War and Enzymes

By James Santiago Grisolía, MD

The Ancient Gothic Columns Of La Llotja1

rang with praise for the late physician Santiago Grisolía: words from King Felipe of Spain, the Nobel laureate Roger Kornberg, and local leaders of Valencia. A survivor of the brutal Spanish Civil War, Santiago dedicated his life to bringing science to medicine, relieving the needless cruelties and coarse medicine he saw as a teen.

Santiago, my father, grew up in the remote, medieval walled town of Cuenca, in the mountains outside Madrid. When war broke out between Spanish fascists and defenders of the republic, he began volunteering at the local hospital from the age of 14. The hospital’s stones were first laid by the military order of St James in 1182, later expanded in 1720 and after. When civil war broke out in 1936, the antiquated facilities were unprepared for wounded soldiers arriving by the truckload.

As a green orderly, Santiago tended wounded republicans, both Spaniards and fighters from the International Brigades, dressing horrific injuries with peroxide or permanganate, their only supplies. The wards echoed with the groans of wounded soldiers and reeked of sweat, of drying blood, and of feculent abdominal wounds.

One day, Santiago was cleaning a pussed-out axilla on a frightened soldier. He patiently cleaned the wound, not knowing the surgeons were afraid to dig out the embedded shrapnel for fear of lacerating the axillary artery. Somehow, he removed the shrapnel without triggering the uncontrollable arterial bleed they feared. After that, the surgeons promoted him to the operating room. There, Santiago’s job was makeshift anesthesiologist, holding an ether-soaked cotton over a soldier’s nose and mouth during amputations, thoracotomies, abdominal surgeries, and whatever the surgeons dared to try with their limited equipment.

After the war he entered medical school at age 16, uncommonly early even for those days. Transferring from Madrid to Valencia, he came under the spell of José García Blanco, the engaging chair of physiology, who put him to work in his lab and published some early research with him. García Blanco opened the world of a life dedicated to research, but cautioned that to become “first class,” he must study outside of Spain. When Santiago gained one of the few Spanish scholarships to study in the U.S, he immediately took his professor’s advice.

Arriving in New York in 1945, he searched for Severo Ochoa, whom García Blanco told him was “the best prepared” of the young Spanish researchers. Santiago began studying enzymes at New York University, before Ochoa even had his own lab. Entering at the dawn of the golden age of biochemistry, he purified and crystallized many enzymes and contributed to working out the urea cycle.

Ochoa notably became the first biochemist to chair the pharmacology department at NYU. Santiago and the other lab workers had to trundle all the equipment and lab reagents down the street to their expanded bench space in pharmacology. Oddly, to reach the new, well-appointed labs, one had to enter through pathology, past the autopsy suite.

In later years, Dad told me that walking by those slabs in the morgue focused his thinking on research that would be clinically relevant, that would answer the wordless questions posed by those silent bodies. How do we create a medicine that better answers their untimely deaths? And better helps the practicing doctors who cared for them? Behind it all, he clearly was still thinking of the wounded and dying bodies he’d seen in wartime.

In his mid-fifties, he stepped down as founding chair of biochemistry at the University of Kansas Medical School, retaining a distinguished professorship. Soon after, he accepted an offer to run a research institute in Valencia2, the city of his birth.

The year 1977 was a promising time to return to Spain, with the dictator Franco dead and the new King, Juan Carlos, pushing for a constitutional monarchy with an elective democracy. Santiago provided new direction and energy to the basic researchers. His wife and our mother, Francis

Thompson, had completed a PhD in physiology and five years of postdoc before becoming a homemaker in 1950s America. With the move to Valencia, she took an unpaid position at the institute, editing the researchers’ papers in English, which enhanced their acceptance in the most prestigious scientific journals.

When Santiago first heard whispered interest in sequencing the human genome, he arranged financing for the first international workshops on the Human Genome Project, bringing together leading researchers from across the globe. At his second meeting in Bilbao, Spain, Craig Venter and Hamilton Smith met and began a collaboration that ultimately finished the first genome map ahead of schedule and under budget.

Santiago then chaired the Human Genome Committee for UNESCO, where he worked to include developing countries in the genome revolution, so their societies could also reap the transformative benefits in medicine and agriculture.

This picture was taken at a Rei Jaume Prize Ceremony on Nov 9, 2018. From left to right are Javier Quesada, CEO of the Rei Jaume Prize Foundation; Joan Ribo, mayor of Valencia; Ximo Puig, president of the Valencian government; Felipe VI, king of Spain; Pedro Duque, then minister of science for the Spanish government; Vicente Boluda, president of the prize foundation; and Santiago Grisolia, founder of the Rei Jaume Prizes.

In many meetings at every level of business or government, and in hundreds of op-eds and interviews in Spanish newspapers, Santiago argued for more funding for basic research as the most efficient way to find unexpected answers to major human questions.

Most importantly for Spain, he began the Premios Rey Jaime I (or in Valencian Spanish, les Premies Rei Jaume I), major prizes that honor Spanish leaders in the fields of basic research, medicine, economics, environmental science, new technologies, and entrepreneurism. Each jury selecting the Spanish prizewinners includes both Spanish experts and international authorities, often Nobel prizewinners in the relevant fields. In the 34 years of awarding the Premios, 170 prizewinners have received 12 million euros in prize money, while 65 Nobel laureates have participated on the juries. By stimulating original research in the

Spanish universities, these awards foment excellence in the areas that form the pillars of modern society.

The prizes helped to radically transform the Spanish system, creating world-class economists and scientists, as well as physicians who continuously research how to do each procedure better, less invasively, or with better results.

Last November brought the 34th annual prizes and the first ceremony since Santiago’s unexpected death from COVID, just five months before his 100th birthday. While each winner was praised, their accomplishments lauded, the speakers returned, again and again, to the striking absence of the driving force behind these prizes. Leaders like Joan Ribó, the mayor of Valencia, cited the importance of science to break down barriers to diversity and inclusion and to fight violence against women. Ximo Puig, the president of the regional government of Valencia, mourned Santiago’s absence, but said this “great void was full of energy for the future.”

Roger Kornberg, a Nobel laureate in chemistry 2006, lauded Santiago with the perspective of longtime service on the Rey Jaime juries and a dear family friendship. His father, Arthur Kornberg, worked with Santiago in Severo Ochoa’s lab and shared the 1959 physiology or medicine prize with Ochoa for discovering the first RNA polymerase. (The Kornbergs are one of four father-son Nobel dyads.) King Felipe noted that his personal relationship with Santiago dated from 1990, when he awarded him the Prince of Asturias Prize in scientific research, and that they had a long relationship, both before and after his ascent to the throne.

The prize ceremonies offered a moment to reflect on hope amid chaos, from a devastating civil war to the waning days of our current pandemic. For Santiago, only the bright sunlight of science and reason can light up the dark, Goyaesque landscape of ignorance and despair.

References

1. La Llotja de la Seda, the ancient Silk Exchange in Valencia, built in 1482–1533 and now used for public ceremonies, while still a functioning mercantile exchange.

2. Then the Institute of Cytological Studies, more recently the Prince Phillip Research Center (Centro de Investigación Principe Felipe)

James Santiago Grisolía, MD, is chief of staff at Scripps Mercy Hospital in San Diego and a clinical neurologist. He is also an SDCMS member and editor of the San Diego County Medical Society’s San Diego Physician magazine.