Mitochondria and the Future of Medicine: The Key to Understanding Disease

Book Preface

A long time ago, in a galaxy far, far away, there were intelligent microscopic life forms called midi-chlorians that lived symbiotically inside the cells of all living things. When present in sufficient numbers, they allowed their symbiotic host to detect the pervasive energy field known as the Force. Midi-chlorian counts were linked to one’s potential in the Force, ranging from normal human levels of 2,500 per cell to the much higher levels in a Jedi. The highest known midichlorian count (over 20,000 per cell) belonged to Jedi Anakin Skywalker. Present in all life, midi-chlorians are the same on every world that supports life—in fact, midi-chlorians are necessary for life to exist. In sufficient numbers, midi-chlorians will allow their host organism to detect the Force, and this connection can be strengthened by quieting one’s mind, allowing the midichlorians to “speak” to their host and communicate the will of the Force. For many reading this book, I’m sure you’re thinking, “What . . . the . . . has he gone completely sideways?” What the heck am I talking about? Well, science fiction fans—and the generation(s) who grew up in the era of Star Wars—might have a better chance at guessing that midi-chlorians are a creation of George Lucas . . . or are they? Midi-chlorians were first conceived by George Lucas as early as 1977. At this time, Lucas sat down with a member of his staff to dictate a number of guidelines for these works, explaining various concepts of his universe. Among them was an explanation of midi-chlorians (even though Lucas did not feel he had the time or opportunity to introduce the concept until 1999, when it was first mentioned during Star Wars: Episode I—The Phantom Menace). Explaining why some were sensitive to the Force while others were not was an issue that he needed to address—an issue that he had left unresolved since the original film Star Wars. Midi-chlorians in Star Wars: Episode 1—The Phantom Menace are part of a recurring theme throughout the movie—that of symbiotic relationships. What’s fascinating to me is that midi-chlorians were loosely based on mitochondria, organelles that provide energy for cells on our non–science fiction, real-world planet. Like midi-chlorians, mitochondria are believed to have once been separate organisms that inhabited living cells and to have since become part of them; even now, mitochondria act in some ways as independent life forms, with their own DNA. Most readers might remember mitochondria from high school cell biology class, described as the “powerhouses” of the cell—the tiny generators that live inside cells and produce almost all the energy cells need to live. Depending on the type of cell, there are usually hundreds to thousands of mitochondria in each cell. They use the oxygen from the air we breathe to burn up the food we eat to produce useful energy. Some people might have heard of “Mitochondrial Eve.” Since mitochondria are inherited maternally, if we trace our genetic lineage from child to mother, to maternal grandmother, and so on, Mitochondrial Eve would be the mother of all mothers. (She is thought to have lived in Africa approximately 170,000 years ago. This does not necessarily mean she was the first human; it only means that she is the most recent ancestor common to all humans living today.) The reason we can trace our ancestry this way is because all mitochondria have their own DNA (the “genes”), which are normally passed on to our children only in the mother’s egg, not in the father’s sperm. This means that mitochondrial DNA (abbreviated as mtDNA) act like a genetic surname. However, unlike typical Western surnames passed down the paternal line (which can change for any reason, including marriage), mtDNA is fairly constant and unchanging, which allows us to trace our ancestry down the female line. This fact also means that it is usually possible to confirm or disprove familial relationships. It also makes mtDNA of great use in forensics (to identify people or corpses). One reason why mtDNA is so useful in forensics is that there is a lot of genetic material in each cell.

Whereas there are only two copies of the DNA in thenucleus (called nuclear DNA, abbreviated as nDNA—the control center of the cell), each mitochondrion contains five to ten copies of its genes. While there is only one nucleus per cell, there are usually several hundred to a couple thousands of mitochondria, meaning there are many thousands of copies of the same mtDNA in each cell. On the medical side of the story there is the “mitochondrial theory of aging.” I’ll discuss this in depth (“The Mitochondrial Theory of Aging,” page 47), but basically, this theory argues that aging—and many of the diseases that come with it—is caused by a slow degeneration in the quality of mitochondria. This is because during normal cellular respiration—the process where the mitochondria burn up the food we eat using the oxygen we breathe—reactive molecules called free radicals are created. These free radicals then go on to inflict damage to adjacent structures, including the DNA in both the mitochondria and nucleus. Free radicals attack the DNA in each of our cells tens of thousands of times daily. Much of the resulting damage is fixed silently by the extensive repair machinery within the cells, but sometimes these attacks can cause irreversible damage—permanent mutations in the DNA. As the onslaught of free radicals continues day in and day out, these mutations build up over a lifetime. Once the damage reaches a threshold, the cell dies, and slowly over time, tissues start to degenerate with each dying cell. This steady erosion is what’s responsible for many age-related degenerative diseases and even the aging process itself. There are also mitochondrial diseases, some of which might be known by the reader, whether inherited or acquired, that typically affect metabolically active tissues such as the muscles, heart, and brain. This leads to a wide assortment of symptoms depending on the location of the most affected tissues. The United Kingdom voted in 2015 to legalize a controversial fertility treatment: a technique called nuclear genome transfer, a type of mitochondrial replacement therapy. This is where the nucleus is removed from an egg cell (called oocyte) of a healthy and fertile female donor (leaving all other components, including the healthy mitochondria), and then the nucleus from the zygote (the fertilized egg) of the infertile woman is transferred into the healthy donor egg. Both ethical and practical concerns have kept this process outlawed throughout the rest of the world, but the United Kingdom continues to push forward, allowing babies to be born with three genetic parents (nDNA from the mother and father, and mtDNA from the donor, or third parent). At the end of 2016, the United Kingdom granted its first license, and the first legal baby using this technique will be born in 2017. (I use the term legal baby because this technique was used in 2015 in Mexico, where there were no regulations regarding it, with its three-parent baby born in 2016.) However, over the last couple decades, one of the most important aspects of the mitochondria has been something that didn’t get a lot of media coverage, and that is its role in apoptosis (pronounced “A-po-TOE-sis” with the second p in its spelling silent), which is programmed cell death or cell suicide. Apoptosis is when individual cells commit suicide for the greater good of the body as a whole. Previously, apoptosis was thought to be governed by the genes in the nucleus. However, in an eye-opening turn of events starting around the mid-1990s, researchers discovered that apoptosis is actually governed by the mitochondria. The implications for the medical field are profound, especially related to cancer research. Cells are constantly aging or being attacked, resulting in mutations of their DNA. When mutations result in a cell that wants to replicate out of control, it ultimately leads to the dreaded C-word: cancer. Cells failing to commit suicide when directed to do so is now considered the root cause of cancers. However, the implications run even deeper. Without programmed cell death, complex multicellular organisms might never have had the direction and organization required to evolve in a controlled manner, and the world we know would likely look completely unrecognizable. Sounds confusing, I know. It’ll make a lot more sense after I explain it further in “The Evolution of the Eukaryotic Cell,” on page 9. This is in addition to the fact that cells in multicellular organisms (called eukaryotic cells) are orders of magnitude larger than single-celled bacteria. There is just no possible way that the energy needs of a eukaryotic cell could be met without mitochondria, as you’ll realize shortly. Although I won’t get into the evolution of the two sexes (male and female), mitochondria even help answer the question, “Why do we have two sexes?” Sex between a male and female, while providing intense pleasure for the participants, is actually an inefficient method of procreation. For humans, it requires two parents to produce a single child (most of the time—of course, there are variants here). Clonal reproduction, on the other hand, requires just a mother—the father is not only useless but actually a waste of resources (coincidentally, I was editing this line on Father’s Day weekend). Moreover, having two sexes means that only half the population is available to procreate, which is mathematically inefficient. Logically, a better scenario would be if we could procreate with anyone, either
because everybody was the same sex or because there was an infinite number of sexes.