Our Beautiful Genomes
A book I'm re-reading lately is My Beautiful Genome by Lone Frank. Essentially, I recommend it, and here's why.
My Beautiful Genome is an account of Lone Frank's journey into finding out what our genomes can say about what, who, and why we are. Or it could be more accurate to say, what scientists thus far understand about the what, who, and why. It's just over 10 years on since the Human Genome Project and Celexa laid out the human genome in its confusing glory- 23 chromosomes, 30,000 genes, 30 billion base pairs- and thanks to techniques, technology and t'internet, times have changed a lot since. The original human genome took 3 billion dollars and 13 years to complete. Nowadays a human genome can be sequenced for almost 1000 dollars in a few hours. So all right, supposing I have a spare 1000 dollars and connections to a world-class lab. Should I get a proof of my own molecular recipe?
Lone, a Danish science writer, sets out to see what can be seen. The easy narrative of the book follows her physical journey to various labs and doctors, countries and universities. It's low on jargon and enjoyable to read, a science travelogue imbued with Lone's own descriptions and inner thoughts, which add a hint of narrative drama to the interview scenes. James Watson gazes at her from thickly bespectacled "golf ball eyes" that are nonetheless "clear without a hint of the common confusions of old age". Lone admits her own faults, such as a blunt personality she feels proud of, while a friend disagrees- "It's cruel!". She describes her fear as she waits to find out if she has BRCA mutations that would show a susceptibility to breast cancer. She reflects openly on mental illnesses in her family and her own experiences in it. She is a likeable, cynical investigator.
The short answer from this book is that genetics still can't reveal much about the average person. However, there are plenty of hints. I daresay that still holds true. This book was published in 2010 so in scientific terms it's a little out of date, especially with a field as fast-moving as molecular biology. Still, I found plenty about the business and politics of genetics that I hadn't been aware of. And Lone's journey contains many interesting tidbits from various research areas that summarise how complicated genomes are. For instance, is human intelligence inheritable? Sure, studies indicate that 80% of a person's intelligence is down to genes. Which genes? Don't know! 20 years of study failed to find any 'IQ genes'. Best case scenario? In another few years, the researchers might whittle it down to a few hundred genes that explain 3-5% of a person's intelligence.
Another surprising fact is that where some genes are concerned, such as a gene that affects how likely you are to get diabetes, it matters who you inherited them from, your father or your mother. You could be more likely to get diabetes if you inherit this gene variant from your father. But you are less likely to get diabetes if you inherit this gene from your mother.
Lone explores the services of a few different companies and research schemes. The Genographic Project can tell you about your ancestry as well as answering bigger, older questions about where early humans lived and moved to. Then there is the big, attractive question of genes and health. Can your genes predict what diseases you might be prone to?
Lone receives a few interpretations of her genes. She has variants that increase her risk of lung and skin cancer, worry and depression, a small hippocampus and obesity. She also has variants giving her higher resistance to malaria and TB.
Lone admits to a few depressive episodes. On the other hand, Lone has always been slim, has a normal-sized hippocampus, and has never had skin cancer. Genomic medicine is still in its infancy, a mix of ambiguity and intrigue. This book cannot be used by a reader as a manual of certified gene variants, but it is scattered with interesting insights from the modern scientists who are wading through the legacy of the Human Genome Project.
Should people get their genomes assessed for probability of diseases? The research continues. Governments such as the UK are funding genomic medicine centres. There's also a scramble of entrepreneurship and commercial ventures. Companies like 23andMe are hoping to be the new Microsoft of personal genetics, offering direct-to-consumer genomic testing. Another genomics motion, deCODE is cataloguing the genomes of most of Iceland. But to me, it seems most of these companies do not provide value for money or time of thought. Studies such as by Erasmus University have shown vastly different results in the answers of your genome analysis, depending on which company you use. Processing errors have happened, resulting in some alarming results and alarming scenes at the consumer's homes. A ruling by the FDA has put a halt on health screening by 23andMe in the USA, but the company is branching out in the UK and Canada.
How long should it be before genomes screening for health is carried out, to prevent misinterpretation and misunderstandings? "It is inevitable that we will come to use it. It would be criminal to decide that people must not use this knowledge before we know how it will affect them biologically, psychologically, and socially," Kari Stefansson, founder of deCODE, argues to Lone. He believes the best way to treat disease is to prevent it, and all would agree. How far back can we prevent disease? Armand Leroi, a geneticist at Imperial College London, has judged the risk of finding disease by screening embryos for known mutations to be around 1 in 256. Lone points out that this level of risk is sufficient to justify cervical and breast cancer screening. Is the stage being set for large-scale embryonic screening?
Then there's the popular topic of how genes influence our behaviour. It's the classic nature vs nurture debate, a popular topic among biologists, psychologists, anthropologists, sociologists, parents, teachers, politicians, everyone... This debate is continually updated with increasingly detailed genetic data, and occasionally thrown to the public forefront by popular books like Richard Dawkins's seminal book, The Selfish Gene. His book launched a thousand debates about whether we were all fleshy vehicles steered by a control-box of self-replicating genes.
"As soon as people hear the word 'heredity' or 'genetic', it immediately gets transformed into 'unchangeable' somewhere in their mind, and that is not the message at all," warns Gitte Moos Knudsen, research director at Center for Integrated Molecular Brain Imaging at Copenhagen University. Lone has gone to see her to see how a personality questionnaire, brain scans, and her genes may be linked up. You'll have to read the book to find out what she discovers. But there's an intriguing mention of a study indicating a genetic basis for differences in behaviour between two major cultures. Gitte also points out that even ostensibly negative genes- like a variant linked to 'oversensitive' behaviour- must give the owner some advantage. Else why would so many people still have this gene?
The media gleefully reports behaviour-gene associations that make the best stories. A discovery of an 'infidelity gene', for example. But there is still no consensus on how to divvy up their own behaviour between nature and nurture, and I suspect there never can be. I think we do have free will. We also have brains housing that free will. Brains are made from both genes and general living. There will just be new and interesting ways to look at our brains from a genetic standpoint.
"People cannot stand the complexity of a nuanced problem. There is a huge desire to lean back and say, 'It's my genes, it's not my fault,'" sighs Kenneth Kendler, a psychiatric epidemiologist at Virginia Commonwealth University, during a discussion on genes, growing up, and psychology. He and Lone discuss the difficulty of linking a person's psychology to their genes. There is no single gene variant responsible for causing Alzheimer's, for instance. Most diseases will involve multiple genes acting in ways scientists still don't understand. The same issue will apply for behavioural traits, or psychiatric conditions like depression.
But studying behaviour from a genetic standpoint will help build up the overall understanding. Kenneth mentions the serotonin hypothesis as an example. The major theory is that depression is caused by low levels serotonin, a molecular messenger, in the patient's brain. Drugs that alleviate the symptoms of depression affect serotonin levels. But scientifically speaking, it's not known why this works. There is no 'normal' level for serotonin throughout the brain. Lone reveals a rather striking quote from David Healy, a psychiatrist specialising in antidepressive remedies. "The theory that serotonin levels are the cause of depression is as well founded as the theory of masturbation causing insanity." This doesn't mean we should toss out our antidepressants or stop the self-love, though. It means that the picture is complex and genes are part of the complexity.
Studying genes in detail could also provide a new way to monitor psychiatric therapy. "Psychiatrists used to ask people endless questions about their mothers, as if we could make good predictions on that basis. At least, genes are objective," said Daniel Weinberger, neuroscientist at NIH. And it does not have to stop at what genes each person has from birth. Epigenetics adds another layer of complexity. Studies have shown that life experiences can alter how your genes behave. In a nutshell, this is caused by life adding molecular labels onto your genes. Moshe Szyf, epigenetics expert at McGill University points out benefits of tracking the labels. "If we know the epigenetic signatures and markers - for abused children, for example - we can design behaviour therapies, talking therapies, and study whether they work. Determine whether they remove the markers in question." This hints that future psychiatry could be a synergy of epigenetics, genetics, behaviour and therapy.
There's also a scramble of entrepreneurship to make money out of genes and love. GenePartner claims it can help you find your ideal social and biological partner. To fall in love may lead to having children, and children are the combination of you and your partner's genes. Do genes secretly steer our choices? Can knowing our genes help us choose the best partners? The enterprise is based on a few scraps of intriguing science. Immune system is coded for by genes, and everyone (save clones and twins) has a unique set of immune genes, known as HLA genes. Zoologist Claus Wedekind noticed that many animal species sniff out mating partners who have the biggest differences in HLA genes from their own. The suggested reason is that such pairs produce offspring who have particularly varied immune systems, and are more likely to resist local germs. This tendency has also been noted in humans, in a handful of studies, starting with Wedekind's own study in 1995. Statistically speaking, women prefer the smell of men with the most different HLA genes, marriage choices in some communities appear based on this effect. It's an exciting thing when pieces of scientific evidence can be tied together with evolutionary reasoning. Once I explained to a new boyfriend that given our respective ethnic backgrounds, our HLA genes were likely very different, ergo another reason why our relationship was destined to succeed. I can't understand why he found this so amusing.
On the other hand, Craig Roberts, behavioural ecologist at University of Liverpool warns, "It's a scam. We're not at the stage where we can say HLA genes make a practical difference." There are other factors to consider here than the immune system, and a few other studies go against the varied HLA connection. Again, statistically speaking, studies show that people tend to prefer faces of others who have similar HLA genes. And has anyone studied if human children from varied HLA matches are actually better off?
Many people are afraid of genetic discrimination in the future. This book goes a long way to explaining why this is unlikely to happen by describing the existing science and viewpoints. Of course it remains a risk, which is why people need a gene lexicon containing terms like 'risk' and 'potential', rather than terms like 'good' and 'bad'. Towards the end of the book, Lone discusses how it is thought both biology and sociology- a new 'biosociality'- needs to be a large part of the consciousness of the future. Understanding of genetic difference may show where lifestyle changes could have the greatest impact. Those with predispositions to stress from poorer backgrounds may benefit more from mentoring, or those at greater risks of certain illnesses will need more assistance avoid these things. It will require a sensitivity of thought by any politicians passing legislation, and a malleability of 'nature vs. nurture' thinking on everyone's part. Lone's view is that in understanding more about genomes, we will also come to understand and appreciate diversity.
So at the end of another enjoyable read, would I want my genome sequenced? I certainly would not be afraid to have it done. Will I have it done? I'm in no hurry. I don't think the science is well understood enough yet from an academic perspective to get any useful results. I'm not yet inclined to approach a company to interpret my genes. But it's getting closer, and I suppose, then, so am I. One day, I'll learn more about myself. It's nice to have such things to look forward to.
My Beautiful Genome - a TED talk by Lone Frank
Picture yourself on a mountaintop. The piercing cold temperature. The unbarred views. The thin air.
Dr Hugh Montgomery presented the mountaintop to us as a natural laboratory space. As Director of UCL Institute for Human Health and Performance, and Professor of Intensive Care Medicine, Hugh is interested in how the human body responds to exercise. And the mountaintop presents an extreme environment for a particularly elite class of exercisers, the mountaineers. Not only is mountain climbing a gruelling challenge for the body's muscles, but climbers must also tolerate low levels of oxygen in the air. The higher they climb, the lower the oxygen levels fall. But by studying the physical changes that mountain climbers undergo on a climb, and scrutinising the underlying genetic causes, Hugh's research group have produced some startling lessons for critical care of hospital patients.
Hugh, smiling and fresh-faced, took to the stand at Bristol M-Shed to discuss his research. He is the kind of researcher who deserves his own HBO television show. This hypothetical show would incorporate genuine scientific research, as well as offering plenty of scope for macho posturing and man vs. death escapades on the mountaintop. Indeed, the man's achievements and hobbies would make any fiction unnecessary. A diver, a record-breaking underwater piano player, an 'occasional' ultra-runner, a mountaineer, author, screenwriter, and a pioneering cardiovascular geneticist. I could easily add more, but I am already lost in awe.
"Studying acute physiology can tell you really important things about yourself, and patients," said Hugh. He began by outlining the key scientific tools that we needed to understand. Angiotensin is an important hormone for your blood system, and the renin-angiotensin system (RAS) controls the blood pressure of the body. It is a network of different hormones, including angiotensin, which tweak the size of blood vessels and the amount of water kept in the blood. A key controlling element is angiotensin-converting-enzyme (ACE). A high level of ACE in your RAS raises your blood pressure.
"That's where it stopped when I was in medical school," said Hugh. "But it turns out, like most things I was taught at medical school, that wasn't half the story. Because these systems are everywhere - in plants, in locusts, in fish, in jellyfish- all things that have been there for millions of years. And jellyfish don't even have blood pressure!"
So RAS and ACE must affect more than blood pressure. In fact, they are found in a huge range of human bodily tissues, from your brain to your eyeballs to your skin. It is now understood that ACE also influences cell growth, inflammation, and metabolism in body tissues, even if the finer details of how it does this are still being uncovered.
In the 1980s, it was observed that increased amounts of ACE in rats leads them to develop bigger hearts. Knockout the ACE gene, and hearts can't grow in size.
In humans, the old romantic maxim is untrue. Having a big heart is not a good thing - unless your heart has become big due to regular exercise. Otherwise, a large heart is associated with a higher likelihood of heart attack. So whatever causes the increase in size also damages the heart tissues.
Based on the studies of ACE and heart size in animals, Hugh needed to see if the link between ACE levels and heart size applied in humans. His group had found two different ACE gene variants - the I allele, and the D allele. People with the I allele produced lower amounts of ACE. People with the D allele produced more ACE. And because everyone has two copies of each gene, any human could have II, ID, or DD. But based on rules of inheritance, in a group of people 25% will have II, 50% will have ID, and the final 25% will have DD.
So if Hugh could take a group of humans, measure the differences in their heart size, and then correlate the heart size to the different genes, he would be able to prove ACE was affecting heart size in humans.
But how could this be done, and more so, done ethically? There could be many confounding factors affecting heart size. Hugh found the perfect experimental subjects in the form of military recruits. Military recruits all undergo the same strict regime of training and diet. Exercise naturally causes heart growth. So at the end of 8 weeks of training, Hugh would be able to measure differences in heart size, and link this to the I or D alleles.
After 8 weeks of training, the recruits with II alleles - producing the lowest levels of ACE - showed heart growth of approximately 2%. In DD recruits, who produced the highest levels of ACE, the heart growth was 6%.
Hugh sketched out the scientific reason that ACE caused heart growth. In the RAS system, ACE breaks down kinins, proteins which are involved in blood vessel dilation. High ACE equals low levels of kinin, which means greater growth in heart size. As in most science, the chain of cause and effect was becoming a little long, but we were still with him.
So the military recruits proved the link between ACE and heart size. And there was more. Through a muscle fatigue test- a fancy way of saying, how long could each recruit hold a weight at arm's length without buckling - it was proved that II recruits have the best response to exercise. ID recruits respond moderately to exercise, showing only small improvement in muscle fatigue after training. DD, statistically speaking, showed no better improvement by end of their training.
Now, back to the mountains. Mountain climbers with II are more likely to reach the peaks than DDs. Similar trends can be seen in other oxygen-hungry sports, like marathon running, where runners are much more likely to have II alleles. Hugh revealed another interesting tidbit. Although gruelling endurance challenges like the Tour de France are dogged by doping scandals, where athletes use erythropoietin hormone to increase red blood cell loads, the ability to accumulate more oxygen on a mountaintop is not actually helpful to your body. To put it more simply- if you put a Tibetan and a Westerner on a mountaintop, the Tibetan's body will generate less haemoglobin. The genetic selection for successful living at high altitudes appears to be in keeping haemoglobin lower.
Hugh explained that I or D alleles affect how efficiently mitochondria use oxygen. Mitochondria are the power plants of the cell, generating ATP energy from oxygen. Low ACE levels make mitochondria better at generating ATP from oxygen, even low levels of oxygen. D alleles are more like "leaky batteries" - they lead to a higher level of ACE in the body, which raises oxygen demand.
"So what genetics is telling us, is that when oxygen availability is low, we should try to increase the efficiency in which we use the oxygen," commented Hugh. He recalled that the convention treatments for ICU patients in hospital is to try, forcibly, to put oxygen into their bodies. But modern treatment needs to change, as studies have shown forcible oxygen transfusions can increase mortality. Based on lessons from mountaineers, new modes of treatment are being introduced into hospitals to allow oxygen levels to reach lower levels than conventional treatment had allowed. A normal person has an oxygen tension of 12 kPA. On a ward, lower levels of 8 kPa is now being allowed. A level of 6 kPA is still considered very worrisome. However one experienced mountaineer has been able to reach 2 kPA. This is conventionally considered terminal... but for him, it was not. His body was attuned to that low level of oxygen.
Many animals adjust their body systems to withstand low oxygen environments. These include a few fish with coincidentally interesting names - the epaulettes shark, the oscar fish, and the Crucian carp - who shut off unnecessary body functions when oxygen levels decline. With a wry grin, Hugh admitted that when he explained his research to his 6-year old son, he was told his research was "very obvious". When a car is low on fuel, you don't leave all its systems running, you tune down to the bare essentials. Why had it taken his father 20 years to work out that the human body does the same?
But the most startling and sobering impact of ACE was yet to come. Hugh showed us the relationship between the ACE gene variants and medical conditions, especially in the ICU. In premature babies with under-developed lungs, high ACE levels are associated with respiratory distress. In patients who undergo bypass surgery, II patients with low ACE show better survival rates. In meningitis patients, having the DD alleles is associated with the most severe examples of sudden meningococcal sepsis. It was sobering to realise that survival, especially in the face of respiratory complications, could be so clearly linked to the ACE gene.
"In this audience, if we all came down with Adult Respiratory Distress Syndrome and ended up in Bristol ICU, the IIs could have a 90% chance of surviving. Whereas DDs have an over 55% chance of dying. That puts my job in perspective. We like to congratulate ourselves as how good we are when someone lives - but a lot of that living and dying, is down to our genes."
Hugh moved onto another lesson of mountaineering - starvation. Hypoxia, meaning low levels of oxygen, causes weight loss. Mountaineers lose both fat and muscle in the hypoxic conditions of the mountain. ICU patients, whose body tissues are low in oxygen, also show weight loss. A key clue is that muscle is lost, along with fat, even in highly active and well-fed mountaineers. A group of Hugh's mountaineers who scaled Everest lost 9 kg each, on average. Hugh explained that the 90% of the body's energy goes into producing protein, to rebuild and renew the body. It used to be thought that in low oxygen conditions, the body's regulation was simply thrown into disarray, causing inevitable weight loss. But now it is shown that the body actually orchestrates sophisticated survival plans. It tries to conserve oxygen by shutting down demanding systems. Essentially, the body willingly creates a 'starvation' mode.
In starvation, a process known as ketosis occurs where fat is broken down for energy, producing chemicals known as ketones. This is the fundamental concept of the Atkins diet. Ketosis is also carried out by hibernating animals. It appears likely that ketones have some kind of beneficial effect. And this is true. Ketones are an anticonvulsant, which is why the severity of epileptic fits can be reduced by putting patients on diets. Ketones protect the brain from hypoxia and low levels of glucose. Even sperm are more motile in ketones, and the heart increases its workload.
In short, starvation can actually be beneficial. A synthetic ketone is being trialled in adults with heart failure in Belgium, and there are more studies which will test ketone compounds with patients and premature babies. And studies have shown that force-feeding of ICU patients in hospital can lead to muscle wasting, a new method of intermittent, low feeding may prove much more helpful. Perhaps a more modern and effective treatment needs to accept starvation as one of the body's natural defence mechanisms. There's some truth in granny's advice - 'feed a cold, starve a fever'.
Ketones, ACE, genes, and fitness. I wondered what would my genotype be. Did I respond to exercise well, like an II, or fall in between, as an ID? I have only ever ventured up a bouldering slope, but I have dreams of climbing Kilimanjaro. How much extra preparation would I need?
"Should I take ACE inhibitors to improve my chances of reaching the summit of Everest?" asked an audience member, a self-diagnosed DD.
"Yes... but we haven't done the study yet." The study is in the planning stage, but they still don't know how ACE inhibitors will react with the body in hypoxic conditions. This is too big a risk to take on a mountaintop.
And throughout his talk, Hugh pointed out that D alleles were not to be perceived as inferior. This is the first gene that was discovered which was directly related to fitness. It has some striking lessons for hospital care. But it is not a case of genetic determinism, stating who is likely to be the best at keeping fit, or surviving overall. The D allele confers its own benefits. People with DD appear to be more resilient to haemorrhage. And they are likely to be stronger, better at swimming and sprinting. They tend to show greater muscle mass in old age which significantly reduces the problems of frailty and falls.
I thought of my father, silver-haired and 70-something, still stomping round, still operating heavy machinery, still involved in the mysterious and never-ending movings of heavy objects around his property. For that matter, I also thought of my mother, thin, frail, and disabled, but who has been doggedly picking up an entire bulldozed bungalow, brick by brick, and assembling them into an array of neat stacked cubes in her garden (don't ask). I might never know my genotype for I or D and I might find it hard to predict, but it probably didn't matter anyway for my fitness. What matters is the mind - willpower, determination. For his part, Hugh was vehemently opposed to casual genotyping for these alleles. The research needed to carry on, and it would be too easy for, say, medical insurance companies to jump the gun and draw broad - and expensive - conclusions.
After all, for all his incredible-sounding athleticism, Hugh himself is a DD.
You can listen to a recording of Hugh's talk here ...
And the following questions here ...
Hugh Montgomery also talks about his discovery of the first gene for fitness to Jim Al-Khalili, on the BBC's The Life Scientific
Not quite a blog, but things that I have written. Please note - these writings are unedited, for the purposes of flexing my fingers, and no doubt contain grammatical errors and carelessness of expression I wouldn't allow in professional writing.