Pioneering Contributions to Genomics and Personalized Medicine

I. ORIGINS OF THE GENOMIC REVOLUTION

The Nobel Prize winner Dr. Renato Dulbecco proposed sequencing of the human genome in 1985 to strengthen cancer research and many scientific leaders adhered to his idea. In 1988 the US government entrusted the Human Genome Project (HGP) to the Department of Energy which collaborated with the National Health Institute and prestigious investigation centers in US, Europe, and Asia. In Latin America, my laboratory was named by the UNESCO headquarters as the center for regional development of the HGP and hosted no fewer than ten theoretical-practical courses. The HGP formally began in 1990 to reveal the complete sequence of accumulated hereditary material on our cells chromosomes. As a result, scientists aspired to learn how many genes constitute an entire genome, to bring greater understanding to the species’ evolution, identifying genomic variations that differentiate people, populations and ethnicities, as well as determining the genetic roots of illnesses and the variations in response to medicine from different patients.

In April 2003, on the fiftieth anniversary of publication on DNA structure by James Watson and Francis Crick, the project was officially concluded with a statement from the White House informing the North American population and the rest of the world that our genome consists of around 3 billion pairs of nucleotides (A, G, C and T) and is made up of approximately 23,000 genes, of which the regions that direct the synthesis of proteins (exons) barely represent 2%.

Throughout the human population, the genome contains similarity of up to 99.9%. The remaining 0.1% that distinguishes individuals is made up of around three million Single Nucleotide Polymorphisms (SNP).

II. PROVIDING EVIDENCE OF THE FEASIBILITY OF THE HGP

The fact that the HGP had managed to gather funds by the beginning of 1990 was made possible thanks to lobbying from Watson, among others, before the US Congress, in addition to numerous scientific and technological advances that were pivotal to considering the project feasible, despite its scale and considerable complexity for that time.

Whilst maintaining proportion, our daring project to manually sequence the chromosomal site or locus of the Human Growth Hormone (HGH) - which also houses the genes for normal human growth hormone (hGH-N), human growth hormone-variant (hGH-V) and human chorionic somatomammotropin (CSH) - was recognized as the most direct predecessor and one of these key pieces The information gathered on this locus (~66,500 nucleoids; which we will refer to as chapter GH of HGP), will become a mine that we have to excavate to extract the basic applied value of genes and other elements, allowing us to illustrate how genomic information can contribute discoveries that can later be transformed into biomedical and clinical innovations.

III. FROM GENERALIZED MEDICINE TO PERSONALIZED MEDICINE

The HGP accelerated the discovery of the genetic causes of many illnesses and, as a result of this knowledge, the development of new laboratory exams for diagnosis, classified in subtypes, evaluate the risk of hereditary illnesses, diagnose the course that the illness will take and even predict the response they will have to treatments. At these levels genomic medicine is referred to as Precise or Personalized Medicine, which in relation to pharmochemicals and its search to explain variability, is called Pharmacogenetics. When referring to medication such as the new biological bases (biomedicine) in which the goal is to anticipate if there would be a response or not, should a cell alteration be present or not as a result of a gene mutation, it is called precise or personalized medicine.

Pharmacogenetics and personalized medicine brought with them the new mantra of modern medicine “the right doses of the right medicine for the right patient at the right time,” revolutionizing the concept of the same pill for all patients with the same illness, and converting it into a different pill for each illness according to the individual characteristics of that group of patients. As a result patients are connected at a genomic level with the correct treatment, avoiding not only ineffectiveness, but also adverse effects that can even lead to fatal consequences. This validates the idea suggested by Hippocrates almost 2,500 years ago, that “it is far more important to know what person has the disease than what disease the person has.”

The causes of a drug being ineffective or toxic are varied. Diverse studies have discovered that certain SNPs present in genes of the proteins responsible for absorption, transport, metabolism, and elimination of drugs (processes jointly referred to as ADME) can be the reason for the level of success of a given drug. The branch of genetics that studies these genes is called pharmacogenetics and is sometimes interchangeable with pharmacogenomics.

IV: PROOF OF ACCOMPANIMENT OF PERSONALIZED MEDICINE

The concept of the existence of particular cellular conditions that are necessary for a medicine to work is not new. For decades, and certainly well before our HG concept was completely formed, it was well known that those children that lacked the gene responsible for the hypothesis of normal growth hormone production (hGH-N) did not respond to injections of the artificial version created with genetic engineering or reengineered HGH (HGHr), because their immune systems detected it as a foreign object and produced antibodies to eliminate it from the body.

When my colleagues in paediatrics heard about our world record involving the human genome they suggested a new challenge for me: to find a way to be able to distinguish the infants a priori that responded and those that didn’t. This challenge motivated me to develop something that, up to that point in time, had been the first diagnostic test of accompaniment invented in the world, to the extent that this case pre-empts the effectiveness of the treatment of slowed growth as a result of a hormone deficiency.

V. REWRITING HGP

Just as described above, translating the discovery of the complete sequence of the hGH locus into a method that would, for the first time ever, facilitate the distinction of infants with a hormone deficit and could benefit from the artificially engineered hormone, was the means for us to become pioneers in two major revolutions in biology and medicine: the HGP and personalized medicine, the history of which is summarized in the box below.

1.  In 1985, the Nobel Prize winner Dr. Renato Dulbecc, reflected that the best way to advance cancer research would be through human genome sequencing.
2.  In 1989, Chen and colleagues sequenced the locus of the growth hormone, supplying crucial evidence to the feasibility of the human genome.
3. In 1990, the HGP was debuted.
4. The first draft of human genome sequencing was published in 2001.
5. The sequencing of our 23,000 genes was registered in 2003.
6. The GenBank became the reference for biology and medical investigation (genetic variation).
7. In the 1990s, the idea of designing individually tailored treatments according to each patient’s genome was conceived, but rarely applied.
8. In 1994, Everardo González defended his thesis on the topic of designing a new method via PCR for the DxM of hGH locus deletions.
9. In 1998 the FDA approved the monoclonal antibody (mAb) anti.EGFR Herceptin® for expressed breast tumors.
10. That same day the diagnostic HerceptTest packet was approved as an accompanying test for said expression.
11. As a result of this group of patients, Herceptin® became the first personalized product/ diagnostic package approved by the FDA.
12. The FDA labelled, recommended or requested accompanying tests for a growing list of cancer therapies, cardio-vascular illnesses, transplants, neurology, and psychiatry.

Currently, it is estimated that up to half of drugs in the development process target cellular alterations that result from genome mutations, which means that their approval will be conditioned by the FDA to accompany therapeutic use with the molecular test that reveals the genomic condition which is indispensable for its efficacy and safety

VI. THE BUSINESS OF GENE DIAGNOSIS

Routine genetic and genome diagnostics are not yet offered either in hospitals or laboratories. This is because it is a highrisk business, since the market is only beginning to prepare to adopt this radical technological change. Moreover, the medical community is not yet sufficiently informed to understand its findings and reach, an indispensable element to organize and incorporate its results into clinical practice. Furthermore, in some cases, not even laboratories that claim to be dedicated to Molecular Biology, possess all the necessary information to offer validity and necessary utilities, especially when many discoveries and genomic predictions have not yet begun to corroborate with clinics’ follow-up, which can sometimes take years of patient care.

Since this requirement of expertise is combined with necessary sophisticated experimental infrastructure as well as considerable investment, in addition to highly skilled personnel and prepared executives to manage the business world, SMEs such as ours, dedicated to Molecular and Genomic Biology, are the most suited to sparking off this kind of promising business - more so if they join alliances with visionary investment groups in the health sector. There are many companies that, having begun as SMEs in the US and having a solid base early on, are becoming huge success stories. One can hope that in our country we will continue to be actors, not just spectators, in this genomic revolution.