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CiQUS

CiQUS

El Centro Singular de Investigación en Química Biológica y Materiales Moleculares (CiQUS) forma parte de la Red de Centros Singulares de Investigación del Campus de Excelencia Internacional – Campus Vida y centra sus objetivos científicos en la aplicación de estrategias transdisciplinares para la resolución de problemas científicamente relevantes en el ámbito de la química biológica y en desarrollo de nuevos materiales funcionales. http://www.usc.es/ciqus/

Entrevista con el Dr. Juan R. Granja

Fuente: Excodra | Publicado: 08-05-2017
La nanotecnología es la ciencia que estudia las propiedades de los materiales de dimensiones nanométricos (un nanómetro es la millonésima parte de un milímetro). Durante mucho tiempo estas dimensiones estaban por debajo de la capacidad de manipulación humana. No podíamos sintetizar ni sobre todo estudiar sus propiedades. Ahora ya podemos hacerlo.
Derechos: Representación de un nanotubo de Venturi. USC.
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Juan, para comenzar, ¿cómo son las nanotecnologías en el ámbito biológico y dónde radica su relevancia para mejorar nuestras vidas?


La nanotecnología es la ciencia que estudia las propiedades de los materiales de dimensiones nanométricos (un nanómetro es la millonésima parte de un milímetro). Durante mucho tiempo estas dimensiones estaban por debajo de la capacidad de manipulación humana.



No podíamos sintetizar ni sobre todo estudiar sus propiedades. Ahora ya podemos hacerlo y por primera vez estamos en disposición de preparar materiales que tienen unas dimensiones similares a los componentes básicos de los seres vivos.


Y no nos referimos a las células sino a los componentes básicos de las mismas, las que realizan las distintas funciones biológicas. Las proteínas, las membranas celulares, los ribosomas, etc., son estos componentes celulares. Por ello, se espera que en un futuro no muy lejano podamos interferir en las funciones de estos componentes mediante estos nuevos nanomateriales. Por tanto, deberíamos esperar reducir o eliminar las deficiencias en el funcionamiento de estos componentes celulares reparando las células enfermas como las de los tumores cancerosos. Tal vez en un futuro se podría incluso sustituirlos, como una ortopedia molecular, en la que componentes moleculares sintéticos se incorporasen en las células para realizar las funciones que la ingeniería genética celular no permite.


Vehículo de entrega de drogas, canal transmembrana, agente terapéutico, catalizador, participante en la construcción de nanocompuestos y dispositivos ópticos y electrónicos, interventor en inclusión molecular… y creo que no se agota la lista, ¿cuáles es situación actual de los nanotubos en cuanto a sus aplicaciones y, qué aportaciones más significativas se espera de ellos para el futuro?


Los nanotubos son estructuras tubulares de dimensiones nanométricas que poseen múltiples aplicaciones tanto en el ámbito biológico como en los materiales. Sus propiedades dependen tanto del material del que están hechos, existen los nanotubos de carbono, los peptídicos o los derivados de los ácidos nucleicos que poseen diferente dureza, rigidez, solubilidad, conductividad eléctrica o al calor, biocompatibilidad, etc. Además, sus propiedades también dependen de sus dimensiones, de su longitud y diámetro, y de las propiedades de su superficie exterior o de su orificio interno. Por tanto, en principio son unas estructuras cuyas aplicaciones dependerán del desarrollo de unos materiales apropiados y en la capacidad para controlar de forma precisa sus dimensiones. Por ejemplo, podemos pensar en que estos tipos de nanotubos se podrían incorporar en las membranas celulares y utilizarse para transportar pequeños iones a través de su orificio interno. Ya existen muchos canales iónicos artificiales desarrollados en los últimos años, sin embargo, ninguna de ellos es capaz de competir con las proteínas naturales en eficiencia y selectividad. Ese es uno de los retos que se deben superar en los próximos años. La incorporación de una direccionalidad en el sentido del flujo de los iones podría desencadenar conductos moleculares que funcionen en contra del gradiente osmótico, o una bomba de iones. En este caso el tránsito de los iones tendría que estar soportado por un aporte energético exterior.


La síntesis de péptidos en laboratorio me parece algo increíble, ese poder formar proteínas a la carta, por ejemplo, que no se dan en la vida de manera natural, entonces, además de desarrollar la síntesis de nanotubos, ¿qué otras investigaciones estáis llevando a cabo mediante la síntesis de biocompuestos y qué tipo de aplicaciones y descubrimientos se espera de ellas?


En primer lugar, me gustaría establecer que nuestro grupo de investigación es un grupo de la universidad, formado principalmente por jóvenes apasionados y con talento que realizan su tesis doctoral. Por tanto, nuestra principal función es la formación de estos jóvenes, darle la mejor formación despertando su curiosidad y ayudándoles a que piensen en cómo resolver los problemas. Por tanto, nuestra investigación es una investigación básica, “fundamental research”, que no tiene un claro objetivo aplicado, aprendemos con lo que se va descubriendo y desarrollando para que sea un posible pilar del conocimiento y que pueda encontrar aplicaciones para las que tal vez en un principio no estaba pensado.



Nuestra investigación como químicos es la síntesis y el desarrollo de nuevos materiales, que no se encuentran en la naturaleza, de una forma rápida, sencilla y eficiente.


Cuando pretendemos simular las máquinas o componentes celulares, pretendemos desarrollarlo de una forma sencilla, simplificando la compleja maquinaria celular, pero sin que pierda su función. Cuando hablamos de la inteligencia de la naturaleza en cierta medida estamos exagerando, no es la inteligencia lo que ha desarrollado la vida hasta los límites que hoy conocemos. La vida es más bien el fruto de la evolución durante cientos de millones de años y como consecuencia de los cambios en el medio; un continuo “prueba y error” hasta encontrar la mejor solución para un problema ambiental, cambio del medio, falta de nutrientes, la predación, competencia, etc. Sin embargo, cada intento se realiza sobre lo que ya se tiene, y por tanto es la mejor solución que se encuentra para las herramientas que se poseen. Hay veces que nos encontramos con seres que claramente no son la mejor solución para la supervivencia. Un ejemplo podrían ser los peces que viven sobre el fondo marino como el rodaballo, son bastante feos y no representan la mejor solución para su modo de vida. Estos peces han surgido de la evolución de un pariente común con otros peces a los que en algún momento se rompió la simetría típica de los seres vivos. Esto supone un gasto estructural adicional que no se tendría que gastar si pudiésemos empezar de cero. Otro ejemplo serían los mamíferos que han vuelto al mar, sus pulmones no les permiten respirar bajo el agua. A donde voy con todo esto, esto, en cierta medida, es la visión de los químicos en esta área.



¿Podemos hacerlo igual o mejorar lo que hace la naturaleza? Para ello los químicos podemos empezar de cero y pensando en una función determinada tratar de construir las máquinas moleculares más sencillas y eficientes. En nuestra contra tenemos el tiempo, sólo unos pocos años de un trabajo de tesis doctoral de nuestros jóvenes investigadores para desarrollar nuestro trabajo frente a los millones de años que emplea la naturaleza.


A nuestro favor está nuestra creatividad, imaginación, inteligencia y que podemos utilizar la naturaleza para inspirarnos. Por tanto, nuestros límites nos lo ponen las leyes de la naturaleza, lo demás con el conocimiento que se va adquiriendo y con la imaginación es posible. Esta es la filosofía que pretendemos implantar en el grupo. Nuestras herramientas básicas, generalmente, son pequeños péptidos. Los péptidos tiene unas propiedades muy especiales, gran diversidad de grupos funcionales diferentes, son relativamente fáciles de preparar y además se pueden plegar para dar formas distintas y se asocian con otras moléculas o consigo mismas para generar estructuras más complejas que pueden desempeñar diferentes funciones. Con estas herramientas tratamos de construir moléculas con nuevas formas, actividades catalíticas, cápsulas moleculares, biosensores, etc.


Acabáis de publicar el trabajo “Self-assembling Venturi-like peptide nanotubes” en la revista Nanoscale, describiendo por primera vez este tipo de estructuras muy particulares, ¿qué hace que estos nanotubos puedan ser tan relevantes a nivel de tratamiento de enfermedades?


Es la primera vez que se preparan nanotubos que posee una zona interna de menor dimensión, estrechamiento, cuyas dimensiones están perfectamente determinadas. Estos tubos podrían actuar como unos filtros moleculares que seleccionen el paso de moléculas mientras las hacen fluir a mayor velocidad. Creemos que podrían ser unos modelos sencillos de las proteínas responsables del transporte de iones u otras moléculas que poseen nuestras células (canales iónicos). Podrían servir para entender y estudiar las propiedades de estas proteínas para que en un futuro se puedan sustituir en aquellas células cuyos transportadores moleculares funcionan de forma deficiente, como por ejemplo en la fibrosis quística.


Quiero poner por aquí un ejemplo de cómo hacéis la síntesis de los compuestos, es algo totalmente asombroso, el nivel de conocimientos y avances en química y en tecnología a los que ya hemos llegado, para ilustrar un poco la complejidad que conllevan vuestros trabajos:
3-azidopropyl-p-toluenesulphonate. A solution of 3-azido-1-propanol (0.909 g, 9 mmol) in CH2Cl2 (36 mL) was treated with Et3N (2.5 mL, 18 mmol) and p-toluenesulfonyl chloride (1.80 g, 9.45 mmol). The mixture was stirred overnight and then washed with H2O (milli-Q grade, 2x25 mL), dried over anhydrous MgSO4, filtered and concentrated. The resulting oil was purified by flash chromatography (0-35% AcOEt/Hexane) to yield the desired product as a colorless oil [2.135 g, 93%, Rf= 0.51 (25% AcOEt/Hexane)].
Bueno, y aún sigue… es algo enorme el ser capaces de comprender y moldear la química a estos niveles de precisión. Juan, teniendo en cuenta que la vida viene a ser un conjunto de elementos químicos ordenados de diferentes maneras y a diferentes niveles de estructuración permitiendo tal o cual función, y viendo lo que somos capaces ya de hacer y entender, para dejar volar un poco a la imaginación: ¿hasta dónde podemos llegar con la síntesis de compuestos biológicos?


Como ya te dije antes, nuestros límites en un principio son las propias leyes de la naturaleza, no es fácil luchar contra la termodinámica o la propia entropía, aunque, como la naturaleza nos enseña, en muchas ocasiones se puede circundar.



En estos años hemos aprendido a manipular la naturaleza a nivel nanoscópico y sobre todo a estudiar sus propiedades a este nivel. Aún estamos lejos de igualar a la naturaleza en muchos aspectos, pero la gran distancia que había hace sólo unos pocos años va paulatinamente disminuyendo y tal vez en unos años se podrá sobrepasar. Podremos desarrollar células artificiales, hoy en día no parece demasiado lejos, aunque de momento las células que hemos visto recientemente publicadas utilizan los mismos componentes moleculares que las células naturales.


Un paso mas allá es que esos componentes no sean proteicos sino otro tipo de polímeros más eficientes y resistentes y que no causen problemas de rechazo. Si ya estamos acostumbrados a ver trasplantes de órganos porque no imaginarnos la reparación de estos órganos remplazando sólo alguno de los componentes “estropeado”, fibras musculares, tejidos a células empleando estas células sintéticas.


Leyendo uno de tus trabajos hay una frase que me ha maravillado e intrigado muchísimo: “Este poro interno tiene una única dimensión por lo que las moléculas incorporadas en su interior tendrán propiedades diferentes a las exhibidas por el mundo tridimensional en el que vivimos.” Me encantaría que nos la explicaras un poco, ponerla en contexto, porque parece ciencia-ficción, pero no lo es…


Las propiedades que observamos a nivel macroscópico son el resultado de la respuesta de miles de millones de átomos o moléculas, la nanotecnología ha demostrado cómo cambian las propiedades de la materia a medida que se reduce su tamaño. Las propiedades del oro a nivel macroscópico se pierden a medida que se reducen sus dimensiones, de ahí, por ejemplo, el interés por las nanopartículas de oro, tienen unas propiedades que no se observan en las joyas que llevamos. Podemos imaginarnos, por tanto, que las moléculas incorporadas en el interior de un nanotubo, que es una cavidad con una sola dimensión, podrían tener nuevas propiedades y que en los próximos años se podrán estudiar.


Hay una parte de las nanotecnologías encargada de la construcción de “materiales inteligentes”, con esos cambios estructurales de por sí según cambia el medio en el que están, la temperatura, por ejemplo, ¿en qué consisten exactamente estos materiales y cuáles son sus aplicaciones, tanto en industria de materiales como en biología y medicina?


Los materiales inteligentes son aquellos que responden de forma diferente ante estímulos externos diferentes, que se pueden adaptar y evolucionar según las condiciones medioambientales. Estamos describiendo los principios de la vida. Las bases de la vida están en que sus moléculas se asocian y disocian de forma reversible, es lo que se conoce como el auto-ensamblaje molecular. De tal forma que las moléculas de ADN, la encargada de almacenar la información genética, forman una doble cadena de estructura helicoidal. Almacenar una información no tiene ningún interés si no se pudiese leer y recuperar esta información.



La doble cadena de ADN se forma mediante el reconocimiento y la unión de las distintas bases que componen la cadena. Pero esta unión se realiza a través de fuerzas de enlace no covalente que al ser más débiles son reversibles. Por tanto, es posible separar las bases para leer la información y copiar (transcribirla) en otra nueva molécula como el ARN, o en duplicarla para su reproducción.


Una vez desparecidas las fuerzas químicas que separan las dos hebras del ADN, estas se vuelven a juntar para recuperar la forma inicial. Este tipo de comportamiento es característico de otros sistemas químicos. Se juega con moléculas que están en el filo del equilibrio termodinámico de tal forma que un pequeño cambio de las condiciones desencadena una variación en las condiciones del equilibrio que inducen un cambio estructural o funcional. Estas deben ser las propiedades que deben tener estos materiales inteligentes. Tendremos que seguir desarrollando los materiales que simulen estas propiedades, pero utilizando moléculas diferentes. Si lo conseguimos nuestro nivel de vida mejorará. Tal vez en los últimos años, nuestra sociedad ha asociado a la química con todos nuestros males porque somos responsables de la contaminación del medio ambiente, porque asociamos a la quimioterapia con los males de nuestras enfermedades. No nos damos cuenta el gran impacto que ha tenido en nuestra sociedad los descubrimientos químicos del siglo XX, los antimicrobianos para combatir las infecciones, muchos otros fármacos para tratar depresiones, el dolor, el cáncer, etc.



El impacto de los polímeros en nuestra vida, ¿se podría volar como los hombres pájaros si no se hubiesen desarrollado materiales tan ligeros y resistentes como los que se utilizan en su equipación? ¿Correrían los coches de formula I, las motos GP con la seguridad y velocidad de las actuales? ¿Se podría alcanzar el espacio, sin combustibles químicos eficientes, etc.?


Todo ello se basa en descubrimientos realizados por la industria química y creo que nuestra sociedad no valora lo suficiente. Seguimos necesitando de jóvenes que se interesen por la química para que nuestro bienestar no decaiga. En el futuro nos vamos a encontrar con nuevos retos y son las futuras generaciones de químicos las que deben resolverlos.


Juan, para terminar, muy genéricamente, ¿el estudio de los péptidos auto-replicantes qué nos aporta sobre el conocimiento del origen de la vida? Y, cuando tengamos la certeza y su comprobación, del origen de la vida, ¿qué hará de nosotros el saber cómo se crea la vida desde sus niveles más básicos?


Este es otro aspecto fundamental que los químicos tratan de desenmascarar, cómo se originó la vida que conocemos, ¿qué condiciones se necesitaron para llegar a ella? ¿Cuáles fueron las moléculas primigenias en las que se basó el surgimiento de la vida? ¿Son unas condiciones muy especiales, o en cualquier sitio en el que tengamos agua, energía y moléculas carbonadas (óxidos de carbono, cianuro, urea, etc.) podría ser suficiente para que surja la vida? Existe una gran controversia sobre todo esto. En lo que todos los científicos coinciden es que en las condiciones prebióticas las moléculas básicas deberían ser capaces de catalizar alguna transformación química y de almacenar una información estructural que pudiese ser transmitidas a las siguientes generaciones, esto es, que puedan auto-replicarse. Durante muchos años los péptidos se descartaron por su incapacidad para auto-replicarse.



En un trabajo pionero que realizamos a mediados de los años noventa en colaboración con el grupo del profesor Ghadiri en Scripps y publicado en la revista Nature, desarrollamos los primeros péptidos auto-replicantes. ¿Podemos ahora asegurar que fueron este tipo de moléculas las que dieron lugar a la vida?


De momento no, pero la facilidad con la que se obtienen a partir de los caldos primigenios soporta su posible implicación en el origen de la vida.  Además, algunos aminoácidos, componente básico de los péptidos y proteínas, se han encontrado en los meteoritos, y por tanto confirma que se pueden generar fuera de la tierra. Además, los péptidos son mucho menos complejos estructuralmente que los ARNs y tiene mejores actividades catalíticas. Conocer de dónde vinimos nos ayudará a saber hacia dónde podemos ir y a descubrir si estamos solos en el universo y qué planetas por sus condiciones ambientales pueden albergar vida. Este conocimiento debería redundar en mejorar nuestras condiciones de vida, en reducir el sufrimiento y en alargar nuestra esperanza de vida.

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Juan R. Granja

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