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12 March 2014

Turning Toxins into Treatments

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We live in a society with an ever greater dependence on science and technology. As evidence for this claim, we only have to look as far as electronic devices such as smart phones, tablets and so on. What’s more this is a global revolution, although it doesn’t affect all countries to the same extent. We are undergoing a paradigm shift in which the differences between people are no longer limited only to the disparity between rich and poor. There is something else, something to do with our understanding of the concepts that underpin the functioning of this technology all around us. However, or perhaps because of this, the rate of scientific illiteracy is on the rise. Technological progress is now of such a standard that it’s practically impossible to keep up with the necessary pace of understanding. If this is true for the professional scientist, it is even more so for the man or woman in the street.

This dearth of knowledge can give rise to paradoxical situations. On the one hand, handling any of these ubiquitous electronic devices is supremely easy. Practically within reach of anyone. Even a child -or more precisely, particularly a child- can quickly learn how to use them by simply using his or her intuition. The global connection between devices in real time is changing our perception of reality and even our way of remembering things. But on the other hand, there is very little genuine knowledge of what is actually going on; practically no one understands the basic scientific concepts that underlie the way these devices work. And here I’m only talking about the matter of “smart device technology”, simply because it seems to me that this is the field that most clearly highlights this paradox, but it can in fact be applied to any field, including the one I am most familiar with, biomedicine. As Prof. Iñaki Vázquez so rightly said at the recent launch of the OpenMind platform last December 2013, we are advancing towards a society of magical instruments (they’re certainly not magical; but we see them as such…). And unfortunately, also relentlessly towards a society that confuses MAGIC and SCIENCE. Even worse, it confuses NATURAL with BENEFICIAL and ARTIFICIAL with HARMFUL.

This confusion is extremely damaging any way you look at it. “Natural” is the Law of the Jungle. If human beings have advanced as far as they have today it is precisely because of the “artificial” things they have developed. We don’t need to look far for examples. If we are nowadays able to eat every day it’s because in the past we artificially developed agriculture and livestock farming. Before this “artificial” development, the “natural” way was to roam around in search of some prey to huntto keep body and soul together; or to collect fruits and berries in the hope that they were not poisonous. As highlighted by Jared Diamond in his emblematic work “Guns, Germs, and Steel” (Pulitzer Prize 1998) there are over 200 different species of natural almonds, and none of them is edible…

There are a large number of poisonous organisms precisely because the Law of the Jungle we mentioned earlier is the natural way. They produce poison, either in order to eat or else in order not to be eaten themselves. We could cite numerous examples, but let us focus on things with limited mobility, essentially plants. They are unable to escape from their predators and are thus obliged to produce powerful toxins to survive. Think of hemlock, for a start. Or who has not had the disagreeable experience of accidentally touching a nettle? These toxins are all incidentally perfectly “natural”. We should stop to consider why plants grown ecologically (in other words, completely artificially like all agriculture) can withstand attack by pests to which their cousins in large-scale agriculture would most certainly succumb. Is it not because they produce toxins? Of course this is a question that requires a complex and nuanced answer, but it is well worth revisiting because normally the answers we hear are extremely simplistic.

One of the poisonous plants I would particularly like to mention is ricin. Yes, the same one that produces the castor oil our mothers used to give those of us of a certain age when we were kids. This shrub produces a protein that is probably the most powerful toxin known to man. It is composed of two “modules” (two subunits, to use the correct term). One of them recognizes a receptor on the cell surface to which it binds very closely, enabling it to enter the cell. Once inside, the other module, an enzyme, acts as an authentic “natural-born killer”, and destroys it by inactivating its ribosomes, the nanomachines responsible for producing the proteins. These characteristics have made it one of the primary candidates in a hypothetical -and let us hope unlikely- biological war.

In our laboratory at the Department of Biochemistry and Molecular Biology I at the Complutense University, we have spent over 20 years studying the action mechanism of a range of toxic proteins.

The idea underlying our research is the molecular study of their behavior. Understanding how they function will allow us -we think- to use them for our benefit. We take our inspiration from the well-known maxim “If you can’t beat ’em, join ’em”. The journal Science has just recognized this strategy as a plausible approach for the treatment of a number of diseases1. And we are now beginning to discover enough about some of them to be able to go into action.

Our oldest line of research focuses on a family of proteins, fungal ribotoxins, which are similar to ricin in that they are also capable of killing cells by inactivating the ribosomes. However, there are significant differences. In the first place they are produced by microscopic fungi which, even though they are also immobile organisms, do not belong to the plant kingdom. The second and more important difference is that they only have one subunit, which combines both the activities necessary for their toxic action: the entry in the cell and the inactivation of the ribosomes. The third difference is that there is no receptor on the cell surface that recognizes them specifically, meaning the ribotoxins are much less dangerous than ricin and making them easier to use for therapeutic purposes.

Our aim is to apply a concept that in spite of having being first framed more than one century ago is still equally valid: the magic bullets of Paul Ehrlich (not to be confused with the ecologist Paul R. Ehrlich, recent winner of the BBVA Foundation Frontiers of Knowledge for Ecology). Following this line of inspiration, we are currently working on the design, production and characterization of chimeric (and thus artificial) proteins that combine the specificity of an antibody with the lethality of a toxin. Using simple genetic engineering techniques we have fused the DNA of a ribotoxin with the DNA on the regions of an antibody that recognizes the characteristic molecule found only on the surface of certain cancerous cells. By doing this we have succeeded in obtaining molecules that do not exist in Nature, but which recognize and kill only the cells of certain colon cancers, and prevent the growth of tumors in immunocompromised rats2,3.

Evidently, there is still a long way to go before we can obtain a really curative molecule, but it appears that not only our research group but many others are moving -albeit slowly- in the right direction.

Álvaro Martínez del Pozo


(1) K. Kupferschmidt (2013) From toxins to treatments. Science 342, 1162-1164.

(2) J. Tomé-Amat et al. (2012) Production and characterization of scFvA33T1, an immunoRNase targeting colon cancer cells. FEBS J. 279, 3022-3032.

(3) N. Carreras-Sangrà et al. (2012) Production and characterization of a colon cancer-specific immunotoxin based on the fungal ribotoxin α-sarcin. Protein Eng. Des. Sel. 25, 425-435.



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