Book Review: ‘A Fatal Inheritance’

In his incredibly compelling and well-researched narrative, A Fatal Inheritance:  How a Family Misfortune Revealed a Deadly Medical Mystery, Lawrence Ingrassia, now in his early 70s, tells us the story of the deadly genetic mutation that killed his mother, brother, and sisters who died early from cancer.  The reader tries to get a handle on who Ingrassia is, and often comes up short. He seems to be simultaneously the luckiest and unluckiest man in the world: an unenviable position to be in. His private nature prevents us from understanding more about his family and his relationships with those he lost, yet we yearn to know more.  Ingrassia keeps his narrative voice steady and at times even optimistic, and if dread and heaviness lurks behind his presentation, we can’t sense it.

Ingrassia seems grounded by the fact-finding mission he has finally set himself on; and leaves spiritual and religious matters to those who have such an inclination. He clearly doesn’t.

Ingrassia’s mother died at 42, and his younger sisters at 32 and 24. All died from different types of cancer, except for his father, who died at 59 from an unrelated illness.  In rare moments of self-sympathy, he reflects upon the fact that the average life span for Americans is 80, and yet in his family, it is around 45. As each family member fell ill, there was no thought it was due to any sort of inherited genetic mutation. The thinking at the time was that viruses or toxins caused cancer; or perhaps patients died from smoking or being overweight and physically inactive. Ingrassia recalls how most of the family thought  their father’s profession brought this upon them accidentally. He worked as a research scientist in the woods product industry in Laurel, Mississippi, and perhaps had unknowingly carried some dangerous or deadly toxin into the home.

Later, Ingrassia learned his family fell prey to  Li-Fraumeni syndrome; named after the two heroic and tireless physicians who devoted their lives to studying early onset cancers that seemed to arise in clusters in certain unlucky families. It wasn’t unusual for a father and son to be battling cancer together. It was their work that led other scientists to discover that those inflicted had inherited a defective p53 gene, which when healthy works as a cancer suppressor gene known as the “guardian of the genome,” because it regulates DNA repair and cell division.

P53 has the power to stop potentially cancerous cells from developing into tumors when it is working properly. Many in Ingrassia’s family and extended family had inherited a defective p53 gene, which is why they were susceptible to repeated cancers and often early deaths. The stark reality, Ingrassia explains, is that those who have this defective gene have more than a 90 percent chance of developing cancer in their lifetimes.

Ingrassia’s brother Paul endured lung, prostate, and pancreatic cancer. His mother had breast cancer. His brother Paul’s son Charlie had cancer at two, and then colon cancer at 30, and finally died at 39. We wonder about these cherished lives crushed by some sort of twisted fate, particularly when we glance at the cover of his book, which looks like a homemade Christmas card; the kind proud parents send out to express their pride, good fortune, and happiness. But Ingrassia seems uncomfortable dwelling too long on this and integrates his family story with others similarly afflicted and the swirl of medical research swirling surrounding them that was racing to find a cure.

Ingrassia spent decades at the New York Times, where he oversaw more than 100 reporters  covering the economy, energy, finance, technology, telecommunications, and healthcare. He is married and the father of two and has several grandchildren. He never discusses how all of this affected his children while they were growing up and says nothing about his wife’s reaction either. We don’t know if his silence is out of respect to his dead mother and siblings, or if there are other forces at play. Ingrassia seems by nature an achiever who is beholden to continual accomplishments. Illness, as those afflicted with it know, couldn’t care less about what promotion you are pining for, or the book you still haven’t written.

Ingrassia is grateful for the work of Dr. Frederick Li and Dr. Joseph Fraumeni, who began to track families like his own who were beset by so much death and the early onset of serious illness. These two men were unconcerned with personal glory, but rather genuine healers who wanted to make things better for those suffering.  Ingrassia shows us in step-by step fashion how their work served as a springboard for other researchers who would use their data to go further. Li and Fraumeni looked at things no one was thinking about at the time. What role do viruses play if any at all? Is it contagious? What role does the environment play? Why wasn’t anyone looking at genetic causes?

After gathering several extensive family histories, their findings astonished them. They realized that genetics seemed to be a vital component in all of this. In one family, there were multiple cancers and two second cousins with the same rare soft-tissue cancer. This defied the odds, since there are only five cases of rhabdomyosarcoma for every one million children in the United States. Other researchers realized that there are trillions of cells in the human body and many of them are continually mutating. Very few of those cells become cancerous. Scientists realized that some of the cells in the body are specifically programmed to regulate cell division and mutation so the body can stop cancerous cells from careening out of control and becoming deadly.

 Gains in cancer research have continued, although not as quickly as doctors would like. Gene therapy has become the new focus on possible ways to treat cancers in the most efficient and least toxic way. But experiments on mice showed how complicated it all is. Scientists saw there were unknown genetic factors at play. By 2015, they had found a thousand different mutation variants that they knew little about. Some researchers began to look for other ways to figure out how to pierce the unknown mysteries about what why certain cells turn on themselves. They studied elephants have been studied since they carry extra p53 genes. They have 40 and human beings have two. Elephants, they learned, don’t try to repair their mutated cells, but rather use their p53 genes to quickly annihilate any cells that are in the process of becoming dangerous to the elephant’s life.

 In 1999, scientists developed a synthetic compound  that seemed to be able to alter the destructive power of p53’s mutation and slow the growth of tumors in mice.  But before human trials could begin, they discovered that this compound had toxic effects on cells in lab tests. Science has come up with other drugs to repair the defective p53 mutation over the last two decades, but there are no definitive results yet. Researchers are grappling with the reality that there seems to be no way to create a one-p53-drug-fits-all therapy that will work for most of those afflicted, since any drug might only have the power to treat tumors with a handful of variants, or perhaps just one. It has become clear that individuals may need treatment catered to their individual genetic make-up which seems an almost insurmountable task.

 Ingrassia spent most of his life climbing the ladder of corporate journalism while trying to be as supportive to his sick siblings as he could. He didn’t test himself for the p53 mutation until his adult children prodded him to and was relieved, as he had been spared this most unlucky genetic inheritance. His already adult children were relieved too, since they would have had a 50 percent chance of inheriting the mutation, as would their own children.

One senses that Ingrassia suffers from a sense of survivor’s guilt, though he never says so directly. But this book seems like a valentine of sorts to his beloved first family whom he regrets having so little time with.  It is an extraordinary piece of work that seems fueled both by his own losses, and his hopes for a brighter future for those similarly afflicted.