George Church rises above most people. He has the long gray beard of the wizard of Middle-earth, and the work of his whole life - to mess with DNA and delve into the secrets of life - is not so far gone from the world of deep magic. The 63-year-old geneticist is in charge of one of the world's largest and most well-funded laboratories, whose headquarters are on the second floor of a massive glass and steel building at the New Research Building of Harvard Medical School. He also works as a consultant and supports dozens of projects, consortia, conferences, divisions and startups, united by the mission to push the boundaries of the available - from creating bio-robots to resurrecting a mammoth. On a foggy August morning, he wanted to talk to me about the limits of my own life.
Church is one of the leaders of the initiative called “Genome Project-Write” (GP-Write), which organizes the attempts of hundreds of scientists all over the world who are working on the DNA synthesis of different organisms. The group is still arguing about how far the human DNA synthesis issue should go, but Church - standing in his office in a crumpled sports jacket behind a narrow chair that he uses instead of the table - says his laboratory has already made its choice on this question: "We want to synthesize modified versions of all genes of the human genome in the next few years."
He is going to develop and create long chains of human DNA, not just cutting and inserting small pieces - this practice is now akin to a routine, thanks to the latest technologies like CRISPR, which allow scientists to edit DNA cheaply and easily - but by rewriting critical chromosomes that can then be connected to genome of natural origin. If successful, this will be an exciting leap in complexity from the genomes of bacteria and yeast, on the synthesis of which scientists have worked so far. “We are planning things that are far superior to CRISPR,” Church says. “It’s like the difference between editing a book and writing a new one.”
When writing his book, Church hopes to change the story of a person in it at will. Replacing selected nucleotides — the symbols of ACGT life scattered across the chromosomes — and replacing, say, T with A or C with G during the transcoding process, Church wants to create cells that resist viruses. “Like HIV or hepatitis B,” he says.
“A cold?” I ask.
He nods, and adds that they have already managed to recode the bacterium, making it immune to viruses. “This is described in our work from 2016,” he says.
Church and others working on the synthesis of human DNA created their own project within GP-Write - the Human Genome Project-Write, HGP-Write. His prospects for success are such that biologists are eagerly discussing the potential for curing diseases, creating cells, and even, perhaps, whole organs with the help of bioengineering. Critics scratch their heads thoughtfully due to technical difficulties, high cost and practicality issues. Francis Collins, director of the National Institutes of Health, admits that the synthesis of the full-fledged human genome is real, but he does not understand the meaning of this idea. “I think this is within the bounds of the possible, if you have enough time and money,” he says, “but why do it? Today, technologies like CRISPR are much more accessible. ”
And there is the question of ethical use of powerful technology for games with the basic code of life. Theoretically, scientists will someday be able to make genomes, human or what else, as easy as writing code on a computer, turning digital copies of DNA from someone's laptop into living cells or even Homo sapiens. Mindful of the controversial situation, Church and his HGP-Write colleagues insist that their goal is not to create new people — although the cheek necessary to make large-scale changes in DNA is enough to cause controversy over this. “People get upset if someone places a different kind of genes in their food,” says Stanford bioethics and jurisprudence expert Henry Greeley. “And here we are talking about the complete rewriting of life? Yes, here the hair stand on end, and it will be perceived with hostility. "
But, despite all the bayonets, Church and the team rush forward. “We want to start with the human Y chromosome,” he says, referring to the male sex chromosome, which, as he explains, has the least number of genes from all 23 chromosomes, therefore it is easiest to create. But he does not want to synthesize any Y-chromosome. They with the team want to use the sequence of this chromosome taken from a real person - from me.
“Can you do this?” I stutter, stammering.
“Of course, we can - with your permission,” he says, recalling that it would be easy to use my genome, since it is stored in digital form in the computers of his laboratory, as part of a project launched by him in 2005, The Personal Genome Project (Personal Genome Project, PGP). PGP attracted thousands of people who agreed to contribute their complete genome to an open database accessible to researchers and anyone; I also provided my genome for this project.
With my permission, after a few keystrokes on the keyboard, Church can effortlessly open digital drawings of my Y-chromosome. Then, scientists in his laboratory will be able to make a synthetic copy of it, but with differences: they recode my sequence so that it resists viruses. If they succeed - and if they can recode all the other chromosomes and inject them into human cells, and these are two big “ifs” - theoretically, they can implant these “corrected” cells into my body, where they, if lucky, multiply, will change the functioning of my body and reduce the risk of viral infection.
But we are running ahead. For now, Church just wants to recode and synthesize my Y chromosome. "When we finish, a small piece of you will be stored in the refrigerator." An optimized version of me, which one day will be able to thaw out - in ten years, or in a hundred thousand. By the time Church says, scientists will be able to more deeply manipulate my genome. He can make me stronger, faster or even smarter. They may be able to create a completely new version of me. Who knows what will be possible in the future?
Synthetic biology, an area dedicated to understanding and modifying the basic building blocks of life, began in the 1970s when a team led by Stanford biochemist Paul Berg made key discoveries in cutting techniques for cutting short DNA sequences from only one organism (from bacteria to humans) and inserting them into other (usually bacteria). This practice has allowed scientists to use cellular microbial systems to produce proteins, which in some cases have become successful drugs, such as
Epogen , used to stimulate the production of red blood cells in people with anemia undergoing dialysis or the Tour de France participants.
Large-scale synthetic biology began to appear in early 2000, when scientists began to synthesize viruses entirely. In 2010, a team from the J. Craig Venter Institute created the first synthetic self-replicating bacterial cell. But no one has yet approached the ambitious plans of the GP-Write or HGP-Write, owing their name to the original project of studying the human genome Human Genome Project, a massive enterprise, in which 3 billion pairs of genes that make up the human genome were sequenced for $ 2.7 billion from US taxpayers money. (The second, private project led by Craig Venter, did the same thing much cheaper). “We consider the HGP-Write project a continuation of the Human Genome Project,” said geneticist Andrew Hessel, one of the founders of GP-Write and HGP-Write, and a former researcher in the life sciences division of Autodesk.
It was Hessel, a slim man, 54 years old, with a short barbed beard, first told me about this new project of studying the human genome three years ago, when I came to visit him in his small, eye-catching cottage next to the Russian River in Sonoma County in California. Sipping red wine next to a wood-burning stove on a foggy evening, Hessel told how he began his career in the late 1990s at Amgen, analyzing data from a private Venter project. “Even when we finished HGP-Read (the human genome project is reading),” he says, using their brief designation of the human genome project, “I was already looking forward to how we could start to create something. I waited and waited, but nothing happened. Lacked imagination. The technology has reached a certain point of development, but no one moved further. ” He watched the emergence of CRISPR and other gene editing technologies, but they did not satisfy him.
In 2015, Hessel seriously decided to start a genome editing project and asked Church to help organize the initiative that became GP-Write (and HGP-Write). Church insisted they need to bring in yet another prominent specialist in synthetic biology, Jeff Boek from New York University. The goals of the group range from helping to develop technologies that work faster and cheaper to develop an ethical platform for the synthesis of life. They already have an answer to the question of Francis Collins and others about synthesizing the human genome - why do this? Hessel, Church and the company talk about the potential for major changes affecting the entire genome, which can be used to develop virus-immune cells, synthetic organs and new drugs. But they draw the line without activating the genome in
germ-line cells that can change the genes that we pass on to our children. “We don't create babies — we only edit genomes,” Hessel insists. “The real work of creating a synthetic baby will remain the next generation.”
Last May, GP-Write held its first public meeting at the New York Genome Center. The two-day conference attracted 250 scientists, ethicists, lawyers, amateur scientists, artists, policy makers and companies from 10 countries, including China, Japan, Britain, Canada, Singapore and the United States. There were reports with names like “Using an isothermal augmentation array to lengthen an artificial gene sequence” or “Prediction and understanding of control systems”.
The conference showed presentations of pilot projects supported by the organization considered or implemented. For example, Harris Vaughn of Columbia University wants to change mammalian cells using bioengineering so that they become nutrient factories, producing the critical amino acids and vitamins that humans need to consume as food. Another project from June Medford of the University of Colorado aims to edit the genomes of plants, which will allow them to filter water or detect chemicals. At the meeting, she showed an image of the airport frame, surrounded by bushes recognizing explosives.
The GP-Write movement made the newest of its breakthroughs last year, when the Boeke laboratory at New York University announced that it had completely created the 6 artificial chromosomes of the 16 that make up the yeast genome. Boeke plans to complete the synthesis of all 16 chromosomes by the end of the year. “We strive to unravel, modernize and redo the genetic drawings of the yeast,” he says. “After we synthesize all 16 chromosomes, we plan to create a working yeast cell.”
This will be a remarkable achievement, but given that yeast has four times fewer genes than humans, it still will not be an approximation to the complex task of synthesizing the entire or even part of the human genome. The longest of the 16 yeast chromosomes contain approximately one million paired bases. The paired base is duplicated genetic letters, running along each segment of the double helix of DNA, in the manner of steps of a ladder. The Y chromosome contains 59 million paired bases, and is one of the shortest of the 23 human chromosomes. Some scientists estimate that recording the entire human genome, all 3 billion paired bases, could cost $ 3 billion, which is not only unrealistically expensive, but perhaps not necessary. “We don’t need to rewrite everything,” to seriously change the chromosome, says Church. “Only important parts of it."
In 2002, as part of our journal’s attempts to explain and bring modern genetically sequencing technology to people, I became one of the first people whose genome was sequenced. Then my genome seemed to be something very personal, and promised to reveal the secrets of my health, buried deep in my DNA. As part of the preparation of the article, Sequenom checked me for several hundred DNA markers associated with the risks of disease, from Alzheimer's disease and high blood pressure to some types of cancer. For example, scientists from Sequenom found a mutation in my sixth chromosome, which was later associated with a slight increase in the risk of a heart attack. Like many people whose genome has been sequenced by services such as 23andMe, I have memorized this information with the tick "good to know about it." Fifteen years later and zero heart attacks, I, looking at my own HGP-Write project, thought about how it is to know that a small part of me is being copied and recoded for the purpose of improvements.
After meeting with Church last summer, I met with his team in a conference room at the Harvard Weiss Institute of Engineering, inspired by biology, an amazing structure of steel and glass located behind the main laboratory building of Church. The team had four researchers and a postdoc from Albania, Erion Hisolli, 32 years old. A very serious Hisolli, with pigtails in her hair, led me through the whole procedure of creating my Y-chromosome.
Gene synthesis, Hisolli explained, begins with the researchers discovering the genetic sequence on a computer. On the luminous screen, she shows me a segment of my sequence, which looks like this:
CGG CGA CGTG AAC CGTG AAC CGGG AAC CGGG AAC CGG AAC GGC CGG CG CG CG CG CG CG CG CG CG CG CG CG CG CG CG CG CG CG CG CG CG CG CG CG CG CG CG CG CG AAG CG CG CG CG CG CG GCT CTA GAG AAT CCC CGA
… and so on. Hisolli explains that, instead of synthesizing each nucleotide on my Y chromosome, the Church team will focus on individual units of the genetic code,
codons that determine which particular amino acid (and, ultimately, protein) the cell will produce. Each codon consists of a maximum of three nucleotides (for example, ATG or TCC), and Hisolly and the team hope that by swapping certain nucleotides in the codons, they will be able to make changes in the whole genome scale that can make the cell resistant to viruses. After transcoding target codons, Hisolli will send this genetic drawing to Integrated DNA Technologies, which produces small segments of real DNA,
oligonucleotides . The company will then dry and freeze these oligonucleotides and send them back to Hisolli. They and their colleagues will connect the resulting segments in ever-longer sequences, and each new segment will bring them one step closer to the finished chromosome.
At least, such a plan - and it may take a whole year to complete. In the meantime, I ask Hisolli to conduct a less ambitious demonstration of the work of DNA editing. At first, she does not want to do something that she considers simple. But then he agrees, and we choose a segment of DNA on my sixth chromosome that contains a mutation identified by my previous genetic test — one that is associated with a slight risk of heart attack. To create a new, improved version of this genetic fragment, Hisolli corrects a risky mutation on a computer. She also recodes this piece of DNA so that it resists viruses - just for order. Then Hisolly orders a recoded DNA fragment from the company, and he arrives a few days later.
After receiving the fragment, the researchers clone it and place it in the cytoplasm of
E. coli , a well-known bacterium. Genetics often use the ability of E. coli for rapid reproduction. A few days later, E. coli produces a sufficient number of copies of my altered chromosome, and Hisolli sends me photos of the bacteria in the Petri dish containing these small pieces of me. Although I can not see these nano-sized particles. But I can see green luminous drops scattered inside the cells. These droplets are reproduced by a fluorescent
reporter gene taken from a jellyfish, which scientists constantly use to mark up the genes. This dirty, brown-green soup of microbes, covered with luminous spots, is very far from the version of me that could be found, but I grimaced, imagining that one day I would be able to look at a more complete version of my genome in a Petri dish, caricatured resembling me.
The last step in creating a synthetic mini-me is replacing the corrected gene in the cells where it should be stored.
But not in all - scientists use my white blood cells to create induced pluripotent stem cells (iPScs) that can grow and become any cell in my body. (The bio-engineering side of the issue is in Cellison Dynamics International, Madison, Wis., That creates stem cells for pharmaceutical companies and institutes). Someday these cells can be introduced into my body, in the hope that they will change the scheme of its work, but so far “putting edited cells into the body is an extremely difficult task,” says Hisolli. - In many tissues, you can simply enter the cells directly and see if a small percentage can survive and thrive. Or you can insert blood stem cells into a vein and see if they are targeting bone marrow or thymus.". And until this technology evolves, my edited cells will be stored frozen so that in the future I or anyone else will turn to them.Church warns that the technology for large-scale genome synthesis is still emerging, expensive and complex. GP-Write has yet to receive significant investments, although some laboratories, such as the Church and Boqueke laboratories, received funding from government agencies, such as the National Science Foundation and DARPA, the Pentagon’s research and development department. So far, I would not hope that in the near future I will be able to receive my recoded Y chromosome - or the tiny correction made by Hisolli on my sixth chromosome - as an implant. But they will be stored in a deep freeze, in case you manage to solve a lot of ethical and technical problems, as well as the issue of security.Still, it’s interesting how one day it will be possible to use this basic code, which makes me who I am. I am using both hands to use this technology to develop new drugs or to develop DNA tweaks across the entire genome, which can prevent diseases if it is safe and does not carry any intentional negative effects - and this is a very big “if”. But if we overcome the therapeutic barrier, I wonder how I feel about the fact that I, or my children, will improve and become stronger or smarter. I repeat that if it is safe and actually works, then I suspect that many people will readily agree to upgrade, although you have to think about whether new, improved genomes will result - we will use transcoding in the genome scale or technologies like CRISPR - to thatthat we change completely.How it will turn out in the coming years and decades - we can only guess. But right now, tools are being made that will enable us to do more than just introduce some new improvements, says bioengineer Pam Silver from Harvard: “Only your imagination will limit you.” She works in a GP-Write project aimed at making amino acids that people get from food. Her opinion is supported by geneticist Charles Cantor, an honorary professor from Boston University, who helped me participate in the sequencing of my DNA in 2002 at the Sequenom. Kantor believes that scientists and ethicists are too timid. “When I imagine genome editing,” he says, “I like to think about the different genres people can write in their essays.Personally, I like fiction - to invent completely new genomes, for example, to create people who receive energy from photosynthesis or walking plants. ”The fact that researchers are already seriously thinking about cells that can resist viruses or walking plants makes it even more important for scientists, such as Church, Hessel and Boeke, as well as young researchers like Hisolli, to talk about their work publicly, and for advanced projects like GP-Write - work transparently and adhere to standards whenever possible. “I think the public should reassure that scientists think about it, and not just take and do something from the category of insane genius,” said Nicole Lockhart, director of the National Institutes of Health program on researching ethical, legal and social consequences. Or, as Hessel says: “Maybe we will not be able to prevent the bad guys from using this technology, but since it will somehow appear, it is always better to talk about it openly.”, , Y.
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