CURRENT BOOKS: A Journey Through Medical Genetics

Jeffrey Weitzman, MD

Inheritance: How Our Genes Change Our Lives and Our Lives Change Our Genes, by Sharon Moalem, MD, PhD (with Matthew LaPlante), 272 pages, Grand Central (2014).

Inheritance, by Dr. Sharon Moalem, is an enjoyable read. It is directed both to lay readers and to those with a medical background. The book gives a good overview of medical genetics and the clinical practice of a geneticist.

Moalem introduces us to many of his patients and their life experiences, and to how unique genetic diseases have led to medical discoveries. He also provides a background for understanding some of the 6,000 rare and common genetic disorders. He uses an anecdotal style to introduce complex topics, which helps keep them understandable. Instead of being an all-inclusive medical text, Inheritance is more of a journey through the field of genetics that helps us understand its past and future impact on the practice of medicine. The book also outlines the surprising effects of our lifestyle on our children’s future inheritance.

Moalem’s book reflects his inquisitive nature, energy and enjoyment of his profession. He describes his research, his clinical practice, his founding of two biotech companies, his 20 patents, and his discovery of a new antibiotic for drug-resistant strains of bacteria. (This antibiotic will start clinical trials next year.) He even has time to write books, although I would assume that his listed coauthor helps him spin his thoughts into text.

The days of Gregor Mendel’s research on peas and the basic genetics that doctors of a certain age studied in medical school (such as determining eye color via autosomal dominant genes) are ancient history. Scientists are now able to decode an entire genome and determine a single nucleotide substitution out of the billions of nucleotides that make up one’s DNA. Meanwhile, the price of genetic testing is coming down. More and more patients want to know their genetic makeup and the implications of certain genotypes on their future health. Genetics is leading us into a brave new world of “personalized medicine.” Much of where we are headed is good, but some parts are worrisome.

According to Moalem, Mendel missed out on the concept of variable genetic expressivity, observing that, “Identical genes don’t always behave identically in different people—even people with completely identical DNA, such as identical twins.” You may say “So what?” but it turns out that your behavior can not only influence the genetic expression of your genes in your lifetime, but also alter the genes you pass on. Moalem is not talking about mutations here, but rather the process of turning genes off and on (epigenetics). The implications are startling, to say the least. “Our genes,” writes Moalem, “aren’t as fixed and rigid as most of us have been led to believe.”

Moalem gives this example, among others: Patients with PTSD or kids who have been bullied have a blunted cortisol response to stress. In studies of identical twins with identical DNA, the bullied twin will continue to show a blunted cortisol response as the twins grow up because the expression of his or her genes has been chemically changed by a life-altering experience. Animal studies show that this type of response can be passed on to the next several generations, leading Moalem to conclude that, “Those epigenetic changes are likely inheritable from one generation to the next.”

In another example, Sherpas in the Himalayas have a mutation in a gene called EPAS1, which leads to a blunted response to erythropoietin. This response makes Sherpas less susceptible to thromboembolic disease at high altitudes. As Moalem notes, “some researchers believe it may be the fastest case of human evolution that has been documented so far.”

In summary, your behavior—including the foods you eat and your lifestyle—can affect the expression of your genes in your lifetime and into future generations. There are implications here for future medical recommendations on diet, stress exposure and substance abuse, along with new advice for pregnant mothers.

Moalem discusses several other genetic topics, including genetic diseases such as the relatively rare osteogenesis imperfecta (OI). As you will recall from medical school, the human genome is made up of billions of nucleotides consisting of A, T, C and G in various combinations. In one gene, COL1A1, there is one nucleotide substitution of a T for a G, which leads to OI. Moalem points out that we can be one letter away from a life-altering genetic condition. Our understanding of OI provides insight into the genetics behind osteoporosis and other common medical conditions. OI and similar single-gene substitution diseases were identified early on as the low-hanging fruit in a complex field. Diabetes and hypertension probably involve multiple genes, so sorting out their genetic basis is much harder at this time.

Another topic is nutrigenomics, which is the “study of the ways in which our genetic inheritance impacts our dietary needs.” Moalem describes the genetic basis for lactose intolerance, Vitamin C metabolism, rate of caffeine metabolism and obesity. “We are now on the cusp,” he writes, “of finally being invited to sit down to a meal that’s been prepared with our own individually inherited genetic profile in mind.” When we consider all the recommended diets out there, it seems plausible that the one-size-fits-all mentality is flawed for genetic reasons.

Moalem also explores pharmacogenetics and genetic dosing, including the case of a child who died from a therapeutic dose of codeine. The child had an extra copy of the CYP2D6 gene. This affected her metabolism of opiates, causing her to overdose on codeine prescribed after a routine tonsillectomy. Relatively simple genetic tests are available or pending to “identify ultra-rapid and ultra-slow metabolizers of certain medications.” Medications that are impacted by our genes include diazepam, metoprolol, paroxetine, phenytoin, risperidone, tamoxifen and warfarin, to name a few.

In one chapter, “Hacking Your Genome,” Moalem brings up the inevitable medical-legal issues of others knowing your genetic information. He notes that the Genetic Information and Nondiscrimination Act, passed by Congress in 2008, was “created to protect people from genetic discrimination in situations pertaining to employment and health insurance.” Unfortunately, there are many loopholes in these laws. Having the BRCA1 gene, for example, increases a woman’s chance of developing breast cancer, which could disqualify her for life or disability insurance if that information becomes available to insurers. Moalem recommends both anonymous testing, and counseling before having genetic testing, so individuals can understand the implications for themselves, their immediate family and their descendants.

Keeping your genetic information anonymous is not as easy as you would think or hope. “It’s common practice,” notes Moalem, “to share genetic and sequencing data with other researchers while removing identifying information.” In one experiment, biomedical experts, ethicists and computer scientists were able to analyze anonymous genetic information with genealogy websites and identify the anonymous patient’s family groups. By combining this information with age and state of residence, they were able to track down the precise identity of many people, thus becoming ”genetic cyber sleuths.” According to Moalem, social media is “a potentially very deep and rich source of information for genetic cyber sleuths.”

The rapid growth of technology on all fronts is having an immense impact on our lives. Inheritance outlines how the development of technology and genetics go hand in hand. I believe we need to be mindful of the potential negative consequences of this new knowledge, including its effect on hiring practices, social relationships, insurance qualification and other unforeseen circumstances. We will need to protect this highly personal information in a more effective way than demonstrated so far with our financial data. Just who would you trust with your genome?

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Dr. Weitzman, an emergency physician at Marin General Hospital, serves on the MMS Editorial Board.
Email: jweitzmanmd@gmail.com