Conversations About Biology

Howard Burton

• Publisher: Ideas Roadshow
• Year: 2021
• eBook ISBN: 9781771701006
• Topic: Biological Sciences
• Subtopic: Genetics in Medicine
• Index: Biological Sciences

FIVE BOOKS IN ONE! This collection includes the following 5 complete Ideas Roadshow books featuring leading researchers providing fully accessible insights into cutting-edge academic research while revealing the inspirations and personal journeys behind the research. A detailed preface highlights the connections between the different books and all five books are broken into chapters with a detailed introduction and questions for discussion at the end of each chapter: I. A Genetic Perspective - A conversation with Jay Gargus, Professor of Physiology, Biophysics and Pediatrics and Director of the Center for Autism Research and Translation at UC Irvine. This wide-ranging conversation examines the recent explosion in our genetic understanding and its implications for the future of medicine, together with the importance of understanding the underlying molecular mechanisms in order to successfully treat a wide range of genetic disorders. Prof. Gargus focuses on autism, dispelling myths associated with the condition, advocating why a treatment should be actively pursued, and illustrating what we can learn from the recent breakthrough in cystic fibrosis research.II. Learning and Memory - A conversation with Alcino Silva, Professor of Neurobiology, Psychiatry and Psychology at UCLA. Alcino Silva runs a learning and memory lab at UCLA that is focused on a vast number of topics, from schizophrenia and autism to learning and memory. This fascinating conversation explores how he and his colleagues focus on understanding the specific molecular mechanisms of neurobiology with the goal of being able to intervene and repair these mechanisms when they go awry. III. A Matter of Energy: Biology From First Principles - A conversation with Nick Lane, Professor of Evolutionary Biochemistry at University College London. After an inspiring story of Nick Lane's career path, this wide-ranging conversation covers his bioenergetic view of early, evolutionary history, the origin of life and how all complex life is composed of a very particular cell type that we all share, and more.IV. Our Human Variability - A conversation with Stephen Scherer, Research Chair in Genome Sciences at the Hospital for Sick Children and University of Toronto. Stephen Scherer discusses his lifelong passion for science that culminated in his groundbreaking discovery of copy number variation. This conversation also covers his exciting work in autism research and how copy number variation brings us a deeper understanding of both human variability and disease.V. Sleep Insights - A conversation with Matthew Walker, Professor of Neuroscience and Psychology at UC Berkeley. This extensive conversation gives a clear and compelling picture of our recent understanding of sleep's essential role in our daily lives, from reinforcing learning and memory to regulating emotion.Howard Burton holds a PhD in theoretical physics and an MA in philosophy. He was the Founding Director of Canada's Perimeter Institute for Theoretical Physics. For his award-winning initiative Ideas Roadshow, Howard has hosted and filmed in-depth conversations with more than 100 world-leading experts, including 3 Nobel Laureates. Ideas Roadshow conversations reveal the inspirations and personal journeys behind the research while providing behind-the-scenes insights into the world of frontline research.

Our Human Variability

A conversation with Stephen Scherer

Introduction

More Things in DNA, Horatio...

Biology fascinates me. But as a non-expert, I’m forced to think of things in pretty simple terms. So when I hear biologists talk about evolution, adaptability and natural selection, I always find myself asking: What’s going on, exactly? What are the physical mechanisms at play?

After all, if a species evolves through mutations of its members, then these mutations must be physically represented somewhere. And where else could that happen other than in our DNA, our own personal “instruction manual” of nucleotides and genes that we carry with us in every cell.

If evolution is as strong a force as we are led to believe, then, these sorts of variations must somehow be happening all around us, resulting in a world replete with manifold diversity and uniqueness that is layered upon our common humanity. Which is—to all intents and purposes—pretty well what we see when we look around and see such differences in the people on all sides of us. So far, so comprehensible.

But when the Human Genome Project announced that their DNA sequencing experiment demonstrated that we were all “99.9% identical”, things took a decided turn towards the unintelligible for me, and my first reaction was one of sceptical confusion, rapidly followed by one of embarrassed withdrawal.

Like many laymen, the conclusions seemed downright perplexing to me, but who on earth was I to question the scientific consensus of thousands of expert researchers from around the world?

Stephen Scherer, on the other hand, a world-class geneticist who built an internationally renowned research program at Toronto’s Hospital for Sick Children, naturally felt less inclined to be deferential to the prevailing wisdom.

“When the rough draft papers came out in 2000, which talked about how we’re 99.9% identical, I remember thinking, ‘But we’re not identical. My brothers and I share 50% of our DNA from our parents, and we’re nothing alike.’ You could probably pick us out in a crowd, but we’re really quite different.”

Let’s run the numbers. For a human genome of roughly 3 billion nucleotides, that 0.1% difference results in variations of about 3.2 million of the individual nucleotides that make up the “human genome”. So that’s one way to look at things.

But, crucially, it’s not the only way.

Many years before the Human Genome Project reached its conclusion, geneticists had also recognized that some 0.4% of the population exhibited large-scale deviations from the norm—so-called “copy number variation”—where huge chunks of DNA, often millions of nucleotides long, were either missing from their genome or present in extra copies. All of these large-scale changes were associated with serious medical conditions like autism or Down syndrome.

There were, then, it seemed two types of variation: one for the “diseased” and one for “the rest of us”. It was a picture that most geneticists and molecular biologists of the time unhesitatingly accepted. But not Stephen.

“I have this figure that I always show the students when I teach. If you plot out the number of different types of genetic variation and divide them into single nucleotide variation and the copy number variations, you’ll see that, in fact, 0.4% of the ‘normal’ population, the average population, carries big chromosome structural changes. Trisomy 21 is mainly associated with Down syndrome, but there are other big segments of DNA in a very small portion of the population that are different from each other. 0.4% of the population have these big, big changes, and we’ve known about that for 50 years.

“On the one hand, The Human Genome Project talked about those 3.2 million potential single-nucleotide changes that everyone is subjected to,and then on the other hand there’s 0.4% of the population who experience these large-scale chromosome changes.

“And when I was teaching back in 2002, I kept thinking to myself, ‘Biology favours balance. There have got to be a lot of other variants here. Why is it that we haven’t seen them yet?’

“Well, because we didn’t have the tools to see them.”

He didn’t develop the right tools himself. But as a self-confessed “technology guy”, Stephen had the presence of mind to aggressively seek out better and different techniques to see what others might have missed.

In 2003, he partnered with Craig Venter’s Celera Genomics to study the DNA of chromosome 7, his primary area of expertise. Venter had pioneered a different sort of DNA sequencing technique, called “shotgun cloning”, that had also been used for the Human Genome Project. Now there was a way of comparing and contrasting the two approaches.

“We published that in Science in 2003 with Craig Venter’s group. Figure 1 of that paper is probably the most underplayed figure in the field of genetic variation. In Figure 1, we compared the sequence we put together with the Celera group approach with the public Human Genome Project reference sequence.

“If you look at that figure we show that there were about 167 or so sites along the chromosome that, when we compared the sequences, showed significant differences, including pieces of DNA in one that were not in the other.

“The reviewers kept saying, ‘These are just technical mistakes. You guys screwed up. You made a mistake.’ We knew that wasn’t the case, because we had used another form of experiments to prove that, indeed, those variations existed. But they still didn’t believe us, and the editor wanted it taken out. But I said, ‘You’re not getting our paper unless you leave it in. The data support it.’

“Those were the first copy number variations that were identified.”

So “copy number variation” again, but this time not necessarily associated with any particular condition or disease. What Stephen and his colleagues had stumbled upon was the groundbreaking possibility that large-scale, DNA copy-number variation might be nothing less than a universal human trait, a key ingredient in allowing evolutionary variability—concrete evidence, in other words, that we were far more distinctive than the Human Genome Project was telling us we were.

More work, though, needed to be done—and, once again, with cutting-edge tools.

“The real breakthrough was this technology called microarrays, which allowed us to scan for dimensional differences in the DNA sequence. What we had previously looked for were binary differences: Was it an adenine or a thymine here? Or a cytosine or a guanine there? These are single letter changes—site by site. There was really no good technology that allowed you to look for what I would call a copy number difference, where instead of having two copies, you might have three copies, or one copy, or in some cases zero copies.

“We actually used DNA from a child that was autistic as our first set of experiments. I wanted to get the most bang for my buck—I wasn’t going to run just anyone’s DNA—these experiments cost thousands of dollars. At any rate, we knew that this boy had about a 6-million-base-pair deletion on one of his chromosome 7’s, right near the cystic fibrosis gene. We knew a lot about this.

“When we looked along his chromosome 7, starting at the beginning, there are a few blips, then you get to where his deletion is known to be, where he only has the one copy, and it drops down a bit, and afterwards it picks up again and continues along. But along the way there were all these other blips.

“It looked to be the same site on the chromosome; and we only saw them in some families and not others. That was really copy number variance. There were all these little blips along the chromosomes where there were segments of DNA of the order of 100,000 nucleotides long (an average gene is about 30,0...

Table of contents

• Textual Note
• Preface
• Autism: A Genetic Perspective
• Learning and Memory
• A Matter of Energy
• Our Human Variability
• Sleep Insights