5.6 — Genomics: Rewriting Our Health

Host Walter Isaacson and guests look at the makeup of our DNA itself and how that knowledge can lead to revolutions in numerous fields.
Transcript
Subscribe
All Trailblazers Podcasts

In this episode:

  • Watson and Crick (0:00)
  • Remixing DNA (2:36)
  • Setting some ground rules (5:31)
  • Uncovering the human genome (8:59)
  • From diagnosis to prediction (14:28)
  • Using CRISPR to preemptively strike (19:59)
  • Still a ways to go (25:31)

Our genes are the very building blocks of life itself, but it wasn’t until recently that we had a deeper understanding of them. Now that we do, a world of possibilities has opened to scientists. In this episode, we explore what can be done with this newfound knowledge.

This episode provided the ABCs of DNA. Here’s a little more on the topic.

Guest List

  • Hallam Stevens is an associate professor of history at Nanyang Technological University (Singapore). His research focuses on the history of biotechnology and the history of information technology. He is the author of Life out of Sequence: a data-driven history of bioinformatics (Chicago 2013) and Biotechnology and Society: an introduction (Chicago 2016).
  • Richard M. Myers, PhD is a biologist who does research in human genetics and genomics, with particular interests in understanding how our genes and their expression contribute to disorders of the nervous system. He serves as President, Science Director and M.A. Loya Chair in Genomics at the HudsonAlpha Institute for Biotechnology.
  • Eric Green is the director of the National Human Genome Research Institute (NHGRI) at the U.S. National Institutes of Health (NIH). For just over two decades, Dr. Green directed an independent research program that included integral start-to-finish roles in the Human Genome Project and groundbreaking work on mapping, sequencing, and characterizing mammalian genomes.
  • Amit V. Khera is a cardiologist and human geneticist who leads a research group spanning the Massachusetts General Hospital Center for Genomic Medicine and the Broad Insitute of MIT and Harvard. His group uses genetic variation as a tool to uncover new biology and enable enhanced clinical care informed by inherited susceptibility.
  • Glenn Cohenn author or co-author of more than 150 articles in journals like Science and JAMA and the author, co-author, editor, or co-editor of 15 books, Glenn Cohen is one of the world’s leading scholars in bioethics and health law. He is a deputy dean and professor at Harvard Law School.
  • Jennifer A. Doudna is the Li Ka Shing Chancellor’s Chair and a Professor in the Departments of Chemistry and of Molecular and Cell Biology at the University of California, Berkeley. Her groundbreaking development of CRISPR-Cas9 as a genome-engineering technology, with collaborator Emmanuelle Charpentier, earned the two the 2020 Nobel Prize in Chemistry and forever changed the course of human and agricultural genomics research.

“Life is, in a sense, a program that is run from the DNA.”

— Hallam Stevens, author of "Biotechnology and Society: An Introduction"

Walter Isaacson :

It’s February 28th, 1953, and a Cambridge University grad student named Francis Crick burst into the Eagle Pub, a well-worn hangout nestled among the colleges of Cambridge university. “We have found the secret of life,” he proclaims to the surprise patrons of the pub. Crick was exaggerating, but not by much. He and his colleague, the 24 year old American student James Watson, had indeed found one of the secrets of life.

Walter Isaacson :

Earlier that day in their lab, they had finished building a tin and wire model of what they believed to be the structure of a molecule called Deoxyribonucleic acid. You probably know it by its acronym, DNA. The model they built in their lab showed that DNA was shaped like a twisted ladder or spiral staircase. The rungs were made up of combinations of four molecules that carry the code for all of our genes. They dubbed it the double helix. James Watson and Francis Crick published their findings in the journal Nature, which included a drawing of the double helix.

Walter Isaacson :

The double helix was arguably the most important biological discovery of the 20th century. And it was a major step on our quest to cure some of the most complex human diseases. It was the birth of the field of genomics. I’m Walter Isaacson, and you’re listening to Trailblazers, an original podcast from Dell Technologies.

Speaker 2:

I should like to tell you that I have seen some of the experiments shown in this film.

Speaker 3:

Scientific achievement undreamed of a few decades past.

Speaker 4:

Using the different instruments and test at our command-

Speaker 3:

Particularly promising the advances being made in the biological sciences.

Speaker 5:

Let us look into the laboratory.

Speaker 3:

Sampling, incubating, plating, and then more incubation.

Walter Isaacson :

James Watson was a biologist. Francis Crick’s background was in physics. Prior to World War II, a collaboration between these two disparate disciplines would have been unlikely. But the war had brought about a fundamental shift in thinking among biologists that made them much more open to working with physicists. After all, physicists had harnessed the power of the atom. So, maybe they could help solve the puzzle of DNA.

Hallam Stevens:

There is this turn in biology, after World War II, to this idea that life should and could be understood on a molecular level.

Walter Isaacson :

Hallam Stevens is the author of Biotechnology and Society: An Introduction.

Hallam Stevens:

Biologists begin to imagine DNA as some kind of code, just like a computer code, some kind of software. Right? So, that DNA is the kind of the software that runs the kind of hardware of the body, like the program that runs out computers. It’s like the operating system. I mean, all of these kinds of metaphors begin to emerge and play a very, very powerful role in the way people begin to think about what DNA is and also what life is.

Walter Isaacson :

The marriage between biology and technology was consummated in the early 1970s with the work of two American biochemists named Stanley Cohen and Herbert Boyer. Cohen and Boyer successfully cut DNA from two different organisms and pasted them together to form a single molecule. They could then introduce this new recombined DNA back into an organism where it would replicate. A genome is the sum total of an organism’s DNA. So, if you think of the genome as a line of text, scientists can now read the text, copy it, and even do some basic editing. They called their discovery recombinant DNA.

Hallam Stevens:

They imagined a whole range of different uses. The main one is that they realized that they could potentially produce human proteins from it. For example, humans produce insulin naturally. Now, what Boyer and Cohen realized that they could do was in fact to take the gene for human insulin, put it inside of bacteria, and then allow the bacteria to produce human insulin. It actually came from a human gene, but it was produced inside a bacteria, and therefore; could then be used as a kind of drug. Right? It could be uses as a treatment, for example, for diabetics.

Walter Isaacson :

Today, it is hard to imagine medicine without recombinant DNA. It’s widely used to develop vaccines, therapeutic agents, and diagnostic tools. But with the discovery of recombinant DNA, scientists had for the first time entered the murky world of genetic engineering.

Hallam Stevens:

I think that what it did was showed people what was possible and kind of inspired this whole idea that we can take control of our genes, take control of life on a molecular level. This idea has existed in the imagination for quite a long time, but this moment in 1972 really basically creates the field of what we would now call biotech or biotechnology.

Walter Isaacson :

The potential benefits of recombinant DNA technology were obvious, but so too were some of the very serious risks. What if it enabled them to produce dangerous toxins or transform them into cancer causing agents? These possibilities were so worrying that, in 1974, scientists involved in recombinant DNA research agreed to pause their work until some guidelines could be established. Six months later, 140 of the world’s top biotech researchers met at the Asilomar Conference Center in Northern California to talk about how recombinant DNA research should proceed.

Glenn Cohen:

This was one of the most important scientific conferences where the who’s who of the biotechnology world kind of got together to try to set the ground rules as this new technology came online. But it’s controversial.

Walter Isaacson :

That’s Glenn Cohen. He’s a professor at the Harvard Law School and an expert on health law and bioethics.

Glenn Cohen:

There’s people who view it as one of the most successful kind of engagements of public policy, and science, and self-regulation for science. Another view is that kind of a situation where only the elites were there and there wasn’t true representation, and certainly not representation of the public. So, what it generated was an internal sort of agreement as to what to do, what not to do, as opposed to external facing public regulation.

Walter Isaacson :

The scientists at the conference established rules on how and where recombinant DNA research could take place. Cloning and experimenting with dangerous pathogens were declared off limits. As for how the rules would be enforced, the scientists were eager to avoid the heavy hand of government regulation. So, they agreed to essentially regulate themselves. Only labs that conformed to the Asilomar rules on safety would be eligible for funding from the National Institutes of Health. Satisfied that they now had appropriate guidelines in place, scientists continued to push the frontiers of genetic engineering. And they would soon receive a critical boost from a project that began almost by accident at another science conference in December, 1984.

Rick Myers:

I was a biochemist. I had no idea what genetics was, but I got invited to a meeting in Alter, Utah. And it was only 19 people, sponsored by the Department of Energy, the U.S. Department of Energy.

Walter Isaacson :

This is Rick Myers. Today, he’s the president of the Hudson Alpha Institute for Biotechnology in Huntsville, Alabama. In 1984, he was a post-doc fellow in biochemistry at Harvard. Now, you might be wondering what the Department of Energy is doing in a story about genetic research. The answer is that the DOE is in charge of America’s nuclear arsenal. And scientists there wanted to learn more about how radiation from an atom bomb might affect the genetic profile of people exposed to it. America detonated the first atom bombs over Hiroshima and Nagasaki in 1945. Now, nearly 40 years later, the DOE wanted to go back and see if they could find any mutations. It wouldn’t be easy. Our cells are very good at copying each other exactly. Mutations are rare and hard to find.

Rick Myers:

We were at this small meeting, and the senior scientists who were discussing how they might measure this said, “The mutation rate is probably so low, we’d probably have to sequence the whole human genome in order to figure this out. And everybody laughed because this was 1984. Nobody had any idea about sequencing the human genome.

Walter Isaacson :

And out of that casual remark was born the largest, most ambitious, most expensive, and arguably the most important multinational science collaboration ever undertaken, the Human Genome Project. The goal was to find all the estimated 25,000 human genes and sequence them by determining the exact order of the three billion DNA base pairs that make up the human genome. If successful, it would be like having all the pages of a manual needed to make the human body. But to do it, using the technology that existed at the time, would be an enormous challenge.

Rick Myers:

It was terrible. It would have taken us 200 years to do it with the technologies that we had then, or maybe even more. I’m not even sure we could have gotten there. And yet, the goal, the reason for doing it was so, so important, not just for this particular project, but for everything we’ve done now in medicine and basic biology of humans, other organisms, even agriculture. And what happened along the way is the techniques got better and better.

Walter Isaacson :

The Human Genome Project was officially launched in October, 1990. And the first decision the scientists made was possibly their most important. In academics, data is usually only released after a study is complete. But the scientists involved in the Human Genome Project decided that all the data generated would be free and immediately available for everyone to use, as soon as it was gathered. Their philosophy was similar to open source software developers who publish their code online so other programmers can freely build upon their work.

Rick Myers:

In biology, it was completely unheard of, but we had a series of three meetings in Bermuda and develop what we called the Bermuda Principles, which was the free and rapid release of data for everyone to use. And it stuck. I mean, this is the way most genomic data are generated. You can’t sit on it. You release it rapidly.

Walter Isaacson :

This was a huge paradigm shift in the scientific community. The goal of this change to research publishing conventions was to reduce the amount of time it would take to sequence the human genome. But, for at least one person involved on the Human Genome Project, things weren’t moving fast enough.

Walter Isaacson :

Craig Venter was a biochemist at the National Institutes of Health, but he was also an entrepreneur interested in securing patents and some pieces of the genome. Venter had developed a technique for gene sequencing that was considerably faster than the one being used by scientists working on the public project. And in 1998, he started a company called Celera Genomics to pursue genome sequencing as a private venture and try to beat the public scientists to the finish line.

Rick Myers:

Craig was part of the public effort at the beginning, and announced to us at one of our meetings that he was going to go do this and no longer be part of the public project. We thought this was horrifying because, here we were using public money to make something public. And Craig was saying, “We need not do it.” He even suggested to Congress that the public effort need not exist.

Walter Isaacson :

Venter’s plan generated fierce opposition from both scientists and the public. But eventually, he and the researchers of the Human Genome Project agreed to cooperate rather than compete. In June, 2000, Venter and Francis Collins, who was then the head of the Human Genome Project stood with president Bill Clinton in the East room of the White House. They were there to announce that a working draft of the human genome had been completed ahead of schedule.

Bill Clinton:

It will revolutionize the diagnosis, prevention, and treatment of most, if not all, humans diseases.

Walter Isaacson :

The president proclaimed. And he was right.

Eric Green:

To be honest with you, even when I was involved with the Human Genome Project, I never envisioned that it would actually be medically used within my career. Maybe in the next generation or the generation beyond that.

Walter Isaacson :

This is Dr. Eric Green. He’s currently the head of the National Human Genome Research Institute. Trained as a pathologist, he got involved in the Human Genome Project because he could see how genetic sequencing might be used to improve diagnostic capabilities. But things have moved far more quickly than he ever thought possible. 20 years ago, it would have cost about a billion dollars to sequence the human genome. Today, it costs under a thousand. A human genome can also be sequenced in just hours, when it once took years. And the affordability and speed sequencing is having an impact. Green sites the example of babies in neonatal intensive care units. Doctors were often unable to make an accurate diagnosis of what was making those babies so sick. But now, they can.

Eric Green:

An investigator, actually somebody we were supporting through our grant, came up with a way to very rapidly use these new methods to sequence the DNA of these acutely ill neonates, doing it literally in 24 hours. And boy, you hear these stories of these neonates that were literally on death’s door, and all of a sudden in 24 hours, using genomics, you could figure out how to treat and save that child. That is truly compelling.

Walter Isaacson :

Today, some researchers have shifted their focus away from using genetic sequencing to diagnose and treat disease. Instead they’re using it to try to predict disease. Dr. Amit Khera leads a research group at the Broad Institute Center for Genomic Medicine at MIT. Dr. Khera has developed a new way of predicting disease using what he calls a polygenic risk score.

Amit Khera:

So, a polygenic risk score is actually a new type of genetic risk factor that integrates information from many different sites where my DNA might differ from yours into a single number. And that number actually reflects our inherited susceptibility to a given disease. There are many, many variants across the genome, across all the chromosomes that can impact your risk for important diseases, breast cancer, heart attack, diabetes, and so forth.

Walter Isaacson :

All the diseases that Dr. Khera just mentioned involve mutations in many locations across a person’s genome. This makes treating them and predicting who might be at risk particularly challenging. In one study, Dr. Khera compared people who had heart attacks to those who didn’t.

Amit Khera:

It turns out they’re about six and a half million spots in our DNA where my DNA might differ from somebody else’s. So, as part of this study, we basically compared how common these variants were in someone who had a heart attack versus someone who didn’t. If the variant was more common in the people who had heart attack, that’s a risk variant. So, at the end of that study, we basically have a list of six and a half million variants and, for each of them, an effect estimate. Does it increase your risk by 5%? Does it decrease your risk by 2%, and so forth.

Walter Isaacson :

Khera likes to point out that genetics is not destiny. And, in many cases, lifestyle changes can mitigate whatever genetic predisposition a person might have for heart disease or other serious illnesses. But, without knowing you have a genetic predisposition, many people won’t choose to make those lifestyle changes. Khera’s work is still in its early stages and not yet publicly available, but one day knowing your polygenic risk score might become as routine as knowing your blood type.

Amit Khera:

The key advantage of the polygenic score is it can actually be calculated from the time of birth, because it’s based just on the DNA you inherited from your mother and your father. So, for heart attack, for example, if a 20 year old comes into my office, we actually don’t have any clinical risk estimator to say whether your risk is high or low, because almost no 20 year olds have been diagnosed with diabetes, hypertension, obesity, and so forth. So, here’s really a totally new tool that could be measured one time from the time of birth that really does predict very, very different lifetime trajectories of your risk for disease.

Walter Isaacson :

Being able to predict the likelihood of a genetic disease is clearly important. But what if you were able to go one step further and actually repair or even eliminate the genetic mutation that was causing the disease? Over the past decade, researchers have made enormous progress in accomplishing that goal, thanks largely to a gene editing technique called clustered regularly inter spaced short palindromic repeats. But you probably know it by its acronym, CRISPR

Jennifer Doudna:

CRISPR is a bacterial immune system. And it’s a system that has been harnessed for something called genome editing, which means changing DNA sequences precisely and accurately in cells.

Walter Isaacson :

Berkeley biology professor, Jennifer Doudna, who is the subject of my next book, is one of the world’s leading CRISPR researchers. In fact, it was a breakthrough in her in 2012 that sparked the current wave of scientific excitement over CRISPR.

Jennifer Doudna:

Well, I was sitting in my office at Berkeley, and I was working on probably my lecture for my sophomore biology class. And Martin Jinek, who was the scientist working in my lab on this project, came into the office and he said, “Jennifer, there’s something really interesting going on with this Cas9 protein.” And I said, “Well, what is it?” And he said, “Well, you have to come to the lab. And I want to show you some of the data that I have from my recent experiment.”

Walter Isaacson :

So, Jennifer Doudna went to her lab to see what had gotten her colleague so excited. It turned out that the Cas9 protein could actually be programmed to seek out and cut a segment of DNA with scalpel-like precision. And it would work in any living organism. All you had to do was find the mutation in the human genome responsible for disease and just turn it off or cut it out.

Jennifer Doudna:

This was just an incredibly exciting moment, as you can imagine. And we realized that we understood the molecular function of this protein, but we also looked at each other and said, “This is really interesting, but it’s also potentially an exciting technology, because it could be used to trigger changes to the DNA in cells.”

Walter Isaacson :

Ever since Stanley Cohen and Herbert Boyer discovered recombinant DNA in the early 1970s, researchers around the world have been looking for ways to edit genes quickly and precisely. With CRISPR Cas9, Jennifer Doudna’s lab had found the key to make it work.

Jennifer Doudna:

It’s one of those things, you see a result like that and, in my experience, there’s only a few times in one’s career when there’s something that happens in the lab where you have a sense that it’s a big deal. And this was certainly a moment like that. And so, I sort of felt the hairs on my neck standing up and sort of realizing that this really has profound implications. And I think what’s so interesting about this technology is that, unlike some other technologies that are very important in biology, this one, really from the very beginning, was clearly incredibly useful and was adopted very quickly by a number of labs that were able to deploy it in different types of cells and systems.

Walter Isaacson :

This wasn’t the first time that scientists had tried to cure a disease by manipulating the genome. In the 1990s, researchers inserted viruses into patient’s cells in order to disrupt gene sequences or add new genetic information. The technique was called gene therapy. But those viruses were hard to control, and they didn’t always do what they were supposed to do. Gene therapy lacked the precision offered by CRISPR Cas9, which has already produced life-saving results.

Walter Isaacson :

Victoria Gray is a 34 year old woman from Mississippi who suffers from sickle cell disease. Sickle cell is a rare blood disorder that’s difficult to treat. The disease is caused by a genetic mutation that produces a defective form of hemoglobin, which is a protein used by red blood cells to carry oxygen. In July, 2019, doctors removed bone marrow cells from Gray’s body, edited the gene inside them using CRISPR, and infused the modified cells back into her system. The hope was that the new cells would produce a protein that alleviated the worst complications of her disease. And it worked. Victoria Gray was the first person to have a disease treated using CRISPR gene editing. And, one year later, the cells are functioning as planned, and she is pain free.

Jennifer Doudna:

I’m incredibly humbled and honored to be part of the science that contributed to that. I mean, I think it’s extraordinary. I think any scientists would say that we all hope that our work will have an impact on humanity in even a small way that will help cure people of disease or solve real world problems.

Walter Isaacson :

There’s no question that treating disease with gene editing has enormous potential, but much work still needs to be done. Jennifer Doudna estimates that Victoria Gray’s treatment probably costs a couple of million dollars. So, it will be years before it can be of any help to the roughly 100,000 Americans suffering from sickle cell disease. And CRISPR is currently most effective with diseases caused by a mutation in a single gene. Most diseases are caused by mutations in hundreds or thousands of genes.

Walter Isaacson :

And there have been serious ethical questions raised about the use of gene editing. There’s widespread agreement in the scientific community that, for now, it should be done only on fully developed cells. Until it is proven safe and medically necessary, it should not be used on cells found in embryos, sperm, or eggs where the edited genes can be passed along to future generations. Editing these so-called germline cells raises the specter of researchers playing God by creating designer babies.

Walter Isaacson :

In 2018, a Chinese doctor did just that. He announced that he had used CRISPR to edit the genes of two human embryos. Scientists around the world condemned the experiment and the Chinese government sentenced the doctor to three years in prison. But CRISPR is a relatively easy technology to master, and no one can be sure that similar experiments aren’t happening in labs somewhere else in the world.

Walter Isaacson :

45 years ago, scientists met at Asilomar to discuss recombinant DNA, that groundbreaking new technology with profound ethical implications. Jennifer Doudna thinks we may now be at a similar moment with CRISPR.

Jennifer Doudna:

We’re living in an extraordinary time when science and technology seems to be moving faster and faster. And that certainly means that there’s a tendency for the developments of technology to outpace the regulation of those technologies. And that’s certainly true for CRISPR, I would say. And so, how do we deal with that? I think that I’ve struggled with this, and I think many scientists do. I think it’s very important for scientists to be, first of all, engaged in those discussions, not throwing it over the fence for somebody else to worry about that, but really themselves thinking about how the work that we do and technologies that come out of our work are being utilized.

Walter Isaacson :

We are learning how to decode and rewrite the human instruction manual. We are disrupting the very essence of what it is to be human. And, when technology is disrupting the very building blocks of life, we have a responsibility to make sure that it’s done right.

Walter Isaacson :

I’m Walter Isaacson, and you’ve been listening to Trailblazers, an original podcast from Dell Technologies. For more information about any of the guests on today’s show, please visit DellTechnologies.com/trailblazers. Thanks for listening.