By recovering well-preserved mammoth tissue, like 40,000 year old baby mammoth Lubya, scientists hope to clone the extinct beast and then birth one via an elephant.

South Korean and Russian scientists have agreed on a project right out of “Jurassic Park.” Maybe not as cool as resurrecting T. Rex, but bringing back a woolly mammoth is sure to attract paying customers. On March 13th, South Korean and Russian scientists agreed on a joint venture to do exactly that.

According to the agreement, the Russian team will collect biological samples and send them to the Korean team for processing. The Koreans hope to create healthy cell cultures from the tissue as a source for high-quality DNA. The mammoth genome was sequenced in 2008 so they have a quality check for the new samples. Once they have quality DNA, they’ll use somatic cell nuclear transfer – the same technique used to clone Dolly – to swap out the nucleus of an Indian elephant egg with a mammoth cell nucleus. The egg will then be implanted into an Indian elephant for a 22-month pregnancy.

Pretty straightforward, right? Of course not. But if all goes well we could find ourselves studying the extinct animal and learning more about it than we ever thought possible. Not to mention, if they allow it, people will come in droves to see the mythical creature with their own eyes. It would be an historical moment for genomics and recombinant DNA technologies, biology, and science as a whole, capturing the imagination of billions around the world.

The biggest challenge right now is to find tissue and isolate cells that have healthy DNA, undamaged from freezing or radiation produced from the ground. Siberia is an ideal place to search for mammoth tissue. They first emerged in the area 400,000 years ago and flourished up until very recently when they died out at the end of the last ice age about 10,000 years ago. The extent of their reign means that the Siberian tundra is stocked with mammoth remains that are relatively well preserved and thus offer hope that healthy tissue may yet be recovered. One source estimates upwards of 150 million mammoths may be frozen beneath the Siberian tundra. Rising global temperatures are said to be thawing Siberia’s permafrost and making it easier to get to the mammoths. And even though the mammoths were mostly dead by about 10,000 years ago due to a rapidly changing climate and human hunters, a small group still persisted on Wrangel Island in northeastern Siberia as recently as 4,700 years ago. Recovering tissue so recently preserved would increase the researchers’ chances for success.

Disgraced Korean scientist Hwang Woo-suk successfully cloned eight coyotes by implanting their DNA into the egg of a domestic dog

But cloning still remains a crapshoot even under ideal conditions. Of the 227 eggs that underwent somatic cell nuclear transfer in Dolly’s cloning, only 29 viable embryos were created. And that procedure involved swapping nuclei from cells of the same species. Interspecies nuclear transfer, what cloning the mammoth requires, is even trickier. As the mammoth’s closest living relative, an Indian elephant egg and female are the best choices to receive the mammoth DNA and then carry the pregnancy to term. But whether or not it will work is anybody’s guess.

It may come as a surprise to some to learn that the Korean team at the Sooam Biotech Research Foundation in Seoul is headed by none other than disgraced stem cell researcher Hwang Woo-suk. Hwang became famous overnight when, in 2005, he claimed to have created human stem cells from a cloned embryo. He was later found to have forced the women in his lab to donate their own eggs, and then later was found to have falsified much of the data anyway. But it was Hwang’s ability to perform interspecies nuclear transfer that caught the attention of Prof. Vasily Vasilyev, the First Vice-Rector of the North-Eastern Federal University in Russia. As described in a press release, Vasilyev became convinced that Hwang’s lab was the right one for the job after seeing a news report. The work has been verified by other scientists.

The Russian lab was already working with a team of Japanese researchers on the mammoth restoration project but failure to reach an official agreement with the Japanese scientists have led to the Russians shifting partners. Along with Hwang’s lab, China’s Beijing Genomics Institute is also involved in the project.

Sooam said they hope to have restored viable cells by the end of 2012. If that happens and they are then able to implant the clone egg into an elephant, it becomes a 22-month wait to see if the pregnancy works. Given the overwhelmingly bad odds for a cloned and implanted egg succeeding to birth, it seems like a really big gamble to put all your ‘eggs’ in one elephant. But no one ever accused Hwang of thinking small. There’s no telling what he’ll do next if he’s successful in raising the mammoth.

[image credits: Britannica, telecomtally.com and Wall Street Journal]
image 1: mammoth
image 2: Lubya
image 3: hwang

Today, genomic interpretation can be like looking at tea leaves, but the CLARITY Challenge is hoping to change that. (Image: micahb37/flickr)

Children’s Hospital Boston recently announced a $25,000 competition for the development of an interpretation and communication system that can deliver genomic information from the lab to physicians and patients. As the cost of genome sequencing continues to fall and may break the $1,000 barrier soon, the issue is no longer about acquiring genetic data but about what all the data means. Scientists around the world have been making progress interpreting the molecular language of DNA but, as the Human Genome Project revealed, the human genome contains at least 25,000 genes, so research can be slow going. Furthermore, what information is obtained and published in journals has a hard time finding its way into practices for physicians to understand and apply toward patient care.

At the heart of the challenge is a rather simple question: can genomic information be analyzed effectively and presented to a doctor in a way that helps the patient?

While the hospital could have just tossed more money at genetic research to promote advances, it’s chosen to host a competition to drive innovation. The CLARITY Challenge, which stands for the Children’s Leadership Award for the Reliable Interpretation and appropriate Transmission of Your genomic information, directs research groups and companies to focus on major bottlenecks in genomic medicine. Competitors will receive raw DNA sequence data from three de-identified children with confirmed, unknown genetic diseases and their families. The challenge is to develop a system to root out the underlying genetic basis for the disease and communicate that information in a way that guides physicians in caring for their patients.

The winner is scheduled to be announced in October.

Frankly, in the healthcare world, $25,000 is really not that much money, considering that research grants frequently are in the millions of dollars. But the prize that awaits the group that wins the CLARITY Challenge is what every researcher on the frontier of medicine can claim and reap the rewards from: being first. For something this significant in genomic medicine, odds are that whoever claims the prize will be winning for years to come.

[Media: micahb37/flickr]

[Sources: PR Newswire, Vector, WSJ]

I took a look inside Complete Genomics' lab. What I saw turned me into a believer.

The future of human genetics will arrive when we understand how each gene in your DNA interacts with every other gene to form who you are. In order to get that understanding we’re going to need to sequence a huge number of genomes. And in order to sequence genomes we’re going to need Complete Genomics. The Mountain View based startup recently went public (NASDAQ: GNOM); with their requisite silent period ended we finally got a chance to tour their facilities and talk again with their CEO Cliff Reid. We were impressed. Complete Genomics isn’t going to conquer the entire world of DNA testing, but the kingdom of human genome sequencing they’ve carved out for themselves looks amazingly well fortified. As far as I can tell, if CG really takes off no one else will be able to challenge them in whole human genome sequencing for years to come. We asked Cliff Reid about the IPO, the genomics market, and some recent advancements in Complete Genomics’ analytical software. Check out his answers in the videos below.

Complete Genomics doesn’t sell a device, they sell a service. Companies like Illumina make DNA sequencers they sell to other companies. Reid and his gang take DNA samples and return with huge amounts of DNA data. Customers never need to deal with the biochemistry. That full service approach helps Complete Genomics focus on increasing the number of human genomes they can sequence for customers, and lowering the price for each. In the following clip, Reid gives us an update on the company, including the success of the IPO, and a look at its production capability and the current price of sequencing human genomes.

Getting to explore Complete Genomics’ Mountain View facilities was pretty amazing. I was struck by the relatively small size of the sequencing lab (though there’s plenty of room for expansion) and the degree to which automation is used. The company can produce 400 whole genome sequences each month, but there’s only ever two technicians working at any given time in the sequencing room. Robotic instrumentation and equipment makes the lab almost seem like a ghost town, but there’s a lot of action going on. I wish we could have turned our cameras on while touring that place, I bet many of you (and all of CG’s competitors) would have loved to see what they had cooking.

While we didn’t get any trade secrets out of Reid, the recipe for Complete Genomics’ secret sauce is pretty clear. This company is about doing one thing and doing it really well. Other big names in sequencing (Illumina, BGI, etc) are looking to handle many different kinds of genetic reading such as examining RNA, sequencing microbes, and sequencing animals. Complete Genomics is doing just one thing – whole human genomes. With that laser-like focus comes the ability to scale their entire company around a central mission. As we’ve said in previous coverage of this company, economies of scale, and single-mindedness in action will help Complete Genomics get cheaper and cheaper, faster and faster.

Eventually that means you’ll have access to inexpensive sequencing for your own genome.

Yet it will take a while to get there. Most of the whole genome sequencing done today is purchased by research labs, not by individuals looking to understand their own health. That’s how it should be. It’s going to take years for researchers to fully understand our DNA and what the variations in our genes mean. Selling genome information to individual customers like you and me would be premature. For now, Complete Genomics is focusing on the research market and helping them make the discoveries that will revolutionize genetics. Once the price per genome comes down, and the science behind genetics is better understood, Complete Genomics will transition into the consumer market. Reid says as much in the following video:

Complete Genomics isn’t 23andMe, Pathway Genomics, or any of the other companies selling genetic tests on the market today. First off, those groups are only testing a small subset of your entire genome for simple variations in individual letters of DNA (single nucleotide polymorphisms or SNPs). Complete Genomics is sequencing whole genomes – all 3 billion letters of DNA. Just as importantly Complete Genomics is waiting until researchers know more about the genome before they try to offer genome sequencing to consumers. That’s different from the current genetic testing companies that the FDA and congress are worried about. Those businesses will sell you genetic tests today, while much of the science is still not completely understood. Don’t get me wrong, I think there’s a place for that. Complete Genomics, however, is waiting until there’s an actual use for you to know your whole genome sequence before they try to sell it to you.

In the years ahead someone is going to have to process thousands (millions?) of genomes before we understand our DNA well enough to make the sort of pinpoint health recommendations that the public expects from this promising technology. Who’s going to sequence all that DNA? My guess is Complete Genomics. Again, getting back to that focus on whole genome sequencing, the company has built it’s entire technology around reading human DNA faster, better, and cheaper than anyone else.

The center of their business is their fluorescent read technology, which analyzes nanoballs of DNA that correspond to different A, C, T, G ‘letters’ of genetic code (learn more about the nanoballs on the Complete Genomics website). In Reid’s words they, “use silicon to read silicon”. A silicon based semi-conductor camera is precisely aligned with a different silicon wafer full of tiny pockets where the nanoballs sit. When I say tiny, I mean tiny – those pockets are just 300 nanometers across. The camera only has to use a few pixels (soon even fewer will be needed) to optically read each nanoball and determine if it contains an A, C, T or G.

According to Reid, Complete Genomics had reached the limits of optical reading technology. They are (or soon will be) using as little digital information to read each letter of DNA as you possibly could. The best other companies could probably do is match them. Add in the fact that their automated reading technologies are getting faster, and their analytical software is getting smarter, and you can see that Complete Genomics is quickly making itself the foremost leader in whole human genome sequencing.

Even if another company finds a way to sequence whole genomes with the same speed as Complete Genomics, I still think Reid and his cohort will come out on top. By focusing on just one product (whole human genomes) Complete Genomics will develop an unprecedented amount of experience in their field. They’ll discover all the little undiscovered idiosyncrasies that make human genomes unique compared to other sequencing projects and they’ll understand those twists and turns better because human genomes will be the only thing they work with. Single minded focus will help Complete Genomics learn all the tricks, and this will help make them more streamlined, faster, cheaper, and better at analyzing human genomes.

In the following video, Reid discusses Complete Genomics’ technology. Recently, the company announced a particularly exciting advancement in their software for digital analysis of DNA. Now when a researcher sends a genome to be sequenced CG will include information about copy number variation and structural variation – data that can illuminate where in a cancer cell genome that DNA has gone bad. Basically Complete Genomics is making it much easier for scientists to translate genomic data into insights about the nature of cancer. Coupled with a growing assortment of open source analytical code (CGA tools), Complete Genomics’ software is accelerating research into genetics. Pretty cool.

Other companies, like Ion Torrent, have developed DNA reading technologies that use semiconductors rather than optics to sequence genes. These CMOS based sequencing technologies have been hailed as the next step forward in genetics. As you saw in the video, Reid explained the reason why they aren’t afraid of semi-conductor based DNA readers. Can we all say that reason together? Complete Genomics only has to worry about whole human genome sequencing. While we toured the Complete Genomics facility, Reid pointed out that if you calculate how much current CMOS tech will cost to sequence a full human genome, the price would be many hundreds of thousands of dollars (or more). The big advantage semiconductor sequencing has is that it can fit on a desktop. Complete Genomics doesn’t want to fit on a desktop and they don’t want to be portable. They just want to sequence whole human genomes.

The same logic applies to those companies looking to push the boundaries of how much DNA they can read at a time. In the sequencing field, there are both ‘long reads’ and ‘short reads’. The human genome has more than 3 billion base pairs (those A,C,T, G letters). In order to sequence a genome you end up first sequencing smaller chunks of those letters, and then pasting those chunks together to get the full 3 billion letter code. The shorter the chunks you use, the more you need to double check your work and the more complex it is to paste things together. ‘Short reads’ sequence each chunk multiple times (10x or more for some Complete Genomics projects) while ‘long reads’ get away with doing that less. Long reads, however, also tend to be slower and more expensive. As Reid explains, long reads are good for some things, but Complete Genomics isn’t into those things. They have improved software that makes short reads the most economic way for them to proceed with human genomes.

This company knows exactly what it wants to do. And it is doing it really well.

That doesn’t mean I’m completely free of concerns. I’ll stop my blatant cheerleading for a second and do a little math. Reid didn’t give us an exact total for how many genomes they’ve sequenced (that’s ok, we know from other press materials that the number is more than 500 – damn impressive) but he did tell us that his current capacity is around 400 genomes per month. Those sell at a price of $10,000 each (or less if bought in bulk). Assuming there’s enough market demand (which I think there is), that means with current levels of production Complete Genomics could make around $4 million a month in revenue. So, maybe $48 million a year? Remember, even as Complete Genomics increases its production to drive up their revenue, the price per genome is planned to recede. This company has spent “tens of millions” on improving their software, and according to their own reports they spent more than $20 million in Q3 of 2010. Is $48 million per year enough for Complete Genomics to grow? Reid says they are very happy with their IPO, but I know that if I were in his place I would have been even happier if they had raised their original target of $80M instead of the $50M or so they got.

I think this next year is going to be a critical time for the company. Depending on funding and revenue they could have to stay on a conservative growth curve. Or, if they secure the finances, they could really ramp up – trust me, the technology looks like it is more than ready.

I really want a whole genome sequence to cost less than $1000 and not simply because I ‘m itching to peer at my own software code. By the time we hit that price point, researchers will have had the opportunity to look at thousands (tens of thousands?) of genomes and finally get the data they need to puzzle out some of the secrets of our DNA. That future may be nearer than we think. For now, Complete Genomics looks like the company that is going to take us there. I can’t wait.

Update: No person at Singularity Hub currently owns any stock in Complete Genomics or owns any financial stake in the company whatsoever.

[image credit: Complete Genomics]
[video credits: Aaron Saenz/Singularity Hub]
[source: Cliff Reid/Complete Genomics]

BGI is the leading sequencing institute in Asia, with interests in a variety of genomic fields.

When it comes to genomics, China seems a little like the proverbial kid in the candy store – she wants a taste of everything. Of course, unlike the child, China might be making a bid to own the candy store outright as well. The Beijing Genomics Institute (BGI), now located in Shenzhen, is the leading genomics facility in China, and all of Asia. BGI has striven to make a name for itself in every major international genome sequencing project of the last decade. The International Human Genome Project, the International Human HapMap Project, sequencing SARS, the Sino-British Chicken Genome Project, etc. It was also responsible for completely sequencing the rice genome, the silkworm genome, the giant panda genome…the list goes on an on. By the end of this year BGI will have 128 of Illumina’s HiSeq 2000 platforms, 27 of AB’s SOLiD 4 systems, and many other sequencing devices. At full capacity this means they will be capable of the equivalent of 10,000+ human genomes per year. And they are still growing. BGI may not be the largest genomics facility in the world, but it is has phenomenal support from its government, ambition to expand quickly, and a hand in dozens of major sequencing projects. You can’t talk about the future of genetics without talking about China.

In late 1999 the Beijing Genomics Institute started to build China into a world leader of genetic research. In the decade that’s elapsed since, they’ve put their name on some major developments. Here are just a few of the biggest newsmakers:

• First Asian Diploid Genome Project – The first sequenced genome for a person of Asian descent in late 2007. Published in Nature 2008.
• Cloned Pigs – BGI was instrumental in creating handmade clones of pigs in 2008.
• Giant Panda Genome Project – BGI sequenced the Giant Panda (whose genome is roughly equal to a humans) on its own in just eight months in 2008-2009! Published in Nature 2009.
• Cucumber, and Rice Genome – Among the first sequences of complex plants used as food crops. Cucumber published in Nature 2009.
• Silkworm and Ant Genomes – Among the first sequences of a domesticated insect, and ecologically important insects. Ants published in Science 2010.
• SARS – Sequenced the SARS virus just hours after a Canadian team completed the first mapping of the pathogen.
• Ancient Human – BGI was the first to sequence an ancient human genome (a paleo-Eskimo). Published in Nature in 2010.

Since its inception, BGI has had a very ambitious attitude when it came to participating in world genomics. Every time they were presented with a new project, they basically said, sure, we’ll be a part of that. They contributed 1% to the Human Genome Project’s reference genome, and 10% to the Human HapMap Project. It was like they never met a sequencing project they didn’t like.

That attitude hasn’t seemed to wane at all. BGI is spearheading efforts that will sequence a wide variety of organisms. There’s the 1000Genomes Project aimed at producing a wide database of human genomes from people all over the world. They are also working to sequence 1000 plants and animals, and have already completed 14+ of the former and around 50 of the latter. In 2009, BGI launched its effort to map the genomes of 10,000 microbes – they’ve managed 800 bacteria, 100 fungi, and 100 viruses so far, with more finished every day. They are looking for collaborators to sequence 1000 Mendelian Disorders in humans. Completion of large genetic databases like these will be part of what could empower genetic research to finally make the discoveries the public has been waiting for since the first human genome was sequenced a decade ago.

Even while BGI is a testament to Chinese ambitions in genomics, it also speaks to the prominence of the US in that field. BGI relies heavily, almost exclusively, on sequencing technology rooted in California. Illumina’s HiSeq2000 and Applied Biosystems SOLiD 4 form the bulk of BGI’s machine workforce. To be fair, most of the world has focused on using these systems as well, and BGI is working to expand its hardware horizons, collaborating with OpGen on new optical sequencing methods. Still, when one sees BGI’s successes in genomics one also has to acknowledge that such capabilities weren’t developed in a vacuum. China’s sequencing projects, like every nation’s sequencing projects, have worked as part of a larger global effort.

The only real question, then, is how much will China simply be a part of that worldwide phenomenon, and how much will it lead? Even if the hardware is largely developed by California companies, those companies themselves are international entities. BGI is officially part of the sequencing club, recognized by Illumina as one of its associated world class facilities. BGI isn’t some second tier group working its way to the top, it’s already at the top, sharing space with the other lead genomics institutions around the world. If BGI and China continue to dedicate money, labor, and insight into genomics, they’ll be able to set the agenda for many sequencing projects around the globe. Actually, they’re already doing this with their various sequencing projects for microorganisms, plants, animals, and humans.

I know that many of us will view BGI’s growing importance through the lens of competitive national spirit. Yet no matter your feelings about China, you have to view BGI’s accomplishments as wonderful gifts to the global scientific community. Every genomics center around the world is going to have different specialties (Complete Genomics is dedicated to bringing down the costs of human whole genome sequencing, for instance) and it’s only through combining these disparate efforts that we’ll create the general understanding we need to move the field of genetics forward. It’s a team effort. Yay China, Yay us.

A map of the populations of major genome sequencing platforms around the world. Not yet updated for the end of 2010. Just some food for thought.

[image credits: BGI, Pathogenomics]
[sources: BGI]

Venter, master of DNA, speaks bluntly to Der Spiegel about genetics.

“We have learned nothing from the genome.” That’s the grim message that J. Craig Venter recently gave Der Spiegel in an amazing interview. Venter, decoder of the human genome and creator of the world’s first fully synthetic bacteria, doesn’t pull any punches when describing the medical benefits we’ve derived from sequencing the human genome. They are “close to zero to put it precisely.” The Der Spiegel interview catches Venter in a blunt mood and we’re given a rare insight into how one of the foremost scientists in the field (probably the foremost scientist) see our progress thus far and our hopes for the future. To paraphrase: we haven’t really accomplished anything yet, people don’t want to believe that at all, and we’re finally taking the first steps to really understanding things now. Some of Venter’s juicier statements have me rethinking the current state of genomics. Check out the quotes below.

As we recently discussed, the 10 year anniversary of the Human Genome Project (and Venter’s competing and more successful Celera Genomics) has raised serious questions about what we have really learned from our foray into genomics. We’ve had success with in vitro screening for certain genetic illnesses, and we’ve used genetics to craft a few new medications, but the public at large has not seen a lot of benefit. Why?

Because we have, in truth, learned nothing from the genome other than probabilities. How does a 1 or 3 percent increased risk for something translate into the clinic? It is useless information.

We’ve seen personal DNA testing become a burgeoning product, with companies like Pathway Genomics, 23andMe, and Navigenics offering to scan your genome for important genes (SNPs) and tell you what their presence may mean. Such tests are all about probabilities, and many have raised the same concerns as Venter – that we what we learn from such studies is practically useless. I for one, enjoyed my DNA test, but mostly for the educational merit. I’ve haven’t changed a single habit in response to the data I was given. Why?

we need a lot more information: Information about your body’s chemistry, your physiology, your complete medical history, your brain and your entire life. We would need to do that a million times on different people and correlate that data with their genetic information.

Essentially we have more DNA than understanding. Until we can correlate massive amounts of genetic data with real-world effects we really don’t know what to tell people when we give them results to personal DNA tests. Even those that have had their whole genome sequenced (not just SNPs) don’t really have much insight into their lives. As Venter says about his own experience with sequencing: “We couldn’t even be certain from my genome what my eye color was.”

But efforts are already underway to correlate medical histories with DNA. We’ve already discussed biobanks of hundreds of thousands of patients that are being created over the next decade. With cheaper whole genome sequencing it will eventually be possible for us to examine this rich pool of data and perhaps discover meaningful and useful insight into how genes affect our bodies and health. What happens then?

It’s not, ‘Oh, we know your genome, we’re going to make this drug for you.’ That will never happen. It is more important that you use the information in the genome about your personal risks and reduce them through intelligent behavior.

I heartedly agree on the last part, but object to the first. We don’t know if it will be practical to tailor drugs to individuals (probably cost prohibitive) but I think it is likely that we’ll be able to customize treatments. Doctors already do that for every patient without a lot of knowledge about genetics. In the future we may not create entirely new medications for each patient but we’re very likely to use fast chip processing to give doctors an idea which drugs will react poorly with the patient due to genetic predisposition. Given enough possible combination of medications the difference between custom making drugs and custom designing a cocktail of them will seem slight. In my opinion.

If you think that Venter’s comments in Der Spiegel are unbearably gloomy, you haven’t read enough of the interview. Yes, the first third is mainly Venter trash talking about Francis Collins, and the second third chastises everyone for thinking that genetics was some magical cure-all or some dreaded infringement on God’s turf. The last bit, however, reveals where Venter’s hopes seem to lie: in creating new life from scratch.

We don’t even know how the simplest bacterial cell works. We want to learn what the minimum cellular components are, so we’re going to be taking out all the non-essential genes.

He’s already assembled bacteria from the building blocks of DNA, and now he has his sights on using that technology to really advance our understanding of genetics. He and his team plan on building a ‘minimal cell’ – the simplest form of bacterial life you can make and still have survive. The hope is that this will lead to a greater understanding of what it takes to be an organism – to understand the basic components and operating system of cellular life.

From that understanding could come the ability to truly design organisms from the ground up. We could design bacteria that produce complex carbon compounds and reduce our need for oil. Exxon Mobile has invested $600 million with Venter in the hopes of creating these new life forms which could radically alter the availability of resources all over the world. Think of what the organisms we design may be able to produce.

Not only gasoline. Plastic, asphalt, heating oil: Everything that we make from oil will at some point be made by bacteria or other cells. Whether that is in five, 10 or 20 years is unclear. Why don’t we have fuel now other than alcohol from microbes? It’s because nothing evolved that can produce great amounts of biofuel out of CO2. That’s why we have to make it.

Venter’s vision of the future seems to be as hopeful as his vision of the past is disdainful. There is so much power in genetic engineering and synthetic biology that it’s hard to fully grasp both its limitations and its potential. If there is one message to take away from Venter’s comments I think it is this: we need more understanding. Thankfully there are many, including Venter and his colleagues, who are pursuing that understanding with a fiery passion.

All quotes are J. Craig Venter,2010 as taken from Der Spiegel. The full Der Spiegel interview with J. Craig Venter conducted by Rafaela von Bredow and Johann Grolle can be found here. It is awesome. Read it.

[image credit]
[source: Der Spiegel]

US District Court ruled in favor of the ACLU against Myriad Genetics, striking down their patents on human genes.

In what is sure to become a landmark case for genomics, a US District Court Judge in New York (Robert Sweet) has ruled that patents on human genes held by Myriad Genetics are invalid. These patents, on the BRCA1 and BRCA2 genes, were issued more than a decade ago and gave Myriad exclusive rights to examine those sections of DNA. Mutations in BRCA 1 and 2 carry important links to breast and ovarian cancer, and Myriad’s BRAC Analysis (Be Ready Against Cancer) genetic screening is used to provide patients with a better understanding of their risk for the diseases. The court decision effectively eliminates Myriad’s rights to solely market tests on the BRCA genes, which may lower costs (previously up to $3000) for those interested in the tests . The American Civil Liberties Union (ACLU) lead the attack against the Myriad patents which it shares equally with the University of Utah Research Foundation. This case has wide ranging implications for the entire genomics community. 20% of human genes are patented, often along with the process of identifying the genes, and these patents are now drawn into question. It is almost certain that this ruling will be appealed and eventually reach the US Supreme Court. It may take years before a final decision is made, but for now it seems like the human genome may no longer be up for grabs as intellectual property. Thank goodness.

Biotech intellectual property rights are big business.  We’ve seen company stock prices surge with the grant of a new patent. Myriad’s price (NASDAQ: MYGN) had a rough drop since the announcement of the court ruling. Investors, not just in Myriad but in all firms with genetic patents, must be asking themselves how far reaching this decision may be.

Judge Sweet’s ruling is long (150+ pages), but you can find a copy of it here thanks to the Genomics Law Report. Likewise, the patents Myriad holds on the BRCA genes are numerous (1,2,3,4, …). Trying to sift through this legal material is difficult, but we can summarize the ruling down to two facts. Sweet found that:

1. The DNA patented by Myriad Genetics (isolated from the human body in a lab, along with mutations there of) are not markedly different from natural DNA (that found in your body, mutated or otherwise).
2. Comparing DNA sequences to identify BRCA genes and their mutations is an abstract mental process.

In other words, you can’t patent nature and you can’t patent a fundamental idea of science. There’s little doubt that the breadth of these two findings are likely to apply to the vast majority of patents on genes in the United States.

Human genes, that is. Patents on plants and animals are unlikely to be called into question at this time. That’s because many such patents are not held on ‘natural’ organisms, but on those that have been genetically modified. Whether it’s pest-resistant rice or artificial meat, GM foods are generally thought to represent an engineered good.

Which begs the question, would Sweet’s ruling cover human genes that have undergone engineering. Probably not, but the germline mutations of humans is still largely opposed so the cases involved are likely to be small. One day, however, we may all carry a few genetic modifications. Gene therapies could alter the DNA (or maybe just the protein production) in our bodies. Would such variations then mean we are carrying some corporation’s intellectual property inside us? What if someone naturally developed such genes on their own…would their bodies be committing copyright infringement?

That’s the sort of terrifying prospect that could await us if we continue to allow patents on human genetic material. It’s one thing to patent a process on making a chemical, or even that chemical itself, but when the chemical is your DNA…your allowing ownership (at least in part) of a human.

Of course Myriad Genetics isn’t trying to enslave humanity. No biopharmaceutical company, as far I can tell, is so stupidly nefarious. MG’s products help patients identify their risks of cancer. That’s certainly not a bad thing – in fact it should be applauded. Indeed, Myriad Genetics has made the claim that such patents on genes allow the holding company to develop techniques secure in the knowledge that they can turn a profit to compensate for their investment. Without such guarantees to their work, MG lawyers have argued, research will be stifled.

But certainly research has been stifled in the other direction as well. By holding exclusive rights to the BRCA genes, Myriad Genetics keeps other companies from freely working on the same gene without fear of legal reprisal. Apply that scenario to the 20% of human genes patented and you begin to wonder how much research has been stunted by this hording of genetic territory. If we applaud MG for developing cancer risk assessments and treatments, we must also reprimand them for preventing others from doing the same.

We may need to rethink patents. Intellectual property as a whole is undergoing a metamorphosis (much like privacy) and it’s becoming increasingly clear that such restrictions may not be enforceable. China seems to violate patents whenever it feels like it. Brazil permitted the creation of generic versions of AIDS medications in spite of patents. Even within a single country (like the US) consumers are pirating copyrighted material. We are struggling with these legal issues (locally and globally) but it seems likely that the free exchange of information (via the internet) is counteracting the premise of intellectual property on a fundamental level.

Even if we somehow managed to find ways to rigidly enforce all patents, I don’t think we would want to extend that enforcement into genetics. We are our genes. Even as we learn to alter and influence how those genes are expressed, humans still need the inalienable rights to their DNA. Anything else would be socially disruptive on a grand scale, not to mention terrifying. In the more limited cases of research and development (patenting just the identification process or a certain technique to refine genetic material for testing) things may become gray. How can we best allow companies to find a return on their investment (and thus encourage investment) without preventing other firms from also developing similar work (thus encouraging research)? It’s a difficult question and one that is likely to be years in the answering. For now, it is enough to look at Judge Sweet’s ruling and wonder how long it will be until the next court case. We’ve only just begun.

[image credit:ACLU]
[Source: US District Court Ruling, Genomics Law Report, Myriad Genetics]

Dr. Cliff Reid, CEO Complete Genomics, Has A Master Plan To Sequence 1 Million Genomes!

Without a doubt the hottest company in the genomics sector right now is gene sequencing powerhouse Complete Genomics. In just the last four years the company has come out of nowhere to dominate the market for low cost sequencing of human genomes in large quantities. Although Complete Genomics is now slated to sequence an incredible 5,000 human genomes in 2010, this is nothing compared to what the company has in store for the years ahead.  Just days ago, in a Singularity Hub exclusive interview with Complete Genomics CEO Dr. Cliff Reid, we have learned that the company is now hoping to sequence 50,000 genomes in 2011 and a whopping 1 million genomes by 2014. Considering that by the end of 2009 only about 100 or so human genomes had ever been sequenced, most of them by – you guessed it – Complete Genomics, this represents an enormous shift in the industry. In the rest of this post I will share with you the juicy details from the interview, followed by the full video of our conversation at the end.

Although companies like 23andme or Illumina have been hogging much of the headlines in genomics recently, the real story may be that Complete Genomics is about to rewrite the game for the entire industry. Simply put, Complete Genomics is the first company to realize that sequencing human genomes is a brute force computational problem that is best overcome through large scale centralization.

Traditionally if a research team wanted to sequence a human genome they would be forced to purchase expensive machines from the likes of Illumina to do the job. These machines, such as Illumina’s latest HiSeq 2000, might cost half a million dollars or more up front, require the hiring and training of several staff to operate and maintain the instruments, and require several different types of expensive, specialized materials as continuous inputs. What’s more, these expensive and wonderful machines might end up sitting around much of the time unused in between projects. In a world that demands the sequencing of millions of human genomes in the coming years, this model of distributing individual sequencing machines is simply too costly and inefficient.

Enter Complete Genomics: Master of Centralization and Scale

In the next decade we may sequence the genome of nearly every person in the developed world. With 6 billion people in the world and approximately three billion base pairs per genome we are talking about an enormous task of scale and computation.  Years ago Complete Genomics realized that centralization in a dedicated sequencing facility was the answer to this challenge.  Today they are bringing their vision to reality.

Instead of building individual machines that can be shipped off to laboratories, Complete Genomics is turning the traditional industry model upside down and doing the sequencing itself.  Researchers send Complete Genomics a sample of human DNA in the mail, allow them to process it in their sequencing center, and shortly thereafter they will ship back the sequencing results at a cost and speed that is crushing the rest of the industry.

What do I mean by “crushing”?  In November of last year Complete Genomics announced that they had sequenced 3 human genomes at an average cost of materials below $5000 apiece, shattering all previous records by nearly a factor of ten!  Last year Complete Genomics was charging its customers $20,000 per genome and this year they will be charging $10,000 or less.  We can expect the company’s costs and the prices it charges its customers to continue to drop dramatically in the next few years. The $1,000 genome is indeed within sight.

Complete Genomics is essentially turning genomic sequencing into an assembly line process with all of its associated advantages. Equipment can run pretty much 24/7 without interruptions, thereby maximizing the output and return from multimillion dollar investments. A small staff can be trained to run an entire facility of sequencing machines. This significantly reduces the human cost of training and labor.  Reagents and other supporting materials can be purchased in bulk on the cheap.

Further streamlining the process and the costs, Complete Genomics is only sequencing human genomes. This is a huge differentiator that people often overlook, yet it is crucial to the competitive advantage of the company. When working with multiple organisms, there are unique factors such as reagents, read sizes, genetic coding idiosyncrasies, and preparation methods that must be accounted for. By focusing solely on human genomes Complete Genomics is further optimizing its operations for low cost and high efficiency.

Although originally slated to go live this January, Cliff Reid says that Complete Genomics’ first large scale sequencing center is now going to launch on April 1. It is because of this delay that Complete Genomics’ is only targeting 5,000 genomes this year instead of its original target of 10,000. Of course 5000 genomes is still nearly 50 times the number of genomes that have ever been sequenced to date by all companies/institutions combined. Not bad!

Can They Really Sequence 1 Million Genomes In 5 Years?

Although Complete Genomics is aiming for 1 million genomes by 2014, we need to take this target with a grain of salt.  Given that the company is set to deliver only half as many genomes in 2010 as originally planned, who is to say that their 2014 roadmap won’t fall equally short?  Yet to focus on a specific number really misses the point.  The key takeaway here is that Complete Genomics is finally ushering in the long awaited era of cheap, high volume genomes through assembly line centralization and scale.  The model seems to be a winner, and even if Complete Genomics were to somehow stumble, it is likely that competitors would be quick to follow suit.

A comparison to Henry Ford’s pioneering of the car assembly line with its hugely successful Model T naturally comes to mind, and this is not lost upon Cliff Reid.  Ford famously said “Any customer can have a car painted any color that he wants so long as it is black.”  In homage to Ford, Reid joked during the interview that “We’ll sequence any organism, as long as its human”.

United States Today…Tomorrow The World

Over the course of the next year Complete Genomics will be creating plenty of waves in the industry with the world’s first human only large scale sequencing facility here in Mountain View, California.  This facility will single handedly sequence on the order of 50,000 human genomes in the next 18 months.  Impressive – yes – but to get to 1 million genomes in the next 5 years Complete Genomics is going to need more large scale sequencing facilities.  Many of them will need to be in other parts of the world, such as Asia.

Can you say CAPEX?  According to Reid, the current plan is to build up to 10 sequencing facilities in the next several years, each of them able to produce anywhere from 50,000 to 100,000 genomes per year.  Although increased output and redundancy of operations is a key driver of these added facilities, Reid points out that political jurisdiction is an equally important driver.  Governments will be reluctant to see their citizens’ genomic data crossing borders.  If Complete Genomics wants to be in the game of sequencing genomes of major countries in Asia they are going to have to go inside those countries to get the job done, and that is indeed where they will go.

More Genomes, More Money – An IPO?

As we can see it is going to take a fair amount of capital for Complete Genomics to pull off its master plan.  Last quarter the company secured $45 million in funding despite a very harsh economic environment.  Yet this cash infusion is only a temporary measure to get the first facility or two up and running.  More money will be needed to realize the company’s vision for ten or more sequencing facilities and 1 million genomes in the next 5 years.  As Reid says in the interview “Fast growing companies like ours inhale cash”.

Of particular interest to many following this hot story is whether or not an IPO is in the company’s future.  Although legally and strategically we can’t expect Reid to full out confirm an upcoming IPO, he does the next closest thing with the following comment “We also hear rumblings of the public offering market becoming open to certain companies and we would consider that a very attractive option”.  Investors get your cash reserves ready – an IPO looks like a strong possibility.

What Will We Do With 1 Million Genomes?

One argument I often hear from people is that all this genome sequencing business is a big waste of time.  After all, more than fifty genomes have already been sequenced and what do we have to show for it?  Where is the medical revolution that genetics was supposed to unleash?  Will there really be a demand for the sequencing of 1 million genomes in the next 5 years even if Complete Genomics can provide it?

Are you freaking kidding me!  One million genomes is just the tip of the iceberg folks!  Over the next decade or two we will probably sequence tens of millions of human genomes, and – yes – this data WILL be useful.

As with nearly all hot topics of the day – and genomics is no exception – our imaginations have gotten ahead of the technology.  The medical revolution promised by genomics will indeed become reality, but it will take many more years than people thought.  It turns out that by sequencing only a handful of human genomes there is only so much information that can be learned.

As Reid likes to say, there are only about 1,000 major human diseases out there.  One million sequenced human genomes will allow us to study the genetics of each of these 1,000 diseases, each with a pool of 1,000 genomes for comparison.  The information that will be teased out of this data will indeed produce the medical revolution that we have all been waiting for, but first we need tens of thousands of genomes to perform the required analysis.  We need the data!

We Are A Data Company

One of the things I love most about Complete Genomics is their laser focus on doing only one thing: sequencing human genomes.  This extreme focus on doing one thing well has been a proven secret to success for many of the world’s greatest companies.  It will be no different with Complete Genomics.

Rat genomes, worm genomes, and the genomes of countless other organisms will need to be sequenced in the coming years, but Complete Genomics is going to ignore those.  As Complete Genomics comes to dominate the market for human genome sequencing in the next several years, it may be the sequencing of non-human genomes that will provide a still enormous market for the Illuminas of the world.  It is great when a field is so large that there is enough room for pretty much everybody to win.  Genomics is one such field.

In the end Complete Genomics is a data company.  Their gift to the world in the next several years will be to deliver the vast store of data that is locked within the individual genomes of each of us.  Understanding this data, and converting this understanding into real world medical solutions, however, is not Complete Genomics’ game.  They will leave that task to other companies.  Complete Genomics is not the company that will directly give us the medical revolution that we have been waiting for, but indirectly their role is equally important.  They are giving us the data.

But Who Are The Customers?

Although it is exciting to think of average citizens purchasing their genomes directly from Complete Genomics, at least for the next two years Reid explains that the real demand will come from research institutions and corporations.  These organizations have the budgets, not to mention the desire to discover the next big medical breakthrough, to justify the purchase of thousands of genomes from Complete Genomics.  Individuals will indeed be able to purchase there own genomes in the future, but at least for the next 2 years individuals will not be the key driver in this business.

Complete Genomics – We’re Watching You!

Well, that about sums up the interview with Complete Genomics, but our coverage of the company has only just begun.  We will be monitoring the progress of the company closely, so stay tuned for more posts in the future.  In the meantime, be sure to check out a full video of the interview below:

Complete Genomics uses a sequencing technology called “short read”, which means that they decode the DNA in small segments and then stitch all of these small segments together to make the whole sequence.  This same technique is used by many of Complete’s competitors, and is plagued with the problem that errors are sometimes introduced into the sequence during the stitching process.  MacArthur notes that Complete Genomics’ current error rate of 0.1%, which is reasonable by current industry standards, would result in 300,000 errors in a 3 billion base pair whole human genome.

So what does this mean?  It means that although Complete Genomics’ ability to accurately decode genomes seems to be within the range of its competitors, it falls short of the 100% accuracy that is ultimately desired.  The upshot is that the coming revolution in genomics in the next few years will be somewhat limited by sequencing that is not 100% accurate.  There is still a great deal of work that can be done on genomes that are 99.9% accurate and great scientific progress will undoubtedly result.  Ideally though, in the next ten years the technology will improve to true 100% accuracy, at which point further doors will be opened in the field of genetic analysis.

MacArthur reminds us that Complete Genomics is committed to only sequencing human genomes, even though genomes of monkeys and other organisms could easily be performed.  The reason:

“focusing only on large-scale human -omics will allow Complete to avoid the worst complexities of the service model (i.e. receiving many types of sample that require processing in many different ways), but still focus on the area where the market is the strongest.”

“Reid says that the goal of Complete is to create “a stream-lined factory” producing complete human genomes; by focusing on just one application (unlike any other genome facility) they can hone this process down to the point that they can do it cheaper and better than anyone else.”

Our interpretation: Complete Genomics is smart!  These guys are carving out the position as the company to go to for human genomic sequencing.  The genomics field is competitive and wide.  By narrowing their focus to human only genome sequencing, Complete Genomics is simplifying their business model and further solidifying their position in the lucrative market for human genome sequencing.

Image: source

When reading Daniel’s post you can feel the intensity at the conference as companies at AGBT fight for top bragging rights to deliver the fastest and cheapest genome sequencing capability to the world.  The stakes are extremely high: literally billions of dollars in sales await the company that can dominate in the delivery of affordable, rapid, whole genome sequencing to every human on the planet.

The intensity at the conference reached a climax when Clifford Reid, the CEO of Complete Genomics, delivered his much anticipated presentation to confirm whether or not the company’s industry shattering claim of $5000 sequencing of a whole human genome by mid-2009 was really true.  According to MacArthur, Complete Genomics did not disappoint, and hence a company that nobody had even heard of until it came out of stealth mode in October 2008 now appears to have cemented its position solidly at the front of this high stakes race.

So what is the secret behind Complete Genomics’ stunning success?  The secret is that Complete Genomics’ has completely upended the business model for genetic sequencing, focusing on computational might and centralization while its competitors have focused on flexibility and distribution.

Complete Genomics’ competitors have built their business models around the production of devices that their clients can purchase and install at their own facilities.  This business model offers customers the flexibility of performing their own genetic sequencing, but in exchange for this flexibility customers are limiting the computing capacity they can throw at the problem to what can be squeezed into a deliverable product.

Complete Genomics, on the other hand, does not produce anything that its customers can install or use.  Realizing that genetic sequencing is a raw horsepower problem of who has the most computing capacity,  Complete Genomics has built a server farm that can be continuously expanded to throw more and more computing muscle at the problem.  Complete Genomics has optimized the computation of genetic sequencing, building one centralized, giant super sequencer that now seems poised to leave its competitors in the dust.  Within the next 5 years Complete Genomics is aiming to sequence a whopping 1 million human genomes!

It is important to point out that being the fastest doesn’t mean anything if your output is littered with errors.  MacArthur notes that investigation is still required to confirm the accuracy of Complete Genomics’ sequencing technique when he writes:

“I was convinced by the SNP data, but I will be very interested to see how the system performs in terms of calling large-scale structural variants, and in dealing with highly repetitive regions. These are major problems for very short read technologies that can’t be solved by simply increasing coverage; information on these issues was largely missing from Reid’s presentation, aside from an almost cursory mention of a technology called “long fragment reads” that might help to address such problems. Large-scale structural variants play an important role in human variation and disease, so Complete will need to deal with these areas effectively if it is to generate genome sequences that can realistically be called “complete”.”

As an aside, many might mistakenly think that genomes are already being sequenced for less than $1,000 by companies like 23andme and decodeme, but these companies do not offer full genome sequencing.   Instead they only analyze a few hundred hot spots in your dna called SNP’s that can tell you lots of interesting things about your dna, but not the whole story.  Fully sequencing every single one of the approximately 3 billion base pairs of your dna is a completely different scenario, and this is where the real battle is being fought.

Update: More information has recently been revealed about Complete Genomics