A House of Proteins

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My ENTIRE PROFESSIONAL CAREER in biomedical research has centered on protein. Like an invisible leash, protein tethered me wherever I went, from the basic research laboratory to the practical programs of feeding malnourished children in the Philippines to the government board- rooms where our national health policy was being formulated. Protein, often regarded with unsurpassed awe, is the common thread tying to- gether past and present knowledge about nutrition.
The story of protein is part science, part culture and a good dose of mythology. I am reminded of the words of Goethe, first brought to my attention by my friend Howard Lyman, a prominent lecturer, author and former cattle rancher: "We are best at hiding those things which are in plain sight." Nothing has been so well hidden as the untold story of protein. The dogma surrounding protein censures, reproaches and guides, directly or indirectly, almost every thought we have in biomedi- cal research.
Ever since the discovery of this nitrogen-containing chemical in 1839 by the Dutch chemist Gerhard Mulder, protein has loomed as the most sacred of all nutrients. The word protein comes from the Greek word proteios, which means "of prime importance."
In the nineteenth century, protein was synonymous with meat, and this connection has stayed with us for well over a hundred years. Many people today still equate protein with animal-based food. If you were to name the first food that comes to mind when I say protein, you might say beef. If you did, you aren't alone.
Confusion reigns on many of the most basic questions about protein:
• What are good sources of protein?
• How much protein should one consume?
• Is plant protein as good as animal protein?
• Isitnecessarytocombinecertainplantfoodsinamealtogetcom-
plete proteins?
• Is it advisable to take protein powders or amino acid supplements,
especially for someone who does vigorous exercise or plays sport?
• Should one take protein supplements to build muscle?
• Some protein is considered high quality, some low quality; what
does this mean?
• Where do vegetarians get protein?
• Can vegetarian children grow properly without animal protein?
Fundamental to many of these common questions and concerns is the belief that meat is protein and protein is meat. This belief comes from the fact that the "soul" of animal-based foods is protein. In many meat and dairy products, we can selectively remove the fat but we are still left with recognizable meat and dairy products. We do this all the time, with lean cuts of meat and skim milk. But if we selectively remove the protein from animal-based foods, we are left with nothing like the original. A non-protein steak, for example, would be a puddle of water, fat and a small amount of vitamins and minerals. Who would eat that? In brief, for a food to be recognized as an animal-based food, it must have protein. Protein is the core element of animal-based foods.
Early scientists like Carl Voit (1831-1908), a prominent German scientist, were staunch champions of protein. Voit found that "man" needed only 48.5 grams per day, but nonetheless he recommended a whopping 118 grams per day because of the cultural bias of the time. Protein equaled meat, and everyone aspired to have meat on his or her table, just as we aspire to have bigger houses and faster cars. Voit figured you can't get too much of a good thing.
Voit went on to mentor several well-known nutrition researchers of the early 1900s, including Max Rubner (1854-1932) and WOo Atwater (1844-1907). Both students closely followed the advice of their teacher. Rubner stated that protein intake, meaning meat, was a symbol of civi- lization itself: "a large protein allowance is the right of civilized man." Atwater went on to organize the first nutrition laboratory at the United States Department of Agriculture (USDA). As director of the USDA, he recommended 125 grams per day (only about fifty-five grams per day is now recommended). Later, we will see how important this early prec- edent was to this government agency.
A cultural bias had become firmly entrenched. If you were civilized, you ate plenty of protein. If you were rich, you ate meat, and if you were poor, you ate staple plant foods, like potatoes and bread. The lower classes were considered by some to be lazy and inept as a result of not eating enough meat, or protein. Elitism and arrogance dominated much of the burgeoning field of nutrition in the nineteenth century. The en- tire concept that bigger is better, more civilized and perhaps even more spiritual permeated every thought about protein.
Major McCay, a prominent English physician in the early twentieth century, provided one of the more entertaining, but most unfortunate, moments in this history. Physician McCay was stationed in the English colony of India in 1912 in order to identify good fighting men in the In- dian tribes. Among other things, he said that people who consumed less protein were of a "poor physique, and a cringing effeminate disposition is all that can be expected."
PRESSING FOR QUALITY
Protein, fat, carbohydrate and alcohol provide virtually all of the calo- ries that we consume. Fat, carbohydrate and protein, as macronutrients, make up almost all the weight of food, aside from water, with the re- maining small amount being the vitamin and mineral micronutrients. The amounts of these latter micronutrients needed for optimum health are tiny (milligrams to micrograms).
Protein, the most sacred of all nutrients, is a vital component of our bodies and there are hundreds of thousands of different kinds. They function as enzymes, hormones, structural tissue and transport mol- ecules, all of which make life possible. Proteins are constructed as long chains of hundreds or thousands of amino acids, of which there are fifteen to twenty different kinds, depending on how they are counted. Proteins wear out on a regular basis and must be replaced. This is ac- complished by consuming foods that contain protein. When digested, these proteins give us a whole new supply of amino acid building blocks to use in making new protein replacements for those that wore out. Various food proteins are said to be of different quality, depending on how well they provide the needed amino acids used to replace our body proteins.
This process of disassembling and reassembling the amino acids of proteins is like someone giving us a multicolored string of beads to re- place an old string of beads that we lost. However, the colored beads on the string given to us are not in the same order as the string we lost. $0, we break the string and collect its beads. Then, we reconstruct our new string so that the colored beads are in the same order as our lost string. But if we are short of blue beads, for example, making our new string is going to be slowed down or stopped until we get more blue beads. This is the same concept as in making new tissue proteins to match our old worn out proteins.
About eight amino acids ("colored beads") that are needed for mak- ing our tissue proteins must be provided by the food we eat. They are called "essential" because our bodies cannot make them. If, like our string of beads, our food protein lacks enough of even one of these eight "essential" amino acids, then the synthesis of the new proteins will be slowed down or stopped. This is where the idea of protein qual- ity comes into play. Food proteins of the highest quality are, very sim- ply, those that provide, upon digestion, the right kinds and amounts of amino acids needed to efficiently synthesize our new tissue proteins. This is what that word "quality" really means: it is the ability of food proteins to provide the right kinds and amounts of amino acids to make our new proteins.
Can you guess what food we might eat to most efficiently provide the building blocks for our replacement proteins? The answer is human flesh. Its protein has just the right amount of the needed amino acids. But while our fellow men and women are not for dinner, we do get the next "best" protein by eating other animals. The proteins of other animals are very similar to our proteins because they mostly have the right amounts of each of the needed amino acids. These proteins can be used very efficiently and therefore are called "high quality." Among ani- mal foods, the proteins of milk and eggs represent the best amino acid matches for our proteins, and thus are considered the highest quality.
While the "lower quality" plant proteins may be lacking in one or more of the essential amino acids, as a group they do contain all of them.
The concept of quality really means the efficiency with which food proteins are used to promote growth. This would be well and good if the greatest efficiency equaled the greatest health, but it doesn't, and that's why the terms efficiency and quality are misleading. In fact, to give you a taste of what's to come, there is a mountain of compelling research showing that "low-quality" plant protein, which allows for slow but steady synthesis of new proteins, is the healthiest type of protein. Slow but steady wins the race. The quality of protein found in a specific food is determined by seeing how fast animals would grow while consuming it. Some foods, namely those from animals, emerge with a very high protein efficiency ratio and value. 1
This focus on efficiency of body growth, as if it were good health, en- courages the consumption of protein with the highest "quality." As any marketer will tell you, a product that is defined as being high quality instantly earns the trust of consumers. For well over 100 years, we have been captive to this misleading language and have oftentimes made the unfortunate leap to thinking that more quality equals more health.
The basis for this concept of protein quality was not well known among the public, but its impact was-and still is-highly significant. People, for example, who choose to consume a plant-based diet will often ask, even today, "Where do I get my protein?" as if plants don't have protein. Even if it is known that plants have protein, there is still the concern about its perceived poor quality: This has led people to believe that they must meticulously combine proteins from different plant sources during each meal so that they can mutually compensate for each other's amino acid deficits. However, this is overstating the case. We now know that through enormously complex metabolic sys- tems, the human body can derive all the essential amino acids from the natural variety of plant proteins that we encounter every day. It doesn't require eating higher quantities of plant protein or meticulously plan- ning every meal. Unfortunately, the enduring concept of protein quality has greatly obscured this information.
THE PROTEIN GAP
The most important issue in nutrition and agriculture during my early career was figuring out ways to increase the consumption of protein, making sure it was of the highest possible quality: My colleagues and I all believed in this common goal. From my early years on the farm to my graduate education, I accepted this virtual reverence for protein. As a youngster, I remember that the most expensive part of farm animal feed was the protein supplements that we fed to our cows and pigs. Then, at graduate school, I spent three years (1958-1961) doing my Ph.D. re- search trying to improve the supply of high-quality protein by growing cows and sheep more efficiently so we could eat more of them.2.3
I went all the way through my graduate studies with a profound be- lief that promoting high-quality protein, as in animal-based foods, was a very important task. My graduate research, although cited a few times over the next decade or so, was only a small part of much larger efforts by other research groups to address a protein situation worldwide. Dur- ing the 1960s and 1970s, I was to hear over and over again about a so- called "protein gap" in the developing world.4
The protein gap stipulated that world hunger and malnutrition among children in the third world was a result of not having enough protein to consume, especially high-quality (i.e. animal) protein.I, 4,5 According to this view, those in the third world were especially de- ficient in "high-quality" protein, or animal protein. Projects were springing up all over the place to address this "protein gap" problem. A prominent MIT professor and his younger colleague concluded in 1976 that "an adequate supply of protein is a central aspect of the world food problem"5 and further that "unless...desirably [supplemented] by modest amounts of milk, eggs, meat or fish, the predominantly cereal diets [of poor nations] are ... deficient in protein for growing chil- dren .... " To address this dire problem:
• MIT was developing a protein-rich food supplement called INCA- PARINA.
• Purdue University was breeding corn to contain more lysine, the "deficient" amino acid in corn protein.
• Theu.s.governmentwassubSidizingtheproductionofdriedmilk powder to provide high-quality protein for the world's poor.
• Cornell University was providing a wealth of talent to the Philip- pines to help develop both a high-protein rice variety and a live- stock industry.
• Auburn University and MIT were grinding up fish to produce "fish protein concentrate" to feed the world's poor.
The United Nations, the U.S. Government Food for Peace Program, major universities and countless other organizations and universities were taking up the battle cry to eradicate world hunger with high-qual- ity protein. I knew most of the projects firsthand, as well as the indi- viduals who organized and directed them.
The Food and Agriculture Organization (FAa) of the United Nations exerts considerable influence in developing countries through their ag- riculture development programs. Two of its staffers6 declared in 1970 that ". .. by and large, the lack of protein is without question the most serious qualitative deficiency in the nutrition of developing countries. The great mass of the population of these countries subsists mainly on foods derived from plants frequently deficient in protein, which results in poor health and low productivity per man." M. Autret, a very influ- ential man from the FAO, added that "owing to the low-animal protein content of the diet and lack of diversity of supplies [in developing countries]' protein quality is unsatisfactory."4 He reported on a very strong association between consumption of animal-based foods and an- nual income. Autret strongly advocated increasing the production and consumption of animal protein in order to meet the growing "protein gap" in the world. He also advocated that "all resources of science and technology must be mobilized to create new protein-rich foods or to derive the utmost benefits from hitherto insufficiently utilized resources to feed mankind."4
Bruce Stillings at the University of Maryland and the U.S. Depart- ment of Commerce, another proponent of consuming animal-based di- ets, admitted in 1973 that "although there is no requirement for animal protein in the diet per se, the quantity of dietary protein from animal sources is usually accepted as being indicative of the overall protein qualityofthediet."1 Hewentontosaythatthe"...supplyofadequate quantities of animal products is generally recognized as being an ideal way to improve world protein nutrition."
Of course, it's quite correct that a supply of protein can be an im- portant way of improving nutrition in the third world, particularly if populations are getting all of their calories from one plant source. But it's not the only way, and, as we shall see, it isn't necessarily the way most consistent with long-term health.
FEEDING THE CHILDREN
SO this was the climate at that time, and I was a part of it as much as anyone else. I left MIT to take a faculty position at Virginia Tech in 1965. Professor Charlie Engel, who was then the head of the Department of Biochemistry and Nutrition at Virginia Tech, had considerable inter- est in developing an international nutrition program for malnourished children. He was interested in implementing a "mothercraft" self-help project in the Philippines. This project was called "mothercraft" because it focused on educating mothers of malnourished children. The idea was that if mothers were taught that the right kinds of locally grown foods can make their children well, they would not have to rely on scarce medicines and the mostly nonexistent doctors. Engel started the program in 1967 and invited me to be his Campus Coordinator and to come for extended stays in the Philippines while he resided full time in Manila.
Consistent with the emphasis on protein as a means of solving mal- nutrition, we had to make this nutrient the centerpiece of our educa- tional "mothercraft" centers and thereby help to increase protein con- sumption. Fish as a source of protein was mostly limited to the seacoast areas. Our own preference was to develop peanuts as a source of protein because this was a crop that could be grown most anywhere. The peanut is a legume, like alfalfa, soybeans, clover, peas and other beans. Like these other nitrogen "fixers," peanuts are rich in protein.
There was, however, a nagging problem with these tasty legumes. Considerable evidence had been emerging, first from England7- 9 and later from MIT (the same lab that I had worked in)10, 11 to show that pea- nuts often were contaminated with a fungus-produced toxin called af- latoxin (AF). It was an alarming problem because AF was being shown to cause liver cancer in rats. It was said to be the most potent chemical carcinogen ever discovered.
So we had to tackle two closely related projects: alleviate childhood malnutrition and resolve the AF contamination problem.
Prior to going to the Philippines, I had traveled to Haiti in order to observe a few experimental mothercraft centers organized by my col- leagues at Virginia Tech, Professors Ken King and Ryland Webb. It was my first trip to an underdeveloped country, and Haiti certainly fit the bill. Papa Doc Duvalier, president of Haiti, extracted what little resourc- es the country had for his own rich lifestyle. In Haiti at that time 54% of the children were dead before reaching their fifth birthday, largely because of malnutrition.
I subsequently went to the Philippines and encountered more of the same. We decided where mothercraft centers were to be located based on how much malnutrition was present in each village. We focused our efforts on the villages in most need. In a preliminary survey in each vil- lage (barrio), children were weighed and their weight for age was com- pared with a Western reference standard, which was subdivided into first, second and third degree malnutrition. Third degree malnutrition, the worst kind, represented children under the 65th percentile. Keep in mind that a child at the lOOth percentile represents only the average for the u.s. Being less than the 65th percentile means near starvation.
In the urban areas of some of the big cities, as many as 15-20% of the children aged three to six years were judged to be third degree. I can so well remember some of my initial observations of these children. A mother, hardly more than a wisp herself, holding her three-year-old twins with bulging eyes, one at eleven pounds, the other at fourteen pounds, trying to get them to open their mouths to eat some porridge. Older children blind from malnutrition, being led around by their younger siblings to seek a handout. Children without legs or arms hop- ing to get a morsel of food.
A REVELATION TO DIE FOR
Needless to say, those sights gave us ample motivation to press ahead with our project. As I mentioned before, we first had to resolve the problem of AF contamination in peanuts, our preferred protein food.
The first step of investigating AF was to gather some basic information. Who in the Philippines was consuming AF, and who was subject to liver cancer? To answer these questions, I applied for and received a National Institutes of Health (NIH) research grant. We also adopted a second strat- egy by asking another question: how does AF actually affect liver cancer? We wanted to study this question at the molecular level using laboratory rats. I succeeded in getting a second NIH grant for this in-depth bio- chemical research. These two grants initiated a two-track research inves- tigation, one basic and one applied, which was to continue for the rest of my career. I found studying questions both from the basic and applied perspectives rewarding because it tells us not only the impact of a food or chemical on health, but also why it has that impact. In so doing, we could better understand not only the biochemical foundation of food and health, but also how it might relate to people in everyday life.
We began with a stepwise series of surveys. First, we wanted to know which foods contained the most AF. We learned that peanuts and corn were the foods most contaminated. All twenty-nine jars of peanut butter we had purchased in the local groceries, for example, were contami- nated, with levels of AF as much as 300 times the amount judged to be acceptable in U.s. food. Whole peanuts were much less contaminated; none exceeded the AF amounts allowed in U.s. commodities. This disparity between peanut butter and whole peanuts originated at the peanut factory. The best peanuts, which filled "cocktail" jars, were hand selected from a moving conveyor belt, leaving the worst, moldiest nuts to be delivered to the end of the belt to make peanut butter.
Our second question concerned who was most susceptible to this AF contamination and its cancer-producing effects. We learned that it was children. They were the ones consuming the AF-Iaced peanut butter. We estimated AF consumption by analyzing the excretion of AF meta- bolic products in the urine of children living in homes with a partially consumed peanut butter jar.12 As we gathered this information an inter- esting pattern emerged: the two areas of the country with the highest rates of liver cancer, the cities of Manila and Cebu, also were the same areas where the most AF was being consumed. Peanut butter was almost exclusively consumed in the Manila area while corn was consumed in Cebu, the second most populated city in the Philippines.
But, as it turned out, there was more to this story. It emerged from my making the acquaintance of a prominent doctor, Dr. Jose Caedo, who was an advisor to President Marcos. He told me that the liver cancer problem in the Philippines was quite serious. What was so devastating was that the disease was claiming the lives of children before the age of ten. Whereas in the West, this disease mostly strikes people only after forty years of age, Caedo told me that he had personally operated on children younger than four years of age for liver cancer!
That alone was incredible, but what he then told me was even more striking. Namely, the children who got liver cancer were from the best-fed families. The families with the most money ate what we thought were the healthiest diets, the diets most like our own meaty American diets. They consumed more protein than anyone else in the country (high quality animal protein, at that), and yet they were the ones getting liver cancer!
How could this be? Worldwide, liver cancer rates were highest in countries with the lowest average protein intake. It was therefore widely believed that this cancer was the result of a deficiency in protein. Fur- ther, the deficiency problem was a major reason we were working in the Philippines: to increase the consumption of protein by as many mal- nourished children as possible. But now Dr. Caedo and his colleagues were telling me that the most protein-rich children had the highest rates of liver cancer. This seemed strange to me, at first, but over time my own information increasingly confirmed their observations.
At that time, a research paper from India surfaced in an obscure med- ical journal.13 It was an experiment involving liver cancer and protein consumption in two groups of laboratory rats. One group was given AF and then fed diets containing 20% protein. The second group was given the same level of AF and then fed diets containing only 5% protein.
Every single rat fed 20% protein got liver cancer or its precursor lesions, but not a single animal fed a 5% protein diet got liver cancer or its pre- cursor lesions. It was not a trivial difference; it was 100% versus 0%. This was very much consistent with my observations for the Philippine children. Those who were most vulnerable to liver cancer were those who consumed diets higher in protein.
No one seemed to accept the report from India. On a flight from De- troit after returning from a presentation at a conference, I traveled with a former but much senior colleague of mine from MIT, Professor Paul Newberne. At the time, Newberne was one of the only people who had given much thought to the role of nutrition in the development of can- cer. I told him about my impressions in the Philippines and the paper from India. He summarily dismissed the paper by saying, "They must have gotten the numbers on the animal cages reversed. In no way could a high-protein diet increase the development of cancer. "
I realized that I had encountered a provocative idea that stimulated disbelief, even the ire of fellow colleagues. Should I take seriously the observation that protein increased cancer development and run the risk of being thought a fool? Or should I turn my back on this story?
In some ways it seemed that this moment in my career had been fore- shadowed by events in my personal life. When I was five years old, my aunt who was living with us was dying of cancer. On several occasions my uncle took my brother Jack and me to see his wife in the hospital. Although I was too young to understand everything that was happen- ing, I do remember being struck by the big "C' word: cancer. I would think, "When I get big, I want to find a cure for cancer."
Many years later, just a few years after getting married, at about the time when I was starting my work in the Philippines, my wife's mother was dying of colon cancer at the young age of fifty-one. At that time, I was becoming aware of a possible diet-cancer connection in our early research. Her case was particularly difficult because she did not receive appropriate medical care due to the fact that she did not have health insurance. My wife Karen was her only daughter and they had a very close relationship. These difficult experiences were making my career choice easy: I would go wherever our research led me to help get a bet- ter understanding of this horrific disease.
Looking back on it, this was the beginning of my career focus on diet and cancer. The moment of deciding to investigate protein and cancer was the turning point. If I wanted to stay with this story, there was only one solution: start doing fundamental laboratory research to see not only if, but also how, consuming more protein leads to more cancer. That's exactly what I did. It took me farther than I had ever imagined. The ex- traordinary findings my colleagues, students and I generated just might make you think twice about your current diet. But even more than that, the findings led to broader questions, questions that would eventually lead to cracks in the very foundations of nutrition and health.
THE NATURE OF SCIENCE-WHAT YOU NEED TO KNOW TO FOLLOW THE RESEARCH
Proof in science is elusive. Even more than in the "core" sciences of biol- ogy, chemistry and physics, establishing absolute proof in medicine and health is nearly impossible. The primary objective of research investiga- tion is to determine only what is likely to be true. This is because research into health is inherently statistical. When you throw a ball in the air, will it come down? Yes, every time. That's physics. If you smoke four packs a day, will you get lung cancer? The answer is maybe. We know that your odds of getting lung cancer are much higher than if you didn't smoke, and we can tell you what those odds (statistics) are, but we can't know with certainty whether you as an individual will get lung cancer.
In nutrition research, untangling the relationship between diet and health is not so straightforward. Humans live all sorts of different ways, have different genetic backgrounds and eat all sorts of different foods. Experimental limitations such as cost restraints, time constraints and measurement error are significant obstacles. Perhaps most importantly, food, lifestyle and health interact through such complex, multifaceted systems that establishing proof for anyone factor and anyone disease is nearly impossible, even if you had the perfect set of subjects, unlimited time and unlimited financial resources.
Because of these difficulties, we do research using many different strategies. In some cases, we assess whether a hypothetical cause pro- duces a hypothetical effect by observing and measuring the differences that already exist between different groups of people. We might observe and compare societies who consume different amounts of fat, then ob- serve whether these differences correspond to similar differences in the rates of breast cancer or osteoporosis or some other disease condition. We might observe and compare the dietary characteristics of people who already have the disease with a comparable group of people who don't have the disease. We might observe and compare disease rates in 1950 with disease rates in 1990, then observe whether any changes in disease rates correspond to dietary changes.
In addition to observing what already exists, we might do an experi- ment and intentionally intervene with a hypothetical treatment to see what happens. We intervene, for example, when testing for the safety and efficacy of drugs. One group of people is given the drug and a sec- ond group a placebo (an inactive look-alike substance to please the patient). Intervening with diet, however, is far more difficult, especially if people aren't confined to a clinical setting, because then we must rely on everyone to faithfully use the specified diets.
As we do observational and interventional research, we begin to amass the findings and weigh the evidence for or against a certain hypothesis. When the weight of the evidence favors an idea so strongly that it can no longer be plausibly denied, we advance the idea as a likely truth. It is in this way that I am advancing an argument for a whole foods, plant-based diet. As you continue reading, realize that those seeking absolute proof of optimal nutrition in one or two studies will be disappointed and con- fused. However, I am confident that those seeking the truth regarding diet and health by surveying the weight of the evidence from the variety of available studies will be amazed and enlightened. There are several ideas to keep in mind when determining the weight of the evidence, including the following ideas.
CORRELATION VERSUS CAUSATION
In many studies, you will find that the words correlation and association are used to describe a relationship between two factors, perhaps even in- dicating a cause-and-effect relationship. This idea is featured prominently in the China Study: We observed whether there were patterns of associa- tions for different dietary, lifestyle and disease characteristics within the survey of 65 counties, 130 villages and 6,500 adults and their families. If protein consumption, for example, is higher among populations that have a high incidence of liver cancer, we can say that protein is positively correlated or associated with liver cancer incidence; as one goes up, the other goes up. If protein intake is higher among populations that have a low incidence of liver cancer, we can say that protein is inversely associ- ated with liver cancer incidence. In other words, the two factors go in the opposite direction; as one goes up, the other goes down.
In our hypothetical example, if protein is correlated with liver can- cer incidence, this does not prove that protein causes or prevents liver cancer. A classic illustration of this difficulty is that countries with more telephone poles often have a higher incidence of heart disease, and many other diseases. Therefore, telephone poles and heart disease are positively correlated. But this does not prove that telephone poles cause heart disease. In effect, correlation does not equal causation.
This does not mean that correlations are useless. When they are properly interpreted, correlations can be effectively used to study nu- trition and health relationships. The China Study, for example, has over 8,000 statistically significant correlations, and this is of immense value. When so many correlations like this are available, researchers can begin to identify patterns of relationships between diet, lifestyle and disease. These patterns, in turn, are representative of how diet and health processes, which are unusually complex, truly operate. However, if someone wants proof that a single factor causes a single outcome, a correlation is not good enough.
STATISTICAL SIGNIFICANCE
You might think that deciding whether or not two factors are correlated is obvious-either they are or they aren't. But that isn't the case. When you are looking at a large quantity of data, you have to undertake a sta- tistical analysis to determine if two factors are correlated. The answer isn't yes or no. It's a probability, which we call statistical significance. Sta- tistical significance is a measure of whether an observed experimental effect is truly reliable or whether it is merely due to the play of chance. If you flip a coin three times and it lands on heads each time, it's prob- ably chance. If you flip it a hundred times and it lands on heads each time, you can be pretty sure the coin has heads on both sides. That's the concept behind statistical Significance-it's the odds that the correlation (or other finding) is real, that it isn't just random chance.
A finding is said to be statistically Significant when there is less than 5% probability that it is due to chance. This means, for example, that there is a 95% chance that we will get the same result if the study is repeated. This 95% cutoff point is arbitrary, but it is the standard, none- theless. Another arbitrary cutoff point is 99%. In this case, when the result meets this test, it is said to be highly statistically significant. In the discussions of diet and disease research in this book, statistical signifi- cance pops up from time to time, and it can be used to help judge the reliability, or "weight," of the evidence.
MECHANISMS OF ACTION
Oftentimes correlations are considered more reliable if other research shows that two correlated factors are biologically related. For example, telephone poles and heart disease are positively correlated, but there is no research that shows how telephone poles are biologically related to heart disease. However, there is research that shows the processes by which protein intake and liver cancer might be biologically and caus- ally related (as you will see in chapter three). Knowing the process by which something works in the body means knowing its "mechanism of action." And knowing its mechanism of action strengthens the evi- dence. Another way of saying this is that the two correlated factors are related in a "biologically plausible" way. If a relationship is biologically plausible, it is considered much more reliable.
METANALYSIS
Finally, we should understand the concept of a metanalysis. A met- analysis tabulates the combined data from multiple studies and ana- lyzes them as one data set. By accumulating and analyzing a large body of combined data, the result can have considerably more weight. Met- analysis findings are therefore more substantial than the findings of single research studies, although, as with everything else, there may be exceptions.
After obtaining the results from a variety of studies, we can then be- gin to use these tools and concepts to assess the weight of the evidence. Through this effort, we can begin to understand what is most likely to be true, and we can behave accordingly. Alternative hypotheses no lon- ger seem plausible, and we can be very confident in the result. Absolute proof, in the technical sense, is unattainable and unimportant. But com- mon sense proof (99% certainty) is attainable and critical. For example, it was through this process of interpreting research that we formed our beliefs regarding smoking and health. Smoking has never been "100%" proven to cause lung cancer, but the odds that smoking is unrelated to lung cancer are so astronomically low that the matter has long been considered settled.

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