Has synthesized a megabyte chromosome. Everything in the cell was derived from the chromosome and the natural traces were all deleted. They are digitizing biology. Converting analog genetic code to digital. Now they can go the other way, from ones and zeros to living organisms. Huge progress over past two decades. Big breakthrough new algorithm in 1995. New approach to sequencing pieces by breaking them down and putting into the computer. Government review process said it couldn’t work, so they had to find their own money. After it proved they worked, more money than they knew what to do with. Worked from microbes to humans in five years. First published in Science about ten years ago. First diploid genome in 2007. Used his own to avoid having to get permissions. It has now become de rigeur to put your genome on the Internet. Found that there is 1-3% difference between unreleated humans, which is ten times more than previously thought.
Had hoped for first synthetic species last year, but was wrong. Needed proofreading software. Had a sequence that could boot with ten synthetic sections and one natural one, so they knew where the problem was.
44% of genes have more than one heterozygous variant. Amazing that we have so much in common, and that things work as well as they do. Now can buy a small machine for half a million dollars that will sequence a genome in a couple days. Seeing more variation in Africa than between African, Venter, and Chinese.
NASA has been doing selection for a long time, but not calling it that, by screening for things like inner-ear changes, rapid bone regeneration, DNA repair, strong immune system, small stature, high energy utilization, low risk for genetic disease, etc. Have more microbes than human cells (we have several trillion bacteria), and their gene population exceeds ours by orders of magnitude. Millions of genes in mouth, intestinal tract, vagina, etc., and we don’t know much about them. Thousands of new ones brought up to ISS every trip. Have to understand out own genetic code, the codes of the microorganisms, and the interactions between them and the environment. Starting to make progress as we learn more. Esophageal cancer fastest growing one since seventies, and don’t know if microbes are causal, or symptom. Studying metabolomics of microbes. Ten percent of chemicals in our bloodstream are bacterial metabolites, and we don’t know if they help, hurt, cause or suppress disease, cause mood, etc. Need to know microbes and correlate. Important for space trips, and more important for long ones. Synthetic biome community might eliiminate disease organisms (infections and dental decay). Eliminate methanogens and sulfur producers. Body odor primarily caused by microbes. Best way to eliminate smell of armpits is to kill microbes (alcohol works better than perfume). Add cells that help metabolize algae-based food. There is an abundance of microbes (half of earth’s biomass). Has taken samples every two hundred miles in the ocean by filtering seawater, and sequence everything on the filters. Don’t know what they look like, but know what their genomes look like. Expected limited diversity in each area, but discovered great amount, and discovered many new organisms from sequencing. Also looked at deep-sea microbes near volcanic vent. Don’t need organic compounds, make everything from CO2 and hydrogen as energy source. Found same level of diversity deep in the earth, but more clusters like people expected in the oceans, perhaps because of radiation protection and less mutations. No point in sequencing new mammals to look for new genes — have probably seen it all, but microbes can provide new genes from any new sample.
Minimal life — smallest genome, 482 protein-coding genes and 43 RNA, discovered in 1995. Don’t know how small one can go, how many are essential for cellular life. Did gene knockouts, but discovered that only way to get there was synthesis. Comparative genomics can only take us so far. Over half of human genome are transposons, that can randomly insert in the cell. If cell survives gene replacement, defined as non-essential, but what’s essential and non-essential depends on context (e.g., sucrose and glucose can keep alive, but one or the other can’t). Knocking out a gene doesn’t tell you whether its function is essential, because there may be redundancy. Questions: could they make a synthetic DNA, and could they boot it up? Longer the genes, more errors, so needed error-correction methods. Discovered that the software could build its own hardware for virii. Thought it would be harder to boot up a full bacterium than a virus. Converted one species into another by reprogramming DNA. Isolated DNA, figured out ways to inject in a related cell. Thought would have to eliminate chromosome in recipient cell, but discovered that enzymatic processes in the cells would do it for them. Cell briefly has both chromosomes, it starts to make new enzymes, including restriction enzymes that chew up the original DNA, and a new cell with the coding of the donor cell. This allowed transplants (2007). They could then start to build up a new organism, piece by piece.
D/ radiodurans: “the ultimate DNA Assembly Machine.” Highly radiation resistant, but couldn’t get it to work outside the cell. Based on yeast, managed to assemble 600,000 base-pair organism, but couldn’t boot it up. Breakthrough was simple in-vitro recombination, with three enzymes, and one-step reaction at 50 degrees centigrade, allowing automation (just synthesized mouse genome). Can imagine robot that can “learn” how to do this, accelerating learning rate. Problem was assembling in a eucharyot, but having problem getting the chromosome from yeast and transplanting into another organism. Discovered that they had to methylate it. Now can modify things with yeast, isolate it, methylate it, and transplant into target organism. DNA synthesis no longer the barrier.
Now they’re watermarking the genes with things like quotes from James Joyce (got complaints from his estate for copyright violation). Idea is to put stop-codes in to not overrwrite critical parts.
They’re now up to a millions base pairs, and now that things are automatable, entering a new era. 40 million genes discovered to date, are the design base for the future. Will be able to specify metabolism to design future organisms. Because so much gene diversity, and so few scientists, need more approaches for rapid screening, and pass results on to the humans. select for chemical production, viability, etc.
Could use for mitigating carbon buildup, provide medicine, food, clean water as population grows. Three people alive on the planet for every person in 1946 when he was born, and soon four. Need new approaches. Plants not very productive systems, very limited, but microalgae has good potential (orders of magnitude better for fuel production). Only making ethonol from corn because there is a corn lobby, not because it’s smart. Designing fuels with CO2 as a carbon source. Instead of squeezing cells, getting them to pump the fuel out continuously. Exxon has put $600M on the line to do this. Expect useful economic processes in ten years. Have to design new algae strains to get there, because no natural ones will do the job. Food production for spaceflight very inefficient, but new designs can improve. Totally within the realm of the next few years. Microbial fuel cells also key application, with drinking water as output. Some bacteria use nanowires that can interface with the metal. Also working on reverse vaccinology, focusing on meningitus B and flu. Could help with rapid production of new vaccines, no longer grow them in chicken eggs.
Many reviews of the ethics of this: first priority of the Obama bioethics committee. This is likely to be the number one wealth generator for the next century. At early stages — first stage took fifteen years (longer than expected). What took years can now be done in a day, and shortly will be able to do millions of times per day.
For spaceflight, need to look at human genetic code, sequence microbiome to understand their influence on health and disease, and then all the issues from food, recycling waste, and perhaps even improve on stem cells to make us more radiation resistant/protective.