Speaker #0For four-year-old Nicholas Volker, every meal was a struggle. Little Nick had undergone over 100 surgeries by the age of four. His intestines were riddled with holes, and digesting food was one of the most difficult things imaginable. In each of his surgeries, doctors tried to patch up his intestines, but every fix was temporary. And the worst part was that they didn't know what was going on. His doctors suspected he had an autoimmune disease, but but they weren't sure. They couldn't find any evidence for it. His parents were running out of hope. Then, an email changed everything. It landed on the screen of Dr. Howard Jacob, a geneticist at Medical College of Wisconsin. It was Nick's doctor's last hope. He asked, Could Nick's entire genome be sequenced to find the cause? At the time, in 2009, sequencing a whole human genome was rare. astronomically expensive, time-consuming, and unproven as a clinical tool. But Nick was out of options. It didn't take long for Howard Jacob to say yes. Buried deep in Nick's DNA, they found a mutation in a gene called XIAP that was linked to a deadly immune disorder, X-linked lymphoproliferative syndrome type 2, a condition so rare it might never have been found through conventional medicine. With this discovery, Nick's doctor finally had a plan. He needed a bone marrow transplant, and that could save his life. Nick's story immediately went viral. This was the first time that human genome sequencing solved the medical mystery. This was all possible after the Human Genome Project, one of the most consequential projects in the genetic field. The goal of the project was to map out the entire human genome, and that means determining exactly what sequence of base pairs human DNA has. and exactly what types of protein it creates. Now, you might be thinking, each human has a different DNA sequence. And you're right, each human does have a unique DNA. But 99.9% of human DNA is the same across everyone. All of our genetic differences come from that 0.1% variation. We also share 99% of our DNA with chimpanzees and 60% with a banana. And these were all discovered after the Human Genome Sequencing Project, and we will get to these interesting facts in later episodes. But the Human Genome Project went through quite a journey, and frankly, a lot of drama. Today we are going to talk about the story behind this project. So get ready for some science-based drama. You are listening to Scientific Tales. In the late 1990s, the tensions in the genetic science world were so high that the president of the United States, Bill Clinton, told his science advisor, fix it. Make these guys work together. But what could cause such chaos? At the center of it all were two rival scientists, Craig Venter and Francis Collins, two brilliant scientists who didn't see eye to eye on how to sequence the genome. And their clash became a matter of everyday news. But to get into their showdown, we should rewind about a decade to the 1970s and 80s. At that time, the idea of sequencing the entire human genome sounded like pure science fiction. It seemed impossible. It was too big, too expensive, too ambitious. But something started to shift in the 1980s. Afrogeneticists and biologists saw massive big-budget projects like NASA space shuttles and telescopes, they thought. we can have a big project too. The man leading the charge was James Watson. And yeah, he is the same James Watson, the co-discoverer of DNA's double helix structure. Still a towering figure in genetics, and still actively in the genetic field. And he decided to rally the troops. He brought the brightest minds together for a meeting at the Cold Spring Harbor Lab in New York. The meeting went well. Like any other scientific meeting, debates were loud. A number of scientists weren't thrilled with the idea of sequencing the whole genome. They thought that this massive, big-money science project might jeopardize the funding for other types of genetic research. But the seeds of the project were planted in that meeting. However, all of these conversations were moot if they couldn't find an organization to fund it. The estimated price tag was $3 billion, equivalent to six space shuttles. And that's not pocket money, so they had to go to the biggest player in town, the National Institute of Health, NIH. These scientists perfectly pitched the idea. They rightly argued that human genome sequencing could revolutionize how we understand humanity and answer some of the biggest life questions, like what it means to be a human. We could diagnose diseases, cure diseases, and find answers to philosophical questions. NIH was finding it harder and harder to say no to the project. And the project was also lucky with the timing. the global political factors played a crucial role. This was all happening in the 1980s, around the time that Japan was dominating global tech industries, and the United States needed a way to stay on top of high-tech innovations. So the Human Genome Project became a matter of national pride for the United States. In the late 1980s, both NIH and Department of Energy were on board, and the Human Genome Project soon became an international effort when scientists across the globe showed interest. The United States directed the efforts, and countries like the United Kingdom, Germany, France, and Japan joined the project. Everything was ready. The money was secured and the scientists were prepared. But when it was time to get into the nitty-gritty of sequencing, some big challenges immediately rose to the top. Gene sequencing was extremely slow. Like, really slow. It would take months to sequence a virus DNA, and that is the smallest DNA possible. So the first step of the Human Genome Project was to come up with methods that could ramp up sequencing on large scale. The first time-limiting factor was DNA replication. Replicating DNA is necessary for sequencing. You need to have enough DNA material to work with. In the early 1980s, the primary method for replicating DNA was Cohen-Boyer method, which was developed in the 70s. This method was brilliant, but cumbersome and slow. You had to basically put the DNA into bacteria and let them replicate as they grow. But there was one scientist, Carey Mullis, that had a better idea. He came up with the polymerase chain reaction method, PCR. If you feel like this method sounds familiar, you probably remember it from the COVID-19 tests. The same method is used to replicate COVID-19 genes in your nasal swabs before inspecting the sample for the COVID gene. PCR is surprisingly simple. It's basically a method to synthetically replicate a piece of DNA. PCR reduced the time of DNA replication from weeks to just a couple of hours. The Human Genome Project got an important technological boost, but there was still a problem, maybe even a bigger one. The general practice for sequencing was based on the Sanger method. Sanger sequencing method is genius, but it's slow. It wasn't practical to use it for such a big project. As a side note, if you're really interested in genetics, you have to search for Sanger method and see how it works. It's just brilliant. You can also find it in our episode's references. But anyway, as always, science came up with a new thing. In 1986, Lee Hood's lab at Caltech came up with a more efficient process. They incorporated fluorescent dyes into the sequencing technique and made the method much faster. The base and the chemistry of the new sequencing method were the same as Sanger method, but it was automated and slightly modified. This modified method was about four times faster. The first phase of the Human Genome Project was refining the sequencing process, and it was slowly but surely moving forward. New methods were devised and implemented to quickly and accurately sequence the human genome. But as scientists were getting closer to finally tackling this enormous project, debates and disagreements started. Some scientists believe that sequencing only the functional DNA portion would be enough and would be much faster. Most of the human DNA is not functional. And by not functional, I mean it won't translate into proteins. So in the early days of DNA science, this part of DNA was referred to as junk DNA. A number of scientists argued, why sequence the junk DNA? There's actually a very fast and easy method to sequence the functional DNA. If you remember, in the DNA translation process, DNA is copied into messenger RNA and then translates into a protein. Some scientists believe that we could just extract the messenger RNA, make their complementary DNA, and sequence those DNAs. Fast and simple. Why exhaust ourselves with the whole genome when most of it is junk? But not everyone agreed with this idea. Some would say it would not substitute the human genome project. These were the ones who wanted to sequence everything to the last base pair. And as a side note, it was later found that some of these DNA sequences that were not translated into proteins play crucial roles. They can switch genes on and off and have important regulatory functions. But anyway, the seeds of the big rivalry in the human genome project were being sown from here. One scientist who got really interested in sequencing the functional parts of DNA was Craig Venter. Venter is an American geneticist that was born in Salt Lake City, Utah. But he was raised in California and got his PhD at UCSD. After Venter had some success in sequencing functional DNAs, a venture capitalist named Wallace Steinberg reached out to him and offered him the opportunity to be the head of a company called the Institute for Genomic Sciences, or TIGER for short. This company aimed to sequence DNAs that translate into proteins. So they did exactly that. And after finding the DNA sequences and their functions, they did something that was very controversial. In a couple of years, Tiger Company filed patents for around 140 genes. This was not received well by the scientific community. Is it ethically or legally right to patent a gene? A gene is a part of the human body. Can you patent a part of human body when you find out some details about it or figure out how it functions? The debates and the legal battles lasted for a long time. Finally, in 2013, a couple of decades later, the United States Supreme Court ruled that naturally occurring DNA sequences cannot be patented. And with that, all of the patents for genes were invalidated. But going back to the mid-90s, Venter introduced himself as a controversial figure with the patenting of the functional human genome. The Human Genome Project was moving forward. It first started by sequencing the DNA of smaller species, such as those from yeast and bacteria, before working on the human genome. And they did all of that successfully in the mid-1990s. Around this time, Francis Collins was the head of the NIH genome effort. The Human Genome Project was slowly moving forward. One of the reasons it was going at a slow pace was the scientists were meticulously identifying and mapping the location of DNA secretes. sequences and chromosomes. I feel like this is the best place to talk about the structure of chromosomes and DNA a little bit, to make sense of the project and its complexity. DNA is essentially a long chain of four base pairs, adenine, guanine, thymine, and cytosine, or for short, A's, G's, C's, and T's. So when we talk about sequencing, we basically want to know the order of the base pairs in a chain. And that order is extremely important. A wrong order can cause a genetic disease, and a different order can cause different physical features and basically define each unique human being. DNA is super long, but it gets tangled and forms a structure that we call a chromosome. Humans have 23 pairs of chromosomes in each cell, and these chromosomes are inside the nucleus of every cell. So when we talk about sequencing DNA, we're essentially breaking down the chromosome structure and then sequencing the DNA itself. And just to blow your mind, if you fully stretch out the DNA in a single human cell, it will be 2 meters or 80 inches. But as we said, it gets packed as tiny chromosomes in each cell. But the chromosome has a very complex structure. First of all, it's extremely small. At its largest state, it is less than 10 micrometers. To put it into perspective, a small ant is 3,000 micrometers. And chromosomes are made from supercoiled DNA. So the DNA in the chromosome is tightly pressed, packed, and coiled. Untangling the chromosome is a difficult process. In the Human Genome Project, scientists were carefully uncoiling the chromosome and sequencing the DNA at specific parts of the chromosome. This would help them to exactly know which DNA sequence is in which location within a chromosome. This was one of the reasons things were going slow. But scientists were not too bothered by it. Until an unexpected scientific paper was published that sent a chill down everyone's spine. It was Craig Venter. In the mid-1990s, Venter became interested in sequencing the whole genome, and he was focused on doing it as fast as possible. In 1995, Venter published a sequence of a small bacterium, and he used a method called whole genome shotgun. This method would chop the chromosome into random chunks of DNA and start sequencing them. Then the sequences would be fed into a computer and using computational methods, the sequences would be put into the right order. So with this method, you didn't need to carefully untangle the chromosome. You basically cut it into pieces, sequenced the pieces and then the computer would figure out where it was in the chromosome. A brilliant idea. This would make the human genome sequencing much, much faster. But was the idea in the wrong hands? Venter was the one who patented the functional genes. What would he do if he sequenced the entire human genome? Venter founded a company in 1998, Clara Genomics, and his goal was to sequence the entire human genome. He purchased high-powered computers with the highest computational power possible to ramp up sequencing the human genome as quickly as possible. Venter estimated that the whole project would cost two years, and the estimated cost was between $200 to $500 million. The human genome project was devastated. They had already used $1.9 billion of public money, and so far they had only genome sequences of small species like mouse. The battle was on. The Human Genome Project was non-profit and soon became recognized as the Public Genome Project, while Venter was leading the Private Project. The media and newspapers were filled every day with acrimonious comments between the heads of the private and the public project. This was the time when President Clinton asked his advisor to fix the situation. The public project needed help, desperately. But the good thing about being a public project is that it's public. So the project wasn't alone. At the time of need, an astute scientist from MIT joined the public effort, Eric Lander. Eric Lander's lab gave the public project a huge boost. All centers that were assigned to the Public Human Project started ramping up sequencing to stay in the game. But... The project was still missing something. After the sequencing, the public project needed computer programmers. They were the ones who would ultimately be needed to make sense of all of the sequence data. All of the A's, T's, G's, and C's. The public project was a little late on this. As they were hustling to get the sequencing done, they overlooked the need for bioinformaticians. The private project was way ahead of them. Their method was in a way that they had to use superpower computers. And they had a lot of computer scientists. The public project was in trouble again. They needed another miracle. And the miracle showed up. A graduate student from UC Santa Cruz, Jim Kent. Jim Kent was a computer genius who started coding and making animation since the early days of computing. In graduate school, he gravitated toward bioinformatics and he wanted to be a part of the Human Genome Project. As the time was getting unbearably tight for the public project, coincidentally, UC Santa Cruz bought 100 computers for teaching purposes. Jim Kent, the natural-born coder, convinced his university to lend him those 100 computers, and the school was kind enough to accept. Jim Kent spent four weeks writing computer programs night and day. The set deadline for announcing the human genome results was June 26. Jim Kent and his 100 not-so-fancy computers managed to finish the draft on June 22nd. Clara Genomics and Venter cut it even closer to the deadline. They finished on the night of June 25th. The race was called a tie, and on June 26, 2000, came President Clinton's announcement. Today we are learning the language in which God created life. We are gaining ever more awe for the complexity, the beauty, the wonder of God's most divine and sacred gift. With this profound new knowledge, humankind is on the verge of gaining immense new power to heal. Genome science will have a real impact on all our lives, and even more, on the lives of our children. It will revolutionize the diagnosis, prevention, and treatment of most, if not all, human diseases. In coming years, doctors increasingly will be able to cure diseases like Alzheimer's, Parkinson's, diabetes, and cancer by attacking their genetic roots. The Human Genome Project remains one of humanity's greatest technical achievements. But as you can predict, scientists didn't stop after this success. Nine months later, Francis Collins, the head of the NIH genome effort, gathered the most influential minds in genetics for a retreat in rural Virginia to answer one pressing question. What comes next? One thing was clear. Sequencing the human genome was slow. cumbersome, and absurdly expensive. If this technology was going to change medicine and help real patients, it would have to be faster and cheaper. Someone in the room threw out a number. What if we could do it for $1,000? It was almost laughable at the time. The original human genome project cost nearly $3 billion. But the scientific community recognized the challenge. And two companies, 454 and Solexa, were the first to take it on. They developed faster methods of sequencing, and they called it next-generation sequencing. It was a massive leap forward from the old Sanger sequencing. Speed had improved, by a lot, but the cost was still sky-high. The first personal genome that was sequenced with this new technology cost $1 million. And the man who had his DNA decoded by this method was James Watson. the veteran DNA figure in the United States.
