Prevention from the genes?

Although Cuba has experience in the identification of genetic predisposition to diseases and the standardization of biomarkers, it still has shortcomings when it comes to clinical practice and precision medicine.

Anthropologist Fernando Ortiz (1881-1969) defined Cuban identity through the use of the "ajiaco" (stew) metaphor. In other words, the inhabitants of the Caribbean island are the result of a mixture of ethnicities, cultures, and languages that fusioned to become their own customs, practices, and manners.

The current people of the country are the direct result of a process of acculturation. Some have even studied it, approaching the genetic complexity of the Cubans from within the social & humanistic sciences, from applied linguistics, and even from historical sources. Others have resorted to other natural sciences such as Medicine, Biology, and Chemistry to decode the Cubans genes.

In mid-2007, a group of researchers empirically observed that the number of elders with lighter skin tones affected by dementia and diseases, such as Alzheimer's in Cuba, was higher than the number of those with darker skin.

Motivated by this observation a group of local geneticists designed an ambitious research project that sought to question whether "the African ethnic component that comes from the enslaved ancestors of many Cubans conferred their descendants any degree of genetic immunity against these types of diseases".

After several years of research their results have started to appear in numerous academic publications, including international journals of high scientific impact.

The team of geneticists, led by Dr. Beatriz Marcheco Teruel, arrived to two main conclusions. Firstly, they demonstrated that the skin color of the participating individuals did not correspond to their true generic ancestors. On the contrary, the DNA samples obtained from the subjects showed a high mixture of genetic information. Regardless of their skin tones, all participants had genes of both African and European origin.

Secondly, the study evinced that the higher the proportion of genes from Africa, the more likely it was that people were the carriers of a risk variant in the apoliprotenin E gene. This is the gene responsible for transporting cholesterol, and it enhances the predisposition to suffer from some cardiovascular diseases and dementia. The hypothesis that skin color could be related to suffering or not from diseases such as Alzheimer's was entirely discarded.

Nonetheless, little by little the main objectives of the research project suffered transformations. Currently, it has led these scientists towards a line of inquiry that is expected to help, first reconstruct, and then understand, the genetic origin of today’s Cubans.

Although the results obtained were not those anticipated by the leading experts, this scientific endeavor has laid the foundations for the expansion of the scope and mission of the Cuban National Centre for Medical Genetics (CNGM). Created in 2003, at present the main function of the CNGM is to coordinate the nationwide program launched and supported by the Ministry of Health Care (MINSAP) for the early diagnosis, management, and prevention of genetic diseases and congenital defects. The CNGM is also the leading institution in expanding the development of personalized medicine in the Greater Antilles.

Beyond science fiction

Professor Robert Williamson who works at the Murdoch Institute for Children's Research of the University of Melbourne in Australia and is a leading expert in genome studies, has defined personalized medicine as one of the major challenges for the 21st century.

Williamson who has shared his expertise with Cuban scientists affiliated with the Cuban Academy of Sciences (ACC), has pointed out that the concept of personalized medicine implies a transformation in the process of decision-making regarding the treatment and/or prevention of diseases.

“Now it is all about adapting medical procedures to each patient. To achieve this we must take as a departure point their genomic and molecular characteristics and consider their clinical situation, and even their lifestyle habits”.

According to Wiliamson, personalized medicine as a medical model on the rise is already having significant results in key areas of healthcare. For example, early interventions during pregnancy or during neonatal care can prevent or correct handicaps, make more effective cancer therapies, and reduce the impact and morbidity of diseases that typically affect elderly people.

“Although personalized medicine is a useful tool for oncology, it has spread to fields such as cardiology. The more traditional clinical approaches to determine whether a patient is at risk of suffering a heart attack today are generally insufficient. We need to study patients more from the point of view of their genetic information and assess their individual conditioning factors,” asserted Professor Williamson during his presentation in Havana.

Hilda Roblejo Balbuena is currently the head of the Department of Teaching and Researching at the CNGM. In this capacity, she is responsible for supervising all studies coordinated by this institution as well as overseeing the training of the researchers affiliated to the CNGM.

When interviewed for this article, Roblejo Balbuena told us that as in many other countries, Cuban scientists linked to the study of genetics, had high expectations regarding the Human Genome Project.

“By 2003, scientists had managed to decode DNA. All this information led to the possibility of identifying the predisposition to diseases and establishing prevention strategies, but it also brought a paradigm shift in the practice of Medicine."

This means that scientists around the globe also hope that personalized medicine will lead to an increase in people's quality of life. Albeit the main results of decoding DNA thus far are mostly connected to the direct fight against specific diseases, experts hope that it will also become a way to strengthen preventive medicine in the future.

The genetic data collected would contribute to facilitate the early identification of possible diseases or harmful conditions. According to Dr. Diana García, tenured professor at the Latin American School of Medicine (ELAM), taking genetics into account could help in making decisions about possible courses of treatments for each individualized patient or, even, foreseing the appearance of diseases.

“It would be ideal that each doctor could have access to the genetic information of their patient and, based on it, they could identify what the individual is predisposed to , and then, establish preventive actions. Also, diagnosis would be facilitated by the histological variable of the disease. The , a third step would be the treatment”, said Dr. García.

This new health model aspires to have records of the genetic codes of as many patients as possible. But, putting into practice all these potentialities of personalized medicine is not an easy task, even for wealthy and developed countries these health strategies are costly.

Dr. Gerardo Guillén, Director of Biomedical Research at the Centre for Genetic Engineering and Biotechnology (CIGB) in Havana, has pointed out for this piece that the quest for potential diseases is not a simple process.

"Biomarkers are the most effective methods for early disease detection and they help ensure the efficacy of personalized medicine. The problem is that these must be validated in specific populations. It may be that a certain marker works for Europeans or Caucasians, but it does not work for Africans or Asian ethnic groups,” said Dr. Guillén.

Nonetheless, Roblejo Balbuena told us that Cuban health authorities, as well as the current government’s administration, support the growth of personalized medicine on the Caribbean island. They are supportive of personalized medicine in spite of being aware of the scarcity of resources at their disposal to fully practice personalized medicine in Cuba.

On a Caribbean island

The Cuban province of Holguín is one of the five located in Eastern Cuba. It is famous worldwide for the richness of its nickel and cobalt mines. However, in health and epidemiology, Holguín province’s name resonates for other reasons.

The World Health Organization (WHO) has recognized that the province of Holguín is the territory with the highest concentration of patients with Hereditary Ataxias in the world. The territory has a prevalence of 8.91 per one hundred thousand inhabitants, and Hereditary Spinocerebellar Ataxia type 2 (SCA2) predominates.

The largest number of people affected by this subtype is concentrated in Holguín (with an incidence rate of 47.86 per 100,000 inhabitants). Several different studies have identified inbreeding as the fundamental cause of the the disease in the Holguín province .

Dr. Jacqueline Negrero Montero, Director of the Centre for Research and Rehabilitation of Hereditary Ataxias (CIRAH), revealed to us the most recent numbers of the incidence of the disease in Cuba. These results were update in an epidemiological study carried out between 2017 and 2018.

“Today there are 848 cases of patients with SCA2 identified throughout the country, belonging to only 124 families. In addition, a total of 9,791 relatives of the patients have been identified as being at risk. These figures show that this condition is a serious health problem in Cuba,” said Dr. Negrero Montero.

Personalized medicine has become a valuable tool for the early diagnose of those people who could end up being victims of this genetic disease in the future.

“At CIRAH we have established two predictive diagnostic programs for presymptomatic patients. The first one is offered to people over the age of 18 who are direct descendants of patients with Ataxias. It should be noted that this condition is inherited in an autosomal dominant manner. In other words, each descendant of a confirmed patient has a 50 percent chance of inheriting the SCA2 gene,” stressed Negrero Montero.

People interested in knowing their "genetic status" have access to testing free of charge. This is one of the principles of Cuban Medicine since 1959.

“Medical tests help determine whether or not people carry the gene. If it is confirmed that they do, this information becomes very valuable to them. It helps them make life decisions, whether in matters of reproduction, family planning, professional careers , and others,” said Dr. Negrero Montero, Director of CIRAH.

The second program devoted to identify SCA2 in direct descendants contemplates studies during the gestational period. During pregnancy, those couples who know in advance the incidence of Hereditary Ataxia in their family can also voluntarily approach CIRAH and have access to testing.

Through this alternative, future parents are informed whether or not their child is a carrier of the gene responsible for the developing the disease. According to Negrero Montero, once they have this knowledge at their fingertips, doctors present different options to them, including termination of pregnancy.

However, this prenatal predictive diagnosis program has been on hold for almost four years.

“At this time, due to various economic difficulties in Cuba, we do not have a gene sequencer. This technology allows us to know the size of the mutation with greater precision”, emphasizes Dr. Negrero Montero, head of CIRAH.

But, is it that the country does not have a gene sequencer device for these predictive diagnostic programs? We asked Dr. Negrero Montero.

“No, we had one in the past, but it happens that technology evolves and the equipment that we had was discontinued, and we couldn’t access backup parts for repairs, and until the present moment the country has not been able to acquire a new one,” Negrero Montero replied.

So, how is the presence of SCA2 studied in people over 18 years of age?

“We are at present carrying out semi-quantitative analyzes and other expanded methods with a certain degree of precision. In addition, we are participating of collaborations that are organized through the CNGM”, commented Dr. Negrero Montero .

After discussing this point with Dr. Hilda Roblejo Balbuena, the researcher pointed out for us that:

“Through international collaborative projects, the genomes of a group of Cubans have been sequenced, and on that basis, at least some work is being done on creating databases of those patients. Furthermore, they are required to be referential, because experts must compare and have an estimate of how the different biomarkers behave in the population”.

Roblejo Balbuena also emphasized that independently, without external aid and collaboration schemes, Cuba has the capacity to do PCR tests in real time. There is currently no infrastructure in the Cuban national territory for sequencing the complete genome of an individual.

About the possible acquisition by Cuba of the necessary tools for conducting these studies, the head of the Department of Teaching and Researching of the CNGM, Dr. Roblejo Balbuena, said:

“The technologies that are mainly used are difficult to obtain, but this does not mean that we do not have tools with which to advance in the field of personalized medicine. The current sequencing of the human genome - Next Generation Secuency - is largely based on equipment developed in the United States of America. Due to the economic blockade (embargo) that that country has imposed on Cuba for more than 60 years, the island's access to this equipment is difficult ”.

Despite these drawbacks, Cuban doctors consider it necessary to follow the tracks and innovations in the field of personalized medicine.

Looking to the future

Professor Gerardo Guillén, from the CIGB, stressed that Cuba has been immersed in cancer research through biomarkers for several years. The CIGB has even lead important studies of potential treatments with biopharmaceuticals developed on the island. However, the Professor Guillén asserted that the country is proposing new goals.

“What is relatively new is that at this moment there is a nationwide multidisciplinary group that will implement a proposal for a new national program related to personalized medicine. This project has the participation of BioCubaFARMA business group, of CNGM, of the Centre for State Control of Medicines, Medical Equipment and Devices (CECMED) as the regulatory authority, and, of course, MINSAP”.

To verify this information, a request for information was sent to MINSAP. The government entity responded by email that "for any details on this regard, the CNGM specialists who are in charge of the project should be contacted."

Once again, Dr. Hilda Roblejo Balbuena answered our questions.

“The National Center coordinates this program. It is a project that seeks to reinforce, among other elements, the training of our doctors. Furthermore, personalized medicine can be a valuable ally in facing the challenge of the growing aging population that Cuba is experiencing today. To the extent that we can determine the genetic predispositions to common diseases of elderly people we will then establish better dynamics for their prevention. Sometimes it becomes a slogan, but prevention is undoubtedly what will make our health system have better results.”

Regarding the objectives and other more specific tasks of the Cuban personalized medicine program, the researcher clarified that these elements cannot yet be shared with the public as they are in a process of improvement.

On the other hand, PhD Eduardo Pentón Arias, member of the ACC and founder of CIGB, added to this report that several Cuban entities, in the health sector plan to create a research group at university level to improve the scientific preparation of those specialists who wish to expand their training into this new medical practice / field.

Moreover, a university level program on Informatics and Biology has also been created. It is devoted to training specialists who, in the future, could dedicate themselves to the interpretation of the data collected through the sequencing of the genome of a larger sample of individuals.

In general, Cuba has done an extensive work in the identification of its population’s predispositions to diseases. The standardization of bio-markers has been given priority by the highest Public Health authorities and received government support. When the technology at present on the island is not sufficient, collaboration with international institutions has been encouraged. . However, the execution of better clinical practices remains pending, the efforts of the researchers interviewed seem to be focused on maintaining a continuous preparation on the academic level that will allow them to be ready when “better times” arrive in the future.

Claudia Alemañy Castilla won second Prize in the International Journalism Competition in Personalised Medicine organised by SantePerso.