5 The
labyrinths
of DNA

• Mayana Zatz is a professor of genetics at the University of São Paulo (USP) Biosciences Institute. She has an undergraduate degree and MA in biology and a PhD in genetics, all from USP, as well as a postdoc in human and medical genetics from the University of California. She is the coordinator of Brazil’s Human Genome and Stem Cell Research Center and the National Institute for Stem Cells in Genetic Diseases. She has authored hundreds of scientific papers, been a columnist for Veja magazine, and worked as a reviser for Science magazine. She is the author of the book “GenÉTICA: Escolhas que nossos avós não faziam” (Globo, 2011).
  
  Eliana M. Beluzzo Dessen is a professor at the Genetics and Evolutionary Biology Department of the USP Biosciences Institute, and the coordinator of the education/outreach area of Brazil’s Human Genome and Stem Cell Research Center. She has an undergraduate degree in biology from USP, and an MA and PhD in genetics from the USP Biosciences Institute. She has worked on several projects aimed at developing new methodologies to facilitate the teaching of genetics, at universities, high schools and in continued education for public school biology teachers. She is the editor of Genética na Escola magazine.

Would you like to know everything that is written in your DNA? Test which genetic diseases may affect your health and perhaps, in future, determine your lifespan? And choose which genes you would prefer to pass on to your children and which ones to cross off the map?

What would you do if you could decipher the information contained in your genome?

Every day, geneticists have a fine balance to achieve: if they are not sufficiently bold, they will not access new fields of science uncovered by DNA sequencing; but if they are too bold, they will go beyond ethical boundaries.

Unlike results found in clinical tests, such as those that measure cholesterol or blood glucose, the alterations found in a DNA test do not change. They remain the same throughout our lives. Thus, the results of a genetic test can have a major impact on our life, affecting family relationships and decisions about having children. Therefore, before revealing a diagnosis or predicting a genetic condition, it is fundamental to discuss the implications of this knowledge, why we want to know it, and what will be done with the obtained information.

To this end, it is first necessary to consider which of our characteristics depend on our genes and which on the environment. In some cases, genes are determinant, meaning they are not influenced by the environment (our blood group, for example). In other cases, the environment is determinant (regarding whether we learn to read and write, for example). For the majority of characteristics, however, there is an interaction between our genes and the environment, activating or silencing genes. Understanding each factor’s role is crucial in order to interpret a genetic test, manipulate the environment (such as through the diet of people with a tendency to suffer from diabetes) and, in future, manipulate genes, so as to achieve desired goals.

According to American biologist Edward O. Wilson, [1] who coined the term “biodiversity”, biology is a three-dimensional rather than a linear science.1 And the code of life, DNA, should also be read in three dimensions. In Wilson’s view, “the first dimension is the study of each species at all levels of biological organization: from the cell to organisms, populations and the ecosystem. The second dimension is the diversity of all species in the biosphere. Finally, the third dimension is the history of each species, encompassing both its genetic evolution and also environmental changes that orchestrated its evolution.”

A large part of the future of biology depends on adopting an interdisciplinary approach to permit a tour of these three dimensions. The starting point is not simple, not even when we examine a cell. Unlike a “bag of molecules”, a cell consists of a functioning biological system, it has basic components – such as DNA, RNA and proteins – with interactions between these components and with the environment. The property that emerges from this biological system – defined as follows – is life.

This awareness of a whole that is greater than the sum of its parts marks 21st-century biology. Unlike the reductionist theories of the past, a biology of systems is now emerging, whose objective is to explain how complex behaviors arise from collections of simpler components. In turn, this knowledge enables synthetic biology, whose goal is to recreate an unnatural chemical system with the properties of living systems, including genetic inheritance and evolution.

All biological systems are complex. They are like living labyrinths; pyramids full of corridors, halls and secrets to be deciphered. Systems are not linear, and when their individual components interact, they create so-called “emerging” properties and functions. These properties can only manifest themselves if the organism is seen as a whole; otherwise it is like getting lost in a three-dimensional labyrinth, without noticing the pyramid.

Even the simplest life forms have unpredictable emerging properties, presenting enigmas for traditional engineering. Understanding the behavior of biological systems, at their various levels of organization, depends on studying the complex, dynamic interactions between their components. This calls for detailed mathematical models of the biochemical and biophysical structure of systems, to experience simulations and, perhaps, arrive at the desired forecasts.

In 2001, the first draft of the human genome was published. In 2003, two years ahead of schedule, Francis Collins and Craig Venter announced the completion of the sequencing of the human genome, although new genes were still being discovered. However, to understand how genes function, how they interact among themselves and with the environment, will require another 100 years of research.

Determining genes that start to function or are silenced, for example, depends on several “epigenetic” factors, which are still the subject of much research. They may vary in line with the type of cell or age. Genes that express themselves during embryonic life or during growth, for example, may be silenced in the adult phase. A same genetic mutation may determine a genetic disease in one individual, while in another individual the conditions to activate this gene may never occur. Understanding what protects some people from the harmful effects of a mutation is of great interest as it may result in new treatments.

In 2001, the first draft of the human genome was published. In 2003, two years ahead of schedule, Francis Collins and Craig Venter announced the completion of the sequencing of the human genome, although new genes were still being discovered.

People with the same mutation responsible for a genetic disease may present completely different clinical conditions, just as, on another timescale, in the spiral of evolution, common ancestors gave rise to very different species. The primary source that originates diversity is mutation, meaning DNA sequence alterations, which may be caused by events occurring during the duplication of DNA or mutagens such as radioactivity, ultraviolet rays or carcinogenic drugs.

Natural selection operates on new sequences generated through mutation: the diversity of life forms on Earth arose from mutations selected in line with the highest reproductive capacity over time. From the very first cell’s DNA, through mutation and recombination mechanisms, there arose an infinity of life forms on Earth.

The time dimension – evolutionary history – shows us how all living beings are to a greater or lesser extent related to each other. Some percentages of shared sequences between the human genome and those of other species are astonishing: we have 95% in common with chimpanzees, 89% with mice, 45% with fruit flies, and even 9% with E. coli, a bacterium found in people’s intestines.[2] This similarity is an indication of the common origin of all living beings and enables the analysis of divergences from one species to another.

Genome sequencing is a way of “reading” the order in which the bases (“letters”) are arranged in a molecule. Once the sequence of bases – the message contained in the molecule – is known, there begins a long and complex study to analyze and understand its meaning. Computers and special programs are used by bioinformatics specialists to predict the location of genes, in other words the segments of the sequence corresponding to protein synthesis information.

The next step is to predict the genes’ function, which is done by comparing the new sequence obtained with well-studied model organisms. Comparison of the genes of different species also makes it possible to infer kinship between these species, establish evolutionary relationships between them and determine the importance of essential genes, conserved through evolution. This comparison may also be made between individuals of the same species, but with different functions, such as social insects organized into castes – ants and bees, for example.

Some species even constitute a super-organism formed of interdependent organisms, which come together to cooperate to solve survival problems. The individual intelligence of army ants is minimal, but together they make up one such super-organism. Using their collective intelligence, they march through the forest, creating their own paths, killing and devouring everything in their way. In the early evening, they pile up so as to form a protective shield with the worker ants on the outside and the young larvae and queen at the center. At dawn, the living ball disassembles itself and the cycle restarts. There is no central controller: collective intelligence creates patterns, uses information and evolves. In this case, the DNA sequence of each ant is the same, but the individuals in each caste take on distinct characteristics, based on epigenetic alterations. In other words, their DNA acquires “marks” and some genes may be silenced or activated.

Human beings also coexist with a huge population of microorganisms (bacteria, fungi and viruses), called microbiota. We have 10 times more microbes than cells, which are born with us and accompany us throughout our life, and which also form a “super-organism” with us. The role of the microbiome, which greatly influences our health, has been the subject of numerous studies. Understanding the relationships between the information contained in DNA (genotype) and phenotype (characteristics) is a central goal in genetics. The biggest challenge lies in our capacity to manipulate, interpret and translate, through predictive models, the enormous quantity of data generated by new molecular analysis technologies (next generation sequencing). This requires the development of bioinformatics and the creation of massive databases.

Through the development of knowledge and the capacity for analysis, science can go far beyond diagnosis. The cloning of Dolly the sheep in 1996 by Scottish researchers demonstrated for the first time that an adult mammal cell could be reprogrammed, return to the embryonic stage and give rise to a copy – a clone – of that animal. The great post-Dolly revolution paved the way for research into stem cells, the future of regenerative medicine.

Adult stem cells, found in adipose tissue, the umbilical cord, dental pulp and bone marrow, among other tissues, have the potential to form fat, cartilage and bone. When injected into model animals, they have been shown to be clinically beneficial for their immunomodulatory role, reducing inflammation, enhancing blood circulation and improving the tissue environment of the recipient organism.

Moreover, mature adult cells, removed from humans or other animals, can be reprogrammed to turn into induced pluripotent stem cells, which have the capacity to generate all types of tissues. They are very similar to embryonic stem cells, but they are not identical, as they retain the “memory” of where they were removed from.

In the near future, bioengineering will make it possible to fabricate or “repair” organs in laboratories. People with heart problems, for example, will be able to have their heart removed, “replaced ” with tissues and/or valves regenerated from stem cells, and then put back in place. We will have organ repair “workshops.”

In agriculture, the genetic improvement of crops is already making an enormous contribution to food production and the reinforcement of resistance against adverse weather, salinity, pests or diseases. Geneticists are now working to accelerate these processes, through molecular markers, genetically modified food, cloning and even synthetic genomes.

By manipulating genomes at this level, bioengineers deal with tens of thousands of genes that make up the DNA of each being. In our organism, around 20,000 genes permit the manufacture of all proteins. Together, however, they only occupy 2% of human DNA molecules. Until very recently, the remaining genes were treated as “junk DNA”: “useless” genetic sequences whose function was unknown.

Nevertheless, these genes are certainly not junk. Quite the opposite. More than 30 papers have been published by the Encyclopedia of DNA Elements (ENCODE) international research consortium, demonstrating the existence of millions of “switches” in this 98% of the human genome. These genes do not encode proteins, but they serve to turn genes on and off in line with the type of cell and the development phase of the organs and tissues in which they are found. They make up a mega control panel, dictating when, where and in what quantities genes will make proteins. Without these regulatory elements for genetic activity, our 20,000 genes would be only inert fragments.

As we have seen, knowledge can make leaps and present us with unexpected keys to decipher the secrets of biological functions. This fact ought to make us more humble: despite knowing a lot about the code of life, this only gives us a faint idea of the infinite possibilities of dealing with the labyrinths of DNA.

In the near future, bioengineering will make it possible to fabricate or “repair” organs in laboratories. […] We will have organ repair “workshops.”

• [1] Edward O. Wilson, “Systematics and the Future of Biology”, Proceedings of the National Academy of Sciences, vol. 102, sup. 1, 2005, p. 6520-6521. (This work was an outcome of the National Academy of Sciences’ Arthur M. Sackler Colloquia, “Systematics and the Origin of Species: On Ernst Mayr’s 100th Anniversary”, which took place from December 16 to 18, 2004, at the Arnold and Mabel Beckman Center of the National Academies of Science and Engineering in Irvine, California.
  [2] The percentages presented in this text were taken from the Genomic Revolution scientific exhibition, created by the American Museum of Natural History in New York and adapted by the Sangari Institute for its Brazilian edition (called “Revolução Genômica”). However, most of the time the percentages obtained by comparing genomes cannot in turn be directly compared. This is because comparisons of the genomes of different organisms (compared genomics) are made at different levels, generally depending on the time when the two compared organisms diverged from their common ancestor. Consequently, these comparisons are not equivalent. Inferences are often drawn about the raw sequence results to make more equivalent comparisons. Nevertheless, for the purpose of informing the general public, the details about how these comparisons are made tend to be left out. A detailed explanation of the types of comparisons made can be found in Ross C. Hardison, “Comparative Genomics”, Plos Biology, vol. 1, no. 2, 2003, p. 156. For complementary comparison sources, see M.D. Adams, “The Genome Sequence of Drosophila melanogaster”, Science, vol. 287, 2000, p. 2185; Frederick R. Blattner et al., “The Complete Genome Sequence of Escherichia coli K-12”, Science, vol. 277, 1977, p. 1453; Eric S. Lander et al., “Initial Sequencing and Analysis of the Human Genome”, Nature, vol. 409, 2001, p. 860; Laurie J. Mullins, “Insights from the Rat Genome Sequence”, Genome Biology, vol. 5, 2004, p. 221; Gerald M. Rubin et al., “Comparative Genomics of the Eukaryotes”, Science, vol. 287, 2000, p. 2204; “The Chimpanzee Sequencing and Analysis Consortium: Initial Sequence of the Chimpanzee Genome and Comparison with the Human Genome”, Nature, vol. 437, 2005, p. 69-87; Ajit Varki and Tasha K. Altheide, “Comparing the Human and Chimpanzee Genomes: Searching for Needles in a Haystack”, Genome Research, vol. 5, 2005, p. 1746-1758; and John Craig Venter et al., “The Sequence of the Human Genome”, Science, vol. 291, 2001, p. 1304.