On My Own – The Self-Assembly of Early DNA

Let’s face it: The young planet Earth was not a pleasant place to be. After coalescing from the protoplanetary disk of gases and dust left over from the formation of the Sun 4.5 billion years ago, the Earth’s surface had finally cooled to solid rock 1 billion years later (in between, it got hit by a planet-sized object to form the Moon and went through something called the “iron catastrophe,” which somehow isn’t being used as a band name). At this time, the Eoarchean Era, Earth’s atmosphere consisted solely of  gases spewed by the planet’s many active volcanoes, meaning you’d find toxic ammonia and methane, but little free oxygen and no ozone layer to stop the Sun’s radiation. But crucially, an atmospheric pressure 10 times that of today’s allowed liquid water to exist on the scorching hot surface, and that was the key to life.

A paper published last month in Nature Communications presents a new take on how that first stirring of life could have formed. In particular, it looks at how “liquid crystals” could have driven the formation of primitive DNA.

The Earliest Days

Abiogenesis is the term for the spontaneous generation of life out of lifeless materials. Yet though this process has a name, it’s mechanics have been the subject of fierce debate since the time of Aristotle. For many centuries, it was thought that abiogenesis occurred all the time – maggots seemed to appear without cause in rotten meat, for example. Eventually, however, the work of Louis Pasteur and other scientists proved that biogenesis (“life from other life”) is the observable cause of all life on Earth, but that didn’t solve the question of where the first living organism came from.

Two overarching explanations have emerged for the origins of life on Earth – that it started here spontaneously, or that it was “seeded” from somewhere else. The “panspermia” theory, as the latter is called, has some interesting research associated with it, but it isn’t the topic of this blog post. The other is that microscopic life spontaneously formed from Earth’s primordial soup of inorganic, volcanic compounds.

Since the 1980s, the dominant theory on the origins of life has been “the RNA World,” which hypothesizes that all life arose from a primitive form of ribonucleic acid, a single-stranded molecule found in all life and even some non-living viruses. RNA is relatively simple, and most importantly is able to self-replicate from non-living molecules, making it a strong candidate for the first biological reproduction. However, the molecules that comprise RNA, known as nucleotides, are complex, leading many scientists to be skeptical of how enough of them could have formed randomly at the same time to form primitive RNA.

In a paper titled “Abiotic ligation of DNA oligomers templated by their liquid crystal ordering,” Italian and American scientists provide by an answer, by showing how a unique physical process could have driven the assembly of nucleic acids to form RNA and DNA.

Liquid crystals are atoms in a state of matter between solid crystals and liquids. They are truly in the middle – they retain the homogenous alignment of solid crystals, but have the ability to flow like liquids. Most people have encountered them in the form “liquid crystal displays,” or LCDs – screens that use liquid crystal molecules to respond to electrical signals to form a picture.

Organic molecules can also be liquid crystals, and this paper found that very short DNA oligomers, or fragments, start to order themselves randomly in solutions in crystalline structures that could have been the basis for nucleotides, and later DNA and RNA.

“We envision our findings as a paradigm of what could have happened in the prebiotic Earth based on the fundamental and simplifying assumption that the origin of nucleic acids is written in their structure,” the authors wrote in the discussion.

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Drugs from DNA: 23andMe’s Next Move

23andMe, the California company that sells DNA sequencing tests, announced yesterday that it will be entering the drug development business. Normally, this wouldn’t turn heads – there is no shortage of companies doing treatment research in America and worldwide, but none of those companies is sitting on a database of nearly 700,000 fully sequenced human genomes.

“I believe that human genetics has a very important role to play in finding new treatments for disease,” said Richard Scheller, 23andMe’s newly hired chief science officer and head of therapeutics in a statement Thursday. “I am excited about the potential for what may be possible through 23andMe’s database. It is unlike any other.”

Scheller previously led Genentech, the company widely considered to have founded the field of biotechnology (Fun fact: Genentech marketed the first synthetic insulin brand in 1982).

Founded in 2006, 23andMe became famous for its easy-to-use tests that could tell one their ancestry, whether or not they liked cilantro and what diseases they were at risk of developing. More than 850,000 people purchased the service, which debuted at $1000 per kit before dropping to $99. In 2013, however, the Food and Drug Administration sternly rebuked 23andMe for marketing a test with medical implications without seeking federal approval. 23andMe removed all health information from its tests, and was only late last month allowed to begin reintroducing tests for whether someone is a carrier of a genetic disorder.

While 23andMe had to stop giving medical information to consumers, it never stopped asking them if it could store their sequenced genomes for future use. About 680,000 people agreed, creating an easily accessible archive larger than all of its predecessors. By accessing this data, Scheller and other scientists could conduct instantaneous genome-wide association studies, which is essentially testing if traits are associated with specific genetic variation. These variations often take the form of single-nucleotide polymorphisms – single base pairs that are mutated from one person to another – making the accurate, whole-genome sequences of 23andMe so useful for study.

This won’t be the first use of 23andMe’s vast DNA database for drug research – in fact in January the company received $10 million from Genentech in a deal to sequence the genomes of people at risk of developing Parkinson’s disease. And the company has also allowed dozens of university researchers access to its data for free.

Don’t expect significant results soon, though – genome-wide association studies are notoriously difficult because of the still largely unknown interactions between many genes that cause traits. At least 16 separate genes seem to factor into one’s eye color, and scientists still aren’t even sure what they all are. Meanwhile, more than 500 specific genetic mutations have been linked to cancer.

23andMe has experienced this difficulty first-hand – a Parkinson’s disease breakthrough that the company’s co-founder bragged about in 2011 didn’t pan out. But that shouldn’t dampen the excitement about this news, because genomics is truly the frontier of drug and therapy development, and 23andMe just built a really big fort there.

23andMe and the Genomics Frontier

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Last Thursday, the US Food and Drug Administration authorized the biotechnology company 23andMe to sell a consumer test for the genes that cause Bloom syndrome, an inherited recessive gene disorder that causes short stature, heightened skin sensitivity to sunlight and an elevated risk of developing cancer. The importance of this news comes not from its conclusion, but because it’s a stark reversal from the FDA’s previous dealings with this California-based start-up.

A New Age

Founded in 2006, 23andMe set out to sell humans a peek at the code that defines them. Simply spit into a vial, mail it away, and you’d soon be able to learn about details gleaned from your DNA, ranging from your ancestry to whether you’re destined to hate cilantro. But the tests’ most attention-grabbing feature was its analysis of one’s genetic predisposition to health problems like Parkinson’s or heart disease.

“The advent of retail genomics will make a once-rare experience commonplace,” wrote Thomas Goetz in a November 2007 article in Wired that declared 23andMe’s launch the start of the “Age of Genomics.”

“Simply by spitting into a vial, customers of these companies will become early adopters of personalized medicine. We will not live according to what has happened to us (that knee injury from high school or that 20 pounds we’ve gained since college) nor according to what happens to most Americans (the one-in-three chance men have of getting cancer, or women have of dying from heart disease, or anyone has for obesity). We will live according to what our own specific genetic risks predispose us toward.”

Though the test originally cost nearly $1,000, 23andMe soon cut the price to $399 in order to build up a database of genetic data for use in pharmaceutical and biotechnology research. Time named the test its Invention of Year in 2008, and continued buzz allowed the company to raise more than $50 million from investors and eventually drop its selling price to $99.

“You’re donating your genetic information,” 23andMe co-founder and CEO Anne Wojcicki told Time in 2008. “We could make great discoveries if we just had more information. We all carry this information, and if we bring it together and democratize it, we could really change health care.”

The Dark Years

2010 turned out to be a bad year for 23andMe. The FDA has long allowed testing kits, such as pregnancy tests, to be sold directly to consumers. 23andMe sold its “personal genome service” (PGS) under the assumption that it was allowable as a home testing kit, but the FDA had reservations, and sent the company a letter that year saying it considered the kits “medical devices,” and thus much more heavily regulated. The company was also dragged before a congressional committee to respond to damaging allegations from a sting operation conducted by the US Government Accountability Office. For a more thorough summary of this affair, check out this post from the excellent (and sadly inactive) science blog Genomes Unzipped.

After years of debate, a stern warning letter in November 2013 seemed to seal 23andMe’s fate – stop selling health tests until you get approval.

“The Food and Drug Administration (FDA) is sending you this letter because you are marketing the 23andMe Saliva Collection Kit and Personal Genome Service (PGS) without marketing clearance or approval in violation of the Federal Food, Drug and Cosmetic Act (the FD&C Act),” wrote Alberto Gutierrez of the Office of In vitro Diagnostics and Radiological Health. […] Most of the intended uses for PGS listed on your website, a list that has grown over time, are medical device uses under section 201(h) of the FD&C Act. Most of these uses have not been classified and thus require premarket approval or de novo classification, as FDA has explained to you on numerous occasions.”

23andMe was chastened, and quickly announced that it would discontinue all of its health-related testing, thus limiting its products only to ancestry information and raw genetic sequencing. Though the FDA intended to limit inaccurate diagnostic use of a person’s genome, its rebuke of 23andMe was widely viewed as overbearing and pointless. Science writer Razib Khan argued in Slate that this decision “highlights the tension between the paternalistic medical establishment that arose to deal with the dangers of 19th-century quack medicine, and a “techno-populist” element of American society pioneering personal health assessment and decision-making by leveraging new information technologies.”

“The glaring weakness in an aggressive strategy against interpretative services is that there will always be firms such as 23andMe, and there’s no reason that they need to be based out of the United States. Not only that, but there are open-source desktop applications, such as Promethease, that provide many of the same results by combining individual raw data with public peer-reviewed literature, if less slickly than 23andMe. To truly eliminate the public health threat that the FDA is concerned about, the U.S. government would have to constrict and regulate the whole information ecology, not just a strategic portion of it, from scientists distributing research about genetic variants, to international genome sequencing firms returning raw results on the cheap.”

On the other side, some argued that 23andMe was brazen in its defiance of the FDA, and it should have seen this coming. In a column for Forbes, health writer Matthew Herper called out the tech company for having gone more than six months at a time without communicating with the FDA.

“Either 23andMe is deliberately trying to force a battle with the FDA, which I think would potentially win points for the movement the company represents but kill the company itself, or it is simply guilty of the single dumbest regulatory strategy I have seen in 13 years of covering the Food and Drug Administration.”

Today

In its announcement last week, the FDA not only authorized the one test for Bloom syndrome, but also exempt all future carrier tests from “premarket review” by the agency. In particular, the language of the announcement seems to express a newfound willingness to accept direct-to-consumer genetic testing as part of 21st-century healthcare.

“The FDA believes that in many circumstances it is not necessary for consumers to go through a licensed practitioner to have direct access to their personal genetic information, wrote Gutierrez. “Today’s authorization and accompanying classification, along with FDA’s intent to exempt these devices from FDA premarket review, supports innovation and will ultimately benefit consumers.”

“This is a major milestone for our company and for consumers who want direct access to genetic testing,” Wojcicki said in a press release. “We have more work to do, but we remain committed to pursuing a regulatory path for additional tests and bringing the health reports back to the US market.”

Now, it seems only time will tell when the Personal Genome Service will return to the United States. I know I’m very eager to try it when it does.