The human genome, 25 years later: how medicine has changed

On June 26, 2000, then-US President Bill Clinton appeared before cameras worldwide to announce a historic milestone: humanity had just obtained the first draft of the human genome, "the most wonderful and important map ever produced by mankind." Beside him were his British counterpart, Tony Blair, a handful of scientists, and representatives from Celera Genomics, the private company commanded by geneticist Craig Venter, who had competed to sequence our DNA before anyone else.

That map, which would be formally published a year later in Science and Nature, two of the world's leading scientific publications, contained for the first time the complete sequence of the 3.3 billion chemical letters that make up our DNA and provided the necessary coordinates to begin navigating a territory until then immensely unknown.

“Before, our knowledge in genetics was comparable to ancient maps, where the unknown was marked with 'here be dragons'”, values for the newspaper ARA geneticist and bioinformatician Ewan Birney, one of the project's co-authors, and current director of the European Bioinformatics Institute (EMBL-EBI). “Obtaining that map allowed us to start filling in those blank spaces,” he emphasizes.

The Human Genome Project had started 15 years earlier, in the late 80s, and it was a titanic, unprecedented collective effort that involved six countries, thousands of scientists, and hundreds of laboratories with unprecedented public funding: 3 billion dollars.

The achievement of that first mapping of human essence inaugurated a new way of doing science based on international cooperation, data exchange, and the ambition to put knowledge at the service of society. It also generated enormous expectation.

“With this profound knowledge, humanity is about to acquire immense healing power,” assured Clinton, who in that global public appearance announced the impact it would have on the diagnosis, prevention, and treatment of most ailments.

“In the coming years, doctors will have an ever-increasing ability to cure diseases such as Alzheimer's, Parkinson's, diabetes, or cancer by attacking their most genetic roots —affirmed the American president, before uttering a sentence that today sounds almost reckless—: Now we can imagine that for our grandchildren, cancer will only be a constellation of stars in space”.

And yet, 25 years later, cancer continues to be one of the leading causes of mortality on the planet, dementias and other neurodegenerative diseases have not disappeared, and we have discovered that genes are not as determining as was thought.

“It is true that the sequencing of the human genome and subsequent genomics have contributed crucially to understanding human biology and have had an important impact on people's lives. But this impact has not been as extraordinary as promised,” qualified the bioinformatician from the Centre for Genomic Regulation Roderic Guigó, one of the two Catalans —and the only scientists from the entire State— who participated in the Human Genome project at the event commemorating the 25th anniversary of this milestone held in Madrid.

And it is that, despite the fact that the genome contains the instructions that determine the biological traits of all organisms, from eye color to height, predisposition to diseases and how we will respond to treatments, “we underestimated the complexity of how these instructions are interpreted,” Guigó acknowledged. In fact, a quarter of a century later, scientists still do not fully understand how a change in any of the sentences written in the book of life leads to a specific trait or disease. The map has allowed them to begin to establish associations, but without fully understanding exactly what causes variations to lead to different results.

A gradual and silent revolution

Although initial expectations were exaggerated, the human genome has indeed brought about a scientific and medical revolution, even though the major changes have arrived gradually. “There are areas where the impact has been enormous,” assures Ivo Gut, director of the National Center for Genomic Analysis (CNAG), located in Barcelona, the reference genetic sequencing infrastructure in Spain and one of the five most important in Europe.

Rare diseases

One of these areas has been rare diseases, where genomics is “almost a diagnostic miracle”. Two decades ago, recalls Gut, many families spent years waiting for a diagnosis that, in a significant percentage of cases, never arrived. Children accumulated invasive medical tests, hospital visits, and ineffective treatments, to the anguish and despair of families. “Today, genome sequencing allows the identification of the responsible gene for the disease in approximately half of the cases,” highlights Gut, who gives as an example Imerslund-Gräsbeck syndrome, a rare disease that affects six out of every million children. It is caused by mutations in the CUBN or AMN genes that prevent boys and girls from correctly absorbing vitamin B12 in the intestine. When identified and a dose up to 12 times higher is administered, neurological recovery can be very rapid and spectacular.

To the personal benefit, we must add what it entails for health services. “When you calculate the cost of not knowing what is happening, the early screening system is much cheaper. Detecting children who have a problem and starting to treat them as soon as possible is much more efficient,” considers Gut.

Cancer

Genomics has also transformed “the emperor of all evils”. For decades, we spoke in singular of breast cancer, lung cancer, colon cancer, as if they were relatively homogeneous diseases. Genetically analyzing tumors made it possible to discover that each of these tumors hides dozens of different molecular subtypes. And this came as a huge surprise.

Projects like that of the International Cancer Genome Consortium (ICGC), created in 2008, a global scientific initiative that aimed to map the alterations of the 50 most frequent types of cancer, discovered that mutations such as TP53 or BRCA1 were not, as was thought until then, exclusive to one tumor. Also, that the reality was much more complex: each tumor had recurrent mutations, but also a long list of less frequent alterations. And many of these were shared by tumors from different organs.

Understanding the enormous genetic diversity of tumors allowed for more precise diagnoses and advanced towards personalized medicine, applying treatments based on the characteristics of each person's tumor. It also made it possible to understand why patients with apparently similar tumors responded so differently to treatments.

And it paved the way for finding better drugs. “Suddenly we realized that a therapy developed for breast cancer could also work in kidney cancer if they shared the same molecular mechanism. Thus began the idea of repositioning drugs,” explains Gut. It was a much faster, more effective, and more economical way to find treatments.

Preventive medicine

For Gemma Marfany, professor of genetics and bioethics expert at the University of Barcelona, another of the most profound changes that genomics brings is just beginning. It's not that knowing the genome allows us to predict the future with accuracy, but it does allow us to identify risks and act before the disease appears. Moving towards preventive medicine.

The researcher uses a very graphic metaphor: a card game. "The genome is the hand we are dealt at birth. We cannot change it, but knowing what cards we have helps us play better." If you have a high chance of developing adult-onset diabetes, and you know it from the beginning of your life, you can take into account that it is a possibility, and this, Marfany considers, can lead you to eat more healthily, exercise, so that, "instead of having diabetes at 40, perhaps it will be diagnosed at 70 or the disease will not even arrive because you have played your cards well".

Biodiversity

The genomic revolution has not been limited to medicine. What is extraordinary about life is that all of it, from that of bacteria to that of whales, orchids, or ours, that of humans, is written by combining four letters —AGCT, the nitrogenous bases that form the chemical alphabet of DNA— capable of generating an infinity of different forms. “The fact that all living beings on Earth are connected makes it impossible to understand the biology of one organism without understanding that of the rest,” points out Icrea researcher Tomàs Marquès, from the Institute of Evolutionary Biology (IBE UPF-CSIC).

The sequencing of the human genome opened the door to also obtaining the genetic map of model animals for research, such as the rat, the mouse, the Drosophila fly, or domestic animals. The same instruments developed to read the human genome are used today to study practically any living organism. And this has opened the door to gigantic projects like the Earth Biogenome Project, the project that aims to sequence all eukaryotic species on the planet.

“We are living an explosion of genomics. Every year thousands of new genomes are incorporated, allowing us to study the evolution, biodiversity, and adaptation of species with unprecedented precision,” highlighted Marquès.

It has also accelerated biodiversity conservation programs. The Iberian lynx (Lynx pardinus) is an example. The analysis of its genome has helped to preserve the genetic diversity of this population of felids endemic to the Peninsula, and to manage its recovery. In just over two decades, it has gone from being on the brink of extinction to exceeding 2,000 individuals.

And now AI

Twenty-five years after its publication, thanks to that map, we now better understand why we get sick, how we have evolved, and what our relationship is with the rest of life on the planet. The human genome, however, remains an unfinished work. What began as a map has today become an essential infrastructure of modern biology that, while it has not revealed all the secrets of life, has forever changed the way we search for them.

Now many researchersclaim that the next great transformation will come from artificial intelligence. In fact, it has already allowed us to predict the structure of millions of proteins, a feat that just a few years ago seemed unattainable. It is beginning to help doctors identify health risks, interpret genetic variants, and better understand complex diseases.

But researchers also ask for caution. AI is only as good as the data it is trained on. And there are still significant biases because the majority of the genomes studied come from European populations.

“At this moment we should have good genomes from many populations already, because otherwise AI will be tremendously unfair”, warns Gemma Marfany, from the UB, who explains that “it will get it right with Europeans, who are the ones with the most data and who have been fed and trained the most, but it will not be equitable and may even be detrimental when interpreting the genetic data of other populations”.

The power of analysis and also of generation of AI applied to genomics opens the door to the design of synthetic life. Also, as Marfany, a recognized expert in the social and ethical applications of genetics, warns, to the selection and modification of human embryos. “There is still a lot of discussion internationally. Mostly, Europe says no, but we are 400 million people in a world of nearly 9,000”.