Note and Disclaimer: This blog gives a bit of background to a health issue of major concern, as it is reaching epidemic proportions, and a glimpse at what we are doing about it through one component of a recently-funded Health Research Council (HRC) programme grant. This post represents the views and research of the author. It was not commissioned by or for the HRC.
It all happens before we’re even born.
One of the earliest times in a person’s life when the factors around them can affect their lifetime health and disease risk is before they are even born. This concept was first appreciated by Professor David Barker and his team, who examined the long-term health outcomes of individuals who were in the womb during the Dutch hunger winter (1944-1945). The newborns of these starving mothers were very tiny, rather to be expected given the starvation conditions in which they developed. Curiously, though, they also had impaired glucose tolerance (a precursor to diabetes) later in life when compared to individuals born in the years before or after, when food was more plentiful . These observations inspired the concept that an individual’s risk of disease across their lifespan could be shaped by events that occurred much earlier in their lives; indeed, during their time in the womb, when the cells that make up their tissues and organs were only themselves just coming into being . Within the Barker study, and a subsequent study of the Chinese famine in the late 1950s-60s, was the further observation that the children who were most affected were those who, as their lives progressed, consumed a relatively high-fat “western-style” diet and became obese [1,3]. Thus, when a mother is malnourished during pregnancy her baby is more likely to be born small, which, somewhat paradoxically it would seem, in turn elevates the risk for obesity and diabetes later in life [4,5]. This phenomenon – that the in utero “experience” affects lifelong health – is referred to by several names, including the Barker Hypothesis, but is now more commonly referred to as the Developmental Origins of Health and Disease. And it embodies the idea that our lifetime health and disease risks begin adding up even before we can do anything about it.
Wait a minute… You mean that starving mums have fat kids?
The most popular explanation for why undernourished mothers have children with an increased risk for obesity is called the Developmental Mismatch Hypothesis. It posits that the developing baby somehow “knows” about the environment that it will be born into and adjusts its own formation so that when it goes out into the world it is not disadvantaged by harsh conditions. Thus, when a mother is starving, the offspring will adjust its development so that when it is born and as it matures it can more efficiently utilise calories or store fat, so as to better survive when food is scarce. Sounds like a pretty good deal. So where do the mismatch and the obesity come in? The theory continues on to suggest that when the child is not actually born into lean times (i.e. when a mismatch occurs between what it sensed and what’s really going on out there), that its improved ability to store energy causes it to gain unnecessary weight. The boon in lean times is a burden in times of largess.
Is this for real? I mean, how does it work?
Whether the theory is actually true or not is still a hot topic of debate, mainly because it is not clear exactly how this might happen. We know that when a mother is undernourished, there are many changes that take place in her body to help her cope, but also changes to her placenta that affect the way nutrients and other factors are supplied to the fetus. Some one or many of these changes must surely affect how the baby is developing; but whether it truly is an act of predicting the future, or merely the result of having to develop and grow in a less-than-optimal environment – “development on the cheap” – is not entirely clear. I am inclined to believe that when times are bad, a whole host of things can happen to a developing organism, but that they do not purposefully improve life outside the womb, as some believe. Rather, I suspect that there are a spectrum of changes, some of which are good, others bad, and still others entirely neutral; and that it is the balance of these that determines long-term health and disease risk for the child borne of a malnourished mother.
The curse of plenty.
Let’s leave malnutrition for now, and flip to the opposite side of the coin. With the recent massive increase in obesity across the western world, research focus has shifted to understanding the long-term health outcomes of individuals whose mothers were obese during pregnancy. Curiously, the public health studies paint a similar picture to that of undernutrition. Children whose mothers were obese during pregnancy are at a significantly higher risk for later life obesity, and “the metabolic syndrome”, which includes diabetes, high blood pressure and heart disease [6, 7, 8, 9, 10, 11, 12]. Perhaps scarier still, they also show increased risk for a constellation of behavioural and mental health problems including autism, attention deficit/hyperactivity disorder, developmental delay (what we sometimes call “slow learners”), anxiety, and depression [13, 14, 15, 16, 17, 18, 19, 20]. One study found a 67% increased risk of autism in the children born to mothers with obesity and gestational diabetes . To give you some perspective on what this means for the future long-term health of New Zealanders, here some statistics for you. Over 25% of people in NZ are obese . Sure, it’s not the 35% of the USA, but it’s not flash. In Australia, which has a similar proportion of obese people, 50% of pregnant women are obese or overweight (stats not available for NZ). And what’s more over 75% of already overweight women, gain excessive amounts of weight during pregnancy . Even without doing any arithmetic, I hope it’s pretty clear that if half or more of the babies born nowadays are at increased risk of later life disease, it might be useful to try to do something about it. But what should we do? Some people are fond of blaming women for being obese during pregnancy. But surely that’s not a palatable approach to solving the problem. And it probably misses the mark entirely. After all, if obesity (or malnutrition or other pregnancy complications) begets obesity, then at least for some women, they are themselves victims of their mothers’ or their grandmothers’ health. And I don’t even want to get into the fathers’ contribution to this, but new research suggests that they also play a part in this drama [16, 17]. Essentially, we are stuck with a very real and very devastating health problem; and yet we know only that it happens, not how or why. Understanding what actually goes awry at the level of single cells and molecules during the developing organism’s life in the womb of an obese mother, and how this increases risk of disease years later, are key to stopping this vicious cycle dead in its tracks.
OK. So, what are we doing about it?
My component of a recent Health Research Council programme grant “Healthy pregnancy, healthy babies” led by Professor Dave Grattan from the University of Otago, aims to address just this issue. We will probe deeply into the brains of the developing offspring before they are born, to discover how brain formation and gene regulation are changed by gestation in an obese mother; and to identify the factors that cause the changes. We have already identified some of these factors , and the ways in which some brain regions are altered . This new grant will allow us to put these pieces of the puzzle together to reveal a bigger picture of how the factors do their nefarious deeds. This funding will also allow us to identify additional pieces not yet discovered, and to put them into the picture as well. We will use mice for these studies, since they have pregnancies similar to our own, show the same curious phenomenon of elevated offspring disease risk following gestation in an obese mother, and give us unique access to the brains of embryos and fetuses, before birth, when the action is happening. We will focus on the brain because it is here that body weight and metabolic function are regulated ; and because obesity in pregnancy increases the risk of an assortment of offspring neurobehavioural abnormalities, it makes sense to look in the brain. The brain is what’s trending, ad infinitum.
So, maybe I’m a bit heavier than I should be. Howe does this research help me and my children?
One of the great things about the brain is that it is able to be changed or molded by our experiences; it’s what scientists refer to as “plastic”. This is the basis for how we learn new things, like how to catch a ball or the lyrics to that song on the radio. If we knew what regions of the brain were being changed by a mother’s health during pregnancy, then we would be in a position to innovate new therapies that help “re-train” the brain. Similar techniques are already used to help people recover normal daily function after brain injury, and to improve some mental illnesses through cognitive behavioural therapy. Our new research will try to protect the developing baby before birth, as well as to reverse negative health outcomes in early childhood with behavioural therapies. We would also be in a position to diagnose the risk of later life disease much earlier in a person’s life. There was a recent report of a baby whose genome was sequenced before he was born. A tour de force for medical technology, to be sure, but it really only lets us look at the purely genetic part of disease risk. Our study will identify additional, extra-genomic signs of disease risk, which could be used in a combinatorial and personalised manner for estimating later life health and risk of disease. Importantly, the factors that we will identify are much more likely to be correctable than mutations in the genome.
Helping New Zealanders enhance their lives through research-based education
While there is no denying that this funding will be of great personal benefit to my research career, there are a number of less tangible, yet far more important, outcomes that increase its value dramatically. It will give me and my research team an opportunity to give back to people in our communities everywhere, by discovering and understanding the key factors necessary for a healthy start to life and lifelong health for people who’s mothers were obese during pregnancy. A chance to break the vicious cycle I described previously. It will also give us the opportunity to work in an area that the people of New Zealand identified, through the government-sponsored Great New Zealand Science Project, as important and relevant to moving our nation forward into a healthy and prosperous future. Perhaps the most fulfilling aspect of this funding is that it will allow me to continue to train and give opportunities to bright and talented young researchers, from all walks of life and across a broad range of disciplines extending beyond the sciences; and focused on an area of direct health relevance.
All up, I am totally thrilled at this opportunity, and utterly thankful of my teammates – Professor Dave Grattan (programme leader), Professor Lesley McCowan, and Associate Professor Colin Brown – and the Health Research Council for making it happen. Now, let’s do some science for a Healthy Start to Life!