The Human Genome Project Was a Failure

Summary

The video script discusses the Human Genome Project, a landmark genetics endeavor aiming to sequence the human genome. Despite initial overhyped expectations of revolutionizing disease treatment by 2016, the project faced challenges due to the complexity of genetic influence on diseases, which often involves multiple genes rather than single mutations. The script highlights the project's success in advancing sequencing technology and contributing to a better understanding of genetic diversity and disease patterns, emphasizing its role in scientific progress rather than immediate medical breakthroughs.

Takeaways

• 🧬 The Human Genome Project (HGP) aimed to sequence and publish the entire human genome for the first time, starting in 1990 and concluding in 2003.
• 🌐 The project was an international collaboration costing approximately 2.7 billion dollars and was considered a major scientific achievement.
• 🔍 Despite high expectations, such as curing diseases by tweaking genes, the practical applications of the HGP did not fully meet initial hype and promises.
• 🧠 Early claims that single genes could cause major conditions like bipolar disorder and schizophrenia were not supported by later research, revealing that most diseases are influenced by many genes and environmental factors.
• ⚕️ While the HGP did not revolutionize disease treatment as expected, it did enhance understanding of some genetic conditions and led to improvements in personalized medicine for certain diseases.
• 📊 The complexity of the human genome, with only 1-2% coding for proteins and the rest involving regulatory or non-coding regions, challenged initial assumptions and required more in-depth research to understand its functions.
• 🧩 The HGP's greatest success was in developing techniques for genome sequencing, significantly reducing the cost and time required for genetic analysis, which now benefits a wide range of scientific fields.
• 👥 Subsequent projects, such as the 1000 Genomes Project, expanded the genetic diversity represented in genomic studies, providing a broader understanding of human genetics.
• 🔬 Genome-wide association studies (GWAS) emerged from the HGP era, helping to identify genetic patterns associated with various diseases and leading to better understanding and treatment options.
• 🏆 The HGP laid the groundwork for modern genetics research, proving to be a technical success and a foundation for future scientific advancements, even if it did not immediately transform medical practice as initially anticipated.

Q & A

What was the primary goal of the Human Genome Project?

The primary goal of the Human Genome Project was to decipher and publish the entire human genome for the first time ever.

What was the time frame and cost of the Human Genome Project?

The Human Genome Project ran from 1990 to 2003 and cost approximately 2.7 billion dollars.

What was the initial hype surrounding the Human Genome Project?

The initial hype suggested that the project would revolutionize the care of almost every disease, with predictions like personal genomes being carried in wallets and doctors prescribing specific gene therapies.

Why did the hype about the Human Genome Project not fully materialize?

The hype did not materialize because most diseases are not caused by a single mutated gene but are influenced by many different genes, making a 'magic bullet' cure unlikely.

What are Mendelian conditions in the context of genetics?

Mendelian conditions are diseases that follow Gregor Mendel's basic rules for inheritance, where a single mutation is enough to cause the disease, such as Huntington’s or sickle cell.

How does genome sequencing impact medicine today?

Genome sequencing can help in specific cases like identifying cancer genes or choosing treatments based on specific mutations in cancer cells, but it is not a routine practice for general disease treatment.

What is the significance of the genome being more than just a sequence of letters?

The genome is complex, with most of its sequences not coding for proteins but playing roles in gene expression, cellular structure, and other functions, making it more akin to a library than a simple book.

What is the role of non-coding DNA in the genome?

Non-coding DNA includes sequences that affect gene expression, introns that are cut out of mRNA, and other elements that contribute to cellular function and structure, rather than coding for proteins.

How has the Human Genome Project influenced modern sequencing technologies?

The Human Genome Project developed techniques that paved the way for modern sequencing technologies, making it cheaper, faster, and more reliable.

What are genome-wide association studies (GWAS) and their significance?

GWAS involve analyzing a large number of genomes to find patterns or associations between diseases and genetic variants, which can lead to discoveries about diseases and their treatment.

Outlines

00:00

🧬 The Hype and Reality of the Human Genome Project

The first paragraph introduces the Human Genome Project, which aimed to sequence the entire human genome by 2003 at a cost of 2.7 billion dollars. It discusses the exaggerated expectations surrounding the project, such as the prediction by U.S. President Bill Clinton that it would revolutionize disease treatment. The paragraph acknowledges that while the project was a success in sequencing the genome, it did not live up to the promises of revolutionizing disease treatment. It also touches on the reasons behind these overpromises, including initial findings of single-gene causes for complex diseases that later could not be replicated. The paragraph concludes by emphasizing the complexity of diseases influenced by multiple genes rather than single mutations.

05:03

📚 The Metaphorical Misunderstanding of the Genome

The second paragraph delves into the metaphorical comparison of the genome to a book and challenges this notion by highlighting the complexity and non-protein-coding aspects of DNA. It reveals that the majority of the human genome does not code for proteins, contrary to initial assumptions. The paragraph describes various non-coding DNA sequences, such as promoters, enhancers, repressors, silencers, introns, and other structural elements like telomeres. It also mentions pseudogenes and the 3D architecture of the cell's nucleus, which affects gene expression. The paragraph concludes with an alternative metaphor, likening the genome to a library with various components beyond just informational texts, to better capture its complexity.

10:06

🚀 The Technical Triumph and Scientific Legacy of the Human Genome Project

The third paragraph refutes the idea that the Human Genome Project was a failure by emphasizing its significant technical achievements and its lasting impact on scientific research. It discusses how the project's methodologies have led to modern, cost-effective, and rapid sequencing technologies. The paragraph also highlights the benefits of sequencing multiple genomes, such as understanding genetic diversity and conducting genome-wide association studies (GWAS), which have contributed to discoveries related to diabetes, autoimmune disorders, and schizophrenia. It concludes by acknowledging that while the project did not directly revolutionize patient care as initially expected, it has indirectly supported scientific advancements that will eventually benefit medicine.

Keywords

💡Human Genome Project

The Human Genome Project (HGP) was an international research initiative that aimed to map and understand all the genes of human beings. Running from 1990 to 2003, it successfully sequenced the human genome, providing a foundation for modern genetics. Despite its revolutionary potential, the project's promises, such as drastically changing disease treatment, were somewhat overhyped.

💡Genome sequencing

Genome sequencing refers to the process of determining the complete DNA sequence of an organism's genome. It was a key achievement of the HGP, allowing scientists to read and analyze the genetic information encoded in human DNA. This process has become much faster and cheaper since the HGP, transforming scientific research.

💡Gene therapy

Gene therapy involves altering the genes inside a person's cells to treat or prevent disease. The video mentions the early hopes that genome sequencing would lead to specific gene therapies for various conditions. However, the complexity of genetics has made such straightforward treatments challenging.

💡Mendelian conditions

Mendelian conditions are diseases caused by mutations in a single gene, following inheritance patterns first described by Gregor Mendel. Examples include Huntington's disease and sickle cell anemia. Unlike complex diseases, these conditions are more straightforward to study and potentially treat through genetic approaches.

💡Genome-wide association studies (GWAS)

GWAS involve scanning genomes from many people to find genetic variations associated with specific diseases. These studies have helped identify multiple genes involved in complex diseases like diabetes and schizophrenia, highlighting the genetic diversity and complexity underlying these conditions.

💡Proteins

Proteins are large, complex molecules that play many critical roles in the body, from building tissues to regulating biological processes. The video explains that only a small fraction of the human genome codes for proteins, with the rest being involved in regulatory functions or considered 'junk' DNA.

💡Mutations

Mutations are changes in the DNA sequence that can affect how genes function. While some mutations can lead to diseases, others may have little to no effect. The video discusses how the impact of mutations is often complex and context-dependent, complicating the development of gene-based therapies.

💡Genetic diversity

Genetic diversity refers to the total number of genetic characteristics in the genetic makeup of a species. The HGP and subsequent projects like the 1000 Genomes Project have highlighted the extensive genetic variation among humans, which is crucial for understanding disease mechanisms and developing personalized medicine.

💡Single-gene disorders

Single-gene disorders are diseases caused by mutations in a single gene. These disorders, such as cystic fibrosis and Tay-Sachs disease, often follow clear inheritance patterns. Unlike complex diseases, they are easier to study genetically, although they still present significant challenges for treatment.

💡Non-coding DNA

Non-coding DNA refers to portions of an organism's DNA that do not code for proteins. Despite being termed 'junk' DNA, these regions can have important regulatory roles, such as controlling gene expression. The video highlights the complexity of non-coding DNA in understanding the human genome and its functions.

Highlights

The Human Genome Project aimed to sequence the entire human genome for the first time.

Hyped as a revolutionary tool for disease treatment, it was compared to the moon landing.

The project was an international collaboration costing 2.7 billion dollars from 1990 to 2003.

Despite sequencing the genome, the promise to revolutionize disease treatment did not materialize.

Early findings of single-gene causes for major diseases could not be replicated.

Most diseases are influenced by many genes, not just one, complicating the idea of a 'magic bullet' cure.

Mendelian conditions, like Huntington’s or sickle cell, are caused by single gene mutations.

Genome sequencing is used in specific cases, such as identifying cancer mutations for targeted treatment.

The Human Genome Project was a technical achievement that paved the way for modern sequencing technologies.

The project revealed that 98-99% of our DNA does not code for proteins, challenging initial assumptions.

DNA sequences affect gene expression in various ways, such as promoters, enhancers, and silencers.

The genome includes non-coding RNA, cellular scaffolding, and structural elements like telomeres.

Some DNA sequences are considered 'junk', such as pseudogenes.

The genome is more complex than a book; it's more akin to a library with various functions and structures.

Knowing a patient’s entire genome sequence has limited practical applications in medical care.

The Human Genome Project’s sequencing techniques have made significant contributions to scientific research.

The project helped understand the diversity of the human gene pool through broader sample sizes.

Genome-wide association studies (GWAS) have identified genetic patterns linked to various diseases.

The Human Genome Project was a success in technical terms, despite not meeting all initial promises.

Transcripts

Back around the year 2000,  there was this thing that was

kind of a big deal in genetics:  the Human Genome Project.

Its goal was to decipher and publish the

entire human genome for the first time ever.

And people, including some  scientists and politicians,

really hyped it up. U.S.  President Bill Clinton claimed

it would revolutionize the care of  almost every disease, for example.

One kind of sky-high prediction  even said that, by 2016,

we’d all carry around our own  personal genomes on a card

in our wallets next to our driver’s  licenses and that doctors would be

able to prescribe specific gene  therapies to anyone who needed them.

When we look back at those kinds  of news stories, it’s clear that

the potential of the Human  Genome Project was overpromised.

In this episode, we’ll talk about what

the “Human Genome Project” was and why so much

of the hype that was promised didn’t come to pass.

But also, how it still kind of  revolutionized science anyway?

[♪ INTRO]

I don’t know about you, but I do  not have my genome in my wallet.

Though, to be fair, the Human Genome Project was,

in many ways, a success.

The project was an  international collaboration that

ran from 1990 to 2003 to the  tune of 2.7 billion dollars.

They did end up sequencing  the genome, or just about

all of it anyways, which was  an incredible accomplishment.

But as the years rolled on, it became obvious that

the promise to revolutionize how we approached

every disease just hadn’t panned out.

There was no magic bullet for  all our ills hidden in our genes.

Why did some advocates promise this, then?

Some of it was no doubt hype or excitement.

Even scientists and science  communicators can get caught up.

But there was also some reason to buy in.

A couple of papers in the late  80s claimed to find single-gene

causes for some pretty big medical issues.

That included mental health  conditions like bipolar disorder,

schizophrenia, and alcohol use disorder.

If these conditions really did  come down to just a single gene,

all we needed to do to treat them  was tweak that one gene, right?

Unfortunately, many of those  papers later came under scrutiny

and their findings couldn’t be replicated.

The truth is, most diseases are not  caused by a single mutated gene.

A lot of diseases, especially  the big, common problems

like diabetes or the aforementioned  mental health conditions,

are influenced by genetics.

But they’re the result of  a lot of tiny nudges from

many different genes, not just one big mutation.

Today, we know that dozens  or even hundreds of genes

may affect your risk of  developing diabetes, for instance.

This means those genes do not lend themselves

to a magic-bullet cure, because  just changing one of them

probably won’t have any observable effect.

Worse, it may have unexpected side effects.

Especially when you consider  that a person’s environment

and life history also play a  role in their risk for diabetes.

And scientists and doctors,  well, they kind of knew

this was the case, even back in the 90s.

So you’ve probably noticed doctors  don’t routinely screen your DNA!

Now, to be fair, there are some conditions,

what we’d call Mendelian  conditions since they follow

Gregor Mendel’s basic rules for inheritance,

where a single mutation is enough to matter.

Diseases like Huntington’s or sickle cell are

caused by mutations in a single gene.

There are certain cancer genes, like the BRCAs,

where certain mutations make  it much, much more likely

for you to get breast cancer.

And there are some medicines,  like the blood-thinner warfarin,

that work significantly better or  worse in people with certain mutations.

Also, and this is cool, if you  already have certain cancers,

doctors will sometimes do  genome sequencing on samples

of the cancer cells themselves, since  screening for specific mutations

can help your care team spot weak  points and choose treatments.

So there are times genome sequencing really

does make a big difference in medicine.

But it’s worth noting that, in all these cases,

scientists already know  specific things to look out for.

Doctors don’t really just blindly  sequence an entire person’s

DNA and then go looking for oddities.

Because, to be honest,  knowing that a DNA mutation is

there doesn’t really help until you  figure out what that mutation does.

Like, let’s say you have a single nucleotide

difference between two people’s DNA.

Even if you know it’s part of a  gene – which we’ll come back to –

it doesn’t necessarily tell you what the gene does

or whether the mutation matters.

At this point, it’s all  still T-A-G-C gobbledy-gook.

It’s possible that a scientist could look at that

and make a guess about what that change would do.

But unlike computer code, the genetic code doesn’t

contain helpful annotations  to say “this part does this.”

You can’t tell what the genome does by reading it.

You have to sit down and do experiments to see

what a change functionally does.

It’s much easier to start with a  known disease – like diabetes –

and then work backwards, looking  for mutations in proteins we

already know are important  or comparing and contrasting

a lot of sequences from people  with and without the disease.

So that’s what we mean when we say people back

around the year 2000 probably overpromised things

about the Human Genome Project.

The project did successfully sequence the genome,

but saying it was going to  revolutionize how we treat

nearly every disease was skipping  a lot of steps in the middle.

And there was something else they

couldn’t really have known just yet.

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Now back to the show!

Here’s part two of the video,  because what scientists

didn’t know was what all those  letters in the genome actually do.

Now stop me if you’ve heard this one before,

but it’s a really common metaphor to refer to DNA

as a kind of writing and the genome as a book.

Metaphors are good!

They’re a good starting point  our brains can hold onto

as we learn something new and complicated.

But metaphors are also at  least a little bit fiction.

And it turns out the real genome  is much weirder than a book.

The human genome is about 3 billion letters long.

At the time, it was assumed that most of

those letters would code for proteins.

As a quick reminder, DNA gets read out

or transcribed into messenger RNA,

which gets processed and then further read out

or translated into protein, and proteins are what

do much of the work of being alive.

So it was not actually a stupid  assumption to think most of

the genome would code for protein.

But, hoo boy, it does not.

The sequence of the genome revealed that

the vast majority of our DNA –  something like 98 or 99 percent –

doesn’t code for proteins.

It was as if most of the pages of  the book were filled with nonsense,

what some scientists called “dark  matter” or, more pejoratively, “junk”.

Firstly, for instance, there’s  DNA sequences that affect

how genes are expressed without  actually being genes themselves.

Promoters, for instance, are stretches of DNA

just ahead of the protein-coding part of a gene.

They are where a bunch of cellular  machinery will come sit down

to read that gene out, a little  like markings on a runway.

There are also enhancers,  repressors, and silencers,

which are sequences of DNA that either

increase or decrease expression of a gene.

There are also parts of the DNA  sequence that are transcribed

into mRNA, but, for some reason,  do not end up in the protein.

Introns are DNA sequences that get cut out of

the mRNA before it gets translated into a protein.

Sounds weird, but it’s actually a flexible system

that can lead to different  versions of the same protein

by chopping the RNA up in different ways.

Sometimes DNA codes for RNA that has

a specific job other than becoming a protein.

For instance, the ribosomes that  translate mRNA into protein are,

ironically, themselves mostly made out of RNA!

There are also bits of DNA  that seem to be more like

cellular scaffolding or  structure than instructions.

Like telomeres, which are long  sequences of repetitive DNA that kind

of cap off the end of a chromosome  and keep it from unravelling.

And, finally, yes, some of it  does seem to actually be junk.

There are things known as pseudogenes, which seems

to essentially be “broken”  genes that no longer function.

Even the 3D architecture of the cell’s nucleus

can affect gene expression.

Like very long noodles in the  worst plate of spaghetti ever,

chromosomes have to be arranged  in 3D space in order to work.

The enhancers I mentioned earlier loop around

from really far away to affect  the genes they regulate.

In contrast, DNA that’s packed  up really tightly is harder

for cellular machinery to get  at, so it’s expressed less.

And all that’s just scratching the surface.

There’s more weird stuff  going on, as well as stuff

we still don’t quite understand yet.

But the point is that the  genome is really complicated,

and it’s about a lot more than  reading letters from beginning to end.

Basically, our book is making House  of Leaves look straightforward.

So here’s an alternate metaphor.  It’s still a bit of a fiction,

because all metaphors are a  bit of fiction, but humor me.

The genome may be less like a  book and more like a library.

There are books with blueprints, and

people copying down what they see inside.

But there is also scaffolding and shelving.

There’s Dewey Decimal Numbers and reference maps,

locked-up sections and big  open promotional display cases,

and internal documents and memos.

You might be able to see a few  librarians reshelving things

or shuffling them around  and, yes, even a few tattered

“junk” books destined for recycling.

I think that’s a much cooler concept than a book.

So combining both the points about diseases

and the complexity of our DNA, we arrive here.

In sum, knowing the entire  sequence of a patient’s genome

would likely do very little for their  care outside of certain situations –

and that probably won’t ever  change much in the future.

The big diseases are usually the  result of many small nudges, rather

than one big push, and not all of  those nudges lie in the genome.

And the genome itself is really  complex, so even if you know

of a mutation, that doesn’t  necessarily tell you that much.

So that specific promise, about  being able to sequence everyone’s

DNA leading to easy cures to  everything, never came to pass.

But… here comes the twist.

Does that mean that the HGP a failure for science?

No! It does not!

All that stuff I just talked about,

we were able to learn about  because the Human Genome Project

provided a scaffold for  everyone else to work from!

In many ways, the Human Genome  Project, like the moon landing,

was primarily a technical achievement.

The techniques they used paved the way

for modern sequencing technologies.

Today, what once cost billions of  dollars and took two years is down

to less than a thousand dollars and  can take as little as five hours.

A scientist can whack a sample  down in a fancy sequencer,

go have a sandwich and look  after a few other experiments,

and come back to results before  it’s time to quit for the day.

And this proliferation of  cheap, reliable, and fast

genome sequencing did indeed  revolutionize science.

The tools we got out of it are used  in everything from understanding

basic cellular processes to studying  evolution to ancient archaeology.

What’s more, going wide and  being able to test the genomes

of a lot of different people  may deliver some of the benefits

that we didn’t get from just doing it once,

because there’s power in being  able to sequence a lot of people.

For one thing, it helped us better grasp

the diversity of the human gene pool.

The original sequence the  Human Genome Project published

was a patchwork of just a handful of people –

actually, about 70% of the genome came

from one anonymous sample.

Today, though, subsequent efforts  like the 1000 Genomes Project

give us a much broader sample size to work with,

allowing us to understand not  just one person’s genome works,

but how genetics affects  people all around the world.

The Human Genome Project era  also gave way to the era of

what’s known as genome-wide  association studies, or GWAS.

In general, this involves  rounding up a bunch of genomes

and looking for patterns or associations between

a disease and a bunch of genetic variants.

Results from GWAS may translate  into discoveries for diabetes,

autoimmune disorders, and schizophrenia.

Like, that’s how we got those  hundreds of diabetes genes.

The contribution of each one  is so small that a pattern only

emerges when you’re looking  at loads and loads of people.

There still will probably never  be a single magic bullet gene

therapy-type thing for every  disease, but these discoveries

can give us a better understanding of how these

diseases occur and the best ways to treat them.

The Human Genome Project  helped scientists at the lab

workbench more than it helped  patients in the doctor’s office.

Of course, the scientists at the lab bench do help

the people in the doctor’s office eventually.

It’s just more roundabout than we’d hoped.

So that’s the story. The Human Genome Project

was a huge achievement that  may have been overhyped,

but which still was a huge technical success

and is still leading to exciting new things.

That said, with the benefit of hindsight,

we’ll resist making any huge promises about

what’ll end up in your wallet in the future.

As we’ve learned, genetics can be far more

complex than it initially appears.

If you liked this episode about  why the Human Genome Project

was a failure but still a good  idea, you might also like our video

about why the moon landings were  a failure but also a good idea.

Thanks for watching.

[♪ OUTRO]