4. The Fourth Law of Zero: Genomics

Over the last 25 years the sequencing of the human genome has gotten a million times faster and a million times cheaper. Soon, it will cost about as much as a Starbucks Frappuccino and be accessible through your smartphone.

That pace of change is why genomics – the branch of molecular biology concerned with the structure, function, evolution, and mapping of genomes – is now a foundational tool in every field of science related to biology, including agriculture, environment, health, medicine, and zoology. Imagine, for example, the Covid-19 pandemic without the identification and tracking capabilities, therapeutics, and vaccines enabled by recent advances in genomics.

In this week's serialization of "A Brief History of a Perfect Future: Inventing the world we can proudly leave our kids by 2050," by Paul Carroll , Tim Andrews and Chunka Mui , we explore how the Fourth Law of Zero on genomics, building on the Laws of Zero on computing, communication, and information, will advance our understanding at an accelerating pace.

We are truly reading and writing in the language of life — and we’re getting better at an exponential rate. Gregor Mendel would be proud. Stunned, but proud.

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CHAPTER 4

The Fourth Law of Zero: Genomics

Our ability to understand and map genetic structures traces back to the garden of an abbey in Moravia in 1856, where an Augustinian monk raised peas. That monk, Gregor Mendel, spent seven years purifying his strains of peas based on seven characteristics, then cross-pollinating the peas to slowly deduce the properties of inheritance. He published a paper in 1865 on a novel theory of what he called dominant and recessive genes — and that was pretty much the end of it. Mendel soon became the head of the abbey, in what is now the eastern part of the Czech Republic, and set aside his scientific work. The paper was promptly forgotten: It was cited all of three times in the next 35 years.[1]

It’s fair to say genomics – the branch of molecular biology concerned with the structure, function, evolution, and mapping of genomes – got off to a slow start. But, remember, that’s how exponentials work: slow start, overwhelming finish.

Mendel’s paper was rediscovered in 1900 and led to a series of discoveries that built on each other and ignited the interdisciplinary branch of science that we now call genomics.[*] If DNA is “the language in which God created life,” as President Clinton once put it, then genomics’ acceleration has brought us to the point that we can read and write in the language of life. And in recent decades, the progression, moving even faster than Moore’s law, suggests we’re very much looking at a Law of Zero: The benefits will keep expanding so fast that we’re barely able to discern their outline at this point.

Let’s resume the story in 1975, when Frederick Sanger and Walter Gilbert separately unveiled techniques for decoding genes by directly determining the sequence of the bases that make up ?DNA.[2] The sequencing processes, while miraculous, were arduous. The Sanger Method, which was more widely used, required expert laboratory skills and the precise use of dangerous chemicals, including acrylamide (a neurotoxin), chloroform (a carcinogen), and hydrazine (a rocket fuel). Initially, there were no computer programs to analyze the results; researchers had to interpret the results by eye. The entire process of preparing, sequencing, and analyzing even small fragments of the genome was novel and complex enough to earn one a Ph.D.

Tom Maniatis, the head of the New York Genome Center, observed that, when he was a postdoctoral fellow in Sanger’s lab, it took him a year to sequence a piece of DNA that was about 35 base pairs. At that rate, it would’ve taken him 86 million years to sequence the full human genome. Sequencing the COVID-19 virus would have required about 860 years.

But the Laws of Zero feed off each other. And advances in computing, in particular, kept speeding up sequencing. In 1990, the U.S. led the formation of an international cooperative, the Human Genome Project, to sequence the entire genome. Francis Collins was put in charge, and the venture was funded with $3 billion through the Department of Energy and the National Institutes of Health. In 1998, Craig Venter decided that the government effort wasn’t moving fast enough and announced a rival, privately funded attempt. A race ensued, and both groups declared success in June 2000, five years ahead of the original timeline for the Human Genome Project.

What had once been a messy problem for scientists handling test tubes and making slides in the lab soon enough became a problem for computers, not just lab technicians — and, as we’ve seen, computers have become unbelievably fast. Thirty years after Maniatis was a post-doc, the Illumina NovaSeq 6000 machines in Maniatis’ center can sequence an entire human genome overnight.

From 86 million years to overnight. Yeah, that works.

Cost comparisons are similar. It cost billions of research dollars to sequence the first human genome in 2003. Today, sequencing a genome costs roughly $600. You can see the plunge in Figure 4. Note that it’s logarithmic. The line based on Moore’s law doesn’t show a steady decline of maybe 50 percent in the cost of computing over the past two decades, as the line would if the chart were using normal, Cartesian coordinates. Each of the horizontal markings represents an order of magnitude, so the chart shows that Moore’s law has brought a decline of roughly a factor of 1,000 since 2000 — and the cost per human genome has declined far, far faster.

We’re not even close to done, either. Multiple makers of sequencing machines predict the path to a $100 genome test doesn’t even require further breakthroughs, just incremental technical improvements.

In mid-2021, as we write this, the high-end NovaSeq 6000 in Maniatis’ lab costs roughly $1 million, and there are only about 1,000 of them in the world. They’re the sequencing supercomputers of the moment. But those prices will come down, and there’s no reason sequencers need to stay in labs — think of all the mainframes in computer labs in the 1970s and 1980s, then look at the (more powerful) smartphone in your hand. Even now, lower-power desktop sequencers cost only around $10,000, and there are early versions the size of smartphones, which cost about $1,000. Oh, and there are already attachments that let you sequence a genome from an app on your smartphone.

When will some version of genomic sequencing be embedded in every smartphone (or whatever device the smartphone morphs into)? We don’t know exactly, but we’re pretty sure that some version of Dr. Bones McCoy’s Star Trek tricorder is in our future.

In the Future Perfect, you can safely bet the cost of testing will drop so low that you can imagine throwing as much genomic sequencing at a problem as you’d like.[?] Gordon Sanghera, CEO of Oxford Nanopore Technologies, the company that makes the $1,000, phone-sized sequencing device, describes his company’s ethos as “the analysis of anything, by anyone, anywhere.”

For a dramatic illustration of the real-world benefits of genomic sequencing today, consider our experience with COVID-19. The genome of the offending SARS-CoV-19 virus was isolated, sequenced, and shared with researchers across the globe within days of when a patient was admitted to the Central Hospital in Wuhan, China, with symptoms of the yet-to-be identified disease. Then, days — we repeat, days — after the sequence was shared, the genetic code of the virus was being used to design the first vaccines, formulate treatments, create testing kits, and monitor for mutations of the virus.

Less than a year later, emergency-use authorizations were approved for multiple vaccines that showed more than 90 percent effectiveness. Soon, millions of shots of those vaccines were being poked into arms to protect those at a high risk from COVID-19, and billions of shots have since followed. Before genomic sequencing, developing and distributing a vaccine could have taken more than a decade — if one ever succeeded. The fact that one succeeded, and so quickly, saved hundreds of thousands or even millions of lives worldwide.

And turning back viruses is absolutely just the beginning of what’s possible — the very beginning. Even more powerful is the potential ability to write in (or at least edit) the language of life. And we’re starting to take baby steps at doing so. Those baby steps are being enabled by a tool named CRISPR/Cas9, called CRISPR, for short. [?]

CRISPR was invented by Emmanuelle Charpentier and Jennifer Doudna in 2012. The duo and their teams developed it by deciphering and adapting a technique bacteria use to fight viruses. Viruses reproduce by injecting themselves into host cells and taking over the cells’ metabolism to reproduce. The host can then fight back by snipping the infecting virus’ DNA out of the host’s DNA, where the virus has embedded itself — and Charpentier and Doudna figured out how a bacterium’s immune system accomplishes that feat. They then designed a process to chemically reprogram that mechanism to cut out any stretch of DNA at a predetermined spot in a bacterium’s genome and replace it with a molecule of the scientists’ choosing. (They shared the Nobel Prize in Chemistry in 2020.) Other researchers soon developed methods to edit the genomes of any other organism, including ours. (Zhang Feng at MIT deserves special recognition.)

Yes, CRISPR is almost like magic.

Other techniques existed for editing DNA before CRISPR, but they were much less precise and could take months to prepare. CRISPR was a generalized, programmable method that was easily repeatable and cut the time to hours — or even minutes. The Nobel committee called the CRISPR advance “epoch-making” and dubbed it “a tool for rewriting the code of life.”[3]

Already, the applications are wide-ranging. CRISPR is being applied to major staple foods in Africa, such as wheat, cassava, and banana, to help them resist disease.[4] Another group showed that CRISPR can snip out a family of viruses in pig DNA and potentially increase the opportunity to use pig organs for human transplants. A third group has developed a CRISPR-based treatment that appears to fix the genetic mutation responsible for muscular dystrophy in dogs.[5] And CRISPR-enabled technology is poised to revolutionize medicine: Researchers are developing CRISPR-Cas9 therapies for a wide range of diseases, including inherited blood and eye diseases, neurodegenerative conditions such as Alzheimer’s and Huntington’s disorders, and even non-inherited diseases such as cancer and HIV.[6]

Now, think more broadly: Imagine what’s called a gene drive, a genetic engineering approach designed to spread a gene across an entire species. A gene drive could potentially spread an advantageous trait — or could even wipe out an entire dangerous species.[7]

A gene drive tool changes the genes of a single creature in a way where those genes become dominant, are passed on to all offspring and, eventually, are spread to the entire species. A gene drive could alter female mosquitoes to not bite — the males don’t bite, so the alteration would end malaria. A gene drive could produce rats that only have male offspring, eliminating a threat to, say, the native bird and turtle populations of Galapagos. Gene drives could fight invasive crop pests like the fruit flies that eat up the raspberry patch of one of your authors every season, no pesticides required.

Actually, you don’t have to imagine any of these things. All these possibilities have been demonstrated. CRISPR lets us alter both individuals and entire species.

We’re not saying we should make any of these fundamental changes. Ecosystems are remarkably complicated, and there are loads of examples of attempts to handle a pest by introducing a predator for that pest — only to find that the predator created many more problems than it solved. Even if you go after something as clearly vile as rats, well, what animals feed on the rats and will now struggle for food? What animals feed on the animals that feed on the rats? What else did the rats feed on, besides the eggs of the species you want to protect? And so on.

We favor slow changes so that we can see what the full ramifications turn out to be for an ecosystem. We’re taking great strides and baby steps at the same time. And many of our steps are in the dark — or, at the very least, the fog.

While we still have much to learn even about the meaning of the genomes we can read, genomics already provides hope for addressing a number of diseases caused by variation in a single gene. These diseases include sickle cell anemia, cystic fibrosis, Huntington’s disease, and Duchenne muscular dystrophy — debilitating diseases that afflict some 400,000 people just in the U.S. CRISPR is helping researchers to better understand these diseases, and a number of therapies are currently in the midst of clinical trials for treating and even curing them.

Eric D. Green, who heads National Human Genome Research Institute (NHGRI), a part of the National Institutes of Health (NIH), wrote in Wired in late 2020 that he believes genomics will provide a platform for discovery that broadly accelerates the pace of biology research.[8]

“A lot of times people hear CRISPR and think of?therapies for people. But by far the bigger use is at the bench. With CRISPR, we can?make edits to little pieces of DNA?that never go into a person — they go into cell lines or bacteria, which then get tested to see if those edits have functional consequences. The combo of?genome editing?and?genome synthesis methods?getting better, coupled with better and better computational tools, is really going to change the pace of biological discovery. Right now, we rely on one paper being published about one genomic variant to give us one drip of information at a time. That doesn’t scale.

So we’ve got to get to a point where we’re making millions of changes, generating massive amounts of data, and then hopefully we can use?AI to train computers to look for patterns. At that point, we won’t even have to do the experiments, because we can make predictions about what a mutation means based on the last 1,000 times we’ve done this. Going forward, those are the sorts of tools that might make the difference.”

Think of his approach as science in hyperspeed. Progress in genomics rides on the coattails of the Laws of Zero in computing, communications, and information. If Green is right that research can increasingly move from the lab bench to the computer, then progress can happen at the speed of electrons. That means the Laws of Zero can exponentially amplify the capabilities in genomics, enabling a platform for discovery about the workings of life itself.

And who knows where that takes us?

In medicine, almost every new drug and vaccine is already based on genomics,[9] which is also a foundational tool in almost every field of science related to biology, including agriculture, environmental studies, health, and zoology. So, the Law of Zero for genomics will exponentially amplify science and engineering’s impact over the next half century to a degree that will likely surpass the impact of the computing platform it’s built upon.

Just in the next five to 15 years, Green, Collins (the director of NIH), and their colleagues predict genomic testing will become as routine as complete blood counts and will guide prevention, diagnosis, and therapy. They expect that the biological function(s) of every human gene will be known and that studies involving analyses of genome sequences will be so routinely available they’ll appear at school science fairs.[10],[11]

The sorts of techniques and computing power that are opening up genomics will allow for other “-omics” with extraordinary potential, too – proteomics, metabolomics, and other fields that will provide deep understanding of how our cells function.

One limiting factor for genomics lies in the difference between a genotype and a phenotype. A genotype is the genetic characteristics of an organism as detailed by its genome while a phenotype refers to the actual physical characteristics of that organism. It’s analogous to the difference between a blueprint for a house and the actual house itself. The physical characteristics of an organism are determined not just by the genetic blueprint described in the genome but by the complex interaction between an organism’s many genes and environmental factors beyond the genome itself.[§] This complex interaction, known as epigenetics, very much affects health, albeit in complex ways. Even when we have all the data in front of us, as we do with many cancer genomes, the epigenetics are so complex that we can’t yet decipher the diseases.

But the Law of Zero on genomics, building on the Laws of Zero on computing, communication, and information will steadily advance our understanding — at an ever-accelerating pace.

We can also envision harnessing the power of genomics to create healthier foods; to eliminate the microbes that cause disease; to eradicate the most dangerous pests; to correct the genetic errors that cause disease; and to do all of the above in an ethical and equitable manner with a deep understanding of the implications of our choices.

We are truly writing in the language of life — and we’re getting better at an exponential rate. Mendel would be proud. Stunned, but proud.

?

Other parts of this serialization (Subscribe to be notified of upcoming chapters as they are released):

A Brief History of a Perfect Future: Inventing the world we can proudly leave our kids by 2050 by Chunka Mui, Paul B. Carroll, and Tim Andrews

Table of Contents

Introduction

Part One: The Laws of Zero

Chapter 1 The First Law of Zero: Computing

Chapter 2 The Second Law of Zero: Communication

Chapter 3 The Third Law of Zero: Information

Chapter 4 The Fourth Law of Zero: Genomics

Chapter 5 The Fifth Law of Zero: Energy

Chapter 6 The Sixth Law of Zero: Water

Chapter 7 The Seventh Law of Zero: Transportation

Part Two: The Future Histories

Chapter 8 Electricity

Chapter 9 Transportation

Chapter 10 Health Care

Chapter 11 Climate

Chapter 12 Trust

Chapter 13 Government Services

Coda What is the Future Isn't Perfect?

Part Three: Jumpstarting the Future (Starting Now)

Chapter 14 What Individuals Can Do

Chapter 15 What Companies Can Do

Chapter 16 What Governments Can Do

Prologue: Over to You

[*] The science of genomics also stands on the shoulders of many other genius researchers, many of whom became well-known but some others who deserve much more recognition beyond scientific circles. Albrecht Kossel discovered the nucleic acids that are the chemical building blocks (called “bases”) of DNA and RNA. James Watson and Francis Crick, building on the work of Rosalind Franklin, deciphered the double helix structure of DNA. Marshall W. Nirenberg and Har Gobind Khorana cracked the code on DNA by showing how the bases determine protein synthesis. And many more.

[?] We’ll still have to face the fact that more and better testing isn’t always a good thing. Mammograms keep improving, but breast cancer mortality hasn’t declined. More and more cases of thyroid cancer are being diagnosed, and more surgeries are being done, but the fatality rate here also isn’t decreasing. MRIs to diagnose back pain have made it easier to spot spinal deformities and justify surgeries — that all too often do nothing to alleviate the pain. We’ll still have to correlate and make sure that fixing the issues surfaced by genomic testing lead to real benefits and that those benefits outweigh risks and other costs.??

[?] CRISPR/Cas9 is short for “Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-Associated Protein 9.” This clunky phrase was chosen more to fit the acronym than the other way around, according to Francisco Mojica, the Spanish molecular biologist who coined it. He thought that “CRISPR” sounded friendly and that the dropped “e” gave it a futuristic sheen. His wife thought CRISPR was a great name for a dog.

[§] The Department of Veterans Affairs (VA), with help from Booz Allen, has a program doing exactly this kind of genomics/epigenetics work. The goal of the program is to sequence the genomes of 1 million vets and match them to the 30-plus years of phenomic data contained in the VA’s electronic health records. The work, which created electronic health records decades ahead of the private sector, provides a treasure trove of phenomic data.

[1] Mendel was no simple country friar. Mendel was immersed in the writings of his contemporary, Charles Darwin, and there’s ample evidence that Mendel interpreted his data on nearly 30,000 plants with Darwin’s theories on evolution and natural selection in mind. The German translation of Darwin’s Origin of Species was published in 1860, in the middle of Mendel’s research, and Mendel made numerous annotations in his copy of the book. Mendel’s papers and letters also used Darwin’s terminology to address evolutionary questions and concepts. https://www.nature.com/articles/s41437-019-0289-9.pdf

Some researchers believe that Mendel’s embrace of science and his interest in studying evolution caused conflict with his church superiors. Mendel told his nephews that he had scientific papers he delayed publishing for fear of “clerical enemies” and that they should look for them upon his death. All of Mendel’s papers, however, were burned by his abbey after his death.

[2] Sanger and Gilbert shared the 1980 Nobel prize in chemistry. Sanger had already won a Nobel prize for his work in sequencing insulin; he is the only person who has won twice in chemistry.

[3] https://www.nobelprize.org/uploads/2020/10/popular-chemistryprize2020.pdf

[4] https://allianceforscience.cornell.edu/blog/2020/04/gene-editing-will-revolutionize-crop-breeding-in-africa-new-paper-predicts/

[5] https://onezero.medium.com/the-7-craziest-ways-crispr-is-being-used-right-now-bcf3bd203f23

[6] https://www.synthego.com/blog/crispr-cure-diseases

[7] https://www.nytimes.com/2020/01/08/magazine/gene-drive-mosquitoes.html

[8] https://www.wired.com/story/30-years-since-the-human-genome-project-began-whats-next/

[9] https://www.scientificamerican.com/article/reflections-on-the-20th-anniversary-of-the-first-publication-of-the-human-genome/

[10] Green, E.D., et. al., “Strategic vision for improving human health at the Forefront of Genomics,”?Nature?2020

[11] Denny JC, Collins FS. Precision medicine in 2030-seven ways to transform health care. Cell. 2021 Mar 18;184(6):1415-1419. doi: 10.1016/j.cell.2021.01.015. PMID: 33740447.