LivingManuel Perucho:

Manuel Perucho:

Can you imagine one of the highest world authorities on oncogenes, cancer causing, smoking Bison, those terrible unfiltered cigarettes? Manuel Perucho used to do it and when he went to Germany to the Max Planck Institute for Molecular Genetics, he rolled his cigarettes himself because tobacco was too expensive. Many years later, in the United States, an asthmatic son would make him stop smoking, a politically incorrect custom given his profession. Between cigarettes, an exciting life of free research and the discovery of some of the unknown mechanisms that produce this genetic breakdown that is cancer.

Why do cancer-causing mutations arise?
-Sometimes I compare this phenomenon with yin and yang. In cells there is a balance between the oncogene and the antioncogene, or suppressor gene. Mutations have two different and opposing origins: those induced by carcinogenic agents in the environment, such as straws, and those that occur due to spontaneous errors in this complex process that is genome replication. Each cell has its genome, the chromosomes; in all, three billion base pairs. As the cell divides, they all replicate. Inevitably, errors occur during the process, both in replication and especially in repair. The cell has a very complicated system to repair them, through proteins. But if the genes that code for repair proteins are damaged by a mutation, they don’t work and spontaneous mutations accumulate. In summary, the mutator phenotype is the new route to cancer, which we discovered in an unexpected way.

Can we say that we carry cancer within but that it is only potentially activated?
-Yes, it is what they call the internal enemy. Fertilization itself is an excessive cell growth: from the zygote to birth, embryonic development occurs, and during it we are capable of producing a very remarkable but controlled cell proliferation, like an accelerated horse that we have well held by the reins. In the same way, somatic mutations can kill the suppressor gene, activating excessive cell growth; we can say in that case that the horse is running amok. Cancer is something that we all have latent.

But in some individuals it manifests itself and in others, it does not.
-Influence environmental factors, random and unpredictable, and endogenous, which are hereditary. It is a predisposition of certain individuals belonging to families in which cancer is transmitted from generation to generation. The mutator phenotype is typical of a very common inherited syndrome in colon cancer, because these individuals already have one of the DNA repair genes, one of the alleles transmitted in the germ line, inactivated by mutation. It is as if you have one of the two columns of the DNA double helix broken. That is why cancer usually manifests itself earlier – around 30 years of age – in hereditary cases and later in non-hereditary cases, because it has to inactivate both alleles.

Can these genetic breakdowns be repaired?
-In 10 or 20 years this will be the hottest field of research, because all oncogenes and antioncogenes will have already been known, and the susceptibilities and resistance related to neoplastic development will be investigated, depending on the genetic differences of the population. Pharmacogenomics can lead to applications based on subtle differences in the repair potency of individual enzymes. Not all of us have the same cellular repair capacity. There are modifier genes that, depending on the genetic context, make it possible for heavy smokers not to develop lung cancer because they have more potential for processing or destroying external agents. This is influenced not only by the activity of one gene but of several, and that is why it is difficult for us to understand it.

Would it be correct to say that all, or practically all, diseases have a genetic origin?
-As we develop the research, we know a greater relative proportion of the hereditary component in cancer and diseases, and a lower proportion of the non-hereditary component. That does not mean that everything is hereditary, far from it. Before, we only knew about 4% of colon cancer cases that were hereditary, but as we learn more, this proportion increases. They are very simple cases in which the mutator phenotype is clearly appreciated. However, there are other less clear cases, in which Mendel’s Laws cannot be applied but a more subtle and weak influence is seen that affects some families. At heart, cancer is a hereditary disease, because it is a disease of the genes, but not in Mendel’s concept of transmission from generation to generation, but in dependence on the mutations that occur in the genes.

Will we use personalized drugs?
-In effect, they will be designer drugs. Due to the subtle differences between different individuals, we can imagine drugs with a certain specificity for each type of population. Based on the knowledge that will exist about the specific mechanisms of action of proteins in certain individuals, it will be possible to design a drug that interacts very efficiently with that protein. We are talking about a term of many years, it is still a bit of science fiction. Pharmaceutical company considerations for profitability will come into play. If a polymorphism only affects 1% of the population, there will be no drugs; if it affects a more significant percentage, they will manufacture it. All these possibilities have been opened by the investigation of the human genome.

Are we a genetically complicated organism?
-We have approximately the same genes as the wormCaenorhabditis elegans, a very simple organism; the difference is in the way in which the expression of these genes is organized. The regulation of the genome makes us, with the same number of genes as an animal, be human and they are mice or worms, vile worms.

Why have pharmaceutical companies led the Human Genome project?
-It is an example of how things work in the United States, the capitalist country par excellence. The Government has the initiative to carry out the Human Genome project because it is important and beneficial for basic knowledge, but the pharmaceutical companies arrive and say: “we do it faster.” The reasons they have is that they believe that this will bring them benefits over gene patents.

The genome is already sequenced. And now that?
-Jim Watson, co-discoverer of DNA, has said that sequencing them was easy, that the difficult thing is to interpret it, that will take a hundred years.

What would it take to be able to make that interpretation?
-Understand how digital information where only 30,000 or 50,000 genes have coding power -a very small proportion compared to 3,000 million base pairs- ends up giving rise to a human baby or a worm; how to go from the one-dimensional world of genetic digital information to the three-dimensional world of man, fly or mouse. Everything is in the information, there is nothing else, but we must understand the mechanisms that are already in the infected egg and that lead to birth, to the complete organism.

Is there proteomics in?
-Yes, because it studies the cascade interaction of proteins in the three-dimensional world of the cell, but that is not enough. It is utopian to think that with the sequence of the genome everything is already done, and proteomics will not be the culmination either. They are fashions. The great challenge is to know how we go from linear to three-dimensional information. An example of what we have advanced is homeotic genes. On the flyDrosophilaToday we know a cluster of homeotic genes that correlate exactly with your body: one is the head, another is the abdomen … How is such accuracy possible? Overwhelms me.

Have you considered working in a pharmaceutical company?
-No, because I consider that research is pure freedom, and entering a pharmaceutical company means being constrained in producing as many or as many potential drugs each year. It terrifies me.

Jose Angel Martos

 

This interview was published in February 2001, in number 237 of VERY Interesting.

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