The human genome: A way to read the “book of life”
Fifteen years after the international program
to sequence the Human Genome was launched
and almost a decade after it was published in 2003,
how do the chances of applying this flood of knowledge
look in impoverished countries such as Nicaragua?
Could we gain access to this scientific-technological program?
And what use would it have for us?
Jorge A. Huete Pérez
The saga of sequencing the Human Genome has been modern science’s most significant international undertaking to date. It has been considered the greatest event in the history of contemporary scientific cooperation. Describing the genome could be considered a scientific watershed equal to what Charles Darwin’s Origin of the Species was in its day.
A scientific epic surrounded by controversyIn June 2000 the leaders of the two big genome-sequencing consortia, Francis Collins and Craig Venter, standing on either side of US President Bill Clinton, announced to the world the conclusion of the Human Genome Project. They published their findings, initially in draft form, the following year, with the complete sequence appearing in 2003.
At the inauguration of the First Nicaraguan Biotechnology Congress a few months after the publication of the genome, Dr. Richard Roberts, a Nobel Prize winner, underscored the enormous prospects this “great book of life,” which contains the operational instructions for a human being, holds for science and for social expectations. In his opinion, knowledge of the human genome, which is made up of all the DNA in our chromosomes and in our mitochondria, is a fundamental tool for unlocking the secrets of our genetic heritage and offers the basis for a new, personalized medicine. Given his firsthand knowledge of the intrigues stirred up around the Human Genome Project, however, he also expressed regret about the controversy that, although overcome, left a bitter taste for the researchers involved.
Every great feat has its theatrical side and this one was no exception. The race for the genome finished earlier than envisaged thanks to the competition among those taking part and their bitter disputes. After several years of controversy and at incredible expense, the three billion nucleotide bases—chemical units that make up the human genome—were finally decoded, accompanied by academic and media disputes including accusations of usurping data and technical disqualifications.
How can we prevent illnesses? The great medical expectations raised by this project start from the principle that most illnesses have a genetic factor. With its possibility of detecting pre-disposition and genetic risk, the genome as a new discipline steers medicine towards a more predictive and preventive model.
How are we humans different?
Mapping the genome of the human species has not only awakened interest because of its medical applications. It has also stirred up curiosity about the differences that exist among the various ethnic groups that people the world. Conscious of the rainbow that is the human species, the question arises: How does the new knowledge apply to different human groups? Because if we’re talking about medical applications, it would be neither sufficient nor fair to study only the European genome, as if it was the ‘standard.’ New pharmaceutics would need to be designed to correspond to genetic variations in the wide range of human groups.
Although genome research was initially centered on the study of Europeans, we now have genome sequences of people from diverse origins: China, Mongolia, West Africa... In an effort to make the most of the store of knowledge offered by the genome, different countries have been organizing their own genome programs. The Human Genome Diversity Project, which proposes to create a database that represents the infinity of human groups, stands out among these initiatives. One would think this idea of attempting to reconstruct our evolutionary history would be received with enthusiasm but this by all accounts necessary and exemplary task has not been exempt from criticism and skepticism.
No shortage of prejudice or mistrust When the Central American University’s Molecular Biology Center in Managua presented the results of its genetic research into the Nicaraguan population in August 2005, one newspaper, with typical journalistic license, titled the coverage “Description of the Nicaraguan genome,” without noting that, while important for the country, our study was technically much more modest then the groundbreaking discovery of the human genome in 2000.
With public interest in the genetic characteristics of Nicaraguans thus awakened, somebody ironically insisted that if genomes have a nationality, an explanation would be needed on how the national one differs from that of immigrants. Suspecting discrimination, a sociologist mercilessly assailed the university laboratory on his blog, insinuating eugenic and racist motives on the part of the study’s authors. One could reply by asking if it would be fair to condemn sociological research into homosexuality because it might unleash homophobia and intolerance.
These different reactions and conflicting positions are understandable given that we’re dealing with complex matters, the understanding of which requires technical knowledge. Furthermore, these are issues of public interest. Nonetheless, it’s disappointing that, on the pretext of avoiding discrimination and racism, any genome research is condemned a priori based on unfounded prejudice and mistrust.
Research on Nicaraguan indigenous groups, planned as the logical consequence of our center’s genetic studies, was unforeseeably thwarted by the interference of a foreign cooperation agency in 2005. The Center, armed with obligatory bio-ethical permits and informed consent after having successfully negotiated with the head of an indigenous group in Masaya to involve and empower his community, was all set to identify the genetic factors in cases of diabetes and hypertension which the director of the local health system said were rapidly increasing in the community. But the investigation couldn’t even get off the ground because the aid agency cooperants of a small central European country put multiple obstacles in the way. Using dilatory tactics similar to the sociology blogger, arguing that any genetic research must be rejected with concern and mistrust, the cooperants, who represent a means of support for the indigenous groups that is hard to relinquish, obliged the indigenous leader to withdraw the permission granted.
The ironic tragedy of this case is that, on the pretext of preventing racism and eugenics, these indigenous groups are being denied access to the benefits of science and to discovering their origins and understanding the illnesses that affect them disproportionally, which thus even ends up denying them their self-determination.
Beyond the contempt for science, which has become epidemic among some sociologists, the challenge to overcoming the profound ignorance that exists about the fundamental underpinnings of modern biology in general and the genome in particular, is clear. Contrary to discrimination, it is about celebrating human diversity. The study of different human groups doesn’t seek to prolong discrimination against them but rather to consolidate their identity, accept their ancestral origins and recognize their contribution to the evolution of the human species.
Forensic medical and genetic If scientific research in Nicaragua is incipient, genetics has been one of the least attended areas. In 2011 Nicaraguan researchers published some 70 articles in international journals, but only three were on genetic issues. One of those was the publication of a database on the Nicaraguan population in the international journal Legal Medicine.
research in Nicaragua
Our Molecular Biology Center entered the field of genetic research in the late nineties with the intention of supporting medical research in the country. Our work subsequently extended to forensic genetics in response to a request from the National Police. They wanted our help in solving the murder of four police officers which had triggered impressive national indignation. The officers, on duty in Bluefields in the early hours of May 4, 2004, had been stabbed and decapitated when several men burst into police headquarters.
In connection with these studies, the Center had to identify the genetic profile of more than 50 blood samples the police collected at the crime scene. The investigation determined that the profiles did not incriminate suspects held by the police. Frustrated by the impossibility of resolving the case through the DNA route, police authorities requested support from their Spanish counterparts, but they’re still awaiting the results after seven years. Inexperience in the correct way to take samples for genetic analysis very likely influenced this case.
Genetic identification in rape cases Having established the technology for forensic genetic identification, another obvious application of this technical advance has been the resolution of cases of disputed paternity and responsibility in rape cases. To date the Center has resolved dozens of rape cases whose victims are mainly teenagers and children.
Our investigations corroborate that incest is a high-frequency crime in Nicaragua, with a high incidence of rape cases committed within the family. In 2008 a Managua court sent us the case of a teenager who had given birth to a baby boy as a result of multiple rape. On analyzing the genetic profiles, the laboratory found that the rapist was none other than the teenager’s father, making him simultaneously the baby’s father and grandfather.
Hundreds of anecdotes like this one reveal the social drama suffered by Nicaraguan families and the help this new technology can provide to solving them; they should also serve to illustrate the social and psychological dimensions of domestic violence. Unlike some well-known murder cases and other crimes, rape and child abuse don’t appear to consternate or move the authorities. The truth is that rape is often treated as a minor crime and even accepted as an expression of the idiosyncrasy of Nicaraguan men. A recent emblematic rape was characterized by Nicaragua’s highest court as a “fit of passion” by the attacker. The situation of women and teenagers who have been raped has become even worse since the October 2006 repeal of therapeutic abortion, which placed Nicaragua among the few countries in the world where the termination of a pregnancy is outlawed even when the mother’s life is in danger.
A weapon against irresponsible paternity Organizations working to defend children’s rights believe that more than 35,000 children in Nicaragua are not recognized by their fathers. Considering that the number of children born outside of marriage is increasing, this problem must be understood as extremely important for the country. According to Nicaraguan researcher Oswaldo Montoya, paternal desertion has an influence on the premature insertion of children and teenagers into the labor market to generate income for the family. Almost 25% of children between 10 and 14 years old are part of Nicaragua’s economically active population.
Manuel Ortega Hegg, another scholar on masculinity in Nicaragua, explains that the father’s absence abandonment of his family perpetuates poverty and frequently causes inadequate socialization processes in minors. It is also detrimental to children’s developmental opportunities, thus denying them basic human rights. A few years ago the Paternal Responsibility Law (law 623) was passed in Nicaragua, making a DNA test compulsory for confirming paternity. Although sufficient laboratory infrastructure has been established in the country to allow all the cases in dispute to be easily resolved in less than a year, the law hasn’t made a huge difference because the political will is lacking.
Our genetic profile is like our fingerprint One of the great achievements of our Molecular Biology Center has been to set up a genetic database of the Nicaraguan population. It consists of a series of allelic frequencies, also commonly known as markers. Any interpretation of results, be it paternity tests or genetic profiles of forensic interest, must be based on reference to the specific population group to which the individual belongs. These genetic tests, which provide numerical data and percentages, need the statistical support given by the database of a specific population. For this reason, the statistical support of research into the paternity of a Nicaraguan child cannot be undertaken using a database from China or Australia, populations that differ significantly from the Nicaraguan one in genetic terms.
Using available molecular markers based on the methodology practiced in Nicaragua, each person could be assigned his or her corresponding genetic profile, which could be regarded as a sort of fingerprint or bar code for the individual. For example, in my own case, this code is: 10-11/28-32.2/11-12/10-11/15-16/9-9.3/11-11/11-11/19-23/12-14/16-16/11-12/18-11/12-13/25-26/X-Y.
The usefulness of having this sort of profile has been demonstrated when identifying those disappeared for political motives during military dictatorships or individualizing human remains found in common graves. It is also useful for identifying people following earthquakes, hurricanes, tsunamis and other disasters.
More recently the utility of these techniques and genetic profiles has been seen in the search for youngsters who might be victims of sexual exploitation and human trafficking. This is precisely what one of our own projects is about. Using modern genetic identification techniques, we’re trying to improve the work of several organizations that are combating the trafficking of children and adolescents. In particular, we’re aiming to establish the genetic identity of at-risk minors for whom no biological background is known. In Nicaragua a child disappears every three days. Genetic identification would make it more feasible to prevent the abduction of minors and to repatriate them in cases of fraudulent adoption.
Race is becoming an obsolete conceptMost people are curious to know what defines a normal Nicaraguan, i.e. whether the prototype is tall or short, what color eyes and hair they have, their biometric characteristics; in short, all those features you can see at first glance. Nevertheless, a population’s genetic characterization or “bar code” doesn’t necessarily focus on this kind of information, but rather on characteristics that aren’t necessarily visible or obvious, such as those of medical interest. You can’t tell just by looking whether a person is genetically predisposed to lactose intolerance or are at risk of developing arthritis or heart problems.
The differences we can distinguish, such as skin color, are genetically insignificant and virtually negligible statistically. This is why it’s currently argued that the social concept of race is very different from a genetic interpretation. It has been proven for example, that two Africans taken randomly from anywhere in Africa may be more unlike each other genetically than they are from a European or Asian person. The study of the genome has thrown a lot of light on our similarities and differences, as well as on our social prejudices.
What are our genetic origins as Nicaraguans? Another use for this technology is the study of human migrations. With the help of these technological innovations, it’s possible to determine the genetic structure of the existing populations, their susceptibility to illnesses, their origins and the migrations of their ancestors. Occupying the geographical position of a bridge that connects both extremes of the American continent, Nicaragua is home to indigenous populations with a certain degree of genetic uniformity as well as others that are the result of long mixing.
You can use three types of DNA to study a human population. Two are clearly related to the paternal (the Y chromosome) or maternal (mitochondrial DNA) inheritance and the other to a block of information that could come from either the father or the mother (autosomal and X chromosome inheritance). In Nicaragua, information inherited from the father’s side reveals a predominance of western European inheritance, while that from the maternal line is linked to an Amerindian origin, most clearly the Uto-Aztec groups, Chibchas and Mexican Mayans.
The fact that most of the colonizers were men explains this asymmetry of predominantly European (Spanish) origins through the father and indigenous origins through the monther also coincides with historical documentation that relations between indigenous men and European women were punished. The resultant genetic profile of our population is largely due to the extermination of indigenous people that reduced the original population by up to 95%, giving rise to the predominance of a new group of Nicaraguan mestizos.
Judging by the information coming from the autosomal material unrelated to sex chromosomes, Nicaragua’s mestizo population contains a strong European genetic component (almost 70%), followed by African and indigenous components (20% and 10%, respectively). Genetic studies also reveal a significant paternal and smaller maternal component of African origin related to populations from western and northern Africa.
Since these studies are based on Nicaragua’s mestizo population, which is known to be above 65% of the total population, the results would have to be validated with the results from still pending studies of the most prominent indigenous communities and groups: Miskitus, Ramas, Garífunas, Mayangnas, Matagalpas, Sutiavas and Masayas.
This genome, which we could call “standard” for the Nicaraguan mestizo as it is shared by the great majority of the population, is contributed to both from the genome of indigenous groups that have already disappeared and those still in existence. It would be worth studying them before it’s too late, to be able to vindicate the importance of the contribution of these groups to the national identity. Nicaraguan historian Eddy Kuhl recently revealed the existence of a peasant family in Matagalpa that was probably the carrier of a language thought to be extinct since 1875. According to Kuhl, it could have been the original language of the first people to settle in Nicaragua.
Mexico is at the head Following the Human Genome Project, a catalogue of genome groups from different parts of the world was put together that should facilitate, among other things, the identification of specific characteristics of different ancestral ethnic groups. All this information is incredibly valuable to learning, for example, about differences between groups with regard to a predisposition to certain illnesses. As only the oldest ethnic groups were included, Mexico justifiably set up its own program to study Mexican groups of more recent origins as well.
of genome medicine
Mexico stands out as the only Latin American country with a National Institute of Genome Medicine, specifically created to relate knowledge of the genome of its populations to their precise health problems. Knowing that genetic variations are related to the migratory history of populations, the 65 Mexican indigenous ethnic groups were studied to determine the risk of suffering from hereditary diseases: diabetes, cancer, obesity, high blood pressure and heart disease. The common profile of the Mexican genome is a component of at least 35 indigenous groups. The variations found between mestizos from different areas of Mexico can be explained by the genetic influence of different ethnic groups.
Results from each genome map contribute to the development of pharmaceuticals more suited to one group of individuals from a particular ethnic group and allow for the design of less harmful medicines with fewer secondary or toxic effects. In Mexico’s case, genome studies make it possible to open up new areas of research to correlate genetic variations with different responses to medicines, as well as identify a predisposition to different illnesses such as arthritis and diabetes. The latter is a chronic illness associated with diet, but we now know there are also genes associated with obesity that actually provoke it, some of them identified for the first time in the Mexican genome.
Can Nicaragua enter the genome era? Little by little the cost of genome technology has been going down, making it more accessible. If the decoding of the first genome cost some US$2 billion and took more than a decade, the goal for which hundreds of bio-technology companies are currently competing is for anybody’s genome to be worked out in a few hours for less than US$1,000.
This aim appeared to have been reached on January 10, 2012. Almost simultaneously Life Technologies and Illumina became the first companies to announce that the first sequencing machines were going on the market, although a few technical details still need to be ironed out, among them the speed of delivering the results. Progress is promising and dozens of people, among them millionaires, Hollywood stars and some scientific and cultural celebrities, have already had the privilege of finding out the sequence of their own personal genome.
In Nicaragua we mustn’t have too many illusions for the next ten years. Modern technologies always take time to reach poor nations, where the capacity to join big projects is usually scarce and dispersed. Nonetheless, even without the new massive sequencing techniques, many less developed countries have been making progress with their own innovations. Nor is it necessary to sequence the entire genome of an individual to diagnose their main genetic conditions.
A joint study between the Nicaraguan Alzheimer’s Foundation, the Psychiatric Hospital, the Lenín Fonseca public hospital, Health Ministry doctors and experts from our own center proposes to determine the incidence of Alzheimer’s disease in our country and characterize the genetic risk factors in the Nicaraguan population. An estimated 35,000 people are currently affected by Alzheimer’s in Nicaragua, and as our population’s life expectancy is slowly growing, serious difficulties are foreseen for both families and the health system. A positive note sounded by the study was that the main risk factor, known as ApoE, variant E4, isn’t very common in the country. Nonetheless, variant E2 does occur more frequently in Nicaragua and while these people may be at less risk from Alzheimer’s, E2 is associated with cardiovascular risks. Early diagnosis of Alzheimer’s and an awareness of the risks of getting it allow for implementing preventive measures to delay or avoid it.
As we can see in the case of Alzheimer’s, available knowledge can be used to make innovations in some diagnoses based on identifying some well defined markers. It’s proof that small, impoverished countries like Nicaragua can also use genomics to find solutions to specific problems.
Isn’t it too expensive for Nicaragua?Nicaragua’s present population is mostly made up of mestizo people, while including significant indigenous and Afro-descendant populations. Although few genetic studies have been done, we have enough elements to conclude that the Nicaraguan population’s genetic structure is rather peculiar, displaying its own unique characteristics. This genetic differentiation is reflected in its diverse propensity to and risk of illnesses, which would merit a different medical approach for different cases. In light of this new awareness, Nicaragua should set up a genome medicine program that fuses a new approach to care with scientific investigation aimed at improving health care, as increasingly more countries in the region have been doing.
Although initial investment could appear significant, resources would ultimately be saved in the treatment of chronic degenerative diseases such as diabetes and cancer that currently head the list of our country’s serious public health problems. It’s about taking advantage of opportunities offered by new technological applications in medicine to contribute to social development and improve people’s quality of life.
Where to start in our country?The starting point for a genome program in Nicaragua is human resources. Exploiting the national strengths we already possess in epidemiological research, it’s worth linking them up today with the centers or institutes with genome research potential, favoring training for young people with a talent for clinical research. Considering the lack of current capacity, efforts could focus on five or six big health problems affecting Nicaragua’s population that would benefit from the innovations in genome medicine.
Genetic characterization of Nicaragua’s population would also help detect our propensity for genetically-based chronic, metabolic and neurological diseases, which would facilitate the treatment and prevention work provided by the national medical community. To attain this objective, doctors would need to know more about the basics of molecular biology and keep up to date with scientific literature.
Taking advantage of the new models for doing science, which are increasingly more collaborative, multidisciplinary and international, could also encourage synergic growth with the national and regional biotechnological sector, which has been getting more dynamic in the past decade. In this way we would be gestating the embryo for future national genome development, similar to what’s already happening in neighboring countries. The success of these coordinated efforts would also have an additional impact on the development of biological and biomedicinal sciences.
The corruption “gene”A worrying parenthesis has to do with the damage caused to research possibilities by the atmosphere of generalized corruption our country suffers.
Once the Human Genome Project finished, Craig Venter, the great guru of genomics, went off to explore the ocean and study the genomes of marine microorganisms. During his voyage (2003) he sailed from the Bermudas in the Caribbean to the Panama Canal. In an international Biovision conference held in Lyon, France, Venter referred to the obstacles he encountered, making particular reference to the corruption he faced in some countries. He mentioned that in his trip through Nicaragua they hindered his access to research permits, imposing exorbitant bribes. As well as being disgraceful, this violates international agreements and acts to the detriment of national scientific cooperation.
In his research, Venter discovered several million new genes, some with potential for the design of new pharmaceuticals. How many new applications could have come from cooperation with Nicaraguan laboratories? How many patents benefiting the country could have been negotiated?
The big obstacle is cultural taboosFirst of all, as with any innovation, successfully implementing a genome program requires a nurturing environment that favors change in the educational paradigm. We know this is a prickly challenge, but the possible results, both in response to national needs as well as in education, justify this effort.
Genome research touches profound and inextricable matters such as the origin and complexity of life, so special attention must be paid to the need to educate the population on these subjects. To achieve maximum benefit from the new technological resources, it’s essential to raise the population’s awareness, promoting growth in human talent through forums, talks and courses and through information and outreach policies on their optimum use. It is also necessary to establish a suitable legal framework, as is done with other technologies of equal impact.
Among the current challenges we find lack of interest from the State, scarce human resources and financial limitations, all of which are resolvable. The Mexican experience shows the important role the State can play in promoting this development. Also, as has been seen in the history of Nicaraguan science, the determination of those interested can bring about some progress even without state support.
Whenever investment in science and technology is suggested, the first argument against it is that poor countries don’t have the money and have other urgent priorities. The many obstacles to research are also mentioned. But clinging statically to the difficulties discourse can have disastrous consequences. Pessimistic attitudes keep our country under the thumb of mediocrity.
For countries with little scientific heritage like Nicaragua, perhaps the most important challenge is rooted in counteracting cultural taboos, whether our own or those imposed from outside, that perpetuate ignorance. Anti-genome or anti-scientific positions would appear to be trifles pardonable because of their ingenuous or idealistic nature, but for small countries such simplification is an unacceptable luxury.
All these challenges pre-suppose the obligation of overturning institutional barriers and obstacles and improving the system of teaching science, energizing it so that it stirs up a thirst in young people for new ideas. In spite of the institutional voids and the generalized disdain for the law in Nicaragua today, a better educational and scientific-technical effort could encourage greater citizen empowerment and commitment to the changes our country needs. In this way genome science will open another path for us towards the future and development.
Jorge A. Huete Pérez is a molecular biologist, director of the Central American University’s Molecular Biology Center in Managua.