The Boy Who Wasn't Short

by Kirk, Edwin;

  The Boy Who Wasn’t Short

  Professor Edwin Kirk is both a clinical geneticist and a genetic pathologist, a rare combination. As a clinician, he sees patients at Sydney Children’s Hospital, where he has worked for more than 20 years; his laboratory practice is in the New South Wales Health Pathology Genomics Laboratory at Randwick.

  Kirk is a conjoint appointee in the School of Women’s and Children’s Health at the University of New South Wales, an experienced medical educator, and currently Chief Examiner in Genetics for the Royal College of Pathologists of Australasia. He is also a respected researcher, working in the fields of cardiac genetics, metabolic diseases, and intellectual disability, as well as studying reproductive carrier screening, and is a co-author of more than 100 publications in scientific journals, which have been cited by other researchers more than 4,000 times. He is one of the co-leads and public faces of the $20 million Mackenzie’s Mission carrier screening project.

  Kirk lives in Sydney with his wife and three children. In his spare time, he competes in ocean swimming races, slowly, and plays the saxophone, loudly.

  Scribe Publications

  18–20 Edward St, Brunswick, Victoria 3056, Australia

  2 John Street, Clerkenwell, London, WC1N 2ES, United Kingdom

  3754 Pleasant Ave, Suite 100, Minneapolis, Minnesota 55409, USA

  First published in Australia and New Zealand as The Genes That Make Us by Scribe 2020

  Published in the United Kingdom and United States 2021

  Copyright © Edwin Kirk 2020

  All rights reserved. Without limiting the rights under copyright reserved above, no part of this publication may be reproduced, stored in or introduced into a retrieval system, or transmitted, in any form or by any means (electronic, mechanical, photocopying, recording or otherwise) without the prior written permission of the publishers of this book.

  The information in this book is general in nature and should not be considered to be personal medical advice. Readers are advised to contact their own doctors or other health professionals in relation to any medical concerns regarding their own or their children’s health, and should seek medical advice in relation to pregnancy-related issues, including screening and other tests during or before pregnancy.

  9781912854363 (UK edition)

  9781950354726 (US edition)

  9781922586087 (ebook)

  Catalogue records for this book are available from the National Library of Australia and the British Library.

  scribepublications.co.uk

  scribepublications.com

  scribepublications.com.au

  To my parents, Robin Enfield Kirk and Rosalie Saxby.

  With much love and thanks, for nature and nurture.

  Author’s note

  This book contains numerous descriptions of patients I have seen. In order to protect patient confidentiality, the descriptions have been extensively altered, sometimes by combining events that happened to several people. Consent has been provided as appropriate. Where the stories are based on real events, my intention is that it should be impossible to identify any particular individual from their descriptions here. An exception is that, if a patient’s story has previously been published in the medical literature, I have generally kept the key elements from the published version. I also tell the stories of some people who were not my patients, including Jesse Gelsinger and Mackenzie Casella. For both of the latter, extensive media coverage has already occurred. Mackenzie’s parents have read and approved the account of her life in chapter 11.

  Contents

  Preface: An end, and a beginning

  1. Easier than you think

  2. The DNA Dinner

  3. The boy who wasn’t short

  4. Uncertainty

  5. Needles in stacks of needles

  6. Power!

  7. Dysmorphology Club

  8. How to make a baby

  9. Complexity

  10. A spoonful of mannose-6-phosphate

  11. Please, screen me

  12. Where to from here?

  Glossary

  Acknowledgements

  Notes

  Preface

  An end, and a beginning

  Genetics has taken me to some unexpected places. A basement stacked with hundreds of boxes of mice. A mosque in Pakistan, and another in the suburbs of Sydney. A ballroom filled with hundreds of people, every one of them seated in front of two small glasses of poison.

  Mostly, though, there’s nothing about the life of a geneticist that would strike a casual observer as exotic. Our days are filled with meetings and paperwork. We see patients in clinic rooms, or on the wards, like any doctor. Our labs have as much room devoted to generic-looking office space as they do to high-tech machinery. And even the high-tech machinery doesn’t look like much. There’s an occasional device with futuristic flair, but much of our equipment sits squarely in the ‘boring grey box’ school of industrial design.

  Yet you shouldn’t let yourself be fooled by outward appearances. Remarkable things are happening in genetics, a quiet revolution that has already dramatically changed some parts of medicine, and is coming for the rest. Within the next few years, having your genome sequenced will become routine. There’s a good chance you’ll have yours done one of these days, if you haven’t already. A decade or two from now, your family doctor will have your genetic information on file, as much a part of your record as your blood pressure, your weight, and the medications you take.

  There’s a standard job-interview question: ‘where do you see yourself in ten years from now?’ When this question gets asked of a clinical geneticist, the possibility often comes up that, in ten years from now, this will be a dying specialty — not because genetics will become less important, but because it will be so important that every doctor will need to have mastery of the field, and nobody will need a doctor who just does genetics. I’ve been hearing predictions like this for nearly a quarter of a century, but they have never seemed further from coming true than they are today. Instead, a handful of specialists — neurologists particularly, but some cardiologists, endocrinologists, and others — have embraced genetics, while most doctors have been way too busy with all the advances in their own fields to even try to keep up with ours. Meanwhile, our numbers have grown steadily, but from a tiny base, so that we are still relatively obscure. Even other doctors are often rather vague about what a geneticist does.

  So what do we do? Unusually for medical specialists, our patients are not limited to one age group, or to people with problems affecting a particular organ. Sometimes, we are involved in peoples’ lives before they are even conceived; sometimes, when they are in the womb. We see babies, and children, and adults who are hoping to have children. We see grandparents because they have developed a genetic disorder late in life, or because a faulty gene is being tracked through a family to find people who are at risk. Sometimes, the first time a person has a genetic test is after they have died. My colleague David Mowat talks about the scope of our job being to provide care not just ‘from womb to tomb’, like a general practitioner, but ‘from sperm to worm’.

  The thing that links all of our patients is, of course, genes — and genetic disease in particular. The questions we try to answer are fundamental ones. How can we have a healthy baby? What caused my child’s heart condition? Will I develop Huntington disease, like my father and his father?

  In asking questions like these, people are letting us into their lives, often at times of strong emotions, often when there is loss and grief. Over my career so far, I’ve been privileged to share pa
rt of the lives of thousands of people. Luckily for me, this time has also been an unprecedented period of growth in our understanding of genetics, a time of ever-accelerating discovery.

  For me, it began in the mid-1990s. I was a junior doctor then, working in the intensive care unit of a children’s hospital in Sydney. One of my patients was a tiny baby, born with congenital heart disease, smaller than she should have been, and seemingly unwilling to breathe on her own. Machines were keeping her alive.

  The results of genetic testing had come back, and a meeting was arranged so that one of the hospital’s clinical geneticists could explain the result to the parents. Someone from the intensive care unit would usually sit in on such meetings, and so by chance it happened that I was there, witness as a young mother and father received the worst news of their lives.

  The clinical geneticist was Dr Anne Turner. Later, she would become a colleague, and one of my closest friends. Anne is witty, kind, loyal, an inveterate traveller and a bon vivant, a loving mother, and now a besotted grandmother. Back then, I knew her only as my senior in the medical hierarchy, a respected specialist in a small and somewhat obscure field of medicine.

  Anne does not remember our first meeting as I do, because her focus was on the difficult task she had come to do. She was there to tell those parents that their daughter was going to die.

  Testing had shown that the little girl had an extra copy of chromosome 13, a condition known as Patau syndrome. Affected babies are small, and often have heart conditions and brain malformations or other physical problems. Their brains do not function normally, even to the point that they cannot control the body’s breathing normally. Almost all babies with Patau syndrome die within the first year of life, mostly within a few days or weeks of birth. The rare survivors have severe intellectual disability and other health problems.

  This diagnosis explained all the problems we had been struggling to treat — and, particularly in a baby who could not breathe by herself, it meant the prognosis was grim.

  Giving bad news is hard. The shock and grief parents feel when they hear bad news about their children is intense, difficult to bear for those in the room with them. It puts particular pressure on the person delivering that news, in part because it is difficult to escape the feeling that you are the cause of the pain. Sometimes, you have had time to get to know and like the people you are hurting, but, even when it’s someone you’ve only just met … it’s tough.

  So why did being present at such an occasion draw me towards a career in genetics, rather than pushing me away? Mostly, I think, it was the way that Anne approached the task. Her warmth and gentleness tempered a direct, sure manner. She explained what a chromosome was, what it meant to have an extra chromosome, and what that meant for the little girl. One of the parents asked if it wasn’t possible to fix the problem, to remove the extra 13. Patiently, Anne explained that the problem was deep inside every cell of the child’s body, that it had been that way since conception, and that there was no way to undo this. She listened when it was time to listen; she spoke when it was time to speak. She acknowledged the love the couple had for their daughter, and the pain they were feeling. But she gave no false hope. What Anne showed me on that day was a way to practise medicine in a place where the most advanced science and the deeply human meet.

  My goal in this book is to reveal the humanity in human genetics, through the stories of those whose lives are most affected by it. If you’ve come for the science, keep reading — genetics is by far the most exciting of the modern sciences, and there’s plenty of science in these pages.

  But the story of human genetics is, above all, a story of people. It is the story of the people whose lives are affected by genetics — which is everyone, really, but some far more obviously, and some far more harshly than others. It is the story of that tiny baby, doomed from the moment she was conceived. It is the story of the scientist in the lab, looking down her microscope and reading the news of the little girl’s fate, written in the language of the cells. It is Anne’s story, and mine. It is the story of the people who first learned what a chromosome was, and how it might link to disease.

  Most of all, perhaps, it is the story of two young parents, grieving and bereft — but armed with knowledge and understanding, allowing them to face the future.

  1

  Easier than you think

  Professor Kirk makes genetics as easy as A C G T.

  SEAMUS KIRK1

  [1 It’s possible that my son is not an entirely impartial critic.]

  My friend and colleague Steve Withers, a geneticist himself, often refers to others as having ‘a brain the size of a planet’. Many people think that you need a bulging cranium to understand genetics. There’s an aura of difficulty around the subject … which turns out to be a complete con. Genetics is remarkably straightforward. If, by the end of high school, you could manage primary-school mathematics with reasonable confidence, you will have no difficulty with the essentials of genetics.

  Why do people think it’s hard? Perhaps it’s just that there is a great deal of detail — thousands of different conditions, all of which vary in their severity, many of which overlap with each other. To fully understand genetic disease, you need to know a bit about how cells work, and there is an awful lot of detail there, too. It’s all just information piled on information, though — anyone can understand any individual part of it.

  To prove the point: perhaps the most important piece of information in genetics is the relationship between DNA and proteins. This relationship is similar to, but much simpler than, the relationship between letters and words. Here are the facts:

  Proteins form a lot of the ‘stuff’ of the body — they are the building blocks of cells, and of the padding between the cells. Anytime your body has a job to do, it gives it to a protein. If your cells wanted to make a car, every single mechanical and electrical component would be made from proteins … and so would the garage you parked the car in; it’s not just for moving parts. Proteins themselves are made up of amino acids.

  DNA is a chemical that contains information. This information is written in an alphabet with only four letters: A, C, G, T. They stand for four nucleobases,2 the chemical building blocks of DNA.

  [2 You may be more familiar with the term ‘nucleotide’, which is a nucleobase attached to the other structural elements of DNA.]

  Unlike English, the language of DNA has only 21 words. The spelling for those words always involves three nucleobases — it’s a code of threes. In English, CAT means a furry parasite, but, in this language, it means the amino acid histidine. There are 20 amino acids represented in this language, and the 21st word is ‘stop’. A gene is a stretch of DNA that codes for a particular protein — so it’s a string of groups of three that say, ‘Put a histidine in. Then put a glycine in. Then a proline. Okay, now stop.’

  You can think of nucleobases as the letters, amino acid names as the words they spell, and genes as sentences. Each sentence explains how to build a particular protein, and each molecule of DNA contains many of these sentences. It’s a manual for building parts of the body.

  That’s it. The fundamental basis of genetics. Far simpler than learning to read, and we ask six-year-old children to do that. Even better, there’s no need to actually learn the language — you just need to understand that there is a language, and how it works. After more than 20 years in genetics, I only know the spelling of three or four of the words in the code. The rest I look up when I need to.

  There are no concepts in genetics more complex than the one you just learned, if you didn’t know it already. The rest is just detail.

  Fortunately, although genetics is simple, it is also fascinating. Take chromosomes, for instance.

  Chromosomes, the physical form our DNA takes within cells, are wholly remarkable structures. You’ve probably seen pictures before, but, just in case, here’s an example.

&nb
sp; This is a particularly good set of chromosomes — they’re mine. One of the lesser known perks of training in genetics used to be the chance to prepare and examine your own chromosomes, and who could resist an opportunity like that? Today’s trainees don’t get the chance, for fear they might find out something they don’t want to know. It’s a pity — there is something immensely satisfying about staring at your own genome down a microscope. I imagine it’s a bit like seeing video of your own heart after an operation, but without the inconvenience of having your chest cracked open to get the pictures.

  A genome is the totality of an organism’s genetic information, and every living thing has one — you, me, a slug, a blue whale, the kale in the salad you had for lunch, the microbes living under your waiter’s fingernails.3 Bacteria have genomes; protozoa and fungi have them; viruses have them, too. And in everything from bacteria on up, the genome is organised into chromosomes. The number of chromosomes varies enormously between species, and there is no clear link between how complex an organism is and how many chromosomes it has. Bacteria, to be sure, have only one or two, compact and circular. Male jack jumper ants — far more complex than a bacterium — also have only a single chromosome. But Atlas blue butterflies have 450.

  [3 Eww.]

  The chromosomes you see in the picture were captured at a very particular moment in their existence. It’s easiest to look at chromosomes when they are like this, at a point part way through cell division. They are compressed, and easily recognised as separate structures. Humans (mostly) have 23 pairs of chromosomes. They are 46 long, thin threads of DNA, totalling about two metres, in each of the trillions of cells in your body. Two metres may not sound like much, until you remember that a typical cell nucleus — which holds almost all of the cell’s DNA — is only six millionths of a metre across. If the nucleus were the size of your lounge room, and DNA were made of string, there would be 1,000 kilometres of string in the room with you — enough to stretch from London to Berlin, or from San Francisco to Portland.