by Greg Gibson
Cancer is fundamentally a product of disequilibrium between our genome and our culture. All of a sudden, in the space of a couple of generations, humans are living 20 years longer than ever before. Cryptic genetic susceptibility factors that have only a miniscule effect up to the age of 50, too small an effect for natural selection to do anything about, are now uncovered. These variants account for maybe a quarter of all mortality in old age, but they just have not played a significant role in human history hitherto.
Third, those cases where we can blame specific genes, account for only a small proportion even of cancer that seems to run in families. BRCA1 and BRCA2 are the two best-known susceptibility genes. If you are a woman who inherits a mutation in one of these two genes, you have a high lifetime probability of having breast cancer. Literally hundreds of mutations of this type are in the human gene pool, most very rare, but some at a frequency as high as a few percent in particular populations. Yet, the mutations only account for one-tenth of familial breast cancer, which in turn is one-tenth of all breast cancer. Geneticists are just now uncovering a few other genes that harbor mutations that also contribute, but the bottom line is that we just do not know what genes account for the majority of breast or any other type of cancer.
In fact, we don’t really have a good model for how they act either. Knudson’s two-hit hypothesis has served pretty well as a starting point. The idea is that you need at least two mutations to initiate cancer. If you inherit one from your parents, you are off to a bad start, because you only need one more during your life. Since that first mutation is insufficient to cause cancer, it can hang around in the gene pool, ever so slightly increasing the incidence of cancer and contributing to its tendency to run in families. Presumably there are hundreds of genes harboring such mutations and hundreds of different mutations in each of these genes, each of which increases cancer susceptibility a fraction of a percent. Eventually we will find many if not most of these, but it is doubtful it will do us much good.
Though not discussed here, a lot of cancer susceptibility has more to do with what happens in the progression from initial lesion to mature tumor, than in the initial appearance of cancer. The potential of cancer cells to metastasize (start migrating around the body), their ability to vascularize (attract blood vessels to support malignancy), and the capacity of the immune system to detect and deal with an early stage cancer are all affected by our genes. Our psychological and nutritional status can play an enormous role here as well.
Putting all this together, the inescapable conclusion is that we are dealing with an immensely complex foe. The media, naturally, likes to report from time to time that scientists have identified a new gene for cancer. Our response is to assume that this is something like a gene for blue eyes or male-pattern baldness: If you get it from your parents, you are going to get cancer, and the reason why we cannot yet predict cancer is because we haven’t found the genes yet. The truth is otherwise.
3. Not so thrifty diabetes genes
jackie and ella Up to a third of the world’s population may be diabetic by the next century, and it can afflict just about anyone.
the pathology of diabetes There are two major types of diabetes, both due to lost regulation of blood glucose by insulin.
type 1 diabetes The rare form of diabetes arises because a child’s own body destroys the pancreatic cells that make insulin.
an epidemic genetic disease Fast foods and sedentary lifestyles add up to a whole lot of extra pounds and burgeoning diabetes risk.
genetics of obesity Hundreds of genes contribute to whether a person is likely to put on weight more than average.
type 2 diabetes Several alleles have recently been identified that promote diabetes in Caucasians, but they are slowly being displaced by protective variants in the human gene pool.
debunking the thrifty genes hypothesis Arguments that diabetes is caused by alleles that favored rapid assimilation of carbohydrates in times of famine fall short.
disequilibrium and metabolic syndrome We’ve pushed our genetic legacy to the limits of its ability to cope with modern diets and stress.
Jackie and Ella
Diabetes is the global warming of public health. A crisis that will affect the lives of literally billions of people is looming with an inevitability that borders on irrepressible. We pretty much know the causes and even have a fair idea about how to prevent it. Yet inertia is such that somewhere between one-quarter and one-third of the world’s population will become diabetic in the next few generations. These are the proportions about to beset North America and Europe, but the developing world is rapidly following in step. So pervasive is the switch to fast foods and sedentary lifestyles that obesity and its consequences will soon replace malnutrition as the predominant food-related malady of even the poorest nations.
Diabetes is also an equal opportunity killer. Young or old, man or woman, rich or poor, black or white, thin or fat: Everyone is at some risk. The list of prominent diabetics cuts across professions and includes some surprises that buck the popular impression that it is solely a disease of the morbidly over weight. Spencer Tracy, Mary Tyler Moore, and Halle Berry head a long list of actors; Menachem Begin, Anwar Sadat, and Mikhail Gorbachev suffered; Howard Hughes was afflicted as was, ironically enough, Ray Kroc, the founder of McDonald’s.
Like tens of millions of ordinary folks, these individuals were able to overcome daily discomfort and pain to lead highly productive lives. In most cases, though, the disease exerts its authority in the end. The brief life stories of two of the most influential African Americans of the twentieth century tell how.
Jackie Robinson was the man who broke the color barrier in professional sports. Born in rural Georgia and raised by a single mother in Pasadena, California, he encountered plenty of prejudice as a kid, yet managed to turn sorrowful lessons into his positive expression that “there’s not an American in this country free until every one of us is free.” Despite lettering in four sports, financial difficulties forced him to leave UCLA early and join the Army. That career was cut short by a court-martial and subsequent honorable discharge following his objections to racial slights such as being ordered to the back of the bus—11 years before Rosa Parks famously refused to do so. After one season in the Negro Baseball League, Jackie was noticed by the president of the Brooklyn Dodgers and invited to the big leagues. He went 0 for 4 in his first game on Opening Day, April 15, 1947, and took 21 at bats over a week to get his first hit, but then went on to win Rookie of the Year honors, a Most Valuable Player Award a couple of years later, and eventually induction to the Hall of Fame. A lifetime .311 hitter, extraordinary base runner, and natural second baseman over a ten-year career, Jackie Robinson would have been one of the greats of his era even had he not also changed the face of the game.
Tragically, Jackie’s life was cut short by heart disease at the age of 53, just 15 years after the end of his playing days. His relatively short life had been dedicated to opening doors for others, as a campaigner for the NAACP, and as a businessman, notably founding a construction company that built housing for low-income families. In the dozen years after retiring from baseball, he had gone almost blind, while chronic heart problems had taken away his athleticism. We could be forgiven for assuming that it was the burden of bearing daily insults while carrying the torch for a new generation of athletes that had eaten away his strength.
In actuality, it was the burden of too much glucose in the blood, slowly but surely eating away at the cells of his retina and his heart muscle. No doubt, stress did not help. The combination of high blood pressure with depositions of fatty materials inside the artery walls increases the demands on the heart. Diabetics who have already had one heart attack, as Jackie Robinson had a few years before his death, are at extreme risk. He didn’t have the benefit of our knowledge about the effects of saturated fats and of smoking, nor did he have access to all the modern drugs that make diabetes manageable.
Ella Fitzgerald’s story is equa
lly inspiring, her battle with diabetes equally devastating. Someone once said of Ella that, “Music comes out of her. When she walks down the street, she leaves notes.” In a career that spanned five decades, she became synonymous with scat, legendary for the clarity and range of a distinctive voice that often borrowed from the horns in the big bands she accompanied. Orphaned at the age of 15, she managed to survive the endemic abuse of a reform school for girls, only to be turned out onto the streets of Harlem. In 1932 she was discovered at an amateur night and quickly found herself the leading lady of jazz, performing to packed houses at the fabled Savoy Ballroom, collaborating with all the greats: Count Basie, Duke Ellington, Nat King Cole, and Charlie Parker. A shy girl, born to poverty and disadvantage, she turned an untrained voice into one of the most improvisational instruments of a golden era, and one of the surest cures for the blues ever devised by humankind.
Inexorably, though, diabetes took over. Her eyesight fading, circulatory problems started to eat away at her body, and at the age of 66 she underwent quintuple coronary bypass surgery as well as heart valve replacement. Eight years later, ongoing heart disease drained the vessels of her legs of the lifeblood they needed, causing her to lose both to amputation. Then in 1996, the 81-year-old Ella Fitzgerald’s heart finally gave way due to complications of diabetes. Today, her Charitable Foundation, like Jackie Robinson’s, carries on her legacy. It provides educational opportunities for children; fosters a love of music; provides health care, food, and shelter for the needy; and supports medical research relating to the eye and heart disease caused by diabetes.
The Pathology of Diabetes
Diabetes mellitus is actually now recognized as a spectrum of diseases that converge on a common symptom, chronically high blood glucose. The name translates roughly from the Greek and Latin into “passing through honey,” meaning that a diabetic’s urine has a sweet taste. I’m not sure how the English physician Thomas Willis worked this out. Maybe urine tasting was more common back in the seventeenth century.
For some time, physicians have recognized three forms of the disease, which we know as juvenile, adult-onset, and gestational diabetes. Since so many obese children are now contracting the adult form in their teens, these terms are out the door and have been replaced by insulin-dependent and non-insulin-dependent diabetes mellitus (IDDM and NIDDM, respectively). Since these are confusing, we will stick to type 1 and type 2, or more simply T1D and T2D. The gestational form afflicts pregnant women and can be thought of as a special class of T2D that thankfully usually disappears after childbirth.
By far the more common of the two types of diabetes is T2D. This is the epidemic form that is now seen in more than 20 million Americans and 170 million people worldwide. Another 40 million Americans are considered prediabetic and at risk for full-blown disease. T1D by contrast has a relatively constant prevalence of a fraction of a percent of the population. Very few environmental factors are even suspected to increase the likelihood that a child will have T1D. By contrast, T2D is very much a product of modern diets and modern lifestyles.
The major difference between the two forms is the way that hyperglycemia (high blood glucose) comes about. When we eat, the food is rapidly broken down into sugars, and in particular into a sugar building block called glucose. This is the major source of energy for the body. As anyone who has ever taken college level biochemistry knows all too painfully, most carbohydrates are broken down into glucose through convoluted pathways of metabolism. Sheep and cows just let their food ruminate in the stomach for days, slowly releasing sugars, but other mammals have a highly evolved way to regulate glucose so that the levels stay fairly constant throughout the day. This way we can handle more complex and diverse diets, dining at Spago’s should we wish, instead of on the front lawn.
The main way that glucose levels are regulated is through the hormone insulin. Insulin tells your fat and muscle cells that you’ve just eaten and that they should be prepared to take up the sugars that find their way into the bloodstream. If insulin isn’t working, then glucose metabolism is out of whack and bad things follow. In T1D, insulin doesn’t work because the cells that make the hormone have been destroyed. T1D is an autoimmune disease, just like arthritis, lupus, and multiple sclerosis. The difference between these diseases lies in the nature of the cells that a person’s own immune system destroys. In T1D it specifically attacks just the islet beta cells in the pancreas. Without those cells, no insulin can be made, and glucose remains in the blood. In T2D by contrast, insulin levels are fine, but the body does not respond to the hormone. It is said to be insulin-resistant. You get the message, but just don’t respond to it.
It follows that treatments for these two classes of diabetes need to be different. People with type 1 diabetes must take insulin on a daily basis, mostly by injections that after a time become extremely painful. Drug companies are working on forms of the hormone that can be taken orally, but it tends to be digested before it can get to the liver where it is most needed. Long term, it will be better if physicians can work out ways to transplant healthy islet beta cells back into the pancreas, possibly using stem cell technology. Type 2 diabetics manage the disease with a variety of drugs that act principally to lower blood glucose levels. Even better, changes in lifestyle such as increased exercise, healthier eating habits, cessation of smoking, and generally reducing stress can all turn the tide of disease.
What is so bad about high blood glucose? If the whole point of eating is to provide energy for cells, what can be the problem with allowing them to bathe in sugar? Basically it is a matter of all things being better in moderation, that sometimes too much of a good thing can be bad for you. Harm manifests itself at several levels.
One of the most important is actually an indirect side effect of cells not absorbing glucose. Even though the glucose levels may be high in the blood, if the cells do not take up enough of the sugar, because they are not responding to insulin, they are forced to use a different source of fuel. This is the reserve of fats and proteins that they have. But burning fats produces things called ketones, which are acidic. If there are too many ketones, then the pH of the blood drops. If it gets below 7.35, the result is acid rain in the body: Our cells don’t like acid any more than trees do.
Turning to the direct effects, often the first problem is that the kidneys are upset. Their role is to clean up toxins in the blood, which they do by filtering them from the blood into what will become urine. The whole system depends on appropriate osmotic pressure, on the balance of electrolytes and sugars. If too much sugar is in the blood, it must be pumped into the urine, and excessive urination—often the first sign of diabetes—ensues. The lost fluids have to be replenished somehow, generally by excessive drinking (preferably of water), lest the body coaxes its own cells into giving up their water. Should this dehydration happen to cells in the brain, dizziness and fainting spells will result, and in extreme cases even unconsciousness.
Eventually the imbalance puts so much strain on the kidneys that they start to fail. Diabetic nephropathy is the most common cause of the need for dialysis in the United States. Once pathology starts to develop, it can progress quickly, particularly if blood pressure is poorly controlled.
A second common sign of diabetes is blurred vision. For one thing, constant absorption of glucose changes the shape of the cells in the lens of a person’s eye, which affects eyesight. But the bigger problem is that the blood cells of the retina are very sensitive and easily damaged by buildup of obstructions that cut off oxygen supply and kill the cells. When this happens new blood vessels start to grow in, and blood can seep into the back of the retina, so clouding the image that blindness ensues. Diabetic retinopathy will affect 80 percent of patients who have the disease for 15 years or more, unless they take careful steps to control the symptoms.
Local damage to the small blood vessels throughout the body has other consequences. As glucose builds up, the vessels thicken and can constrict, resulting in mini strokes in the periphery
of the body rather than the brain. These disrupt the general flow of blood. Starved of oxygen, nerves eventually stop working as diabetic neuropathy sets in. Impotence may be one concern, but numbness and diarrhea, loss of bladder control, and muscle weakness are all common signs of advanced disease.
From there, things can only get worse. Completely deprived of blood flow, the arms and legs start to waste away, and deprived of feeling it is easy for cuts, bruises, and calluses to turn into ulcers and open sores if not gangrene. Diabetes is the primary cause of nontraumatic amputation. The heart itself also needs a constant supply of blood, so cardiac failure is common. As blood pressure rises, so too does the risk of atherosclerosis, particularly in obese or hypertensive patients. Ultimately, heart disease and stroke are the most deadly consequences of all forms of diabetes.
Type 1 Diabetes
Somewhere in the vicinity of 1 in every 300 children will contract the fat-free form of diabetes, T1D. We currently have no way of identifying those at risk in advance and are powerless to stop the progression. On the other hand, we can be fairly confident about who will not be type 1 diabetics. The reason is that almost everyone who has the disease has one of a handful of genetic markers at one particular place in the genome. The Human Genome Project is telling us that they are likely to have a few other risk factors as well.
Even a cursory look at the distribution of T1D in families makes it clear that there is a sizeable genetic component to the disease. If one identical twin has it, then just over half the time the other one will as well. By contrast, regular brothers and sisters of a type 1 diabetic have only a 1 in 20 chance of contracting T1D, reflecting the fact that they only share half of their genes. But this incidence is itself 20 times greater than the prevalence of the disease in the whole population.