Explained (2018) s01e02 Episode Script
Designer DNA
1 [narrator.]
What you're looking at is the fertilization of a human egg with a sperm cell.
There's nothing new about that.
It happens all the time in fertility clinics.
But there's something different happening.
That needle is also delivering a tiny tool that will change the embryo's DNA.
A new technology called - CRISPR.
- CRISPR.
- CRISPR.
- A revolutionary technology that can edit DNA with incredible precision.
To get why this is such a big deal, consider this: life has existed on this planet for nearly four billion years.
99.
99% of that time passed before Homo sapiens showed up.
And then for 99.
9% of human history, we, too, were oblivious to the genetic code tucked inside the cells of all living things.
In fact, it's just in the last 65 years, a single lifetime, that we've figured out how DNA works, built machines that could read it, and then tools that could rewrite it.
Now a question we've been asking for decades is becoming very real.
If humans had the technology to control the source code of life, what happens when we turn it on ourselves? [man 1.]
Take what we now know about the DNA molecule in our cells.
It's entirely possible we may learn to use it.
in order to tinker with our blueprints, genetic makeup.
Once you start tinkering, where do you stop? [man 2.]
And that's where things get complicated.
crucial to finding cures for diseases like cancer.
Critics say it's opening up a Pandora's box.
[man 3.]
Is this the way we want to nurture the next generation of children? [man 4.]
This makes man his own god.
Today we celebrate the revelation of the first draft of the human book of life.
As a society, we've spent about $3 billion dollars to sequence the first human genome, a really landmark achievement, equivalent to maybe, you know, constructing the pyramids in Egypt.
The genome is our entire genetic blueprint, three billion pairs of As, Ts, Cs, and Gs, that each of us carry in almost every cell.
Mapping it was the biggest undertaking in the history of biology.
[Sanjana.]
In the 15 years since then, the price of sequencing a genome has fallen dramatically.
That's many, many zeros off the price tag.
Take a closer look at that chart.
That's not a typical scale.
The numbers are decreasing by a factor of ten.
With all that data, researchers can identify genes that cause diseases.
But to actually change those genes, you'd have to track them down within the genome.
Humans didn't have an easy way to do that, but it turns out bacteria did.
See, they've been battling viruses for billions of years, and some of them developed an immune system that records segments of viral DNA within their own genome.
So when that virus attacks again, its DNA is easy to recognize and to cut, with enzymes that act like scissors.
That prevents the virus from replicating.
That immune system is called CRISPR.
Its discovery was cool enough, but in 2012, Jennifer Doudna and her collaborators showed that they could reprogram the CRISPR system to track down and edit a gene of their choice, taking CRISPR from an interesting fact to a powerful tool.
For harnessing an ancient bacterial immune system as a powerful gene editing technology, the breakthrough prize is awarded to Emmanuelle Charpentier and Jennifer Doudna.
It was a result of curiosity-driven research that was aimed in a very different direction from where it ended up.
I never thought I'd become a genome engineer.
The ease of use of the CRISPR system has enabled it to really spread like wildfire through the scientific community.
There are so many papers every day being published with CRISPR and using it in plants, in bacteria, in yeast Really, in every living organism, 'cause all living organisms run on DNA.
The technology is so affordable that you can now tweak the DNA of bacteria at home with a DIY CRISPR kit.
I've been doing science professionally for about 25 years and I have never seen a technology take off the way gene editing has.
[Sanjana.]
I think back to Silicon Valley 40, 50 years ago, when it's just becoming clear that we had this ability to program computers.
It was really hard, I think, to see all the developments like the internet, or computers inside everyone's pocket.
What will happen 20, 30, 40 years from now? Piglets that might one day provide livers, hearts, and other organs for humans.
[man.]
Now they're making mosquitoes that are resistant to malaria.
[woman.]
The woolly mammoth could be making a comeback.
[narrator.]
That last one might remind you of a certain sci-fi classic.
Don't you see the danger in what you're doing here? Genetic power's the most awesome force the planet's ever seen, but you wield it like a kid that's found his dad's gun.
All of these experiments raise difficult ethical questions, perhaps none more than the use of CRISPR in human embryos.
Nobody has tried to start a pregnancy with those embryos, but if they ever do, we will be crossing a line that people have debated for decades.
This debate has long had some important distinctions.
First of all is the distinction between somatic gene editing and germline gene editing.
[narrator.]
Somatic cells are most of the cells in the body: blood, brain, skin cells, where the DNA doesn't get passed down to offspring.
Germline edits involve sperm, eggs, or embryos, basically changing the DNA of future generations.
It's a profound difference, because in germline editing, we're talking about making changes that ultimately affect the human population and human evolution.
Another major divide that emerged early on in the debate was between therapy and enhancement.
[narrator.]
Therapies treat diseases, and enhancements give advantages to people who are already healthy.
The top left box is where the real action is happening, treatments for people living with diseases.
The challenge here is delivery.
For different diseases, different cells in your body are affected.
Some diseases affect the liver, some affect the heart, some affect the lungs, and some organs have much easier deliveries.
The most promising experiments are for conditions like sickle cell disease, HIV, and certain cancers where the disease lives in the blood or the bone marrow.
Those cells can be removed from the body, edited outside, where you don't have to worry about delivering into an entire person, and after the editing is confirmed, replaced in the patient.
Somatic gene editing has always been much less controversial, primarily because any change you would make would end with that person.
Generally that's considered to be medicine.
Somatic gene enhancement is like plastic surgery.
Any change you make ends with them.
There are no genetic plastic surgeons yet.
Researchers are focused on diseases, and as those trials begin, the big debate will be here, whether we should move beyond treating the sick to editing diseases out of future generations.
[man.]
That hasn't happened.
As far as anyone can tell, nobody is trying to make CRISPR babies yet.
That's a temptation that I think has to be grappled with.
I think the technology is not quite there yet, but I think it's close.
Creating a genetically modified baby is already illegal in at least 25 countries.
In much of Europe, it's been banned for decades.
If you look at a pattern across countries, one of the primary variables that would explain differences is proximity to the Nazi experience.
What you find is much more skepticism of the idea that somehow we're going to improve the human species.
Two power centers of CRISPR research, the US and China, have restrictions on germline editing, but they don't have laws against it.
In 2015, the UN called for a worldwide moratorium, saying that germline modifications could jeopardize the dignity of all human beings, because the problem with crossing the germline is that this other line might not hold.
[Evans.]
The line between therapy and enhancement has, over time, gotten a lot more fuzzy.
For one thing, not everyone agrees on which genetic conditions need fixing.
[Evans.]
Is deafness a disease? Many in the deaf community would say it is not.
Is dwarfism a disease? Many would say not.
The idea that we're all sick, that we're suffering, that I "suffer" from dwarfism No, I live with dwarfism.
I've lived with dwarfism for 39 years.
I'm proud to be a second generation raising a third generation of people living with dwarfism.
I don't suffer, I suffer from how society treats me.
But the line is fuzzy even for diseases we agree on.
Depending on which variant you have, the APOE gene increases, decreases, or doesn't affect the risk of Alzheimer's disease later in life.
Say you switched your child's DNA from a high-risk to a low-risk variant.
Would that be a therapy or an enhancement? There are rare genes linked to lower risk of heart disease, diabetes, immunity to HIV, stronger bones, bigger muscles, less body odor, the ability to get by with less sleep.
Where would you draw the line? In the '90s movie Gattaca, society is divided into genetic classes, because fertility clinics sell enhancements to their customers.
We didn't want I mean, diseases, yes, but Right, we were just wondering if if it's good to just leave a few things to chance.
You want to give your child the best possible start.
Believe me, we have enough imperfection built in already.
When I watched that movie, it was completely science fiction.
It's amazing to think that now we're on the cusp of that being a real possibility.
And that raises one of the most profound ethical threats in genetics, or as you may know it, "designer babies.
" - Designer babies.
- Designer babies.
[man.]
where parents can pick eye color, intelligence, and height.
Imagine if I could choose kids that could go on in the NBA.
That's where people get a little carried away.
Some traits are relatively simple, like eye color, freckles, and this is true, how sticky your earwax is.
But intelligence, height, athletic ability, these are all complex traits.
They're partly nature and partly nurture, and the part that's nature involves hundreds, even thousands of locations on the genome, interacting in ways we don't understand.
And that makes them bad targets for something like CRISPR.
If governments give a green light to germline editing, it would start with preventing the transmission of diseases caused by a single gene.
But the thing is, most of the people who carry those genes already have a way to do that without editing any DNA, which is why the shorter path to designer babies isn't gene editing, it's gene selection.
People who know that they're carriers for a genetic disease have long had this option called preimplantation genetic diagnosis.
Which is a mouthful, so people call it PGD.
When I describe this, most people I talk to think it's science fiction, but it's actually been around for over 27 years.
In PGD, a fertility clinic removes cells from embryos created through IVF and tests their DNA for genetic diseases.
They can then select the embryos without the disease to implant in the woman.
But that technology has also been used to screen for genes that raise the risk of disease, but don't guarantee it, and to check for other traits, like an embryo's sex, or its eye color.
As the technology advances, it'll be possible to get an entire genomic report card for your embryos, like the kind you get when you send your saliva to a personal genomics company.
And for complex traits, like intelligence, height, or diabetes, we may not be able to edit them directly, but we might be able to predict them to an extent.
[Greely.]
I don't think we're ever going to be able to say honestly this embryo is going to get 1450 on the two-part SAT.
But I do think we'll be able to say a 60% chance of being in the top half, 13% chance of being in the top 10%.
These predictions are called polygenic scores and they're based on statistical correlations from across the genome.
Most of them aren't very accurate, so they've stayed in the realm of academic research.
But they get better with more data, and now a company called Genomic Prediction says they'll soon be the first to offer polygenic tests to fertility clinics.
Their CEO has said he was inspired by the movie Gattaca.
There's nothing in the current US law that would keep a clinic from using genetic trait prediction immediately.
Whether that'll be true in the future, when people start using this to select babies for reasons that other people think are wrong, that's going to be a really interesting political fight to watch.
But we're still talking about a small number of people, because IVF is hard.
[Greely.]
The problem with IVF right now, what accounts for 90% of its cost, and 99% of its discomfort and risk, is egg harvest.
But he predicts that we'll eventually be able to grow human eggs in a lab from skin cells and use them to create dozens of embryos.
[Greely.]
This sounds like science fiction.
It is if you're a person.
It's not if you're a mouse.
It's already been done in mice, both eggs and sperm, and healthy little mouse pups have been born.
If that works in humans, and that's a big if, then IVF becomes a whole lot easier, and gene selection more powerful.
Add gene editing to that process and you can see how the fertility industry could steer the future of human evolution.
But we don't need to speculate about the distant future to see how the genomic revolution could change us.
[Cokley.]
In 1994, Dr.
John Wasmuth found a gene for achondroplasia.
A lot of dwarf parents were scared, because we thought it was the and, you know, in many ways it really still could be, the first step towards eradicating our kind of dwarfism.
Genetic technologies can narrow the range of human variation.
We've already seen how individual choices about prenatal testing can shift whole populations.
There are now only 918 girls for every one thousand boys in the country.
In Iceland, Down syndrome is on the verge of being eradicated and it's due in large part to the widespread use of genetic testing.
Is there really no place for us in the world? It's a hard conversation.
I mean, I'm a pro-choice woman and I have to accept the fact that for me, being a pro-choice woman and a woman with a disability means that I have to accept the fact that non-disabled women see a fetus like me as not viable.
And since unequal access to healthcare is a fact of our world, we risk giving the wealthy an extra genetic advantage.
This will not be made available to everyone on the planet.
It would only be the wealthy people who would have access to this.
Already, rich kids are 10-15% healthier than poor kids.
It's not enormous, but I wouldn't want to add another 10-15% on top of it.
And we've seen how easily we can fall prey to simple answers for complex problems when they're dressed in the language of science.
[Evans.]
The Immigration Act in America of the 1920s was based upon an entire faulty scientific premise, that the genes of the Nordic countries were superior to the other races.
It doesn't even need to be true, gene editing doesn't actually even have to work, to have social effects.
But gene editing gives us a chance to massively reduce human suffering.
That's why the stakes are so high.
My biggest fear, honestly, is that we'll see the use of gene editing getting ahead of itself.
What I mean by that is an application that causes harm, that creates a backlash against a technology that I think has really the potential to be incredibly positive and have a positive effect on society.
[Greely.]
Unless we're in nuclear war, unless the world ends, we're going to be using genetics more and more in human reproduction, and that will have consequences, but I do the work I do in the hopes that if we think about these things, we worry about them, we talk about them enough in advance, we're a little bit less likely to screw up.
What you're looking at is the fertilization of a human egg with a sperm cell.
There's nothing new about that.
It happens all the time in fertility clinics.
But there's something different happening.
That needle is also delivering a tiny tool that will change the embryo's DNA.
A new technology called - CRISPR.
- CRISPR.
- CRISPR.
- A revolutionary technology that can edit DNA with incredible precision.
To get why this is such a big deal, consider this: life has existed on this planet for nearly four billion years.
99.
99% of that time passed before Homo sapiens showed up.
And then for 99.
9% of human history, we, too, were oblivious to the genetic code tucked inside the cells of all living things.
In fact, it's just in the last 65 years, a single lifetime, that we've figured out how DNA works, built machines that could read it, and then tools that could rewrite it.
Now a question we've been asking for decades is becoming very real.
If humans had the technology to control the source code of life, what happens when we turn it on ourselves? [man 1.]
Take what we now know about the DNA molecule in our cells.
It's entirely possible we may learn to use it.
in order to tinker with our blueprints, genetic makeup.
Once you start tinkering, where do you stop? [man 2.]
And that's where things get complicated.
crucial to finding cures for diseases like cancer.
Critics say it's opening up a Pandora's box.
[man 3.]
Is this the way we want to nurture the next generation of children? [man 4.]
This makes man his own god.
Today we celebrate the revelation of the first draft of the human book of life.
As a society, we've spent about $3 billion dollars to sequence the first human genome, a really landmark achievement, equivalent to maybe, you know, constructing the pyramids in Egypt.
The genome is our entire genetic blueprint, three billion pairs of As, Ts, Cs, and Gs, that each of us carry in almost every cell.
Mapping it was the biggest undertaking in the history of biology.
[Sanjana.]
In the 15 years since then, the price of sequencing a genome has fallen dramatically.
That's many, many zeros off the price tag.
Take a closer look at that chart.
That's not a typical scale.
The numbers are decreasing by a factor of ten.
With all that data, researchers can identify genes that cause diseases.
But to actually change those genes, you'd have to track them down within the genome.
Humans didn't have an easy way to do that, but it turns out bacteria did.
See, they've been battling viruses for billions of years, and some of them developed an immune system that records segments of viral DNA within their own genome.
So when that virus attacks again, its DNA is easy to recognize and to cut, with enzymes that act like scissors.
That prevents the virus from replicating.
That immune system is called CRISPR.
Its discovery was cool enough, but in 2012, Jennifer Doudna and her collaborators showed that they could reprogram the CRISPR system to track down and edit a gene of their choice, taking CRISPR from an interesting fact to a powerful tool.
For harnessing an ancient bacterial immune system as a powerful gene editing technology, the breakthrough prize is awarded to Emmanuelle Charpentier and Jennifer Doudna.
It was a result of curiosity-driven research that was aimed in a very different direction from where it ended up.
I never thought I'd become a genome engineer.
The ease of use of the CRISPR system has enabled it to really spread like wildfire through the scientific community.
There are so many papers every day being published with CRISPR and using it in plants, in bacteria, in yeast Really, in every living organism, 'cause all living organisms run on DNA.
The technology is so affordable that you can now tweak the DNA of bacteria at home with a DIY CRISPR kit.
I've been doing science professionally for about 25 years and I have never seen a technology take off the way gene editing has.
[Sanjana.]
I think back to Silicon Valley 40, 50 years ago, when it's just becoming clear that we had this ability to program computers.
It was really hard, I think, to see all the developments like the internet, or computers inside everyone's pocket.
What will happen 20, 30, 40 years from now? Piglets that might one day provide livers, hearts, and other organs for humans.
[man.]
Now they're making mosquitoes that are resistant to malaria.
[woman.]
The woolly mammoth could be making a comeback.
[narrator.]
That last one might remind you of a certain sci-fi classic.
Don't you see the danger in what you're doing here? Genetic power's the most awesome force the planet's ever seen, but you wield it like a kid that's found his dad's gun.
All of these experiments raise difficult ethical questions, perhaps none more than the use of CRISPR in human embryos.
Nobody has tried to start a pregnancy with those embryos, but if they ever do, we will be crossing a line that people have debated for decades.
This debate has long had some important distinctions.
First of all is the distinction between somatic gene editing and germline gene editing.
[narrator.]
Somatic cells are most of the cells in the body: blood, brain, skin cells, where the DNA doesn't get passed down to offspring.
Germline edits involve sperm, eggs, or embryos, basically changing the DNA of future generations.
It's a profound difference, because in germline editing, we're talking about making changes that ultimately affect the human population and human evolution.
Another major divide that emerged early on in the debate was between therapy and enhancement.
[narrator.]
Therapies treat diseases, and enhancements give advantages to people who are already healthy.
The top left box is where the real action is happening, treatments for people living with diseases.
The challenge here is delivery.
For different diseases, different cells in your body are affected.
Some diseases affect the liver, some affect the heart, some affect the lungs, and some organs have much easier deliveries.
The most promising experiments are for conditions like sickle cell disease, HIV, and certain cancers where the disease lives in the blood or the bone marrow.
Those cells can be removed from the body, edited outside, where you don't have to worry about delivering into an entire person, and after the editing is confirmed, replaced in the patient.
Somatic gene editing has always been much less controversial, primarily because any change you would make would end with that person.
Generally that's considered to be medicine.
Somatic gene enhancement is like plastic surgery.
Any change you make ends with them.
There are no genetic plastic surgeons yet.
Researchers are focused on diseases, and as those trials begin, the big debate will be here, whether we should move beyond treating the sick to editing diseases out of future generations.
[man.]
That hasn't happened.
As far as anyone can tell, nobody is trying to make CRISPR babies yet.
That's a temptation that I think has to be grappled with.
I think the technology is not quite there yet, but I think it's close.
Creating a genetically modified baby is already illegal in at least 25 countries.
In much of Europe, it's been banned for decades.
If you look at a pattern across countries, one of the primary variables that would explain differences is proximity to the Nazi experience.
What you find is much more skepticism of the idea that somehow we're going to improve the human species.
Two power centers of CRISPR research, the US and China, have restrictions on germline editing, but they don't have laws against it.
In 2015, the UN called for a worldwide moratorium, saying that germline modifications could jeopardize the dignity of all human beings, because the problem with crossing the germline is that this other line might not hold.
[Evans.]
The line between therapy and enhancement has, over time, gotten a lot more fuzzy.
For one thing, not everyone agrees on which genetic conditions need fixing.
[Evans.]
Is deafness a disease? Many in the deaf community would say it is not.
Is dwarfism a disease? Many would say not.
The idea that we're all sick, that we're suffering, that I "suffer" from dwarfism No, I live with dwarfism.
I've lived with dwarfism for 39 years.
I'm proud to be a second generation raising a third generation of people living with dwarfism.
I don't suffer, I suffer from how society treats me.
But the line is fuzzy even for diseases we agree on.
Depending on which variant you have, the APOE gene increases, decreases, or doesn't affect the risk of Alzheimer's disease later in life.
Say you switched your child's DNA from a high-risk to a low-risk variant.
Would that be a therapy or an enhancement? There are rare genes linked to lower risk of heart disease, diabetes, immunity to HIV, stronger bones, bigger muscles, less body odor, the ability to get by with less sleep.
Where would you draw the line? In the '90s movie Gattaca, society is divided into genetic classes, because fertility clinics sell enhancements to their customers.
We didn't want I mean, diseases, yes, but Right, we were just wondering if if it's good to just leave a few things to chance.
You want to give your child the best possible start.
Believe me, we have enough imperfection built in already.
When I watched that movie, it was completely science fiction.
It's amazing to think that now we're on the cusp of that being a real possibility.
And that raises one of the most profound ethical threats in genetics, or as you may know it, "designer babies.
" - Designer babies.
- Designer babies.
[man.]
where parents can pick eye color, intelligence, and height.
Imagine if I could choose kids that could go on in the NBA.
That's where people get a little carried away.
Some traits are relatively simple, like eye color, freckles, and this is true, how sticky your earwax is.
But intelligence, height, athletic ability, these are all complex traits.
They're partly nature and partly nurture, and the part that's nature involves hundreds, even thousands of locations on the genome, interacting in ways we don't understand.
And that makes them bad targets for something like CRISPR.
If governments give a green light to germline editing, it would start with preventing the transmission of diseases caused by a single gene.
But the thing is, most of the people who carry those genes already have a way to do that without editing any DNA, which is why the shorter path to designer babies isn't gene editing, it's gene selection.
People who know that they're carriers for a genetic disease have long had this option called preimplantation genetic diagnosis.
Which is a mouthful, so people call it PGD.
When I describe this, most people I talk to think it's science fiction, but it's actually been around for over 27 years.
In PGD, a fertility clinic removes cells from embryos created through IVF and tests their DNA for genetic diseases.
They can then select the embryos without the disease to implant in the woman.
But that technology has also been used to screen for genes that raise the risk of disease, but don't guarantee it, and to check for other traits, like an embryo's sex, or its eye color.
As the technology advances, it'll be possible to get an entire genomic report card for your embryos, like the kind you get when you send your saliva to a personal genomics company.
And for complex traits, like intelligence, height, or diabetes, we may not be able to edit them directly, but we might be able to predict them to an extent.
[Greely.]
I don't think we're ever going to be able to say honestly this embryo is going to get 1450 on the two-part SAT.
But I do think we'll be able to say a 60% chance of being in the top half, 13% chance of being in the top 10%.
These predictions are called polygenic scores and they're based on statistical correlations from across the genome.
Most of them aren't very accurate, so they've stayed in the realm of academic research.
But they get better with more data, and now a company called Genomic Prediction says they'll soon be the first to offer polygenic tests to fertility clinics.
Their CEO has said he was inspired by the movie Gattaca.
There's nothing in the current US law that would keep a clinic from using genetic trait prediction immediately.
Whether that'll be true in the future, when people start using this to select babies for reasons that other people think are wrong, that's going to be a really interesting political fight to watch.
But we're still talking about a small number of people, because IVF is hard.
[Greely.]
The problem with IVF right now, what accounts for 90% of its cost, and 99% of its discomfort and risk, is egg harvest.
But he predicts that we'll eventually be able to grow human eggs in a lab from skin cells and use them to create dozens of embryos.
[Greely.]
This sounds like science fiction.
It is if you're a person.
It's not if you're a mouse.
It's already been done in mice, both eggs and sperm, and healthy little mouse pups have been born.
If that works in humans, and that's a big if, then IVF becomes a whole lot easier, and gene selection more powerful.
Add gene editing to that process and you can see how the fertility industry could steer the future of human evolution.
But we don't need to speculate about the distant future to see how the genomic revolution could change us.
[Cokley.]
In 1994, Dr.
John Wasmuth found a gene for achondroplasia.
A lot of dwarf parents were scared, because we thought it was the and, you know, in many ways it really still could be, the first step towards eradicating our kind of dwarfism.
Genetic technologies can narrow the range of human variation.
We've already seen how individual choices about prenatal testing can shift whole populations.
There are now only 918 girls for every one thousand boys in the country.
In Iceland, Down syndrome is on the verge of being eradicated and it's due in large part to the widespread use of genetic testing.
Is there really no place for us in the world? It's a hard conversation.
I mean, I'm a pro-choice woman and I have to accept the fact that for me, being a pro-choice woman and a woman with a disability means that I have to accept the fact that non-disabled women see a fetus like me as not viable.
And since unequal access to healthcare is a fact of our world, we risk giving the wealthy an extra genetic advantage.
This will not be made available to everyone on the planet.
It would only be the wealthy people who would have access to this.
Already, rich kids are 10-15% healthier than poor kids.
It's not enormous, but I wouldn't want to add another 10-15% on top of it.
And we've seen how easily we can fall prey to simple answers for complex problems when they're dressed in the language of science.
[Evans.]
The Immigration Act in America of the 1920s was based upon an entire faulty scientific premise, that the genes of the Nordic countries were superior to the other races.
It doesn't even need to be true, gene editing doesn't actually even have to work, to have social effects.
But gene editing gives us a chance to massively reduce human suffering.
That's why the stakes are so high.
My biggest fear, honestly, is that we'll see the use of gene editing getting ahead of itself.
What I mean by that is an application that causes harm, that creates a backlash against a technology that I think has really the potential to be incredibly positive and have a positive effect on society.
[Greely.]
Unless we're in nuclear war, unless the world ends, we're going to be using genetics more and more in human reproduction, and that will have consequences, but I do the work I do in the hopes that if we think about these things, we worry about them, we talk about them enough in advance, we're a little bit less likely to screw up.