommended reading that mentions various literary works. This book reminded me of the villain in “The Name of the Rose.” I hope nobody wants to eliminate laughter.
  • Bonus. Albert Camus wrote “The Plague” over 70 years ago. It’s still in force. The end is very suggestive “to finish, and here end the notes of Tarrou, that there was always an hour in the day when the man is a coward and that he was only afraid at that hour.”

The pandemic continues. Books, family, and friends make it more bearable. See you next time!