Читать книгу Secrets of the Human Body - Andrew Cohen - Страница 9
ОглавлениеBABY TO BABY-MAKER
The simple process of growing is an extraordinary thing. During a lifetime our growth rate is truly staggering: from starting out as a single fertilised egg at the moment of conception, we multiply into a mass of trillions of cells made up of over 200 different cell types organised into around 80 organs (the exact number depends on how you define an organ … not as straightforward as you might think!), and that’s before we are even born.
At birth the average human weighs about 3.5 kg and is approximately half a metre in length from head to heel. On our journey from baby to adult we then go through an amazing transformation: we quadruple in height. We add, on average, 70–80 kg to our body weight, although far more than this is increasingly common. At our fastest rate of growth we can elongate by up to 1.5 cm in a single day. It’s a process that we hardly notice but exploring how, why and when we grow reveals an extraordinary secret inside our bodies, which ultimately leads to a transformation that every one of us goes through. In this chapter we will explore the latest understanding of that process of growth and the magic ingredient that fuels it through the beginning of our lives. We will uncover the mystery of human childhood, a childhood longer than any other creature on earth, and explore the mysterious moment that triggers the body of a child to suddenly transform itself into an adult. We will also discover that growing doesn’t just end at adulthood, because throughout our lives our bodies are endlessly replenishing and regenerating, and even in old age, in some ways, we still continue to grow. We are now using this knowledge at the very cutting edge of medical science to redefine our perception of human growth by learning how to replicate it, control it and ultimately build new human organs and tissues grown entirely in the laboratory.
I was born at 13.45 on 18 August 1978 with Chris taking an extra seven minutes to emerge into the welcoming arms of a midwife at the Queen Charlotte Hospital in London. At birth I weighed in at 6 lb 12 oz (3.06 kg) with Chris a slightly chubbier 6 lb 14 oz (3.12 kg). Thirty-nine years later and the vital statistics have not played out in my favour. Chris is not only an entire half an inch taller than me at 6 ft 1 in (185 cm), but he is also from the last available records approximately 5 kg lighter than me as well. Small differences to you perhaps but when you’re an identical twin it’s these differences that really matter! But the changes in our height and weight are just two of the miraculous transformations that we have gone through over the last 39 years. Each one of us sees our body transform throughout our childhood and beyond under the influence of a multitude of different factors, a complex web of genes and environment that combine together to turn a baby into a baby-maker. As we’ll see in the ‘Learn’ chapter, the transformation of our brains from newborn to highly skilled adult is a miraculous journey of its own, but our bodies undergo an equally extraordinary transformation. The size, shape, strength, appearance and function of our bodies are completely altered through those first 18 or so years of our lives. It’s such a gradual process that until we compare young and old photographs we often miss just how comprehensive and extreme a physical change this is.
To put the extraordinary nature of this process into a slightly different context, just imagine attempting to build a machine that has such an inherent ability for self-transformation in both its structure and function, adapting constantly to the demands made on it. In engineering terms it would be a plane strengthened by turbulence, a car that got faster the more you drove it and used less fuel per mile, a computer that got quicker and more accurate with age. On top of that these machines would be able to fuel and reproduce themselves. As we will see in this chapter, attempts at bioengineering reveal just how superb and precise a designer nature is compared to even our most impressive innovations.
For most animals on the planet the journey to maturity is a quick and efficient process. Many mammals, including dogs and cats, reach adulthood within six months of birth, blue whales (the largest animals on the planet) are able to reproduce as quickly as five years after birth and our nearest cousin the chimpanzee completes its journey to maturation years ahead of us, being fully grown, sexually mature and reproducing on average by the age of 13. It seems an elongated childhood is a uniquely human process. No other animal on the planet takes longer to reach maturity and no other animal goes through such a convoluted stop–start process of growth and development than a human child. In many parts of the developed world the average age of a first-time mother is well into her thirties. Many of the reasons behind this elongated adolescence are of course cultural, heavily influenced by the way we structure our societies and the growing balances between the lives of men and women. But underneath the social influences there is an intriguing biological story with mysteries that we are still trying to understand. Why, for instance, do we have two discrete growth spurts, one just after birth and one on average more than 10 years later, just before puberty? What is the reason for this elongated lull in our growth? And what triggers the sudden onset of puberty? All of these are questions that until very recently we have struggled to answer, but in the last few years many of the secrets of the journey from baby to reproduction are beginning to be revealed.
SELF-REPLICATING MACHINES
A quick interesting side note while we are talking about this is that the concept of self-replicating machines has a long history in both fact and fiction with perhaps the most famous being devised by the Hungarian mathematician, scientist and general genius John von Neumann. Von Neumann machines that could explore and colonise whole galaxies have been the subject of much conjecture for decades and the fact we have never found one has been used by some as evidence that advanced civilisations are absent from this and perhaps every other nearby galaxy.
MIRACLE MILK
There is only one substance on earth that is specifically produced as a nourishing food: milk.
A few fruits have evolved to be palatable, persuading animals to eat them and distribute seeds in faeces, but these are just sweet-treats. And yes, we can extract nutrition from animal flesh and a handful of plants and fungi, but our relationship with these foodstuffs is more complex, more competitive. They didn’t evolve specifically to be food. Milk, and only milk, did.
Breast milk is what makes mammals, mammals. There are other characteristics that most mammals share but the platypus, and a few of its Australasian friends, mess things up, with their egg-laying and lack of placentas. But even the platypus makes milk.
Milk is extraordinary stuff. It is, most obviously, a complete source of nutrition. It contains fat, protein, carbohydrate, water, vitamins, minerals, amino acids and fatty acids, all in an available form, tailored perfectly to each stage of development. You can build a human child for several years entirely on breast milk. But it’s not just food. It also contains an immune system in the form of antibodies, and a cocktail of hormones and other factors that regulate and stimulate infant development. And far from being a single substance, it is constantly changing, as the child grows, between left and right breast and throughout the day. Even within a single feed the milk shows complex fluctuations in what it contains in terms of lipids, carbohydrates and total calories.
Milk composition. Note how much more protein there is in cow’s milk and how much less HMO mass.
Breast milk is made when a set of genes are turned on in the cells of the mother’s breast during pregnancy. These genes encode proteins, including the enzymes that turn the mother’s body into the end product. The genes for milk production have been selected by evolution over around 150–200 million years since the first shrew-like creatures gave their young primitive breast milk from barely modified sweat glands. Yes, for all its erotic and maternal associations, the breast is a modified sweat gland. It’s impossible to know what that first milk, produced somewhere around the late Jurassic era, would have consisted of, but considering that modern shrews can barely get enough calories to sustain themselves for more than a few hours, that early milk may have been more about the transfer of antibodies, to fight infection, than calories.
THE COST OF A PINT OF MILK
For Bruce German, a chemist at the University of California, Davis, milk was the obvious starting point to understand nutrition. Nutritional science made a few huge leaps early in the twentieth century, before stalling around the 1970s. It had been established that to stay alive, we need three macronutrients (carbohydrate, protein and fat) and all but invisible amounts of a few vitamins, minerals, amino acids and essential fatty acids. Biochemists figured out the chemical reactions that are required to turn what we put into our mouths into flesh and energy. They discovered the enzymes that enable these reactions to happen. They described how the molecular constituents of our cells are recycled and replaced in response to the world around us. But the ideal human diet continues to elude detailed description. There are some broad brushstrokes that we’re confident about: eat lots of plants. Meat seems to be OK in small amounts. Fish is good. Refined sugar may be bad. But dig a little deeper and confusion reigns: saturated fats were bad, then good, then bad. Oily fish, vitamin supplements, low-carb vs. high-carb? These questions still generate inconsistent answers.
A MOTHER WILL, ON AVERAGE, MAKE ABOUT 750 ML (ALMOST A PINT AND A HALF!) OF BREAST MILK PER DAY FOR THE FIRST FIVE MONTHS AFTER BIRTH.
‘Milk offered the opportunity to take an evolutionary perspective. What food should we eat?’ says Bruce. It’s worth saying that there is a lot of bad science based on an evolutionary perspective. It usually involves scientists discovering something about the way people behave towards their mates, friends or enemies and then inferring causality from hypothesised ancestral sabre-tooth tiger encounters. This is often not very useful because we don’t understand much about how we used to interact with sabre-tooth tigers (probably very little). Bruce German and his team at UC Davis do not involve sabre-tooth tigers in their evolutionary perspective. They study the genes, enzymes and constituents of milk. Not all genes in the human body are treated equally by evolution. There are many ancient genes that remain stable, barely changing over long periods of evolutionary time. But the genes involved in breast milk production have been under intense evolutionary scrutiny since it first evolved. Because while milk is great for the offspring, it’s pretty bad for the mother. This is because it is massively expensive for her to produce. And this was the reasoning that the team at UC Davis started with: human breast milk has evolved to be perfect nutrition for a human infant but it needs to be extremely efficient because it is so costly for the mother.
How costly? A mother will, on average, make about 750 ml (almost a pint and a half!) of breast milk per day for the first five months after birth. This will gradually increase with demand to almost a litre a day if exclusive breast feeding continues, assuming the mother is herself well-nourished and hydrated. As drinks go it is rich in energy containing around 65 calories per 100 ml. Unsurprisingly this is about the same as whole milk from a cow. By comparison a sugary cola drink will have about 40 calories per 100 ml. The cost to the mother is immense. She will produce milk by breaking down her own body. Even if milk was made 100 per cent efficiently, it would still be a huge number of calories stripped from the mother, but to calculate the true cost you have to first work out the efficiency of milk production. And it’s not a trivial calculation. Experiments have been done all around the world using isotope labelled water, special metabolic chambers and biochemical calculations about milk composition. Estimates vary, but 1 calorie of milk takes about 1.2 calories of energy from the mother. All this adds up such that, on average, exclusively breast feeding a 6-month-old child will demand a large burger’s worth of energy from the mother each day. And I mean a proper 650-calorie burger. So that’s with bacon. And cheese. For the vast bulk of mammalian evolution, obtaining this amount of energy came at a huge cost. It costs the mother her own body, but there is also the evolutionary cost of the risks required to obtain nutrients. Foraging isn’t just exhausting, it increases the risks of being eaten (but probably not by sabre-tooth tigers).
All this told Bruce and his collaborators two things about breast milk. Firstly, since you can grow a healthy human for many years exclusively on breast milk, it will have everything that a baby needs. Secondly, there is not likely to be anything in it that the baby doesn’t need. From the moment the earliest mammals started producing milk, any mothers that wasted energy on putting unnecessary stuff into it would have quickly been plucked out of the gene pool. The solid components of milk that cost the mother most of the calories by order of amount are 1) fat; 2) sugar; 3) complex chains of sugar molecules called Human Milk Oligosaccharides or HMOs; and 4) protein. Each of these must be of absolutely vital importance to the infant. But here’s the bizarre thing. The third largest solid component of milk, those Human Milk Oligosaccharides, are totally indigestible by a human infant. More than bizarre, it seems absurd. In the words of Bruce German, ‘the mother is expending tremendous amounts of energy to produce these varied and complex molecules and yet they have no apparent nutritional value’.
Human Milk Oligosaccharides are chains of sugar molecules. To put that in context it may be useful to understand a little about different sugar molecules. Monosaccharides are single molecules, usually rings of carbon with a few hydrogen and oxygen atoms added on. Glucose is a familiar example. As a single molecule, it can be absorbed into cells and used for making energy without any breaking down in the gut. Disaccharides are made of two molecules. The white refined sugar in your kitchen is a disaccharide called sucrose, made of a glucose molecule joined to a fructose molecule. The chemical bond that joins the two molecules needs to be broken down by enzymes in your gut before you can use the individual sugar molecules for generating energy. Polysaccharides are long chains of 200–2,000 sugar molecules. They’re often indigestible, like cellulose. Oligosaccharides sit in the middle. The ones in breast milk are branched chains of between 3 and 22 sugar molecules with unhelpful names like di-sialyl-lacto-N-tetraose and lacto-N-fucopentaose V. There are around 200 unique and different types of oligosaccharide in human breast milk, each with different sugar molecules joined together in different chains. Crucially these all need different enzymes to digest them. And humans have none of them. We know that because, in the words of Bruce, if you feed a modern American child human breast milk, ‘the HMOs come out the other end’.
So why is there the same amount of these totally indigestible oligosaccharides as there is protein in human milk? To feed bacteria. In fact, to feed a single bacteria: Bifidobacterium infantis.
BUG FOOD
The idea that the HMOs might be present to feed bacteria rather than humans is an old one. Over a century ago paediatricians, microbiologists and chemists were already trying to understand the health benefits and constituents of breast milk. In the last part of the nineteenth century in Europe and America one in three children died before the age of 5, but it was clear that the chances of survival were higher for breast-fed infants. By 1900 Austrian doctors and scientists had detected differences in the bacteria found in the faeces of breast-fed compared with bottle-fed infants, a remarkable achievement considering the technology of the time. As early as 1888 sugars other than lactose were identified as being in milk, and by 1926 it was reported that there were factors in human milk to promote the growth of a genus of bacteria called Bifidobacterium, but the extraordinary details of the relationship between human mothers and these bacteria took almost another century to determine and required huge advances in genetics and microbiology.
THE HUMAN MICROBIOTA
Estimates for the total number of bacterial cells found in association with the human body have varied between 10 and 1.5 bacteria for each and every human cell. The total number of bacterial genes associated with the human microbiota could exceed the total number of human genes by a factor of 80 to 1. Conservative estimates suggest that an average 70 kg human being is composed of about 30 trillion human cells … and 40 trillion bacterial cells.
The human body provides a rich and varied environment for bacteria with different parts of the body hosting very different communities. In the right location the bacteria perform useful functions, but the concept of ‘good and bad bacteria’ is simplistic. The crucial thing is to have the right bacteria in the right place. Mouth bacteria on a heart valve are bad. Gut bacteria in the urinary tract are bad.
There are a wide range of Bifidobacteria species but they all have a bifurcating shape under a microscope. Aside from that, distinguishing them all is not easy. Starting with the hypothesis that Human Milk Oligosaccharides would nourish them, Bruce German, together with David Mills, a microbiologist, started testing different bacteria, including multiple Bifidobacteria species, to see if they could be cultured in the laboratory using Human Milk Oligosaccharides as their only source of food. Surprisingly initial tests showed very unenthusiastic growth by any of the species tested. They seemed to lack the enzymes necessary to digest the wide variety of sugars in breast milk. But then the team tested B. infantis, a bacteria first isolated from the stool of a breast-fed infant, and it flourished.
If digesting HMOs required a single enzyme, then this ability could be put down to coincidence. Perhaps B. infantis had evolved to digest similar molecules in other environments. But digesting HMOs requires a vast toolkit of genes. B. infantis, and only B. infantis, has them all. An analysis of the genome of the bacteria revealed over 700 unique genes compared to other Bifidobacteria. These include genes for grabbing the HMOs and taking them inside the cell, as well as a series of enzymes able to break down the full range of linkages between the sugar molecules. They are the only bacteria able to completely break down HMOs and there can be no doubt that they have evolved to do this. More importantly the evidence from other species shows a process of co-evolution. As the bacteria evolved to digest milk so the milk evolved to feed them. In the case of humans, the reason why we produce such a complex range of HMOs must be to specifically advantage B. infantis over other bacteria.
So what do we get from the deal? Why do we want a single bug flourishing in our infant gut? The primary reason is probably competition. Human infants are born with a gut that is ostensibly sterile and provides an amazing opportunity for bacteria. It is warm, wet and full of a steady supply of nutrition from food and milk. It is also relatively unprotected by the naive infant immune system. From the moment the mother’s waters break, the baby starts swallowing a range of bacteria. The vagina is full of a carefully controlled mix of bacteria. And what strikes anyone watching a normal vaginal delivery is that the baby is born, face down, into a pile of faeces. It was my job as a medical student to hold a little gauze over the stool, protecting the child and to some extent the dignity of the mother (today, with our advancing knowledge of the microbiome, I wonder if it would have been better not to). Part of the role of breast milk then is to encourage the growth of ‘good’ bugs. This is the most obvious way in which B. infantis protects us: by binding to the cells lining the baby’s large intestine, preventing other, more harmful bacteria doing so. And crucially it seems to bind more strongly when grown on breast milk.
It’s not just a matter of outcompeting the pathogens – B. infantis may keep them at bay with secretions. When grown on HMOs it produces short chain fatty acids (SCFAs). These are molecules that have become famous from their beneficial effects shown in adults eating a high-fibre diet, but they seem to be equally important in children. Some of them may directly kill harmful bacteria. Bruce describes this in terms of the concept of a ‘shelf stable baby’; preserved from the inside by the secretions of the friendly bacteria. Other SCFAs like acetate may feed the developing infant brain. This role in brain development may in part explain the huge complexity of the HMO in human milk compared even to our closest chimpanzee cousins.
AT THE END OF MY CONVERSATION WITH MARK I ASKED IF HE HIMSELF HAD BEEN BREASTFED. ‘NO,’ HE REPLIED. ‘PERHAPS IF I HAD BEEN BREASTFED I’D HAVE BEEN A SURGEON.’
There is a catalogue of other benefits, too. It’s been shown to be anti-inflammatory, specifically in infant gut tissue when compared to adults. Understanding of the development of the infant immune system is still in its early stages, but Bruce thinks that the specific culturing of B. infantis, and the relative lack of diversity in the infant gut, may be crucial to the development of a mature immune system. In fact he is evangelical about this. He believes that the current epidemic of asthma, allergy and atopic disease in the US may be largely due to the loss of B. infantis from infant guts.
B. infantis also seems to reduce intestinal permeability, tightening up the joins between cells. Leaking infant guts may cause sickness directly but also affect the long-term development of the immune system. Evidence for this comes from an extraordinary study in Bangladesh. The dominant species in the stools of the infants in the study was B. infantis and they were 96 per cent breast-fed. The more B. infantis in the stool, the more weight gain and the better the responses to oral polio, tuberculosis and tetanus vaccines.
And there are the extraordinary little considerations that B. infantis makes in order to be a good houseguest. Other similar species of bacteria are not directly harmful but they do digest human mucus. When they do this they accidentally produce sugars that are useable by dangerous bacteria. By contrast B. infantis leaves the complex sugars in human mucus intact, starving the pathogens.
Just as the early efforts to understand the link between breast feeding and infant health required collaborations between chemists, physicians and microbiologists to make remarkable progress, Bruce German has forged a multidisciplinary team at UC Davis. While Bruce was starting to dissect the chemistry of milk in the lab, neonatologist Mark Underwood, at the UC Davis children’s hospital, was treating and studying children born long before 37 weeks’ gestation. Over 10 per cent of children are born prematurely in the United States and they face a few singular challenges. Inadequate lung development is the most immediate problem, but in the weeks spent in intensive care after birth a devastating condition called necrotising enterocolitis, or NEC, claims many infant lives. In NEC the tissue of the gut becomes inflamed and dies, allowing the contents of the gut to leak into the abdomen, causing massive infection. It affects approaching 10 per cent of infants who are born weighing less than 1,500 g and half of those affected will die. In the decades he has spent caring for premature babies, the death rates from NEC have not changed significantly, but some clues that B. infantis may help to reduce this death rate are starting to emerge. Breast milk improves outcomes in NEC and additionally, a lack of Bifidobacteria seems to increase risk.
Neonatal intensive care is a dangerous place to be. Paradoxically this may be because it is too clean, or perhaps clean in the wrong way. Antibiotics and continuous cleaning keep Bifidobacteria at bay, but disease-causing organisms flourish in even the most fastidiously clean units. A trial is just starting at UC Davis but the evidence from other studies shows that administering B. infantis as a probiotic (a dietary supplement containing live bacteria that promotes health benefits) together with human breast milk serving as a prebiotic (a dietary supplement to stimulate the growth or activity of commensal microbes), may help to further reduce the incidence of NEC.
Bruce is enthusiastic about the use of probiotics even in term infants and suggested that I give my own child some B. infantis prebiotic. I asked why simply breast feeding wouldn’t be enough. ‘Because B. infantis is extinct in much of the developed world. It’s not a bacteria which acquires resistance easily and particularly in the USA the use of formula milk for multiple generations has simply starved it out of existence.’
Bruce has the infectious enthusiasm required for truly visionary science but I wondered if I was being seduced by his ideas too easily. The genetic case was certainly persuasive that B. infantis had co-evolved with breast milk to be the main colonist of the infant gut. Why else would it have the entire genetic toolkit to use molecules found only in human breast milk, molecules which humans were totally unable to digest? But I wanted a clinical perspective so I asked Mark Underwood for his view. Mark is no less visionary than Bruce but he has the sort of quiet, clinical caution that comes from being a doctor in a speciality where a lot of child patients die. He was no less enthusiastic than Bruce. He believes the evidence stacks up from all sides and he is about to start a trial of giving B. infantis as a probiotic in the neonatal ICU. From the second week of life, I have been giving Lyra once-daily B. infantis supplements sent by Bruce.
At the end of my conversation with Mark I asked if he himself had been breast-fed. ‘No,’ he replied. ‘Perhaps if I had been breast-fed I’d have been a surgeon.’ He was being ironic: surgeons may think of themselves as being at the top of the tree, but physicians like to joke amongst themselves that surgeons are mere technicians. But his answer contained an interesting truth. He was a healthy, successful person. It is true that the mother–infant pair are what Bruce calls a ‘powerful Darwinian engine’ driving extraordinary evolutionary change. Together they have co-opted another species as the world’s most effective nanny, supporting brain development and the development of the immune system, as well as fighting pathogens. And loss of B. infantis from our ecosystem may well explain the rise in allergic and atopic disease. But contained in Mark’s answer is the idea that, despite multiple generations of formula-feeding and antibiotics rendering this seemingly vital bacteria functionally extinct, it’s possible to become a healthy professor without it. People continue to live longer and longer. The human body has extraordinary resilience and redundancy; regaining B. infantis in our infant guts may well have wide-ranging benefits, but it is testament to our adaptability that we can survive without it.
