The First Cell with a Synthetic Genome

The big news in biology last week is the creation of a viable, replicating cell with a wholly synthetic genome. The work was done at the J. Craig Venter Institute and you can hear Venter himself talk about the breakthrough at TED:


Or, if you want more of the nitty-gritty, you can read the paper published last week in Science (free access).

And, of course, there are plenty of reactions. Nature has collected the opinions of a handful of experts, as has Edge.org. That something like this can be done, conceptually, is unsurprising. We've seen viable cells with exogenous genomes - albeit not synthetic genomes - before. (Think Dolly or the resurrected ibex) Technologically, though, the successful synthesis and transplantation of a Mbp genome is pretty exciting, particularly if synthesis costs follow the trends of gene sequencing. The implications for genetic engineering are obvious, and with the publication of the Neanderthal genome earlier in the month the imagination really gets going.

Naturally there are some confused objections, fears and doomsday predictions as well, which are dutifully taken-down by P.Z. Myers.

Cancer Research Blog Carnival

The bayblab is proud to host the first ever blog carnival on cancer research. The purpose of the exercise was two-fold: Find out who blogs about cancer research, and share ideas on this topic. Hopefully this will be the first step in creating a community of cancer research bloggers and readers. So please visit the links and share your comments!

Synthetic biology:
The first story comes from our very own bayman. Bayman is the original founder of the bayblab blog, part philosopher part mad scientist he's done some great work on oncolytic viruses and is dreaming up methods to engineer smart cells to deliver virus payloads. In this post he tells us how synthetic biology may carve the way to create bacteria that essentially function as organic computers capable of discriminating between cancer and normal tissue: "The gate integrates two environmental inputs to produce a phenotypic output. As an example, they show how their circuit can be used to program bacteria to invade mammalian cells when the concentrations of two different extracellular chemicals fall within a certain range."

Imaging:
Our next story comes from Ramūnas Janavičius a clinical genetics doctor from Vilnius University in Lithuania. He maintains a blog about cancer genetics and is particularly interested in a personalized approach to treatment. In this post he tells us how a recent study in Lancet has shown that MRI scans are vastly superior at detecting ductal carcinoma in situ compared to standard mammograms: "What is a connection between MRI, DCIS and cancer genetics, you may wonder? It is now well established, that BRCA1-positive breast tissue has different histopathological appearance and course - its usually G3, estrogen negative and expressing basal-like phenotype. Recently published studies from Canada, Italy, Germany (btw, by the same author), the Netherlands and UK (MARIBS study) all similarly showed, that MRI outperforms mammography in BRCA1 breast cancers and annual MRI is now included as addition to mammography for TP53, BRCA1 and BRCA2 mutation carriers screening programs, performed from 30 till 49 years in UK and other countries. Cost effectiveness of MRI is also proven." Check also his post about a novel biomarker for prostate cancer...

Diet:
Next we have Ruth from the Biotech Weblog. Ruth originally from the Philippines studied paddy soil microbiology at the international rice research institute. She is now a freelance writer based in Singapore. In her post she talks about how some green tea components may be protective against cancer: "epigallocatechin gallate (EGCG) equivalent to 8-16 cups of green tea, might help some people strengthen their metabolic defense against toxins capable of causing cancer by boosting the production of enzymes which belong to the glutathione S-transferase (GST) family."

Smoking:
Next we have Ben, who is a medical/PhD student in Chicago studying lung cancer and lately RNAi. He is mostly famous for having been mentioned on the bayblab podcast. In this post he tells us how Phillip Morris had troves of unpublished data about side effects of smoking. Also does a good job of explaining how second hand smoking is worse than toking, which had always been a mystery to me: "While the group that published this article had previously shown that secondhand smoke is fourfold more toxic than mainstream smoke (that is, the smoke to which a smoker is exposed), the primary findings of the present paper indicate that NNK formation increases rapidly in the local surroundings over a period of several hours after a cigarette is put out. That is, secondhand smoke clearly is harmful, and it becomes worse, and potentially more carcinogenic, even after that which is generating it is eliminated. This suggests that the dangers of smoking extend far beyond the localized duration of a single lit cigarette and the time it takes to smoke it—specifically, up to 11 hours’ worth of danger, according to Philip Morris themselves, over 20 years ago"

Clinical trials:
Next we have Joe, from the Joe Oncology blog. Joe is the leader of two cancer centers in the southeast United States. Joe shares with us the difficulties of running clinical trials, with all the agency red tape and patient recruitment nightmares: "Another problem we have is recruiting enough patients to go on trial. Patients like the idea of clinical trials but they don't like the idea of possibly receiving a placebo. I wouldn't either. Thus many opt for traditional treatment until there are no other options. Many by then don't have the will, the energy, or the qualifications to go on a clinical trial."

Pharmaceuticals:
Next we have Konstantinos Vougas, a molecular biologist from Greece who specializes in proteomics and maintains the life sciences blog. In his post he wonders what will happen with overpopulation if a cancer sure is found, and whether pharmaceutical companies are going to share it with the less fortunates: "If you were the CEO of a pharmaceutical industry giant and your R&D team came up to you one day and said “We have the perfect anti-cancer vaccine and we can get rid of cancer once and for all”, would you give this vaccine to the public? In other words would you give up on a $75 billion/year market in the US only?"

Diagnostic:
Finally we have Lim from Singapore who maintains the wacky Fresh Brainz blog. Lim is a frequent commenter on the bayblab and quite a joker. He tells us how early diagnosis can cut mortality rates: "Current work is focused on DNA-based therapeutics. Prof. Hartwell gave an example of how this is helpful: in esophageal cancer, which used to have a very poor prognosis. This is because by the time clinical symptoms appear, the patient has already entered the late stage of the cancer. Now, the outlook for patients has improved because of the availability of new screening techniques. Samples are taken from people who suffer from Barrett's esophagus and examined for DNA changes, allowing a much earlier diagnosis of cancer. "

Well that concludes our first ever blog carnival on cancer research, I hope you've enjoyed these links. I want to thank all the bloggers who submitted posts, and hope we can do this again sometime!

Discover's scientist of the year

Discover magazine came out with their scientist of the year selection, with two runner-ups. While the scientists themselves are interesting, it's the fields that I'm most curious about. What's the sexiest science in 2007? Well the first scientist is Jay Keasling, working in, you guessed it, synthetic biology. He's famous for making a bug that spits out artemisin, a natural anti-malarial drug. He's now set his sights on making biofuel. Synthetic biology + biofuels is definitely the sexiest science right now. I must admit it wouldn't be my first thought to apply synthetic biology to producing fuel, it doesn't seem like a natural fit to me, and there is so much to figure out before making something as complex as a fuel. maybe it's just me.

The second runner up is John Donoghue, who works on brain/machine interface. Also sexy sexy science. He's working on wireless chips to implant in the brains of paraplegics to allow fine motor control. There has been a lot of progress lately in this field, with artificial retinas etc... A good choice.

The third runner up is Svante Pääbo, who wants to sequence the entire Neanderthal genome. To date, they've only managed 30Mb, still it's no small feat. However it's not the sexiest field, I mean 1999 called and they want their genome project back.

So whatever happened to stem cell biology, the former darling of hot science?

Travel Back in Time to Synthetic Biology 3.0, Zurich

For those interested in synthetic biology (and if you're not you should be), videos of almost all the talks from Synthetic Biology 3.0 in Zurich are now available for download. Here are my personal favorites and some reflections on the conference:

George Church, Harvard Medical School
Reading , Writing and Evolving Genomes
Although I did find the talk a bit disjointed and rushed (I guess my brain was too slow to keep up), this talk gets you up to speed on the state of the art and the current challenges in genome-scale DNA synthesis. If you look really closely you can see me in the front row struggling to take in everything displayed on the giant IMAX-like projector screen a few feet away.

Pam Silver, Harvard Medical School
Designing Biological Memory and Logic
Pam had some great videos of eukaryotic cells programmed with genetic circuits to show fluorescent "memory" through mitotic generations. Also a nice little idea about reprogramming microorganisms to make hydrogen for fuel.

Ham Smith, The J Craig Venter Institute
The Quest for a Minimal Cell: a Synthetic Genomics Approach
Undoubtedly the most anticipated and hyped talk with Venter's God-like visage and imminent "second creation" being splashed all over the media in the weeks leading up to the conference. Nobel Laureate Ham Smith was surprisingly low-key, and showed everyone that real molecular biologists can still kick it old school and remain at the cutting edge. I especially loved the solution for pipette-free genome handling. Ham showed how his team have successfully transplanted a genome to change one species of Mycoplasma to another, and it looks like the Venter group now really are poised to make the first synthetically-encoded cell.

Miroslav Radman - University of Paris
Reconstructing the genome from hundred pieces: Deinococcus radiodurans
I felt privileged to take in this talk by the brilliant and animated Radman, in which he reviewed his fundamental contributions in the discovery of the SOS response, a form of post-replication DNA repair. With more recent data, he showed how the extremophilic bacterium Deinococcus radiodurans seems to be able to miraculously reassemble its entire genome after it is fragmented into tiny pieces upon dessication or irradiation. Some very elegant experiments further illuminated the mechanistic details of the process, mediated through homologous recombination. With the talk following others who are attempting to assemble full genomes from smaller synthetic precursors in vitro, the immediate question from the audience was whether the assembly of synthetic genomes might somehow instead be performed by endogenous machinery of the recipient cell itself.

Laurie Zoloth, Northwestern University
Hide and Seek: The Ethics of Curisoity and Security in Synthetic Biology
Despite the fact that Laurie is an ethicist and religious scholar, this was one of the most though-provoking scientific discussions I've come across. Exploring the idea of secrecy in science and its impact on society, the talk was full of subtle provocations that I'm pretty sure are still gnawing away somewhere deep in my subconscious. The talk was followed by a panel/audience discussion which was also excellent.

Jeff Tabor, UCSF
A Massively Parallel Biological Edge Detector
One of the major goals of synbio is leveraging the sophisticated circuit design techniques pioneered in electrical engineering to genetically program living cells. Lot of people are talking, but so far I think Chris Voigt's lab is the group most obviously putting this concept to work, with visual results that can't be denied. Jeff Tabor of the Voigt lab showed how an elegantly-designed circuit (involving intra- and extracellular components) can be used to produce sophisticated images with bacterial cell "pixels" (cellixels?).

Justin Gallivan, Emory University
Engineered bacterial chemonavigation
One of the most well-spoken presenters at the conference, Justin gave a great talk with some nice videos that pretty convincingly demonstrated successful reprogramming of bacterial chemotaxis using a riboswitch-based detector circuit.

Winston Timp, MIT
3D Living Cell Microarrays Assembled Using Optical Tweezers
Check out the priceless videos of Winston deftly pushing cells around a dish with lasers. As if driven by unseen forces (he actually used a joystick) the cells are assembled one-by-one into neat little rows and columns. Beautiful!

Ron Weiss, Princeton
Artificial Signaling Pathways for Pattern Formation and Programmed Tissue Generation
Ron laid a lot of the conceptual groundwork for synthetic biology in his PhD thesis "Cellular Computation and Communications using Engineered Genetic Regulatory Networks" under Tom Knight at MIT. His images of fluorescent cells programmed to form spatial patterns were printed on the Synbio3.0 conference organizer's T-shirts, and have pretty much attained the status of cult symbol. Ron is working on making circuits to reprogram mammalian embryonic stem cell differentiation and behavior and discussed this in his talk.

IF ({x} AND {y}) THEN {phenotype}; Programming Bacterial Invasion

Anderson, Voigt and Arkin (UCSF and UC Berkeley) have teamed up to demonstrate the operation of an exquisitely-designed genetic AND gate to control the behavior of E coli (original paper here). The gate integrates two environmental inputs to produce a phenotypic output. As an example, they show how their circuit can be used to program bacteria to invade mammalian cells when the concentrations of two different extracellular chemicals fall within a certain range. You can bet Anderson will be using this circuit to fine tune the specificity of his tumor-invading bacteria in the future. For example:

IF ({hypoxia} AND {acid pH})
THEN
invade

Very nice tricks for making tumor-specific microorganisms. However based on our experience with ad hoc-engineered tumor-killing microbes, the biggest challenges will come in trying to deliver these agents in vivo.

Bayblab podcast Episode11-part1of2

On this episode we talk about recent findings regarding p53 in aging which drastically change the balance between cancer and senescence, we talk about the implication of the reversibility of Rett syndrome and finally Bayman reports on the 3rd international conference on synthetic biology. With special musical guest Kevin Z.

Reprogramming Mammalian Cell Motility

Wendell Lim's lab continues to lead the way in engineering synthetic cell-signaling pathways (not to mention lab website design). This time it's a Nature paper showing how modular protein-protein interaction domains can be swapped onto Rho guanine nucleotide exchange proteins to rewire morphological signaling pathways to respond to novel inputs.

Synthetic Biology

We have discussed 'biohacking/biopunk' topics before on the bayblab. Here is an interesting essay on synthetic biology possibilities. It's a bit 'out there' but an entertaining read.
Things such as:
"It’s easy to imagine grafting an electric eel’s electromagnetic sensitivity into our brains so we can pick up wireless signals. There’d have to be an fail-safe off switch, of course, but the net effect could be amazing. We’d have true telepathy, and the ability to form group minds."
make me laugh.

1010 by 2010

That's 10¹⁰ base pairs of DNA sequenced or synthesized by one person in a single day. That's a hell of a lot. More than enough to cover the whole human genome several times. And that's just one person. Imagine how much a factory full of monkey could do. If you think this sounds ridiculous, read the rationale for the prediction in this great article. As shown below, the projection is based on the current exponential growth of biotechnology, mimicking the trend known as Moore's law, where the number of transistors that can be fit on a microchip has been growing exponentially for the last 50-60 years. The article makes some interesting comparisons between the two industries and also features some of the best discussion I've read on the future of biotechnology and its place in society.