Transfer RNA (tRNA) Fragments Are Connected to Diseases

  • Specifically Formed tRNA Fragments (tRFs) can Repress Expression by RNAi 
  • Specific tRFs are Associated with Cancer and Other Diseases
  • Chemical Modifications in tRFs Pose a Challenge for Sequencing 

Researching new, trending topics for Zone in with Zon rewards me in several ways, including learning about important subject matter that I only vaguely knew about, or had been completely unaware of. The present blog is about tRNA fragments (tRFs), which was totally new subject matter for me that I found to be very interesting and worth sharing here.

But before getting to biological formation and functions of tRFs, I want to mention what led me to this intriguing class of RNA molecules. In a nutshell, TriLink’s R&D team decided to “brainstorm” on how its expertise in chemically modified RNA might be leveraged into new product offerings beyond its current lines of modified oligo RNA and modified messenger RNA (mRNA). Since tRNAs were long known to have numerous types of chemical modifications, as detailed elsewhere, TriLink’s R&D started to think about tRFs for reasons outlined below.

Biogenesis of tRFs

Formation of tRNA is a complex process. Initially, tRNA is transcribed in the form of a precursor (pre-tRNA) containing 50-nt leader and 30-nt trailer sequences, and in some cases introns in the anticodon loop. Pre-tRNAs then undergo various types of RNA processing steps to ultimately form mature tRNAs. During tRNA maturation, the 50-nt trailer is processed by RNase P, the 30-nt trailer is removed by RNase Z, and following 30-trailer removal, the 30-nt end of all human tRNAs is modified by enzymatic addition of the universal CCA triplet, as depicted here.

Pre-tRNA (left) and mature tRNA (right); adapted from Anderson & Ivanov FEBS Lett (2014)

Also depicted here are specific types of enzymatic cleavage reactions of mature tRNA by ribonucleases Dicer and angiogenin (ANG) that lead to formation of 5’-tRFs and 3’-CCA tRFs, as well as 5’-halves and 3’-halves. These tRFs derived from mature tRNAs, as well as tRFs from pre-tRNAs that will not be discussed here, have now been extensively characterized by high-throughput short RNA sequencing methods. Among new advances in this sequencing methodology, TriLink’s recent PLOS One publication of its innovative CleanTag™ sample prep procedure has already been viewed an impressive ~6,000 times since appearing online only ~14 months ago as of this writing.

Mature tRNA (adapted from Anderson & Ivanov)

It should be noted that tRFs are not restricted to humans but have been shown to exist in multiple organisms. Two online tools are available for those wishing to learn more about tRFs: the framework for the interactive exploration of mitochondrial and nuclear tRNA fragments (MINTbase) and the relational database of Transfer RNA related Fragments(tRFdb). MINTbase also provides a scheme for the naming of tRFs called tRF-license plates that is genome independent. A recent publication by Kim et al. is a good lead reference for various functions of tRFs, some of which include the following.

Possible Roles of tRFs in Human Diseases

In a review of this subject, Anderson & Ivanov emphasize that, while production of tRFs have been observed in several types of human diseases, it remains to be determined whether these tRFs contribute to disease pathogenesis. Landmark findings regarding functions of tRFs were published by a team, including Andrew Fire—2006 Nobel Laureate for  RNA interference (RNAi)—titled Human tRNA-derived small RNAs in the global regulation of RNA silencing that provided compelling evidence demonstrating that human tRFs can enter RNAi pathways. These findings by Fire & coworkers are now recognized as a previously unknown nexus of RNAi translational repression pathways involving tRFs and microRNAs (miRNAs) depicted here.

Schematic representation of the biogenesis of miRNAs and tRFs associated with Argonaute (AGO) proteins. Taken from Shigematsu & Kirino Gene Regul Syst Bio (2015)

tRFs and Cancer: In 2009, Lee et al. reported that a specific tRF, designated as tRF-1001, is highly expressed in a wide range of cancer cell lines but much less in tissues, and its expression in cell lines was tightly correlated with cell proliferation. Furthermore, siRNA-mediated knockdown of tRF-1001 impaired cell proliferation. Since that discovery, various research groups have similarly found specific tRFs associated with different types of cancer, as recently detailed by Croce & coworkers, who concluded the following:

“We found that tRNA-derived small RNAs (tsRNAs) [i.e. tRFs in this blog] are dysregulated in many cancers and that their expression is modulated during cancer development and staging. Indeed, activation of oncogenes and inactivation of tumor suppressors lead to a dysregulation of specific tRFs, and tRFs-knock out cells display a specific change in gene-expression profile. Thus, tRFs could be key effectors in cancer-related pathways. These results indicate active crosstalk between tRFs and oncogenes and suggest that tRFs could be useful [bio]markers for diagnosis or targets for therapy. Additionally, [overexpression of two specific tRFs] affect cell growth in lung cancer cell lines, further confirming the involvement of tRFs in cancer pathogenesis.”

Biomarkers in blood, which I’ve blogged about previously, are a “hot topic” in disease diagnostics because they offer a more general, less invasive and safer means of patient sample access compared to traditional tumor biopsies.

tRFs and Pathological Stress Injuries: Stress-related cellular damage is central to disease pathogenesis that can be induced by hypoxia, nutrient deprivation, oxidative conditions and metabolic imbalance. Dhahbi et al. sequenced short RNAs from mouse serum and identified abundant 5′-halves derived from a small subset of tRNAs, implying that these tRFs are produced by tRNA type-specific biogenesis. A survey of somatic tissues revealed that these tRFs are concentrated within blood cells and hematopoietic tissues, with very little in other tissues, suggesting that they may be produced by blood cells. Serum levels of specific subtypes of these 5′ tRNA halves change markedly with age, either up or down, and these changes were prevented by calorie restriction.

Taken from Mishima et al. J Am Soc Nephrol (2014)

In a study by Mishima et al., it was shown in vivo that oxidative stress leads to conformational changes in tRNA that thus allows ANG-mediated productin of tRFs. This stress-induced conformational change allows 1-methyladenosine nucleoside (m1A), a modification important for stabilizing the L-shaped structure of tRNA, to be recognized by an m1A-specific antibody, as depicted here. This antibody was used to show that renal injury and cisplatin-mediated nephrotoxicity (which both induce tissue damage via oxidative stress) generate tRFs. Similar results were obtained using m1A-based immunohistochemistry to directly visualize damaged areas of kidneys, brain and liver. Mishima et al. further demonstrated that these tRFS avoid degradation in the blood because they are associated with circulating exosomes, which are extracellular vesicles packed with proteins and nucleic acids.

tRFS and Neurodegenerative Diseases: As detailed in the above mentioned review by Anderson & Ivanov, ANG mutants possessing reduced ribonuclease activity were reported in 2006 to be implicated in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS; aka Lou Gehrig disease), which is a fatal neurodegenerative disease that I have blogged about. In 2012, a subset of ALS-associated ANG mutants was also found in Parkinson’s Disease (PD) patients. Recombinant ANG is neuroprotective for cultured motor neurons, and administration of ANG to a standard mouse model for ALS significantly promotes both life-span and motor function.

Concluding Comments on Analysis of tRFs

Although I started this blog by refering to the fact that mature tRNAs are extensively modified by a wide variety of nucleobase and ribose chemical modifications, these modifcations were not further mentioned. That is because sample prep for short RNA sequencing uses reverse transcription to form cDNA that is then PCR amplified before sequencing, and it is widely acknowledged (e.g. Cozen et al.) that certain chemical modifications in RNA can interfere with reverse transcription. Thus, aside from reported use of demethylases to first remove interfering methyl groups from m1A, N1-methylguanosine, N3-methylcytosine, and N2,N2-dimethylguanosine, sequenced tRFs exclude many tRFs having chemical modifications that prevent reverse transcription.

Recognizing the need for alternative methods of determining structures of chemically modified tRFS, Limbach & Paulines have recently proposed the possibility of developing mass spectrometric (aka mass spec) approaches in a publication provocatively titled Going global: the new era of mapping modifications in RNA. I think this is a great idea, and hope that the mass spec community will soon address this challenge.

As usual, your comments are welcomed.

ADDENDUM

After writing this blog, Eng et al., who investigated the mosquito Aedes aegypti—the primary vector of human arboviral diseases caused by dengue, chikungunya and Zika viruses—reported the following:

Aedes aegypti mosquito. Taken from wcvb.com

“[A]single tRF derived from the precursor sequences of a tRNA-Gly was differentially expressed between males and females, developmental transitions and also upon blood feeding by females of two laboratory strains that vary in midgut susceptibility to dengue virus infection. The multifaceted functional implications of this specific tRF suggest that biogenesis of small regulatory molecules from a tRNA can have wide ranging effects on key aspects of Ae. aegypti vector biology.”

Click here to read my past blogs about Zika virus.

Your Meals, Wines and Much More are Personalized to Your DNA

  • Personalized DNA Sequencing for Lifestyle Guidance is all the Buzz
  • Vita Mojo Provides Meals to Match Your DNA Codes
  • Vinome Promises to Find Wines for Your Unique Palette
  • SlumberType Claims to Analyse Your DNA and Help You Sleep Better

Among the most significant trends in nucleic acids-based R&D these days is personalized medicine, which uses a person’s DNA sequence (or RNA expression profile) to guide the selection of the best available therapy for that person. This approach is opposite to the traditional strategy for drug development leading to “one treatment regimen for all patients.” Thus, as depicted below, major medical facilities now offer patients personalized cancer therapy based on molecular profiling that features analysis of each patient’s DNA and/or RNA markers.

Taken from pct.mdanderson.org

Scientific studies supporting advantages of nucleic acids-based personalized therapies tailored or customized for each individual are quite compelling, and definitely on the rise, based on my PubMed search results. Given this situation for medical therapies, you might wonder whether personalized nucleic acids-based strategies can be extended to other aspects of human biology, perhaps even to what each of us should eat or drink. Well, such wondering has already been done by others, and has recently led to genetic analyses moving from what I describe as “medicine to mainstream,” as you’ll now read.

Your Meals Personalised to Your DNA

Taken from foodsyoucan.co.uk

A chain of cafes in London is now catering to your body’s every whim—right down to its genetic makeup. Vita Mojo is the first in the world to create meals based on a customer’s DNA profile. It’s an avant-garde part of a huge trend for wellness and healthy eating, an industry worth $3.72 trillion—yes, trillion—across the world, according to a report by the Global Wellness Institute.

Vita Mojo customers first arrange to have their DNA analyzed, and then receive a profile of DNA markers which indicate food groups they should avoid and food groups to eat more of. The gene testing service provided by DNAFit, which was founded in 2013, costs $199 and works like this:

  • You receive a DNA collection kit from DNAFit to provide a saliva sample that is mailed to a company called Helix, which uses Illumina’s Exome+ assay to sequence all 22,000 protein-coding genes, as well as generating additional relevant genomic information.
  • DNAFit interprets your genetic data in terms of fitness or nutrition insights, to help you discover more about yourself and make better informed decisions about your wellness.
  • DNAFit provides you with actionable information about your genetics related to:
    • carbohydrate and fat response
    • lactose tolerance
    • genetic detoxification
    • anti-oxidant and omega-3 needs
    • vitamin B and vitamin D needs
    • alcohol and caffeine response

Most importantly, you also receive a 12-week personalised meal plan, recipes and shopping list. I assume this is the information used by Vita Mojo to provide you with your personalized meals. Vita Mojo, which is backed by the $7 billion French catering company Elior, is reportedly in the midst of raising more capital by crowd-funding, about which I have previously blogged. Helix located in San Carlos, California, lists Illumina among its investors in a deal reported elsewhere. Helix also lists numerous corporate partners, which segues into the next section featuring one of these partners with the clever name Vinome derived from vino (wine) and genome.

Your Wine Personalized to Your DNA

Taken from trendwatching.com

Truth be told, I first came across Vinome not via its partnership with Helix but in a Tweet that caught my attention because I enjoy wine, and follow new applications of sequencing. I was most curious about how drinking wine and sequencing were now being linked. In any case, the Tweet about Vinome led me to do some research about this new startup company that offers to personalize your wine drinking experience through sequencing your DNA, and is appropriately located in Healdsburg, which is in the heart of California’s premier wine country.

Here’s how it works:

  • Vinome cost $109.99, which includes $80 for the Helix test (sequencing of a saliva sample), and $29.99 for your Vinome Profile
  • Vinome analyzes 10 genetic markers related to smell and taste
  • The company then combines these DNA markers with your stated taste preferences to reveal your “vinome,” which is defined by the company as “your unique wine preference profile”
  • You can then join the Vinome wine club or shop its wine store to receive “boutique bottles specifically catered to your vinome results”

Vinome states that over 500 volunteers had their DNA sequenced, and then participated in blinded tasting of a spectrum of wines, answering questions about how much they liked the wines and what flavors they could taste. This data was then compared to DNA genetic markers reported in the scientific literature as important for taste and smell. The participants also answered a detailed questionnaire about their taste preferences for various foods and beverages. Vinome then developed an algorithm that combines this genetic data with taste preference information to deliver its personalized wine recommendations. Vinome works with about 50 boutique wineries and offers bottles generally priced from $18 to $50.

Not everyone, however, has hopped on the consumer sequencing band wagon. One media piece quotes a university professor and researcher as saying that “[i]t’s just completely silly. Their motto of ‘A little science and a lot of fun’ would be more accurately put as ‘No science and a lot of fun.’” Personally, I wouldn’t go so far as to say no science, but I do agree that much more correlative genetic and tasting data needs to be obtained to substantiate Vinome’s claims. Interested readers can later consult an entertaining—to me—account in Business Insider written Lydia Ramsey and titled I took a DNA test that claims to reveal the best wine for you — here’s the verdict.

Your Lifestyle Personalized to Your DNA

While researching the above stories, I happened to receive an email advertisement about Exploragen, which was described as “a new DNA lifestyle company to deliver useful DNA-based apps directly to consumers.” It went on to say that the apps from this California startup, which also utilizes the Helix platform, represent “the first online marketplace of DNA-powered consumer products [to] monitor sleep patterns and caffeine metabolism, optimize fitness, personalize cosmetics and much more.”

Taken from livescience.com

If you check out Exploragen’s website, as I did, you’ll find that the latter statements are somewhat misleading because the only app currently available is called SlumberType. This app is stated to “improve your nights and change how you feel during the day” by discovering how your DNA influences your sleep habits such as the quality of sleep and how long it takes you to fall asleep and stay asleep. SlumberType also promises to help you ‘find out how your sleep DNA relates to your diet, productivity, exercise, and caffeine consumption’.

I found some details about how SlumberType works buried in the FAQs on the website. SlumberType checks genetic variants that have been shown to be associated with sleep traits, including how long it takes you to fall asleep, how long you stay asleep, the quality of your sleep, and your genetic similarity to self-reported “morning” or “evening” persons. The SlumberType app is said to make it “simple for you to record your sleep/wake times, your morning and evening mood—plus other factors you choose—with just a few taps.” One important stated caveat is that genetic associations used by this product were originally discovered in European populations and may or may not be applicable to people from a different background.

Visitors to the website are encouraged to stay in touch as more apps are supposedly coming soon. While all of this sounds interesting, and potentially useful for some persons, I’m not convinced there will be enough early adopters to sustain Exploragen’s business model, but that’s just my humble opinion.

Closing Comments

Vinome’s use of genetic markers related to smell and taste led me to research this topic, and in so doing I found a lengthy scientific review article by Reed & Knaapila. This article is well worth a quick read to get a sense—pun intended—of what’s known about genetic markers and our senses.

In a nutshell, it’s a very complicated story because of the complexities and differences in sensory perceptions among individuals. To this point, I found the following hypothetical analysis by Reed & Knaapila to be a good example of how taste and smell genotypes may contribute to different perceptions of the same food (in this case a ham and cheese sandwich containing bread, onion, tomato, watercress, cheese, and ham).

Taken from Reed & Knaapila Prog Mol Biol Transl Sci (2012)

In this hypothetical case, sucrose in the onion will be detected by sweet receptors on the tongue, TAS1R3; glutamate in the tomato (perceived as a savory or umami taste) is sensed by the umami receptor, TAS1R3; bitterness of watercress is due to isothiocyantes detected by bitter receptors, TAS2R38; isovaleric acid in cheese has a “sweaty” odor detected by an olfactory receptor, OR11H7; ham contains androstenone having an odor called boar taint detected by OR7D4.

People with two positive alleles (+/+) perceive the compounds better than people with two negative alleles (−/−). Person 1 can taste the pleasant sweetness of the onion and the umami of the tomato but does not perceive the bitterness of the watercress or the unpleasant odors of the cheese or ham. Thus, Person 1 likes the ham sandwich more than Person 2.

Importantly, in my opinion, Reed & Knaapila note that “[p]eople eat what they like, but they also eat for many other reasons. Simple explanations of the links between sensory perception and food intake are misguided: Just as people do not choose art or music based solely on how well they can hear or see, we do not choose food based solely on the reactions of the tongue or nose. Although genetic differences determine what we can taste and smell (and at what concentration), our taste is ultimately determined by our experiences, learning, and culture, in an artistic sense, as well as in our likes and dislikes of food and drink.”

Bon appétit and à votre santé!

As usual, your comments are welcomed.

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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.

lou

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.

 

 

hawking

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

Prologue

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 

Prologue

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.

Postscript

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.