By Morris Birnbaum, MD, PhD, Senior Vice President and Chief Scientific Officer, Internal Medicine Research Unit, Pfizer
Amidst the greatest public health crisis of the last 100 years, another epidemic is marching along a seemingly unavoidable trajectory: that of cardiometabolic diseases. These complex, interrelated diseases receive less public attention than opioids, cancer and autoimmune diseases – yet they continue to be the number one cause of death on the planet. And, once seen as diseases of the developed world, they are increasing globally due to an aging population, population growth and environmental factors – along with physical inactivity, overnutrition and an intertwined epidemic of obesity.
Cardiometabolic diseases are noncommunicable diseases, contracted not through contact with infected people or animals, but arising due to a combination of genetic, physiological, environmental and behavioral factors. Some of these conditions – obesity, diabetes, cardiovascular disease (CVD), nonalcoholic steatohepatitis (NASH), cachexia – may sound more familiar than others, but collectively they affect over one billion people around the world. They impact not just mortality but quality of life and mental health, and they are some of the largest healthcare and productivity costs to society.
The reason why we study these diseases within a single research unit at Pfizer is that they are linked by biological factors rooted in human metabolism.
The complexities of metabolism
Even before I began my medical training in 1973, I was fascinated with the idea of how Homo sapiens – a species that evolved nearly 300,000 years ago – has struggled to adapt biologically to an environment that has changed drastically over the last century. Although technological, medical and nutritional advances have allowed humans to greatly increase our life expectancy since the advent of agriculture, the truth is that we did not evolve to live this long. And, though our metabolism evolved to promote fat storage in a time of nutritional scarcity to protect us from predation and disease, those selection pressures are greatly reduced in our modern environment, replaced by the high concentration of carbohydrates and fat in our food. It is due to longer lives and imbalanced metabolism that we find ourselves in this current health crisis.
So, what is metabolism? At the highest level, it is the process through which an organism derives energy from processing nutritional constituents, while maintaining a relatively constant internal environment. In humans and animals, metabolism involves: 1) the breakdown of larger and medium-sized molecules present in food, such as glucose, into smaller molecules – capturing the energy contained in the chemical bonds for daily functions like movement, maintaining a normal body temperature and performing functions of the brain; and 2) using the newly derived energy for synthesis of molecules, such as proteins and lipids, which are essential for the growth of new cells and repair of damaged old ones.
When someone has a certain set of genes, their body may struggle to manage the abundance of food in the modern world and might store too many nutrients, leading to obesity. This dysfunction – the “dysmetabolic state” – puts people at greater risk for type 2 diabetes (T2D), CVD and NASH, a serious, progressive form of nonalcoholic fatty liver disease. Interestingly, these same pathways can also become dysfunctional in another way and cause people’s bodies to uncontrollably burn too many nutrients, leading to unintentional weight loss (cachexia – a condition often experienced in addition to cancer and other chronic illnesses).
Disrupted metabolic pathways impact our physiology in other ways, too. For example, the existence of metabolic bodyweight “set points” or “settling points” has been proposed, wherein biological along with environmental factors contribute to the stable maintenance of a particular weight or weights. With slow weight gain, a person can transition to a different stable weight over time, making successful long-term weight loss challenging. Metabolism even affects our experience of hunger and satiety: cachexia is compounded by loss of appetite, while people with obesity feel less full than those who are not obese.
The remarkable effort of the body to maintain a certain weight is why eating less and exercising more is often not a successful prescription for the treatment of obesity in many people. While this suggestion makes sense on paper, in reality it is as reductive as instructing a patient with cancer cachexia simply to eat more to prevent muscle wasting. Both prescriptions ignore the underlying physiological changes that have taken place. To address those changes, we must turn to science.
The power of science
Decades after I first wondered about biological adaptation, scientists are now getting closer to a full understanding of the metabolic pathways linking these diseases – pathways that we at Pfizer are targeting on our quest to develop novel therapeutics. These include the pathways that mediate insulin signaling and satiety, to hopefully direct glycemic and bodyweight control; the pathway that controls fat accumulation in the liver, to potentially prevent or even reverse the effects of NASH; the pathways that control lipid metabolism, with the goal of treating severe hypertriglyceridemia and sustained cardiovascular risk; and the many pathways involved in cachexia, responsible for appetite, nausea, muscle loss and inflammation.
At Pfizer, we realize that behind the science of these pathways are real patients living with cardiometabolic diseases. We recognize that scientific understanding can not only help people adapt to the longevity of modern life, but can help reduce the stigma unfairly attached to people based on factors out of their control.
This knowledge is what drives our team of scientists and patient engagement experts, who are dedicated to learning the needs and wishes of patients and to developing new medicines to improve the lives of hundreds of millions of people. It is precisely because of this expertise and dedication that we view this epidemic not as an unavoidable crisis – but as an opportunity for science to triumph.
Morris Birnbaum is senior vice president and chief scientific officer for the internal medicine research unit at Pfizer, where he leads the discovery of novel transformative therapies to reduce the prevalence of cardiometabolic dysfunction.
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