What is This Hot New Field of Electronic Sequencing?

  • New Technology is Literally and Figuratively Hot
  • Stanford-incubated Startup has Patent for Semiconductor-based Sequencing Using Proton or Heat Detection
  • Sizzling Hot Promises Draw Stellar Scientific Advisor Board and World Renown Venture Capitalists

Truth be told, I’ve been an avid follower—if not addicted technophile—of next-generation sequencing (NGS) ever since the 1990s when inventive researchers—fueled by NIH grant-dollars—dreamed of displacing ABI’s then dominant fluorescent-based (aka BigDye® terminator) DNA sequencing systems. Assessing proposed technology of this would-be-competition was in fact part of my job at ABI back then. At the time, ABI was selling hundreds of millions of dollars of its sequencing instruments and reagents into the then rapidly emerging—if not exploding—field of genomics. So, you didn’t need an MBA from Harvard to conclude that any company that could commercialize significantly “faster, better, cheaper” sequencing would find instant marketability and might achieve even higher revenues.

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Liquid Biopsies Are Viewed as “Liquid Gold” for Diagnostics

  • Invasive Needles and Scalpels Seen as Passé
  • Noninvasive Sampling Advocates Focusing on Circulating Tumor Cells (CTCs) 
  • New Companies are Pursuing the Liquid Biopsy “Gold Rush”

Biopsy Basics

Ultrasound is a real-time procedure that makes it possible to follow the motion of the biopsy needle as it moves through the breast tissue to the region of concern, as discussed elsewhere (taken from oncopathology.info via Bing Images).

Ultrasound is a real-time procedure that makes it possible to follow the motion of the biopsy needle as it moves through the breast tissue to the region of concern, as discussed elsewhere (taken from oncopathology.info via Bing Images).

As defined in Wikipedia, a biopsy is ‘a medical test commonly performed by a surgeon or an interventional radiologist involving sampling of cells or tissues for examination.’ Biopsies can be excisional (removal of a lump or area), incisional (removal of only a sample of tissue), or a needle aspiration (tissue or fluid removal). Despite the value of these traditional types of biopsies, they are more or less invasive, lack applicability in certain instances, and require accurately “going to the source” of concern, as pictured to the right, for ultrasound-guided breast cancer biopsy. Better methodology is highly desirable and is the topic of this post. By the way, if you want to peruse a lengthy list of scary risks associated with various type of common invasive biopsies, click here to see what I found in Google Scholar by searching “incidence of complications from biopsies.”

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San Diego Shines Among Top 10 Biotech Product Innovators in 2014

  • Five of the Top 10 Biotech Products Picked by The Scientist were Developed by San Diego Companies
  • Most of the Innovations Involve Genomics
  • List Includes Several Repeat Winners as well as new Leaders in Cutting-Edge Technology

Recently The Scientist published its annual list of top 10 innovations for 2014. There are several repeat winners this year, including Illumina with two new sequencers and Leica Microsystems with a new 3D superresolution microscope. There are also a number of exciting new products associated with cutting edge technology in fields like human organ models and a Twitter-like site to handle the ever-increasing number of scientific publications. One of the most notable attributes of this year’s list, however, is that half of the award winning companies are based right here in San Diego.

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You and Your Microbiome – Part 2

  • Global Obesity Epidemic is Linked to Gut Microbiome
  • DNA Sequence-Based Microbiomes Accurately Associate with Obesity
  • Blue Agave Margaritas Contain Beneficial Gut Microbes
  • Investments in Microbiome-based Therapies on the Rise, but is there Hype?

Last August, my post entitled Meet Your Microbiome: The Other Part of You dealt with growing recognition that trillions of microbes—mostly bacteria but also fungus—reside in and on each of us, and influence our health status. Moreover, the compositions of these microbiomes change with our diet, what we drink or breath, and who we contact—family, pets, and close friends.

Since then, I’ve collected a string of microbiome articles delving into the implications of this dynamic, symbiotic relationship, and selected some topics that I thought were “blogworthy.” This Part 2, as it were, focuses on overweight/obesity, microbiome therapy, and burgeoning business opportunities.

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ALS Ice Bucket Challenge: What You May Not Know but Should

  • The Story of How this Challenge Began
  • How Baseball and the “Big Bang” are Connected to this Challenge
  • How a Dearth of Genetic Understanding Led to Crowdfunding ALS Research
  • The First Drugs May be on the Horizon

How It Began

For those very few of you who have for some reason been disconnected from mainstream and social media, the ALS Ice Bucket Challenge involves dumping a bucket of ice water on someone’s head to promote awareness of the disease amyotrophic lateral sclerosis (ALS) and encourage donations—typically $100—to research ALS. The challenge dares nominated participants to be recorded having a bucket of ice water poured on their heads, and challenging others to do the same. A common stipulation is that nominated people have 24 hours to comply or forfeit by way of a charitable financial donation.

Those of you already familiar with the ALS Bucket Challenge may, however, not know that it was first issued by golfer Chris Kennedy to his cousin Jeanette Senerchia of Pelham, New York, whose husband, Anthony, has had ALS for 11 years.

Anthony and Jeanette Senerchia of Pelham and their daughter Taya, 6, watch as local politicians participate in the ice bucket challenge, July 25, 2014 outside Pelham (NY) Town Hall. Photo: Tania Savayan; taken from lohud.com via Bing Images.

Anthony and Jeanette Senerchia of Pelham and their daughter Taya, 6, watch as local politicians participate in the ice bucket challenge, July 25, 2014 outside Pelham (NY) Town Hall. Photo: Tania Savayan; taken from lohud.com via Bing Images.

According to a local newspaper story, Jeanette Senerchia, 40, said “I was going to donate,” but they were really relentless with their texts counting down the time.” When she finally poured icy water on herself, having her 6-year-old daughter Taya record it, she posted the video on Facebook and “it went crazy,” she said. In a little more than a week, 1,000 people across the country, in Canada, Europe and Japan had joined in.

Soon the challenge circled back to Pelham, where Town Supervisor Pete DiPaola took a dousing, along with Town Councilman Timothy Case and Court Clerk Fran Ardisi. State Assemblywoman Amy Paulin and Westchester County Legislator Jim Maisano also got in on the act.

Girl Scouts from Troop 1662 did the honors in front of Town Hall, pouring the water from giant, 5 gallon Home Depot buckets baring the words “Let’s DO this.”

Photo taken from lohud.com.

Photo taken from lohud.com.

In drought-stricken regions a cool—pun intended—variant has been proposed as seen in this video wherein San Luis Obispo, California photographer Brittany App—yes, it’s really her last name—has a compromise: instead of dumping a bucket of ice water on one’s head, she is challenging people to live on only 5 gallons of water for a day.

BTW, lest we get caught up in all the fun associated the ALS Ice Bucket Challenge, keep in mind that ALS currently has no cure and affects an estimated 350,000 individuals around the globe, killing more than 100,000 annually. The disease can impact anyone, anywhere, regardless of age, ethnicity, or socioeconomic background.

Famous Persons with ALS

While I will echo the last sentences again, it’s apparent that society in general has a fascination—for lack of a better word—in knowing which famous persons have reached a certain age, or married, or passed away, or become afflicted with a disease. In the case of ALS, a website lists a number of such persons among which the most famous are American baseball great Lou Gehrig and British theoretical physicist Stephen Hawking. Captions for their photos below provide further information about each of these two “professional polar opposites” who nevertheless have ALS in common.


Henry Louis “Lou” Gehrig (June 19, 1903 – June 2, 1941), born Ludwig Heinrich Gehrig, was an American baseball player in the 1920s and 1930s, and set several Major League records and was popularly called the “The Iron Horse” for his durability. His record for most career grand slam home runs (23) still stands today. At the midpoint of the 1938 season, Gehrig’s performance began to diminish. After six days of extensive testing at Mayo Clinic in Rochester, Minnesota, the diagnosis of ALS was confirmed on June 19, Gehrig’s 36th birthday. ALS is commonly referred to as “Lou Gehrig’s disease” in the U.S. Photo taken from exequy.wordpress.com via Bing Images.




Professor Stephen Hawking—born Jan 8, 1942 in Oxford, England—has conducted work concerning the basic laws that govern the universe itself. Along with Roger Penrose, he has shown that Einstein’s General Theory of Relativity implied space and time would have a beginning in the, “Big Bang,” and end in “black holes.” In regards to the disability Stephen experiences, he has some things to say: “I am quite often asked: How do you feel about having ALS? The answer is, not a lot. I try to lead as normal a life as possible, and not think about my condition, or regret the things it prevents me from doing, which are not that many.” Photo taken from picfind.bloguez.com via Bing Images.




ALS Genetics in Brief

Given that this blog deals with “all things nucleic acids,” it’s apropos to mention a bit about the genetics, but quickly add that they are quite complex, as can be read about here.

There is a known hereditary factor in familial ALS. A defect on chromosome 21, which codes for superoxide dismutase, is associated with ~20% of familial cases of ALS, or about 2% of ALS cases overall. This enzyme is a powerful antioxidant that protects the body from damage caused by superoxide, a toxic free radical generated in the mitochondria. Free radicals are highly reactive molecules produced by cells during normal metabolism. Free radicals can accumulate and cause damage to DNA and proteins within cells.

This mutation has over 100 different genotypes. The most common ALS-causing mutation is a mutant SOD1 gene, seen in North American patients; this is characterized by an exceptionally rapid progression from onset to death. The most common mutation found in Scandinavian countries, D90A-SOD1, is more slowly progressive than typical ALS and patients with this form of the disorder survive for an average of 11 years.

In 2011, a genetic abnormality known as a hexanucleotide repeat was found in a region called C9orf72, which is associated with ALS combined with frontotemporal dementia ALS-FTD, and accounts for some 6% of cases of ALS among white Europeans. The gene is also found in people of Filipino descent.

I found it rather surprising that, where no family history of the disease is present—i.e., in a whopping ~90% of cases—there is no known cause for ALS! How stressful it must be to be afflicted with a disease having no known cause and no drug. Consequently, it’s easy to understand the importance of raising more research funding through the ALS Ice Bucket Challenge, and other money raising endeavors such as the following.

Crowdfunded ALS— Project MinE

I’ve previously commented here on the rapidly growing popularity of crowdfunding as a new, socio-web-based mechanism for “reaching out” to obtain money for conducting scientific research—including ALS. Project MinE is an independent, large-scale, whole-genome research project that has been initiated by two Dutch individuals with ALS and started on World ALS day (June 21) last year. These individuals provide their personal views on Project MinE at their Treeway website, which provides several modes of “communal contributing” that include jumping into Amsterdam canals (!!) as well as the now “classic” Ice Bucket Challenge.

Project MinE is a research project aimed at systematically interrogating the human genome for common and rare genetic variation in ALS—aka genetic “data mining.” The project will involve obtaining donated-DNA sequence information for 15,000 ALS samples and 20,000 healthy controls to obtain a large number of single-nucleotide polymorphisms (SNPs). This and additional sequencing will be performed on a sample size large enough to reliably analyze whole genome sequencing data outside of a family context.

The long-term benefit of the approach taken for project MinE is a catalogue of many non-ALS whole genomes that can be used to investigate other human diseases, including Diabetes Mellitus, some types of cancer, and other neurological disorders. Project MinE is the largest genetic study worldwide for ALS and was started in the second quarter of 2013. Complete information—and details on how to donate may be found at the Project MinE website, which I encourage you to visit.

Harvard Team Reports Possible ALS Drug Target

I thought it would be best to end this post on a positive note—specifically a possible drug target for ALS that is the subject of an online account by Cynthia Fox in Drug Discovery & Developement. Snippets of this exciting story are as follows.

A Harvard University team reported they may have found an ALS therapy—or two! When they blocked a gene for prostanoid receptor DP1 in ALS brain glia cells in a dish, neurons made from human embryonic stem (ES) cells were “completely protected” from death.

When they created ALS mice with that same gene deleted, the mice lived 6.7 percent longer.

This helps validate the idea that neurons made from human stem cells—in a dish—can be drug screens, team leader Kevin Eggan told a press conference. The 6.7 percent survival increase may rise even more, he said, if/when their DP1 antagonist is given with a drug his team earlier found has anti-ALS properties. And as both drugs are FDA-approved for other indications, clinical trials could move fast.

“We think this is a significant advance—both in terms of the use of stem cells for understanding disease, and with respect to understanding the degenerative processes of ALS and how we might inhibit them,” said Eggan.

Let’s all hope that this all proves to be true, and soon!

As always, your comments are welcome.

Venter’s Latest Venture: Increasing Human Longevity

  • The Quest to Make 100 the New 60
  • Aiming to Sequence 100,000 Human Genomes Per Year (Wow!)
  • Adding Genomes, Microbiomes, and Metabolomes to Health Records May Lead to Better Health and Longevity


Although this post is mainly about a new start-up called Human Longevity, whose mission is to apply genomics to guide increased longevity, the fact that this company was founded by J. Craig Venter has certainly created a “buzz.” The very name Venter—to me—is synonymous with scientifically unorthodox ideas that are big and bold. If you’re familiar with Venter’s accomplishments and “genomics rock star” status, go to the next section; if not, here are some highlights of his rise to fame.

As an investigator at NIH, Venter gained notoriety when he caused a brouhaha with his intentions to patent genes he discovered using expressed sequence tags (ESTs). The controversy was so extensive that it precipitated resignation of Nobel Laureate James D. Watson in 1992, who was then Director of NIH’s Human Genome Office. This caught the eye of a venture capitalist, Wallace Steinberg, who wanted to start a gene-finding company—with Venter as its head. Venter, however, insisted on a nonprofit venture, so Steinberg set him up in a nonprofit entity called The Institute for Genomic Research (TIGR) supported by a new company, Human Genome Sciences. (A NY Times story by Nicholas Wade entitled A Maverick Making Waves provides a nice overview of Venter’s career path through 2000).

Venter generated thousands of EST’s to the human genome that became the intellectual property of Human Genome Sciences and enabled the company to develop far-reaching claims to many medical genes of interest. In partnership with Nobel Laureate Hamilton O. Smith, Venter next used shotgun sequencing—then unproven, and controversial—to completely sequence Haemophilus influenzae. This gave scientists their first glimpse into the set of genes necessary for life. Moreover, this achievement set off a revolution in medical microbiology, inspiring efforts to decode every major pathogen and learn the microbes’ entire playbook for attacking human cells.

These early sequencing successes in turn led Michael W. Hunkapiller—then President of PE Biosystems, which made the leading brand of DNA sequencing instrument—to recruit Venter to run Celera—a new private company. Venter boldly declared to the media that Celera would decode the human genome using shotgun sequencing by 2001—ahead of the public consortium, sparking a contentious “race for the human genome.”

Fast forwarding from his role in decoding the human genome—described as the single most important scientific breakthrough of modern times—Venter is Founder, Chairman, and CEO of the J. Craig Venter Institute (JCVI), a non-profit research organization with approximately 300 scientists and staff dedicated to human, microbial, plant, synthetic and environmental genomic research, and the exploration of social and ethical issues in genomics.

Venter is also Founder and CEO of Synthetic Genomics Inc. (SGI), a privately held company dedicated to commercializing genomic-driven solutions to address global needs such as new sources of energy, new food and nutritional products, and next generation vaccines. Recently Venter announced his latest venture, Human Longevity Inc. (HLI), “a genomics and cell therapy-based diagnostic and therapeutic company focused on extending the healthy, high performance human life span.”

Venter relaxing on his 95-foot sailboat/research vessel named Sorcerer II.

Venter relaxing on his 95-foot sailboat/research vessel named Sorcerer II. Photograph: Rick Friedman/Corbis (taken from theguardian.com via Bing Images).

Since 2003, scientists at the J. Craig Venter Institute have been on a quest to unlock the secrets of the oceans by sampling, shotgun sequencing and analyzing the DNA of the microorganisms living in these waters. In February 2014, the vessel embarked on a sampling expedition of the Amazon River and its tributaries, which contains 1/5th of the Earth’s river flow.

Human Longevity: Genomics-Based Fountain of Youth?

The Fountain of Youth is a spring that supposedly restores the youth of anyone who drinks or bathes in its waters. Tales of such a fountain have been recounted across the world for thousands of years, beginning with writings by the Greek historian Herodotus. The tale was particularly prominent in the 16th century, when it became attached to the Spanish explorer Juan Ponce de León, who was searching for the Fountain of Youth when, in 1513, he traveled to what is now Florida.

Artistic rendering of Ponce de León accepting water from the Fountain of Youth (taken from tabuherbalsmoke.com via Bing Images).

Artistic rendering of Ponce de León accepting water from the Fountain of Youth (taken from tabuherbalsmoke.com via Bing Images).

Given this legendary history and our collective wish for healthy, long lives, it’s not surprising that Venter’s announcement earlier this year attracted widespread media attention and significant funding—to the tune of $70 million. A story in the NY Times refers to Venter as saying that the largest of the investors is K. T. Lim, a Malaysian billionaire who runs Genting Berhad, a gambling conglomerate. Venter adds that a ‘not insignificant’ part of the funding comes from Illumina—for reasons that will be appreciated by reading further.

The press release goes on to say that HLI’s funding is being used “to build the largest human sequencing operation in the world to compile the most comprehensive and complete human genotype, microbiome, and phenotype database available to tackle the diseases associated with aging-related human biological decline.” HLI is also “leading the development of cell-based therapeutics to address age-related decline in endogenous stem cell function.”

In addition, HLI’s “revenue streams will be derived from database licensing to pharmaceutical, biotechnology and academic organizations, sequencing, and development of advanced diagnostics and therapeutics.”

Venter is quoted as saying that “using the combined power of our core areas of expertise—genomics, informatics, and stem cell therapies, we are tackling one of the greatest medical/scientific and societal challenges—aging and aging related diseases,” and that “HLI is going to change the way medicine is practiced by helping to shift to a more preventive, genomic-based medicine model which we believe will lower healthcare costs. Our goal is not necessarily lengthening life, but extending a healthier, high performing, more productive life span.”

HLI cofounder Peter H. Diamandis, M.D. puts this another and trendier way, according to the NY Times, which quotes Diamandis as saying that the goal was not to make people live forever, but rather to make “100 years old the next 60.” The NY Times goes on to say that “Venter, who is 67, sounds as if he might not need the company to succeed. Quoting Venter, “I feel like I have at least 20 or 30 years left in my career.”

HLI’s humongous database-to-be will surely be, in my opinion, a prime example of Big Data—itself a “hot trend.” It aims to have genomic sequences from “a variety of humans—children, adults and super centenarians [i.e. people who have attained the age of at least 110 years] and those with disease and those that are healthy,” according to the press release.

Illumina Looms Large in Longevity’s Plans

HLI has initially purchased two Illumina HiSeq X Ten Sequencing Systems (with the option to acquire three additional systems) to sequence up to 40,000 human genomes per year, with plans to rapidly scale to 100,000 human genomes per year.

Let me repeat this to be sure you don’t think these are typos.

40,000 and then 100,000 human genomes per year!

As pictured below, each of these newly introduced Sequencing Systems is comprised of ten—count them—instruments, which I’ve previously written about as enabling the long-elusive $1,000 genome cost target. Ironically, this goal was set by Venter as a technical challenge in 2002 at a now monumental TIGR conference.

Each Illumina HiSeq X Ten Sequencing System has a list price of $10 million.

Each Illumina HiSeq X Ten Sequencing System has a list price of $10 million.

Microbiome and Metabolome Data

Relative proportion of sequences determined at the taxonomic phylum level at eight anatomical sites. High-throughput sequencing has revealed substantial intra-individual microbiome variation at different anatomical sites, and inter-individual variation at the same anatomical sites. Such site-specific differences and the observed conservation between human hosts provide an important framework to determine the biological and pathological significance of a particular microbiome composition (taken from nature.com via Bing Images).

Relative proportion of sequences determined at the taxonomic phylum level at eight anatomical sites. High-throughput sequencing has revealed substantial intra-individual microbiome variation at different anatomical sites, and inter-individual variation at the same anatomical sites. Such site-specific differences and the observed conservation between human hosts provide an important framework to determine the biological and pathological significance of a particular microbiome composition (taken from nature.com via Bing Images).

Along with the genomic data gleaned from the sequencing of complete human genomes, HLI will also be generating microbiome data for many of these individuals through its Biome Healthcare division. The division is lead by Karen Nelson, who at TIGR led the first human microbiome study on the human gut published in Science in 2006.

The microbiome— a very “hot” trend in genomics research that I wrote about last year—consists of all the microbes that live in and on the human body that contribute to health and disease status of an individual. By better understanding a person’s microbiome—from gut, oral, skin, lung, and other body sites—the company said that it “anticipates developing improved probiotics and other advanced diagnostic and therapeutic approaches to improve health and wellness.”

HLI will also capture and analyze each individual’s metabolomic data. The metabolome is the full complement of metabolites, biochemicals and lipids circulating throughout the human body. HLI has signed an agreement with Metabolon Inc., a diagnostic products and services company offering a biochemical profiling platform, to capture this information from each of the genomic samples that HLI is collecting. “Metabolomics is important because quantifying and understanding the full picture of circulating chemicals in the body can help researchers get a clearer picture of that individual’s health status, and provide markers and pathways associated with drug action,” according to HLI.

Schematic of the 'omic hierarchy: genomics, transcriptomics, proteomics, and metabolomics—yes, the figure leaves out a few others, e.g. epigenomics and phenomics (taken from schaechter.asmblog.org via Bing Images).

Schematic of the ‘omic hierarchy: genomics, transcriptomics, proteomics, and metabolomics—yes, the figure leaves out a few others, e.g. epigenomics and phenomics (taken from schaechter.asmblog.org via Bing Images).

Stem Cell Therapies

This part of the company’s multi-pronged strategy utilizing stem cell therapy advances is said to be “premised on the theory that as the human body ages many biological changes occur, including substantial changes and degradation to the genome of the differentiated, specialized cells found in all body tissues. There is also a depletion and degradation of healthy regenerative stem cell populations in the body over time. HLI will monitor the genomic changes which occur during stem cell differentiation, normal aging, and in association with the onset of disease.”

In this regard, it’s worth mentioning that TriLink BioTechnologies is a leading provider of biosynthetic modified mRNAs that encode factors used for cellular reprograming and regenerative medicine. Further information about these catalog products and custom services is available here.

Commercial Potential

Robert Hariri, M.D., Ph.D., who cofounded HLI with Venter and Diamandis, is quoted in HLI’s press release as saying that “the global market for healthy human longevity is enormous with total healthcare expenditures in those 65 and older running well over $7 trillion.” He adds, “we believe that HLI’s unique science and technology, along with our business leadership, will positively impact the healthcare market with novel diagnostics and therapeutics.”

Time will tell.

Personally, over the many years since Mike Hunkapiller introduced me to then “NIHer” Craig Venter, I’ve learned not to bet against him.

In closing, I should mention that Venter et al. are not the first to eye the commercial potential of longevity. Last September, Google’s chief executive, Larry Page, announced that his company was creating an anti-aging company, Calico, which is being run by Arthur D. Levinson, the former chief executive of Genentech. Even earlier, Oracle’s chief executive, Lawrence J. Ellison, had financed anti-aging research through his foundation. However, last December, Ellison announced this research would end due to a funding crunch.

Your comments are welcomed.

Searching for ‘Genius Genes’ by Sequencing the Super-Smart

  • Brainchild of a high-school dropout
  • Joined by two renowned Professors in the USA and UK
  • Enabled by the world’s most powerful sequencing facility
  • Jonathan Rothberg to do same for math ability 


Before plunging into this post, those of you who follow college basketball are eagerly awaiting the start of “March Madness” and its “bracketology” for predicting all the winners, with odds of 1-in-9.2 quintillion—that’s nine followed by 18 zeros—and is why Warren Buffet will almost certainly not have to pay out the $1 billion he offered for doing so.

The following short story of how basketball came about is worth a quick read before getting to this posting’s DNA sequencing projects, which are not “madness” but definitely long-shot bets—and criticized by some. 

The original 1891 "Basket Ball" court in Springfield College used a peach basket attached to the wall (taken from Wikipedia).

The original 1891 “Basket Ball” court in Springfield College used a peach basket attached to the wall (taken from Wikipedia).

James Naismith (1861 – 1939) was a Canadian American sports coach and innovator. He invented the sport of basketball in 1891 and wrote the original basketball rulebook. At Springfield College, Naismith struggled with a rowdy class which was confined to indoor games throughout the harsh New England winter and thus was perpetually short-tempered. Under orders from Dr. Luther Gulick, head of Springfield College Physical Education, Naismith was given 14 days to create an indoor game that would provide an “athletic distraction.” Gulick demanded that it would not take up much room, could help its track athletes to keep in shape and explicitly emphasized to “make it fair for all players and not too rough.” Naismith did so using the actual “basket and ball” pictured below.

SNPs and GWAS assist in finding the roots of intelligence

Many studies indicate that intelligence is heritable, but to what extent is yet uncertain (taken from the Wall Street Journal via Bing Images).

Many studies indicate that intelligence is heritable, but to what extent is yet uncertain (taken from the Wall Street Journal via Bing Images).

Many of you are well aware of—if not actually involved in—the use of DNA sequence analysis to identify common single nucleotide polymorphisms (SNPs) that are associated with diseases or traits in a study population, relative to a normal control population. Examples of these genome-wide association studies (GWAS) included and were principally enabled in the 1990s by high-density “SNP chips” developed by Affymetrix and then Agilent. While technically straightforward, there’s a lot of genetics and not-so-simple statistics to deal with in designing GWAS and—especially—properly interpreting the results.

In the future, Junior’s DNA sequence could implicate other reasons for his failing academic performance, e.g. not studying enough (taken from dailymail.co.uk via Bing Images).

In the future, Junior’s DNA sequence could implicate other reasons for his failing academic performance, e.g. not studying enough (taken from dailymail.co.uk via Bing Images).

Now, following the advent of massively parallel “next generation” sequencing (NGS) platforms from Illumina and Life Technologies, whole genomes of larger populations (i.e. “many” 1,000s of individuals) can be studied, and less common (aka rare) SNPs can be sought. All of this has fueled pursuit of more challenging—and controversial—GWAS.

So it is the following two ongoing stories that I’ve referred to as the search for genius genes. One conceived by Bowen Zhao—a teenaged Chinese high-school dropout—aiming to find the roots of intelligence in our DNA by sequencing the “off-the-chart” super-smarties, and a newer project by Jonathan Rothberg—über-famous founder of Ion Torrent, which commercialized the game-changing semiconductor-sequencing technology acquired for mega millions by Life Tech—aimed at identifying the roots of mathematical ability by, need I say, Ion Torrent sequencing.

From Chinese high-school dropout to founder of a Cognitive Genomics Unit

It’s a gross understatement to say that Mr. Bowen Zhao is an interesting person—he’s actually an amazing person. As a 13 year old in 2007, he skipped afternoon classes at his school in Beijing and managed to get an internship at the Chinese Academy of Agricultural Sciences where he cleaned test tubes and did other simple jobs. In return, the graduate students let him borrow genetics textbooks and participate in experiments, including the sequencing of the cucumber genome. When the study of the cucumber genome was published in Nature Genetics in 2009, Mr. Zhao was listed as a co-author at the age of 15.

Tantalized by genomics, Mr. Zhao quit school and began to work full-time at BGI Shenzhen (near Hong Kong), one of the largest genomics research centers in the world. BGI (formerly known as the Beijing Genomics Institute) is a private company—partly funded by the Chinese government—that significantly expanded its sequencing throughput last year by acquiring Complete Genomics of Mountain View, California.

Mr. Bowen Zhao is a young researcher with amazing accomplishments (taken from thetimes.co.uk via Bing Images)

Mr. Bowen Zhao is a young researcher with amazing accomplishments (taken from thetimes.co.uk via Bing Images)

The BGI project is sequencing DNA from IQ outliers comparable to Einstein (taken from rosemaryschool.org via Bing Images).

The BGI project is sequencing DNA from IQ outliers comparable to Einstein (taken from rosemaryschool.org via Bing Images).

In 2010, BGI founded the Cognitive Genomics Unit and named Mr. Zhao as its Director of Bioinformatics. The Cognitive Genomics Unit seeks to better understand human cognition with the goal of identifying the genes that influence intelligence. Mr. Zhao and his team are currently using more than 100 state-of-the-art next generation sequencers to decipher some 2,200 DNA samples from some of brightest people in the world—extreme IQ outliers. The majority of the DNA samples come from people with IQs of 160 or higher, which puts them at the same level as Einstein. By comparison, average IQ in any population is set at 100, and the average Nobel laureate registers at around 145. Only one in every 30,000 people (0.003%) would qualify to participate in the BGI project.

In an article by Gautam Naik of the Wall Street Journal, Mr. Zhao is quoted as saying that “people have chosen to ignore the genetics of intelligence for a long time.” Mr. Zhao, who hopes to publish his team’s initial findings this year, added that “people believe it’s a controversial topic, especially in the West [but] that’s not the case in China,” where IQ studies are regarded more as a scientific challenge and therefore are easier to fund.

According to Naik, the roots of intelligence are a mystery, and studies show that at least half of IQ variation is inherited. While scientists have identified some genes that can significantly lower IQ—in people afflicted with mental retardation, for example—truly important genes that affect normal IQ variation have yet to be pinned down.

The BGI researchers hope to crack the problem by comparing the genomes of super-high-IQ individuals with the genomes of people drawn from the general population. By studying the variation in the two groups, they hope to isolate some of the hereditary factors behind IQ. Their conclusions could lay the groundwork for a genetic test to predict a person’s inherited cognitive ability. Although such a tool could be useful, it also might be divisive.

“If you can identify kids who are going to have trouble learning, you can intervene” early on in their lives, through special schooling or other programs, says Robert Plomin, Professor of Behavioral Genetics at King’s College, London, who is involved in the BGI project and quoted by Naik.

Critics, however, worry that genetic data related to IQ could easily be misconstrued—or misused. Research into the science of intelligence has been used in the past “to target particular racial groups or individuals and delegitimize them,” said Jeremy Gruber, President of the Council for Responsible Genetics, a watchdog group based in Cambridge, Massachusetts. “I’d be very concerned that the reductionist and deterministic trends that still are very much present in the world of genetics would come to the fore in a project like this,” Gruber added.

Obtaining access to ‘genius genes’ wasn’t easy

Getting DNA to sequence from super-smart people was easier said than done. According to Naik, Zhao’s first foray into the genetics of intelligence was a plan to collect DNA from high-achieving kids at local high schools. It didn’t work. “Parents were afraid [of giving consent] because their children’s blood would be taken,” Zhao told Naik.

In the spring of 2010, Stephen Hsu—a theoretical physicist from the University of Oregon (now at Michigan State University) who was also interested in the genetics of cognitive ability—visited BGI and joined Zhao to launch the BGI intelligence project. One part of the plan called for shifting to saliva-based DNA samples obtained from mathematically gifted people, including Chinese who had participated in mathematics or science Olympiad training camps. Another involved the collection of DNA samples from high-IQ individuals from the U.S. and other countries, including those with extremely high SAT scores, and those with a doctorate in physics or math from an elite university. In addition, anyone could enroll via BGI’s website—if they met the criteria—as have about 500 qualifying volunteers to date.

Interestingly, most of the samples so far have come from outside of China. The main source is Prof. Plomin of King’s College, who for his own research had collected DNA samples from about 1,600 individuals whose IQs were off the charts. Those samples were obtained through a U.S. project known as the Study of Mathematically Precocious Youth, now in its fourth decade. Dr. Plomin tracked down 1,600 adults who had enrolled as kids in the U.S. project, now based at Vanderbilt University. Their DNA contributions make up the bulk of the BGI samples.

Frequently asked questions about the BGI intelligence project, as well as a link to the detailed project proposal, can be read by clicking here. The penultimate and last paragraphs of the introductory section of this proposal are the following:

The brain evolved to deal with a complex, information-rich environment. The blueprint of the brain is contained in our DNA, although brain development is a complicated process in which interactions with the environment play an important role. Nevertheless, in almost all cases a significant portion of cognitive or behavioral variability in humans is found to be heritable—i.e., attributable to genetic causes.

The goal of the BGI Cognitive Genomics Lab (CGL) is to investigate the genetic architecture of human cognition: the genomic locations, allele frequencies, and average effects of the precise DNA variants affecting variability in perceptual and cognitive processes. This document outlines the CGL’s proposal to investigate one trait in particular: general intelligence or general mental ability, often referred to a “g.”

On Jan 1st 2014, I contacted Prof. Hsu, who coauthored BGI’s “g” proposal, and asked him to clarify whether genome sequencing was in fact being used, as opposed to SNP genotyping chips that were specified in the aforementioned proposal’s Materials and Methods section. I also inquired as to whether any results have been published. His reply on the same day was that the “initial plan was SNPs but [was] upgraded to sequencing. No results yet.”

Stay tuned.

Jonathan Rothberg’s ‘Project Einstein’ taps 400 top mathematicians

In the October 31st 2013 issue of Nature, Erika Check Hayden reported on ‘Project Einstein,’ Ion Torrent founder/inventor/serial entrepreneur Jonathan Rothberg’s new venture aimed at identifying the genetic roots of math genius.

Jonathan Rothberg, founder of CuraGen, 454 Life Sciences, Ion Torrent, Rothberg Center for Childhood diseases, and RainDance Technologies (taken from nathanielwelch.com via Bing Images).

Jonathan Rothberg, founder of CuraGen, 454 Life Sciences, Ion Torrent, Rothberg Center for Childhood diseases, and RainDance Technologies (taken from nathanielwelch.com via Bing Images).

According to Check Hayden’s news article, Rothberg and physicist/author Max Tegmark at MIT in Cambridge, “will be wading into a field fraught with controversy” by enrolling about 400 mathematicians and theoretical physicists from top-ranked US universities in ‘Project Einstein’ to sequence the participants genomes using Ion Torrent machines that Rothberg developed. Critics claim that the study population, like BGI’s “g” project, is too small to yield meaningful results for such complex traits. Check Hayden adds that “some are concerned about ethical issues. If the projects find genetic markers for math ability, these could be used as a basis for the selective abortion of fetuses or in choosing between embryos created through in vitro fertilization.” She says that Rothberg is pushing ahead, and quotes him as stating, “I’m not at all concerned about the critics.”

On the positive side, Prof. Plomin mentioned above in BGI project “g” is said to believe that there is no reason why genome sequencing won’t work for math ability. To support this position, Plomin refers to his 2013 publication entitled Literacy and numeracy are more heritable than intelligence in primary school, which indicates that as much as two-thirds of a child’s mathematical aptitude seems to be influenced by genes.

I’ll be keeping tabs on the project to see how it progresses and how the ethics issue plays out.

Genetics of intelligence is complex and has foiled attempts at deciphering

After reading about the scientifically controversial aspects of both project “g” and ‘Project Einstein,’ I became curious about the outcomes of previous attempts to decipher the genetic basis of intelligence. There was way too much literature to delve into deeply, but a 2013 New Scientist article by Debora MacKenzie entitled ‘Intelligence genes’ evade detection in largest study is worth paraphrasing, as it distills out some simplified takeaways from the referenced study by Koellinger and 200 (!) collaborators published in Science.

  • This team of researchers assembled 54 sets of data on more than 126,000 people who had their genomes analyzed for 2.5 million common SNPs, and for whom information was available on length and level of education. Study organizer Koellinger admits that educational achievement is only a rough proxy for intelligence, but this information was available for the requisite large number of people.
  • Three SNPs from 100,000 people correlated significantly with educational achievement, and were tested against SNPs from the other 26,000 people. The same correlations held, replicating the first analysis. However, the strength of the correlations for each SNP accounted for at most 0.002% of the total variation in educational attainment.
  • “Probably thousands of SNPs are involved, each with an effect so small we need a much larger sample to see it,” says Koellinger. Either that, or intelligence is affected to a greater degree than other heritable traits by genetic variations beyond these SNPs—perhaps rare mutations or interactions between genes.
  • Robert Plomin adds that whole genome sequencing, as being done by BGI, allows researchers to “look for sequence variations of every kind.” Then, the missing genes for intelligence may finally be found, concludes MacKenzie.

Parting Thoughts 

Most, if not all of you, will agree with the contention that a human being is not merely a slave to his or her genes. After all, hasn’t determinism been swept away by the broom of quantum mechanical probabilities as a physical basis of free will? If so, then what role does inherited genetics actually play in intelligence? While the answer to this rhetorical question is obviously not simple, and still hotly debated, I found my thoughts to be largely reflected by a posting at Rose Mary School paraphrased as follows, keeping in mind that all analogies are imperfect:

Human life has been compared to a game of cards. At birth, every person is dealt a hand of cards—i.e., his or her genetic make-up. Some receive a good hand, others a less good one. Success in any game, however, is almost always a matter of education, learning, and culture. For sure, there are often certain innate qualities that will give one person an advantage over another in a specific game. However, without having learned the game and without regular and rigorous practice, nobody will ever become a champion at any game. In the same way the outcome of the game of life is not solely determined by the quality of a person’s initial hand of cards, but also by the way in which he or she takes part in the game of life. His or hers ability to take part in the game of life satisfactorily, perhaps even successfully, will be determined to a very large extent by the quality and quantity of education that he or she has enjoyed.

When I gave advice to students, as a teacher, it was very simple and what I did—and still do—myself: “study hard, work harder, and success will follow.”

As always, your comments are welcomed.

De-Extinction: Hope or Hype?

  • Can scientists “revive” woolly mammoths?
  • Passenger Pigeons, possibly?
  • Is “facilitated adaption” more realistic?

If you haven’t seen the 1993 movie Jurassic Park, the plot involves a tropical island theme park populated with cloned dinosaurs created by a bioengineering company, InGen. The cloning was accomplished by extracting the DNA of dinosaurs from mosquitoes that had been preserved in amber—not unlike extraction of ancient yeast DNA from extinct bees preserved in amber for brewing “Jurassic beer” that I featured in a previous posting. However, in Jurassic Park the strands of DNA were incomplete, so DNA from frogs was used to fill in the gaps. The dinosaurs were cloned genetically as females in order to prevent breeding.

This is all a great premise for a movie, but will Jurassic Park-like fantasy become reality in the near future?  What’s being investigated now, and are there concerns being voiced? These are just some of the questions touch upon below.

Woolly Mammoths May One Day Roam Real-Life Jurassic Park

Hendrik Poinar, Director of the Ancient DNA Centre at McMaster University in Hamilton, Ontario (taken from fhs.mcmaster.ca via Bing Images).

Dr. Hendrik Poinar, Director of the Ancient DNA Centre at McMaster University (taken from fhs.mcmaster.ca).

Dr. Hendrik Poinar, Associate Professor at McMaster University in Canada, was trained as a molecular evolutionary geneticist and biological anthropologist, and now specializes in novel techniques to extract and analyze “molecular information (DNA and/or protein sequences)” from ancient samples. His work included such projects as sequencing the mitochondrial genome of woolly mammoths that went extinct long ago. Based on that work, Dr. Poinar was recently interviewed by CBC News about the likelihood of reestablishing woolly mammoths. Here are some excerpts:

Q: Without getting too technical, describe what you’re doing to bring back animals like the woolly mammoth?

A: We’re interested in the evolutionary history of these beasts. These lumbering animals lived about 10,000 years ago and went extinct. We’ve been recreating their genome in order to understand their origins and migrations and their extinction. That led to the inevitable discussion about if we could revive an extinct species and is it a good thing.

Q: Why is this so interesting to you?

A: There are reasons why these animals went extinct. It could be climate, it could be human-induced over-hunting. If we can understand the processes that caused extinction, maybe we can avoid them for current endangered species. Maybe we need to think about what we can do to bring back extinct species and restore ecosystems that are now dwindling.

Q: Is it possible to bring these things back to life?

A: Not now. We’re looking at 30 to 50 years.

Woolly mammoths roamed both North America and Asia for hundreds of thousands of years. Many went extinct during the most recent period of global warming (taken from CBC News via Bing Images).

Woolly mammoths roamed both North America and Asia for hundreds of thousands of years. Many went extinct during the most recent period of global warming (taken from CBC News via Bing Images).

Q: How would you do something like that?

A: First thing you have to do is to get the entire blueprint. We have mapped the genome of the woolly mammoth. We’re almost completely done with that as well as a couple other extinct animals. We can look at the discrete differences between a mammoth and an Asian elephant. We would take an Asian elephant chromosome and modify it with mammoth information. Technology at Harvard can actually do that. Take the modified chromosomes and put them into an Asian elephant egg. Inseminate that egg and put that into an Asian elephant and take it to term. It could be as soon as 20 years.

Q: Is this such a good idea?

A: That’s the million-dollar question. We’re not talking about dinosaurs. We’ll start with the herbivores—the non-meat eaters. We could use the technology to re-introduce diversity to populations that are dwindling like the cheetah or a wolf species we know are on the verge of extinction. Could we make them less susceptible to disease? Is it good for the environment? We know that the mammoths were disproportionately important to ecosystems. All the plant species survived on the backs of these animals. If we brought the mammoth back to Siberia, maybe that would be good for the ecosystems that are changing because of climate change.

Q: You are tinkering with the evolutionary process?

A: Yes, but would you feel differently if the extinction was caused by man like it was with the passenger pigeon or the Tasmanian wolf, which were killed by humans? Even the large mammoth, there are two theories on their extinction, one is overhunting by humans…and the other is climate. Do we have a moral obligation?

Bringing Back Passenger Pigeons

Ben Novak has a BS in Ecology and worked with mastodon fossils toward a master’s degree at McMaster University, but he abandoned that to pursue his long-time passion for passenger-pigeon genetics (taken from wfs.org via Bing Images).

Ben Novak has a BS in Ecology and worked with mastodon fossils toward a master’s degree at McMaster University, but he abandoned that to pursue his long-time passion for passenger-pigeon genetics (taken from wfs.org via Bing Images).

Ben Novak, according to an interview in Nature last year, has spent his young career endeavoring to resurrect extinct species. Although he has no graduate degree, he has amassed the skills and funding to start a project to bring back the Passenger Pigeon—once the United States’ most numerous bird (about 5 billion according to Audubon)—which died out in 1914. Following are comments from Ben, taken from the Nature article referenced above, about how his work is funded and its prospects.

“Once I had passenger-pigeon tissue [from the Field Museum of natural History in Chicago, Illinois], I started applying for grants to do population analysis, but I couldn’t secure funding. I got about $4,000 from family and friends to sequence the DNA of the samples. When I got data, I contacted George Church, a molecular geneticist at Harvard Medical School in Boston, Massachusetts, who was working in this area. He and members of Long Now Foundation in San Francisco, California, which fosters long-term thinking, were planning a meeting on reviving the passenger pigeon….The more we talked, the more they discovered how passionate I was. Eventually, Long Now offered me full-time work so that nothing was standing in my way.”

“I have just moved to the University of California, Santa Cruz, to work with Beth Shapiro. She has her own sample of passenger pigeons, and we want to do population genetics and the genome. It’s a good fit. Long Now pays me, and we do the work in her lab, taking advantage of her team’s expertise in genome assemblies and ancient DNA.”

Male passenger pigeon (taken from swiftbirder.wordpress.com via Bing Images).

Male passenger pigeon (taken from swiftbirder.wordpress.com via Bing Images).

For the sad story of how this creature went extinct, click here to access an account written by Edward Howe Forbush in 1917.

Doing more searching about Ben Novak led me to another 2013 interview, this time in Audubon. When asked if it’s realistic to get a healthy population from a few museum specimens, here’s what he said.

“If we’re willing to create one individual [passenger pigeon], then through the same process we can produce individuals belonging to completely different genetic families. We can make 10 individuals that, when they’re mated, will have an inbreeding coefficient near zero…First we need to discern what the actual genetic structure of the species was. We can analyze enough tissue samples to get that genetic diversity.”

While perusing the Long Now Foundation’s website, I was pleased to read a Passenger-Pigeon progress report posted by Ben Novak on October 18th 2013.  The posting gives a detailed update on genomic sequencing of “Passenger Pigeon 1871″ [date of preservation] at the University of California San Francisco‘s Mission Bay campus sequencing facility, as well as some nice pictures. Given what he said above about 10 individuals being theoretically adequate for reviving and restoring an extinct population, you’ll be as pleased as Ben is about the following.

“Passenger Pigeon 1871 was selected as the candidate for the full genome sequence for its superb quality compared to other passenger pigeon specimens. Over the last two years Dr. Shapiro, myself and colleagues have scrutinized the quality of 77 specimens including bones and tissues. Our first glimpses of data confirmed that the samples would be able to provide the DNA needed for a full genome sequence, but as we delved into the work, the specimens exceeded our expectations. Not only do we have one specimen of high enough quality for a full genome, we have more than 20 specimens to perform population biology research with bits of DNA from all over the genome.”

Revive and Restore

Reading about Ben Novak’s support from the Long Now Foundation led me discover the organization’s Revive and Restore Project, aimed at genetic rescue of endangered and extinct species. Its mission is stated as follows:

“Thanks to the rapid advance of genomic technology, new tools are emerging for conservation. Endangered species that have lost their crucial genetic diversity may be restored to reproductive health. Those threatened by invasive diseases may be able to acquire genetic disease-resistance.

It may even be possible to bring some extinct species back to life. The DNA of many extinct creatures is well preserved in museum specimens and some fossils. Their full genomes can now be read and analyzed. That data may be transferable as working genes into their closest living relatives, effectively bringing the extinct species back to life. The ultimate aim is to restore them to their former home in the wild.

Molecular biologists and conservation biologists all over the world are working on these techniques. The role of Revive and Restore is to help coordinate their efforts so that genomic conservation can move ahead with the best current science, plenty of public transparency, and the overall goal of enhancing biodiversity and ecological health worldwide.”

This Project’s website is well worth visiting, as it provides a fascinating mix of species under consideration (such as the Passenger Pigeon and the woolly mammoth), various video presentations by advocates, and an engaging blog. It also provides a very convenient “donate” button should you be so inclined.

While the Passenger Pigeon project and other Revive and Restore efforts are well intended, I’m more inclined at this time to be neutral-to-negative about the projects, and will reserve a final opinion until all parties, pro and con, have extensive debates similar to what was done in the past for then (and still) controversial recombinant DNA technology. Given the amount of concern and caution then for what we can now view as conventional genetic engineering, it seems reasonable to me that, with far more powerful tools for genomics and synthetic biology being available, “an abundance of caution” is in order when dealing with the possibility of resurrecting extinct species. If Jurassic Park serves as any sort of model for what science can accomplish, perhaps we should also consider what the movie highlights as the potential implications of those accomplishments.

For now, I’m intently interested in the continuing debates and I find it fascinating to consider alternatives such as rescuing species from extinction as outlined next.

“Facilitated Adaption” Pros & Cons

Michael A. Thomas, Professor of Biology at Idaho State University, and colleagues authored a Comment in Nature last year entitled Gene tweaking for conservation that is freely available (yeh!) and well worth reading. Some highlights are as follows:

Sadly, if not shockingly, conservative estimates predict that 15–40% of living species will be effectively extinct by 2050 as a result of climate change, habitat loss and other consequences of human activities. Among the interventions being debated, facilitated adaptation has been little discussed. It would involve rescuing a target population or species by endowing it with adaptive alleles, or gene variants, using genetic engineering—not too unlike genetically modified crops that now occupy 12% of today’s arable land worldwide. Three options for facilitated adaption are outlined.

“Poster Child” for facilitated adaption: an endangered Florida panther population was bolstered through hybridization with a related subspecies — a technique that could be refined using genomic tools (taken from Thomas et al. Nature 2013).

“Poster Child” for facilitated adaption: an endangered Florida panther population was bolstered through hybridization with a related subspecies — a technique that could be refined using genomic tools (taken from Thomas et al. Nature 2013).

First, threatened populations could be cross with individuals of the same species from better-adapted populations to introduce beneficial alleles. A good example of this is crossing a remnant Florida panther population with related subspecies from Texas that significantly boosted the former population and its heterozygosity, a measure of genetic variation that was desired. Risks of this approach include dilution of locally adaptive alleles.

Second, specific alleles taken from a well-adapted population could be spliced into the genomes of threatened populations of the same species. This was exemplified by recent work wherein heat-tolerance alleles in a commercial trout were identified for possible insertion into fish eggs in populations threatened by rising water temperature. Such an approach was viewed as low risk because it involves genetic manipulations within the same species.

Third, genes removed from a well-adapted species could be incorporated into the genomes of endangered individuals of a different species. This transgenic approach has been extensively used to improve plant crops toward drought and temperature. However, outcomes are hard to predict, and a major concern is that such an approach could bring unintended and unmanageable consequences—definitely a scary possibility.

What do you think about reintroducing extinct species?  Do you see other pros and cons to facilitated adaption?  As always, your comments are welcomed.


The following, entitled ‘De-Evolving’ Dinosaurs from Birds, recently appeared in GenomeWeb:

Ancient animals could be resurrected through the genomes of their modern-day descendants, Alison Woollard, an Oxford biochemist tells the UK’s Daily Telegraph. For instance, the DNA of birds could be “de-evolved” to resemble the DNA of dinosaurs, the paper adds.

“We know that birds are the direct descendants of dinosaurs, as proven by an unbroken line of fossils which tracks the evolution of the lineage from creatures such as the velociraptor or T-Rex through to the birds flying around today,” Woollard says, later adding that “[i]n theory we could use our knowledge of the genetic relationship of birds to dinosaurs to ‘design’ the genome of a dinosaur.”

In both the book and movie Jurassic Park, the fictional resurrection of dinosaurs relied on dinosaur DNA that was preserved in fossilized biting insects, but as the Daily Telegraph notes, a study in PLOS One earlier this year found no evidence of DNA from amber-preserved insects.

Daily Telegraph adds that any dinosaur DNA recovered from bird genomes would be fragmented and difficult to piece back together. A mammoth, it says, might have a better shot.

Mixed Coupling: “Bite-sized” Topics of Interest

  • What do DREAMing, King Louis XVI, Sasquatch, Abominable Snowman, and “Jurassic Beer” have in common?
  • Hint:  Sequencing

Keeping up with current literature in order to select items to weave into my blog content is greatly assisted by taking advantage of automated alerts. My daily alerts from PubMed and Google Scholar are based on keywords, such as nucleoside/tide analogs, oligonucleotides, sequencing, modified mRNA, etc. Not surprisingly, I come across many interesting or useful articles that are “content-worthy” but not as an entire or lengthy posting. So, today’s content represents a collection of these “bite-sized” topics that I refer to as “mixed couplings”—a termed borrowed from my early publication on analysis of mixed-sequence oligonucleotides derived from mixed coupling of phosphoramidite reagents.

While today’s mixture of topics are loosely “coupled” by virtue of involvement of sequencing, in one form or another, future mixed-coupling content will incorporate other technical aspects of what’s trending in nucleic acid research, development or applications. Hopefully you will find these to be as interesting or informative as I do.

DREAMing…of a patent-free human genome for clinical sequencing

This is the catchy and provocative title of an article in the October 8th, 2013 online issue of Nature Biotechnology by Kevin McKernan et al. at Courtagen Life Sciences. The article  proposes a novel approach for using the genetic code without concern for existing gene patents. They state that, “[i]n our opinion, gene patents are immoral not because of a profit motive but because an ‘armed authority’ ultimately enforces them to protect a piece of ‘imagined property’ or an idea. Property is usually defined as something that consists of matter and is not infinitely replicable (i.e. exhibits scarcity). Ideas are neither of these.”

Kevin McKernan, co-founder, CEO and Director of Courtagen Life Sciences, Inc., which provides innovative genomic and proteomic products and services for physicians and the Life Sciences industry (taken from courtagen.com via Bing Images).

Kevin McKernan, co-founder, CEO and Director of Courtagen Life Sciences, Inc., which provides innovative genomic and proteomic products and services for physicians and the Life Sciences industry (taken from courtagen.com via Bing Images).

The entire legal rationale and technical underpinning of the proposed methodology in this article are not easily summarized, should be read carefully, and thought about deeply. Nevertheless, some of the key points are as follows.

Despite the Supreme Court’s recent decision on the patent ineligibility of natural DNA, cDNAs—a human-made laboratory modification—remain patentable, provided other legal considerations are met. If cDNAs are human-made, PCR amplification of gene panels and exomes would also constitute human-manipulated isolation of the claimed DNA sequence. However, this isolation via amplification significantly alters the DNA by failing to faithfully replicate the molecular epigenetic (i.e. 5-methyl CpG and other minor dinucleotide) patterns in natural DNA. Most gene patents fail to specify methylated sequence IDs. As a result, the impact of methylation on sequence function and utility is of paramount importance in this matter.

The argument continues by reasoning that any composition-of-matter claim to a sequence ID would have to pass a triple identity test: does methylated sequence perform substantially the same function, in the same way to yield the same result as non-methylated sequence. They then provide various reasons for why this argument of equivalence is becoming harder if not impossible to make, and illustrate this point by carrying out Agilent Haloplex v2 target enrichment PCR to sequence 327 genes with varying concentrations (0.05mM – 0.2mM) of 5-methyl-dCTP added to the PCR cocktail. This technique replicates natural CpG and other minor dinucleotide patterns, but also introduces non-CpG methylation, thus producing amplicons even more distant from the claimed 4-nucleotide sequences than the natively methylated versions of the gene not described in most gene patents.

As expected, subtle amplicon mobility shifts and non-identical Illumina MiSeq results were obtained, yet with 50mM 5-methyl-dCTP 99.5% of the sequence information matched the control data set obtained without 5-methyl-dCTP.

A methylation-specific restriction enzyme, MspJI, is employed in this method to digest background 5-methyl-dCTP generated amplicons, not unlike use of UNG and dUTP for “carryover decontamination”. Consequently, they coined the term DREAM PCR for Decontamination Ready Encoded AMplification to describe a PCR method that utilizes additional 5-methyl-dCTP to generate an amplicon set that is susceptible to methylation-specific digestion. This aspect of DREAMing is said to provide additional assurances to clinical sequencing laboratories.

My last check on the metrics for this Nature Biotechnology article indicated that it’s in the 95th percentile of a sample of 10,000 of the 57,603 tracked articles of a similar age in all journals. There were also more than 50 tweets so I expect that it will continue to generate lots of commentary in social media, as well as much controversy, and countless billable hours by patent and litigation attorneys!

Louis XVI’s blood in a gourd?

Application of modern methods for DNA analysis to identify historical individuals’ remains is a fascinating subject that has included analysis of the remains of the Romanov family, the putative evangelist Luke, the American outlaw Jesse James, and the astronomer Nicolaus Copernicus. Now add the French King Louis XVI—and circumstances somewhat reminiscent of a Dan Brown novel, legends about the Holy Grail, or the Shroud of Turin.

Louis XVI became the heir to the throne and the last Bourbon king of France upon his father’s death in 1765. In 1770, he married Austrian archduchess Marie-Antoinette, the daughter of Maria Theresa and Holy Roman Emperor Francis I. After a slew of governing missteps, Louis XVI brought the French Revolution crashing down upon himself, and on January 21, 1793 he was executed.

Displaying the head of Louis XVI-1793 (taken from robinengelman.com via Bing Images).

Displaying the head of Louis XVI-1793 (taken from robinengelman.com via Bing Images).

According to a publication in Forensic Science entitled Genetic analysis of the presumptive blood from Louis XVI, king of France by Lalueza-Fox et al., eyewitnesses stated that many people from the crowd dipped their handkerchiefs in the king’s blood and kept these objects as mementos. For more than one hundred years, an Italian family has owned an ornate desiccated gourd—of a type used to store gunpowder—that presumably contained one of these handkerchiefs. An inscription read “Maximilien Bourdaloue on January 21th, dipped his handkerchief in the blood of the king after his beheading”. Biochemical analyses of a dark, dried spot in the gourd confirmed that the sample was indeed blood. On April 3rd this year the bloodstained cloth was sold at auction for $24,000 to a French collector who is fascinated by the former monarch, according to an online news report.

Gourd containing handkerchief thought to be stained with blood of Louis XVI (taken from u.tearn.com via Bing Images).

Gourd containing handkerchief thought to be stained with blood of Louis XVI (taken from u.tearn.com via Bing Images).

A report entitled Genetic analysis of the presumptive blood from Louis XVI, king of France was subsequently published by a consortium of Spanish and Italian investigators in Forensic Science International: Genetics. This report by Lalueza-Fox et al., which can be freely downloaded via Google Scholar, provides details for how several samples were scraped from the inside of the gourd for extraction of presumptive ancient DNA with standard precautions to avoid contamination. Various DNA analyses were carried out, including PCR-sequencing of mitochondrial DNA (mtDNA) hypervariable region 1 (HV1) and 2 (HV2)—see TriLink’s website for mtDNA analysis and its recently launched mitoPrimers™.

Crystal urn believed to contain the heart of Louis XVII (taken from flickriver.com via Bing Images)

Crystal urn believed to contain the heart of Louis XVII (taken from flickriver.com via Bing Images)

In addition, because Louis XVI had blue eyes, as can be seen in different portraits, these investigators checked a single-nucleotide polymorphism (SNP; rs12913832) that is associated with blue eye color in modern humans, and is located in exon 86 of the HERC2 gene. These results showed that the subject analyzed was a heterozygote, which is compatible with a blue-eyed person. The investigators concluded that to confirm the identity of the subject, an analysis of the dried heart of his son, Louis XVII, could be undertaken. That too is an interesting “story within a story” worth reading by clicking here, especially if you’re into mixing modern forensics with old rumors, mystery and controversy involving royals. According to official historiography, the 10-year-old Louis XVII died in the Temple of Paris on June 8th 1795. However, public rumor spread the theory that Louis XVII escaped and that his descendants would be alive today. One such putative “Louis XVII” was Carl Wilhelm Naundorff, who died in 1845 in Delft, Netherlands. Comparative mtDNA analysis was performed on the heart of the young boy who died in the prison of Paris in 1795.

Sasquatch sequencing

Sasquatch or hoax? (taken from spatzo.net via Bing Images)

Sasquatch or hoax? (taken from spatzo.net via Bing Images)

On October 20th 1967, Roger Patterson and Robert Gimlin recorded this now famous picture of a purported Sasquatch with a 16mm camera at Bluff Creek, California, after large footprints had been found in this region in previous years. Many years later, Bob Heironimus, an acquaintance of Patterson’s, claimed that he had worn an ape costume for the making of the film. Both men have always dismissed allegations that they had hoaxed the footage by filming a man wearing an ape suit.

Fast forward from 1967 to this recent 2013 press by the Sasquatch Genome Project, website I highly recommend visiting for much more information and access to links to various videos:

DALLAS, Oct 1 – On October 1, the Sasquatch Genome Project held a news conference in Dallas to show exclusive footage from the long-awaited Erickson Project, a multi-site effort led by entrepreneur Adrian Erickson to capture definitive video and DNA evidence from the elusive Sasquatch. Along with Erickson participants in the genome project spoke about their areas of expertise and answered reporters questions.

The Sasquatch Genome Project, led by Dr. Melba Ketchum, is the group responsible for the 5-year study and genomic sequencing of Sasquatch DNA, “Novel North American Hominins, Next Generation Sequencing of Three Whole Genomes and Associated Studies,” that passed scientific peer review in January and was published in February of this year. In conjunction with the screening of the new Erickson footage, the DNA study is available for on-line open access on this web site under the tab View DNA Study.

Adrian Erickson presented short clips from his HD footage. Researcher Dennis Pfohl, who personally captured video and collected DNA samples from Sasquatch individuals spoke about the footage and the project. Dr. Ketchum presented physical Sasquatch samples used in the DNA study and new specimens under ongoing investigation, and she also discussed sample chain of custody, study results, and bias encountered from the scientific establishment.

Lest you immediately dismiss the Sasquatch Genome Project and this publication as a modern version of a continuing hoax or scam, you should at least give the publication a quick read, and consider the authors’ affiliations, as well as Dr. Ketchum’s CV that are all accessible on the Project website. I’ll briefly mention here some aspects of the publication.

One hundred and eleven samples of blood, tissue, hair, and other types of specimens were studied. DNA from a subset of these samples gathered from various locations in North America that survived screening for wildlife species identification were subjected to mtDNA sequencing, specific genetic loci sequencing, forensic STR testing, whole genome SNP analysis, and NGS genome sequencing. The authors conclude the “the data conclusively proves that the Sasquatch exists as an extant hominin and are a direct maternal descendent of modern humans. At this time, analysis of the Sasquatch genomes is still ongoing…Additionally, analysis of hair purportedly from a Siberian Wildman is being tested in an effort to determine if relatedness between the Sasquatch and the Russian Wildmen. A species name has been applied for with ZooBank, Homo sapiens cognatus.” Online English translations for the Latin word cognatus are related by blood, a relative, kinsman.

By the way, the Sasquatch Genome Project homepage provides a perhaps not surprising account of difficulties encountered in trying to publish this investigation. After various rejected submissions, a journal agreed to publish the reviewed manuscript, but its legal counsel advised against that for such a controversial subject as it would destroy the editors’ reputations. Rather than spend another five years just trying to find a journal to publish, rights to this journal were acquired and it was renamed to Denovo, but retained the passing peer reviews that are expected by the public and the scientific community.

Abominable Snowman (aka Yeti) Too?

According to an Oct 17th headline for The Telegraph in the U.K., ‘Yeti lives’: Abominable Snowman is ‘part polar bear and still roams the Himalayas’. The article states that research by Bryan Sykes, who is founder and chairman of Oxford Genetics, a genealogical DNA testing firm, and a professor of human genetics at the University of Oxford, has found a genetic match between an ancient polar bear and samples said to come from the Yeti—suggesting the creature known as the Abominable Snowman is still living in the Himalayas.

Sykes conducted DNA tests on hairs from two unidentified animals, one found in the western Himalayan region of Ladakh, in northern India, and the other from Bhutan, 800 miles east. The results were then compared with other animals’ genomes stored on a database of all published DNA sequences. Sykes found a 100 percent match with a sample from an ancient polar bear jawbone found in Svalbard, Norway. That specimen dates back at least 40,000 years, and probably as far back as 120,000 years—a time when the polar bear and the closely related brown bear were separating as different species.

Sykes believes that the animals are hybrids—crosses between polar bears and brown bears. Because the newly identified samples are from creatures which are recently alive, he thinks the hybrids are still living in the Himalayas. He added: “There’s more work to be done on interpreting the results. I don’t think it means there are ancient polar bears wandering around the Himalayas. But we can speculate on what the possible explanation might be. It could mean there is a sub species of brown bear in the High Himalayas descended from the bear that was the ancestor of the polar bear. Or it could mean there has been more recent hybridisation between the brown bear and the descendant of the ancient polar bear.”

Jurassic beer

Given the prestige and widespread readership of Science magazine, it’s not surprising that a lot of attention was given to an article therein by Cano & Borucki in 1995 reporting to have extracted, revived, cultured and identified bacterial spores from the abdominal contents of extinct Proplebeia dominicana bees. The bees were preserved in 25- to 40-million-year-old amber—a polymeric glass formed over time from resins of conifers and plants that provides an excellent preservative matrix. Interest in this amazing report was undoubtedly due to its appearance shortly after the famously popular movie Jurassic Park, with a plot that revolved around cloning a dinosaur from fossilized DNA in dinosaur blood from mosquitos trapped in amber.

Extinct Proplebeia dominicana bee in amber (taken from pinterest.com via Bing Images)

Extinct Proplebeia dominicana bee in amber (taken from pinterest.com via Bing Images)

In a later patent application by Dr. Cano, he describes a novel yeast strain recovered and cultured from a 44-million-year-old piece of amber that he said is “similar to Saccharomyces…and may be used in the manufacture of a fermented beverage (e.g. beer). Surprisingly, in the manufacture of beer, the yeast strain exhibits properties that make it amenable to the manufacture of both a lager and ale.” Dr. Cano now co-owns Fossil Fuel Brewing Co. which is utilizing ancient yeast strains to brew beer. Jay R. Brooks, the tasting director of the

Jurassic Beer (taken from mutineermagazine.com via Bing Images

Jurassic Beer (taken from mutineermagazine.com via Bing Images

exalted Celebrator Beer News Magazine, commented when comparing the Fossil Fuels brew to an identical pale ale differing only in the strain of yeast, “[Fossil Fuels] is smoother, with softer fruity flavor characteristics and just a touch of lemony sweetness that isn’t tart…It has a more complex and well-developed taste profile, and its smoothness makes it great. The fact it is made with such old yeast is fascinating, and given how good the beer is, no mere novelty.”

Caveat on reproducibility

Two years after the aforementioned Science publication by Cano & Borucki in 1995, Austin et al. at the National History Museum in London, U.K. reported rigorous attempts to reproduce these DNA sequences using the same amber sample, as well as others. The only sequences they were able to detect were derived from obvious sources of non-insect contamination. They concluded that “although no negative result can disprove the existence of ancient DNA in amber-preserved fossils, our work shows that isolation of geologically ancient DNA from amber-preserved insects is not reproducible”.

This non-reproducibility was also reported in PLoS ONE in September 2013 by a team of scientists at the University of Manchester in the U.K.  Using high-throughput (NGS) sequencing methods, they concluded that they “were unable to obtain any convincing evidence for the preservation of endogenous DNA in either of the two copal [aka “young amber”] inclusions that [they] studied”. The investigators reasoned that their negative results could not be attributed solely to a lack of technical skill, as they have successfully isolated and sequenced ancient Mycobacterium tubercolosis DNA from human bones as well as DNA from archaeological plant samples, nor to their extraction and preparation methods as those approaches have been used to isolate DNA from air-dried specimens. A GenomeWeb story about this publication quoted one coauthor as saying that “[w]e therefore conclude that our failure to obtain sequence reads was because the copal specimens contained no preserved DNA,” while another coauthor noted that “unfortunately, the Jurassic Park scenario must remain in the realms of fiction”.

But hold on, it’s important to consider the following comment about the aforementioned PLoS ONE publication that is online and reads as follows:

Should be titled “Absence of DNA sequenceable by 454”

Posted by John Thompson on 14 Sep 2013 at 14:31 GMT 

I have no doubt that this work was carefully done and I have no reason to doubt the results. The conclusions, however, are over-reaching. Having no DNA that is sequenceable by 454 (which requires amplification and relatively long, intact, unmodified DNA) is not at all the same as having no DNA. There are examples of DNA that cannot be sequenced by 454 but can be detected by single-molecule methods. A proper study of DNA survivability in amber will require the most sensitive assays and not just the most accessible. Is it likely that Jurassic era DNA has survived in amber? No, but this work does not prove it.

I contacted John Thompson, former Senior Director of Genomic Research at Helicos BioSciences, who kindly agreed to identify himself as having posted the above comment, with which I fully agree. He also added the following:

The two samples I worked with that were completely or initially immune to Illumina and 454 sequencing were the ancient horse DNA recently published in Nature (499: 74-78, doi:10.1038/nature12323, “Recalibrating Equus evolution using the genome sequence of an early Middle Pleistocene horse.” and DNA extracted from remains of Korean war MIAs (http://www.ashg.org/2009meeting/abstracts/fulltext/f21866.htm). The former sample was eventually sequenced by Illumina once Helicos had identified how to best isolate the DNA (see references in Nature paper). The Korean War MIA data was never published beyond the abstract because the informed consent was not broad enough to cover what Helicos sequenced. AFDIL was attempting to get 40 bp of mitochondrial sequence but we actually got the entire mitochondrial genome and could have gotten most of the nuclear genome if we had kept going. Illumina and 454 could not always get the 40 bp.

Given this unique performance of Helicos single-molecule sequencing, it’s worth mentioning that fee-for-service Helicos sequencing is available, as detailed at http://www.seqll.com/.

Ah, how interesting our ever-changing field is! I hope you enjoyed this mixed coupling of bite-size topics and I encourage you to share your own with all readers via a post below. 


Shortly after finishing this posting, I read the following October 14th online Nature headline, byline and story written by Ed Yong that I felt compelled to add as this postscript:

Blood-filled mosquito is a fossil first

Insect’s bloated abdomen carries traces of blood molecules that are 46-million-years old.

Jurassic Park’s iconic image of a fossilized blood-filled mosquito was thought to be fiction—until now. For the first time, researchers have identified a fossil of a female mosquito with traces of blood in its engorged abdomen. A team led by Dale Greenwalt at the US National Museum of Natural History in Washington DC reports the fossil discovery today in Proceedings of the National Academy of Sciences.

Although scientists have found fossils of suspected blood-sucking insects, the creatures’ feeding habits have mostly been inferred from their anatomy or the presence of blood-borne parasites in their guts. But Greenwalt’s fossilized mosquito contains molecules that provide strong evidence of blood-feeding among ancient insects back to 46 million years ago. It is a fortunate find. “The abdomen of a blood-engorged mosquito is like a balloon ready to burst. It is very fragile,” says Greenwalt. “The chances that it wouldn’t have disintegrated prior to fossilization were infinitesimally small.”

A long shot

The insect was found not in amber, as depicted in Jurassic Park, but in shale sediments from Montana. After 46 million years, any DNA would be long degraded, but other molecules can survive. Greenwalt’s team showed that the insect’s abdomen still contains large traces of iron and the organic molecule porphyrin — both constituents of haemoglobin, the oxygen-carrying pigment found in vertebrate blood. These molecules were either rare or absent in the abdomen of a fossilized male mosquito (which does not drink blood) of the same age, found at the same location.

“This shows that details of a blood-sucking mosquito can be nicely preserved in a medium other than amber,” says George Poinar, who studies fossilized insects at Oregon State University in Corvallis. “It also shows that some porphyrin compounds in vertebrate blood can survive under the right conditions for millions of years.”

Greenwalt suggests that this provides support for the controversial claims of Mary Schweitzer, a palaeontologist at North Carolina State University in Raleigh, who has reportedly isolated haemoglobin traces from dinosaur bones.

Sequencing DNA on Mars – Science Far Out or Far Out Science?

There’s no shortage of clever “lab-on-chip” (LOC) devices for all sorts of interesting point-of-use applications; however, investigating the feasibility of an LOC for sequencing DNA on Mars seemed “far out” to me both extraterrestrially and scientifically. After some poking around in the literature to learn more about this research – which turns out not to be too far-fetched – I thought it would be worth sharing here some background about astrobiology and some experimental specifics.

What are Astrobiology and NASA’s Astrobiology Program?

According to the US National Aeronautics and Space Administration (NASA), “astrobiology is the study of the origin, evolution, distribution, and future of life in the universe. This multidisciplinary field encompasses the search for habitable environments in our Solar System and habitable planets outside our Solar System, the search for evidence of prebiotic chemistry and life on Mars and other bodies in our Solar System, laboratory and field research into the origins and early evolution of life on Earth, and studies of the potential for life to adapt to challenges on Earth and in space.”

Future astrobiologist in search of a sample for possible DNA detection? (Bing Images)

Future astrobiologist in search of a sample for possible DNA detection? (Bing Images)

NASA’s Astrobiology Program addresses three fundamental questions:

  • How does life begin and evolve?
  • Is there life beyond Earth and, if so, how can we detect it?
  • What is the future of life on Earth and in the universe?

Needless to say, these are truly profound questions requiring very long-term commitments by interdisciplinary teams supported by huge – dare I say astronomical – budgets. Readers interested in perusing a presentation detailing how NASA’s entire 2014 budget request of ~$18 billion will be spent can click here, while information about NASA funding opportunities can be found by clicking here. Incidentally, NIH’s budget request for FY 2014 is ~$31 billion.

Primordial Soup


Alexander Ivanovich Oparin graduated from the Moscow State University in 1917 and became a Professor of Biochemistry there in 1927. Many of his early papers were on plant enzymes and their role in metabolism. In 1924 he put forward a theory of life on Earth developing through gradual chemical evolution of carbon-based molecules in primordial soup.

Theories and research on how life – as we know it – began and evolved has received considerable attention since 1924 when Soviet biologist Alexander Oparin proposed a theory of the origin of life on Earth through gradual chemical evolution of molecules that contain carbon in the “primordial soup.”

The research continued with Stanley L. Miller’s, now classic paper, “A Production of Amino Acids Under Possible Primitive Earth Conditions” in Science in 1953 – the same year as Watson & Crick’s discovery of the structure of DNA. Miller’s work involved paper chromatography after electrical discharges in a mixture of CH4, NH3, H2O and H2. Extensions of this line of experimentation to detect nucleobases formed under possible prebiotic conditions on Earth that led to evolution are now numerous (click here for more examples).

Possible contamination with terrestrial molecules has been a concern for detection of nucleobases in carbon-rich meteors. However, recent identification of nucleobase analogs 2,6-diaminopurine and 6,8-diaminopurine has been reported by Dworkin and coworkers to strongly support extraterrestrial origin. These investigators conclude that “[b]ecause meteorites may have provided a significant source of prebiotic organic material including purines, it is possible that alternative nucleobases such as 2,6-diaminopurine, 6,8-diaminopurine, xanthine, and hypoxanthine were available for constructing the first genetic molecules” involving an “expanded genetic alphabet,” as proposed in RNA World or all-purine primitive RNA.

According to a NY Times report on September 12th of this year, Dr. Steven Benner – founder of the Foundation for Applied Molecular Evolution – suggested that, if life started out as RNA, minerals containing borate could have been involved in the chemistry of its formation. Since boron has been recently found in a Martian meteorite, Mars might have been a favorable place for RNA to emerge, and for life to start. The report goes on to say that a giant impact could then have kicked up microbe-laden rocks, which latter fell to earth. I should note here that, while this Mars-to-Earth scenario is opposite an Earth-to-Mars pathway discussed below, these “interplanetary nucleic acid-exchange schemes” are, in principle, not mutually exclusive.

Incentive to continue work in this area has been provided in the form of The Origin-of-Life Prize® that is intended to “encourage the pursuit of natural-process explanations and mechanisms of initial ‘gene’ emergence within nature.” Interestingly, this one-time prize worth $1,000,000 that will be paid to the winner(s) as a twenty-year annuity of $50,000 per year “in hopes of discouraging theorists’ immediate retirement from productive careers.”

What is the Possible Origin of Martian Genomes?

One answer to this question is provided by the “common ancestry hypothesis” that involves natural transfer of viable microbes in space, such as from Earth to Mars and Mars to Earth. An international team of scientists, including some from NASA, have published supporting data for the possibility and probability of such transfer of microbes from traveling in meteoroids billions of years ago following the Big Bang development of the universe. Factors taken into account include radiation protection, vacuum, temperatures, acceleration pressures, and spontaneous DNA decay. They conclude that “if microbes existed or exist on Mars, viable transfer to Earth is not only possible but also highly probable, due to microbes’ impressive resistance to the dangers of space transfer and to the dense traffic of billions of Martian meteorites which have fallen on Earth since the dawn of our planetary system. Earth-to-Mars transfer is also possible but at a much lower frequency.” I encourage those of you interested in more information about this possibility, (depicted below), to click here to read Scientific Logic for Life on Mars by Gilbert V. Levin, who was the Principal Investigator of the 1976 Viking mission Mars Lander Labeled Release (LR) experiment.

According to a 2012 article in National Geographic, the LR experiment involved scooping up Martian soil and mixing it with a drop of water containing nutrients from a source of radioactive carbon. The hypothesis was, if the soil contained microbes, metabolism of the nutrients would release either radioactive CO2 or CH4 that could be measured by a radiation detector in the probe. A number of control experiments were also performed. The LR experiment came out positive for life, and the control experiments came out negative.  Unfortunately, two other experiments did not confirm these results and NASA dismissed the possibility of life having been detected. Levin and others have reanalyzed the results and stuck by the claim.

Taken from “Scientific Logic for Life on Mars” by Gilbert V. Levin at www.gillevin.com via Bing Images.

Taken from “Scientific Logic for Life on Mars” by Gilbert V. Levin at www.gillevin.com via Bing Images.

Developing the Search for Extra-Terrestrial Genomes (SETG) Instruments

Feasibility studies aimed at development of instrumentation for SETG have been published in a series of reports by a team of researchers including Christopher E. Carr [MIT & Massachusetts General Hospital (MGH)], Holli Rowedder (MGH), Clarissa S. Lui (MIT), Maria T. Zuber (MIT), and Gary Ruvkun (MGH & Harvard Medical School) – click here for photos and bios of the SETG Team.

In a 2011 report, they addressed various aspects of isolating, extracting, and sequencing nucleic acids in situ on Mars – particularly 16S and 23S ribosomal RNA genes. These genes are used for phylogenic analysis to address whether sequences found on Mars are similar to those on Earth and likely contamination, or indicative of extant Martian life isolated from that on Earth for the past 3+ billion years.

These investigators note that investigating DNA extraction and amplification from Martian soil of unknown composition is a significant issue; however, “Martian soil simulants” have been developed based on spectral characterization of soild matter on Mars from the Viking and Pathfinder landing sites. Among various LOC-compatible DNA purification and concentration methods, synchronous coefficient of drag alteration (SCODA) was said to be a promising new technique—click here for a poster on SCODA applied to a Martian soil analog presented at the Astrobiology Science Conference 2012. Challenges facing all of the other steps in sample-to-answer for a SETG instrument are addressed in the aforementioned 2011 report, which correctly – in my opinion – emphasizes that library preparation will be especially difficult to solve due to there being numerous steps and reagents.


The current SETG instrument contains a 2 cm x 2 cm microfluidic chip module containing tiny nanoliter wells where the real-time polymerase chain reactions occur. Tiny tubes feed in chemicals and blue light illuminates fluorescent dyes that help identify and analyze DNA molecules (picture and caption taken from MIT website).

In addition to the SETG reports, two follow-on reports have been published in Astrobiology this year. In the first of these, Carr et al. demonstrated that Ion Torrent’s semiconductor proton-sensing, optics-free (“no fluorescence”) sequencing chips survive several analogs of space radiation at doses consistent with a 2-year Mars mission, including protons with solar particle event–distributed energy levels and 1 GeV oxygen and iron ions. There was no measurable impact of irradiation at 1 and 5 Gy doses on either sequencing quality or low-level hardware characteristics. The second report by Carr et al. demonstrated that biological and chemical components, such as polymerase, dNTPs, and fluorescent dye molecules survived several analogs of the radiation expected during a 2-year mission to Mars, including proton (H-1), heavy ion (Fe-56, O-18), and neutron bombardment. Other reagents had reduced performance or failed at higher doses. It was concluded that, overall, the findings suggest it is feasible to utilize space instruments with biological components for mission durations up to several years in environments without large accumulations of charged particles, such as the surface of Mars.

After reading these SEGT-related publications, I contacted Prof. Carr to ask if a SEGT instrument was part of NASA’s Mars 2020 Mission that I had read about in a July 27th blog post by Van Kane on The Planetary Society website. The detailed blog was entitled The Mars 2020 Rover In-Depth, which said that NASA’s next major mission to the Red Planet will store samples for eventual return to the Earth. Prof. Carr’s reply to me was that “[w]e are not currently slated for a mission. The Mars 2020 rover mission is likely to include the best package of instruments possible based on the submitted proposals and the priorities outlined in the recent Science Definition Team report….[T]he strawman set of instruments is somewhat similar to those on Curiosity. But there will almost assuredly be some new instrumentation. Sample return caching certainly would be completely new.”

In closing this post, I welcome comments, especially opinions on whether sequencing DNA on Mars is “science far out” or “far out science”?


Doubts about Martian methane: On September 19th the Wall Street Journal reported in an online video that NASA scientists say they cannot find any traces (less than one part per billion) of methane in the thin Martian air, dimming hopes that microbes might lurk under the protective blanket of soil on the cold arid world. Also reported were long-range data to the contrary, and mention of upcoming Martian methane-detection missions by India and the European Space Agency.

Soil samples taken and analyzed from this site have been found to contain Martian water. The left dimension of each scoop is 4 cm (~1.5 in)! Courtesy NASA/JPL-Caltech/MSSS via Bing Images.

Soil samples taken and analyzed from this site have been found to contain Martian water. The left dimension of each scoop is 4 cm (~1.5 in)! Courtesy NASA/JPL-Caltech/MSSS via Bing Images.

Mars has a surprising amount of water! One week later on September 27, Curiosity researcher Laurie Leshin and colleagues told Science Magazine that Mars’ dusty red covering holds about 2% water by weight. This could be a useful resource for future astronauts, they say. “If you think about a cubic foot of this dirt and you just heat it a little bit – a few hundred degrees – you’ll actually get off about two pints of water – like two water bottles you’d take to the gym,” Dr Leshin explained. Aside from drinking or farming, water could also be a source of H2 and O2 for fuel and breathing, respectively.

Do you want a one-way ticket to Mars? Mars One is a non-profit organization that plans to establish a permanent human colony on Mars by 2023. The private spaceflight project is led by Dutch entrepreneur Bas Lansdorp, who announced official plans for the Mars One mission in May 2012. In 2022, four carefully selected applicants will be launched in a Mars-bound spaceflight to become the first residents on Mars. Every step of the crew’s journey will be documented for a reality television program that will broadcast 24/7/365. On August 9th, CNN reported that more than 100,000 people have applied for this one-way trip to Mars, hoping to be chosen to spend the rest of their lives on uncharted territory. Who knows, maybe they will be able to extract Martian soil samples in attempts to detect and sequence DNA.

Coincidentally, it was reported in the September 12th, 2013 issue of Nature that NASA is launching a research program to investigate how human and other tissue reacts to time spent in space. Grant applications for up to $500,000 for a 5-year period will be accepted in Fall of 2014.

Artist rendition of the Mars One colony (taken from oditycentral.com via Bing Images)

Artist rendition of the Mars One colony (taken from oditycentral.com via Bing Images)