Genetic treasure hunters: when finding a gene was a blind journey
In the effervescent pre-human genome era many scientists searched for disease-causing genes within the turbulent waters of the genome, with a mixture of genetic logic, intuition, and perseverance
They say that Archimedes, the great Greek engineer and physicist from Syracuse, said: “Give me a place to stand and I will move the world.” Although he was referring to the law of the lever, the image it generates in our brain is so powerful that we metaphorically refer to it in many other human situations where a problem needs to be solved that could be approached with the right data and tools. This is how we scientists who dedicated ourselves to human genetics felt during the 90s, in the full effervescence of the Human Genome Project. This year we celebrate the 25th anniversary of the publication of the first complete draft of the human genome, the instruction manual that explains what humans are like and which marked a before and after for biomedicine.
Today, however, I would like to talk to you about the prehistory of the human genome, in which numerous women geneticists stand out who ploughed the troubled and unknown waters of our genome, with a pickaxe and a shovel, and imprecise maps, like true treasure hunters. How did they manage to find genes when there was not yet a reference human genome to compare with and extract information from?
Recalling Archimedes, they needed “to find a good fulcrum and a lever long enough” to identify genes. The lever was extensive families with a high number of people affected by a rare disease, which indicated that there was a single mutated gene causing it. The fulcrum was genetic and physical maps, a “manual” and very vague version of the human genome based on genetic markers (variable sequences in the population) from which the inheritance of chromosomal fragments could be traced in individuals affected by the disease compared to healthy individuals within the same family.
Before GPS, to situate ourselves and find a location, we needed a map with reference points and to guide ourselves with a lot of intuition. Well, this would be the big difference between the pre-genome and post-genome eras: from having a map on a parchment, hand-drawn, to having a latest-technology mobile with a built-in navigator and precise instructions on how to get to places. That is, we have gone from taking decades and a lot of effort to identify a disease-causing gene to resolving the genetic diagnosis in a few days with the help of bioinformatics algorithms.
Without GPS, navigating the human genome
To give just a few examples, Marie Claire King, thanks to her double training in statistics and genetics, hypothesized that breast cancer must have a genetic predisposition basis, contrary to the prevailing idea of the time that associated the cause of the disease with a viral infection. King realized that there were families where many women suffered from it, while in others, there were no cases. Thanks to her knowledge in genetics, intuition, and perseverance, in 1994 she published the discovery of the BRCA1 gene, the first of many other genes that, when mutated, predispose to developing some type of tumor. It is just one of the scientific milestones with which King has contributed to knowledge.
Another example is that of Nancy Wexler, a clinical psychologist who became a tireless geneticist to discover the gene causing Huntington's disease, a devastating hereditary neurodegenerative condition that her mother and several maternal relatives suffered from. Again, the support point had to be extensive families with many affected individuals, and this search led her to the shores of Lake Maracaibo, in Venezuela, to a small town where most of the inhabitants are descendants of a sailor who carried the mutation that causes this pathology. Thanks to those very long family pedigrees, and with the help of the imprecise genetic maps of the time, she and her sister Alice founded a foundation to obtain funding for research, and finally, they managed to identify the gene in 1993, after more than a decade of studies, and then they dedicated resources to taking care of patients. Neither sister wanted to know if they were carriers of the mutation causing the disease, but, voluntarily, they gave up having children to avoid transmitting the mutated gene. Currently, Nancy Wexler, 80 years old, knows that the constant tremor she suffers and the first signs of dementia demonstrate that she has Huntington's disease, even though it has appeared late in her life.
I can tell you, as a "gene hunter" that I have been, that in the life of a scientist there are few occasions when after years of effort, of continuous intellectual challenge, of advancing slowly and having to retrace many paths that ended up leading nowhere, you finally discover the gene that causes the disease in a family or describe a new gene in our genome that no one was aware existed. Then, the cocktail of adrenaline and dopamine that invades you makes your whole body tremble, and that sublime moment of happiness is absolute. And, above all, the social impact of providing genetic diagnosis to families, even if they are very few in the world, is immeasurable.