Small RNA is Big Science

  • Most Top-5 Citations in Clinical Chemistry are MicroRNA (miRNA) Biomarkers
  • miRNA Biomarker Bonanza is Predicted by Panel of Experts, Although No miRNA Biomarkers Have Yet Been Approved by FDA
  • Plethora of Potential Short Regulatory RNA Exists Beyond the Typical miRNA Microcosm

I’m always looking for new and hopefully engaging topics to comment on, and a recent “Best of Clinical Chemistry” item featured in a special issue of Clinical Chemistry definitely caught my attention. I wasn’t surprised by MIQE Guidelines being at the top, given that these are the “bible” for doing accurate quantitative PCR (qPCR) that has become a seemingly ubiquitous molecular assay for clinical studies. However, I was totally surprised that the next four “best of” all involved microRNA (miRNA)! Hence today’s blog about these small RNA being big science—play on words intended (although properly speaking I should say short rather than small). Continue reading

Profiling Pseudouridine

  • Two New Methods for Sequencing Pseudouridine Leverage Old Chemistry
  • New Methods Reveal ‘Rewiring’ of Genetic Code by Post-Transcriptional Pseudouridination
  • Exciting Future for New Analytical Methods for Modified mRNA
  • Be Sure to Read the Very End of the Blog for a Special Offer!

At the risk of seeming enamored with pseudouridine, which I previously proclaimed—with justifications—to be The 2014 Modified Nucleobase of the Year, recent reports about this fascinating base lead me now to feature it here once again. In that past post, it was pointed out that uridine, which is incorporated into all RNA during transcription of genomic DNA, differs from pseudouridine—historically abbreviated by the Greek symbol Ψ –by how one nitrogen (shown in red below) switches place with a carbon for bonding to the ribose ring. It was also noted that this switch has been long known to be carried out after transcription (aka post-transcriptionally) by an enzyme called—appropriately—pseudouridine synthase, the exact mechanistic details for which remain controversial. This post-transcriptional process that converts U to Ψ at specific positions in RNA is called pseudouridination.
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The Most Interesting Scientist in the World: George M. Church

  • Mind Boggling Breadth and Significance of Scientific Publications
  • Serial Entrepreneur and Science Advisor to Many Companies
  • Radical Advocate of Total Openness for Personal Genomics

While seeing for the umpteenth time a Dos Equis beer commercial featuring The Most Interesting Man in the World, I was suddenly inspired to write a blog about The Most Interesting Scientist in the World. After scrolling and polling my memory to decide who that would be, it was an easy decision to pick George M. Church, professor of genetics at Harvard. As I’ll briefly highlight herein, Prof. Church’s contributions continually span a mind boggling spectrum of science that cuts across academic theory, ground breaking “how to” methods, serial entrepreneurship, and—perhaps most importantly—radical openness for personal genomics.

George M. Church and The Most Interesting Man in the World: ‘I don’t always read science, but when I do it’s by George M. Church.’ (taken from Bing Images)

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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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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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Children at Risk from Deadly Respiratory Virus EV-D68

  • Frightening Statistics From CDC
  • CDC Updated U.S. Map of Outbreak & Advice of What to be Aware
  • CDC Develops Rapid Real-Time RT-PCR Test for Detection
  • Some Speculate on Linking Outbreak to the “Southern Border Invasion”

Ebola virus is dominating news reports lately, and perhaps rightly so considering the worldwide impact. Turning our attention, however, to actual incidents of infection and death in the U.S., enterovirus (EV) D68 poses a much greater threat and warrants our attention—especially if you or your friends have young children.

On September 24, Eli Waller’s parents were worried that their 4 year-old son had pink eye and kept him home from school so that he wouldn’t infect other children. He seemed otherwise healthy. What happened next was shocking.

Eli Waller (Credit Andy Waller, via Associated Press). Taken from NY Times.

Eli Waller (Credit Andy Waller, via Associated Press). Taken from NY Times.

‘He was asymptomatic and fine, and the next morning he had passed,’ said Jeffrey Plunkett, the township’s health officer. ‘The onset was very rapid and very sudden,’ quoted the NY Times.

A week later the Centers for Disease Control and Prevention (CDC) confirmed that Eli had been infected with EV-D68.

EV-D68 was seen as early as August of this year as hospitals in Missouri and Illinois reported increased visits from children with respiratory illness. Soon, the virus was identified in 43 states and detected in 594 patients, 5 of which died.

After reading this very sad—if not frightening—story, I decided to research EV-D68 for this “hot topic” blog, which I’m dedicating to little Eli Waller.

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Sequence Every Newborn?

  • Envisaged in the 2002 Challenge for Achieving a $1,000 Genome
  • Are We There Yet? Yes…and No
  • So Where Are We, Actually?

The notion of metaphorically ‘dirt cheap’ genome sequencing is now so prevalent that it seems to have been always available—and have virtually unlimited utility—as previously touted in a provocative article in Nature Biotechnology rhetorically entitled What would you do if you could sequence everything? The notion of ‘everything’ obviously includes all people, and—as we’re reminded by the now familiar t-shirt statement—‘babies are people too.’ Unlike the ‘big bang’ origin of the universe, cheap-enough-sequencing-for-everything, including all babies (newborns, actually) just didn’t happen spontaneously, so when and how did this come about?

In the Beginning…

According to the bible, the history of creation began when, “in the beginning God created the heavens and the earth.” The history of cheap-enough-sequencing-for-everything, according to my tongue-in-cheek reckoning, is that “In the beginning Craig Venter convened and moderated a diverse panel of experts to discuss The Future of Sequencing: Advancing Towards the $1,000 Genome.” This was a ‘hot topic’ at the 14th International Genome Sequencing and Analysis Conference (GSAC 14) in Boston on Oct 2nd 2002. The pre-conference press release added that “the panel will explore new DNA sequencing technologies that have the potential to change the face of genomics over the next few years.”

While it’s taken considerably more than a ‘few years’ to achieve the $1,000 genome, continual decrease in sequencing costs has enabled large-scale sequencing initiatives such as the 1000 Genomes Project. Nick Loman’s 2013 blog entitled The biggest genome sequencing projects: the uber-list! outlines the 15 largest sequencing projects to date and takes a look at some of the massive projects that are currently in the works.

According to GenomeWeb on Jan 14th 2014, Illumina launched a new sequencing system that can now produce a human genome for under $1,000, claiming to be the first to achieve this ‘long sought-after goal’—roughly 12 years in the making, by my reckoning. A LinkedIn post on Jan 15th by Brian Maurer, Inside Sales at Illumina, quotes Illumina’s CEO as saying that “one reagent kit to enable 16 genomes per run will cost $12,700, or $800 per genome for reagents. Hardware will add an additional $137 per genome, while sample prep will range between $55 and $65 per genome.” While Illumina is staking claim to the $1,000 genome and customers acknowledge the new system provides a drastic price reduction, the actual costs of sequencing a genome are being debated. Sequencing service provider, AllSeq, discusses the cost breakdown in their blog. While initially a bit negative, their outlook on the attainable costs seems to be improving.

So, with affordable genome sequencing apparently being a reality, are we ready to sequence every newborn?

Yes…and No

Why this conflicting answer of ‘yes…and no’? The ‘yes’ part is based on the fact that NIH has recently funded four studies on the benefits—and risks—of newborn genome sequencing. The ‘no’ part reflects the added facts that these studies will take five years, and will look at how genome testing of newborns could improve screening, and address what some geneticists view as their most sensitive ethical questions yet.

Put another way, and as detailed in the following section, the requisite low-cost DNA sequencing technology is now available but it needs to be demonstrated—through technical feasibility investigations and in clinical pilot studies—that newborns receive health benefits of the type expected, and that numerous ‘tricky’ ethical issues can be dealt with in an ‘acceptable manner’—although to whom it is acceptable is not obvious to me at this time. Likely controversial views on reimbursement also have to be addressed, but that’s a whole other topic—dare I say ‘political football’—vis-à-vis Obamacare, ooops, I mean the Affordable Care Act.

So What’s the Plan?

The following answer is an adaptation of the Sep 13th 2013 Science News & Analysis by Jocelyn Kaiser entitled Researchers to Explore Promise, Risks of Sequencing Newborns’ DNA.

The National Institute of Child Health and Human Development (NICHD) is rolling out a $25 million, 5-year federal research program to explore the potential value of looking at an infant’s genome to examine all of the genes or perhaps a particularly informative subset of them. This genome testing could significantly supplement the decades-old state screening programs that take a drop of blood from nearly every newborn’s heel and test it for biochemical markers for several dozen rare disorders. Diagnosing a child at birth can help prevent irreversible damage, as in phenylketonuria, a mutant-gene metabolic disorder that can be controlled with diet.

Sequence Every Newborn?

Handle with care. Genome testing could enhance newborn screening, but it raises ethical issues [credit: Spencer Grant/Science Vol. 341, p. 1163 (2013)].

Screening for biochemical markers often turns up false positives, however, which genetic tests might help avoid. Moreover, genome sequencing of a single sample could potentially look for all of the ~4,000 (some estimate ~10,000) monogenic diseases—i.e., those caused by defects in single genes. For more information on the subject, the World Health Organization website provides a good introduction.

The ethical concern here is that genome sequencing, unlike the current newborn screening tests, could potentially reveal many more unexpected genetic risks, some for untreatable diseases. Which of these results should be divulged is already controversial, according to Kaiser, who added that “sparks are still flying” over an earlier report described in Science as follows:

Geneticists, ethicists, and physicians reacted with shock to recommendations released last week by the American College of Medical Genetics and Genomics: that patients undergoing genomic sequencing should be informed whether 57 of their genes put them at risk of serious disease in the future, even if they don’t want that information now. The recommendations also apply to children, whose parents would be told even if illness wouldn’t strike until adulthood. The advice runs counter to the long-standing belief that patients and parents have the right to refuse DNA results. This is the first time that a professional society has advised labs and doctors what to do when unanticipated genetic results turn up in the course of sequencing a patient’s genome for an unrelated medical condition.

Given this background, it’s reassuring—in my opinion—that NICHD is taking a ‘go slow’ approach. I’m further reassured that NICHD is funding research of technical and ethical/social issues in four different but interrelated studies (see table below). Kaiser adds that “all will examine whether genomic information can improve the accuracy of newborn screening tests, but they differ in which additional genes they will test and what results they will offer parents.”

New ground: four projects funded at a total of $25 million over 5 years will look at how genome testing could improve newborn screening and other questions [credit: Spencer Grant/Science Vol. 341, p. 1163 (2013)].

New ground: four projects funded at a total of $25 million over 5 years will look at how genome testing could improve newborn screening and other questions [credit: Spencer Grant/Science Vol. 341, p. 1163 (2013)].

More specifically, Stephen Kingsmore at Children’s Mercy Hospital in Kansas City, Missouri, wants to halve the time for his current 50-hour test—discussed in the next section—which he has used to diagnose genetic disorders in up to 50% of infants in his hospital’s neonatal intensive care unit. The test hones in on a subset of genes that may explain the baby’s symptoms. While his group may ask parents if they’re interested in unrelated genetic results, the focus is on ‘a critically ill baby and a distressed family who wants answers,’ Kingsmore told Kaiser.

A team at the University of North Carolina is studying how to return results to low-income families and others who might not be familiar with genomics. It is also dividing genetic findings into three categories—mutations that should always be reported; those that parents can choose to receive, which might include risk genes for adult cancers; and a third set that should not be disclosed, e.g. untreatable adult-onset diseases such as Alzheimer’s.

A team at Brigham and Women’s Hospital in Boston and Boston Children’s Hospital hopes to learn how doctors and parents will use genomic information. ‘We’re trying to imagine a world where you have this information available, whether you’re a sick child or healthy child. How will it change the way doctors care for children?’ asks co-principal investigator Robert Green.

Ethicist Jeffrey Botkin of the University of Utah opined that sequencing might never replace existing newborn screening because of its costs and the complexity, according to Kaiser. However, Kaiser said that Botkin and others believe that it’s important to explore these issues because wealthy, well-informed parents will soon be able to mail a sample of their baby’s DNA to a company to have it sequenced—regardless of whether medical experts think that’s a good idea. ‘There’s an appetite for this. It will be filled either within the medical establishment or outside of it,’ Kaiser quotes Green as saying.

I should add that this parental ‘appetite’ doesn’t seem to be easily satisfied at the moment, based on my—admittedly superficial—survey of what’s currently available in the commercial genome sequencing space. For now, companies such as Personalis and Knome restrict their offerings to researchers and clinicians, not direct-to-consumers, such as parents-on-behalf-of-newborns—yet.

Sample-to-Whole-Genome-Sequencing-Diagnosis in Only 50 Hours

Having been a laboratory investigator during the stunning evolution from manual Maxam-Gilbert sequencing to highly automated Sanger sequencing—the title of this section ‘blows my mind’ and seems impossible—but it’s not! Stephen Kingsmore and collaborators at the Children’s Mercy Hospital in Kansas City, Missouri reported this remarkable achievement in Science Translational Medicine in 2012 and, as noted in the aforementioned table, aim to cut this turnaround time to within 24 hours!

In that 2012 report, they make a compelling case for whole-genome sequence-based diagnostics—and super speedy sample-to-result by noting that monogenic diseases are frequent causes of neonatal morbidity and mortality, and disease presentations are often undifferentiated at birth. Of the ~4,000 monogenic diseases that have been characterized, clinical testing is available for only a handful of them and many feature clinical and genetic heterogeneity. Hence, an immense unmet need exists for improved molecular diagnosis in infants. Because disease progression is extremely rapid—albeit heterogeneous—in  newborns, molecular diagnoses must occur quickly to be relevant for clinical decision-making.

Using the workflow and timeline outlined below, they describe 50-hour differential diagnosis of genetic disorders by whole-genome sequencing (WGS) that features automated bioinformatics analysis and is intended to be a prototype for use in neonatal intensive care units. I should add that an automated bioinformatics analysis is critical for clinical utility, and has been the subject of ‘musings’ by Elaine Mardis in Genome Medicine entitled The $1,000 genome, the $100,000 analysis?

Sequence Every Newborn?Summary of the steps and timing (t, hours) resulting in an interval of 50 hours between consent and delivery of a preliminary, verbal diagnosis [taken from Saunders et al. Sci Transl Med 4, 154ra135 (2012).

To validate the feasibility of automated matching of clinical terms to diseases and genes, they entered retrospectively the presenting features of 533 children, who have received a molecular diagnosis at Children’s Mercy Hospital within the last 10 years, into symptom- and sign-assisted genome analysis (SSAGA)—a new clinico-pathological correlation tool that maps the clinical features of 591 well-established, recessive genetic diseases with pediatric presentations to corresponding phenotypes and genes known to cause the symptoms. Sensitivity was 99.3%, as determined by correct disease and affected gene nominations.

Rapid WGS was made possible by two innovations. First, a widely used WGS platform was modified to generate up to 140 Gb [Gb = giga base pairs = 1,000,000,000 base pairs] of sequence in less than 30 hours (Illumina HiSeq 2500). Secondly, sample preparation took 4.5 hours, while 2 × 100 base pairs of genome sequencing took 25.5 hours. The total ‘hands-on’ time for technical staff was 5 hours.

Readers who are interested in more technical details for sample prep, sequencing, and bioinformatics/analytics should read the full text. However, the authors’ abstract provides the following succinctly described diagnostic ‘payoff’, so to speak:

Prospective WGS disclosed potential molecular diagnosis of a severe GJB2-related skin disease in one neonate; BRAT1-related lethal neonatal rigidity and multifocal seizure syndrome in another infant; identified BCL9L as a novel, recessive visceral heterotaxy gene (HTX6) in a pedigree; and ruled out known candidate genes in one infant. Sequencing of parents or affected siblings expedited the identification of disease genes in prospective cases. Thus, rapid WGS can potentially broaden and foreshorten differential diagnosis, resulting in fewer empirical treatments and faster progression to genetic and prognostic counseling.

These are compelling results, in my opinion. Let me know if you also find this compelling.  As always, your comments are welcomed.

Postscript

After finishing the above post, Andrew Pollack at The New York Times published a fascinating article giving examples of how pharmaceutical companies are heavily investing in genetic studies that employ exome-sequencing of large study groups in a search for clues to aid drug development. Regeneron is conducting one such study that includes 100,000 genomes.

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.

DNA Barcoding Exposes Scary Data for Herbal Products

  • Americans spend $5 billion annually for products with unproven benefits
  • Recent studies show majority of herbal products are contaminated or inauthentic
  • Dietary supplements account for ~20% of drug-related liver injuries
  • What can be done to protect consumers?

In August 1873, Darwin had ‘a fit’, in which he temporarily lost his memory and could not move. He recovered, and busied himself in work on the cross- and self-fertilization of plants. Published in 1876, Effects of Cross and Self Fertilisation in the Vegetable Kingdom provided ample proof of his belief that cross-fertilized plants produced vigorous off-spring that were better adapted to survive. Taken from otago.ac.nz via Bing Images

Since this post comes on the heels of Charles Darwin Day (February 12th ), it’s apropos to recognize Darwin’s plant-related scientific contributions dealing with plant movement and cross-fertilization—largely as the result of his keen observations and powerful reasoning that we should strive to emulate in our scientific pursuits. Darwin’s sense of scientific integrity seems to have been lost on the world of herbal products according to several recent studies and reports. It appears this industry is in need of some policing and compliance that may well come from DNA barcoding.   

According to Anahad O’Connor’s sobering article in the NY Times, Americans spend $5 billion a year on unproven herbal supplements—promising everything from fighting colds to boosting memory. Given the size of this market, it’s alarming that these products are oftentimes contaminated and/or mislabeled. Hmmm, sound familiar?  You may be recalling one of my posts from last year that explored analogous DNA-based findings for meat and fish products indicating global gross negligence or fraud. To quote Yogi Berra, “it’s like déjà vu, all over again”. Before delving into the details of this unsettling—if not downright scary—situation, let’s briefly discuss some background concepts that will enable us to understand how DNA barcoding may help bring honesty and transparency to the herbal products industry.

What is DNA Barcoding?

Since the herbal products exposé described below involves use of DNA barcoding, some readers may want to know what this methodology involves. Fortunately, Cold Spring Harbor Laboratory provides a website called DNA Barcoding 101 that provides the following snippets of information, as well as detailed “how to” protocols in a downloadable PDF.

Taxonomy is the science of classifying living things according to shared features. Less than two million of the estimated 5-50 million plant and animal species have been identified. Scientists agree that the yearly rate of extinction has increased from about one species per million to 100-1,000 per million. This means that thousands of plants and animals are lost each year, and most of these have not yet been identified.

Classical taxonomy falls short in this race to catalog biological diversity before it disappears. Specimens must be carefully collected and handled to preserve their distinguishing features. Differentiating subtle anatomical differences between closely related species requires the subjective judgment of a highly trained specialist—and few are being produced in colleges today.

Now, DNA barcodes allow non-experts to objectively identify species—even from small, damaged, or industrially processed material. Just as the unique pattern of bars in a universal product code (UPC) identifies each consumer product, a “DNA barcode” is a unique pattern of DNA sequence that identifies each living thing. DNA barcodes, about 700 nucleotides in length, can be quickly processed from thousands of specimens and unambiguously analyzed by computer programs. Barcoding relies on short, highly variably regions of the genome. With thousands of copies per cell, mitochondrial and chloroplast sequences are readily amplified by PCR, even from very small or degraded specimens, to enable DNA sequencing of the barcode.

Herbal product DNA barcodes are, in principle, similar to those pictured below that exemplify unique characterization of two different cryptic species of a butterfly, which appear visually to be nearly identical, and two genera of owl that are visually distinct.

Four-color DNA sequencing trace showing sequence of T (red), C (blue), G (black), and A (green) bases that comprises a barcode and can be redrawn as depicted below (taken from srmgenetics.info via Bing Images).

Four-color DNA sequencing trace showing sequence of T (red), C (blue), G (black), and A (green) bases that comprises a barcode and can be redrawn as depicted below (taken from srmgenetics.info via Bing Images).

DNA barcodes identify all living things (taken from boomersinfokiosk.blogspot.com via Bing Images).

DNA barcodes identify all living things (taken from boomersinfokiosk.blogspot.com via Bing Images).

Selling Herbal Products is BIG Business…But Who’s Watching Out for You?

The international trade in herbal products is a major force in the global economy and the demand is increasing in both developing and developed nations. According to a recent report, there are currently more than 1,000 companies producing medicinal plant products with annual revenues in excess of $60 billion. Notably, medicinal herbs now constitute the most rapidly growing segment of the North American alternative medicine market, with over 29,000 herbal substances generating billions of dollars in trade. For those of you who may be interested, I found this list of the top 10 best-selling herbal supplements in the US, among which are Ginseng (#9), Purple coneflower (#6), Ginkgo (#4), Cranberry (#2), and—surprising to me—Soy (#1).

Ginseng berry growth is restricted to certain areas of the world due to climate and weather conditions, making it difficult to cultivate. When this rare berry is picked, it is after a three- to four-year wait, and then the harvest must occur during a short, two-week period. Ginseng berry contains potent antioxidants called ginsenosides—such as Ginsenoside Rg1 pictured here—that are more abundant and different than those found in the root of the ginseng plant. These nutrients are believed to enhance the body's natural defense system to aid against invading free radicals (taken from eexcel.net via Bing Images and Wikipedia.org).

Ginseng berry growth is restricted to certain areas of the world due to climate and weather conditions, making it difficult to cultivate. When this rare berry is picked, it is after a three- to four-year wait, and then the harvest must occur during a short, two-week period. Ginseng berry contains potent antioxidants called ginsenosides—such as Ginsenoside Rg1 pictured here—that are more abundant and different than those found in the root of the ginseng plant. These nutrients are believed to enhance the body’s natural defense system to aid against invading free radicals (taken from eexcel.net via Bing Images and Wikipedia.org).

Although soy has been a staple of Asian cuisine for centuries, Westerners have only recently become aware of its valuable health benefits. Soy is a source of easily digestible protein and contains no saturated fat or cholesterol. Scientists have demonstrated through over 40 studies, spanning a 20-year period that eating 25 grams of soy per day helps reduce the risk of America's number one killer—heart disease. According to the US Food and Drug Administration (FDA), eating 25 grams of soy per day as a part of a low fat, low-cholesterol diet may reduce the risk of coronary heart disease (taken from eexcel.net via Bing Images).

Although soy has been a staple of Asian cuisine for centuries, Westerners have only recently become aware of its valuable health benefits. Soy is a source of easily digestible protein and contains no saturated fat or cholesterol. Scientists have demonstrated through over 40 studies, spanning a 20-year period that eating 25 grams of soy per day helps reduce the risk of America’s number one killer—heart disease. According to the US Food and Drug Administration (FDA), eating 25 grams of soy per day as a part of a low fat, low-cholesterol diet may reduce the risk of coronary heart disease (taken from eexcel.net via Bing Images).

Unfortunately, product adulteration and ingredient substitution is not uncommon in the medicinal herb and dietary supplement markets, as species of inferior quality are often substituted for those of a higher value. This practice constitutes not only product fraud, but according to the World Health Organization (WHO), it is a serious threat to consumer safety, as commented on below.

Currently, there are no best practices in place for identifying the species of the various ingredients used in herbal products. This is because the diagnostic morphological features of the plants cannot typically be assessed from powdered or otherwise processed biomaterials. As a result, the marketplace is prone to contamination and possible product substitution, which dilute the effectiveness of otherwise potentially useful remedies. Fortunately, DNA barcoding can now be used to combat this serious situation.

Report Reveals Rampant Contamination and Substitution

Dr. Steven G. Newmaster, Associate Professor, Centre for Biodiversity Genomics, Biodiversity Institute of Ontario, University of Guelph, Guelph, Ontario, Canada (taken from uoguelph.ca).

Dr. Steven G. Newmaster, Assoc. Prof., Centre for Biodiversity Genomics, Biodiversity Institute of Ontario, University of Guelph, Ontario, Canada (taken from uoguelph.ca).

In October of 2013, a team of Canadian and Indian scientists led by Dr. Steven G. Newmaster published in BMC Medicine a report entitled DNA barcoding detects contamination and substitution in North American herbal products that has received widespread media attention. This study utilized blind sampling of commercially available herbal products, which were tested for authentication of plant ingredients using a Standard Reference Material (SRM) herbal DNA barcode library. The research questions focused on the following three areas. (1) Authentication: is the herbal species on the label found in the product? (2) Substitution: is the main herbal ingredient substituted by other species? (3) Fillers: are any unlabeled fillers used?

They tested the authenticity of 44 herbal products (41 capsules; 2 powders; 1 tablet) representing 12 companies. The samples were collected in the greater Toronto area in Canada, with several samples mailed from distributors in the US. All products are available to consumers in both Canada and the US. The herbal product samples represented 30 herbal species that were each represented by 2 or 3 different companies. The samples were submitted in a blind test for authentication (product no. label only) using PCR-BigDye® Sanger sequencing-based DNA barcoding at the Centre for Biodiversity Genomics within the Biodiversity Institute of Ontario, University of Guelph.

The following are some of their sobering findings:

  • Only 2 of the 12 companies tested provided authentic products without substitutions, contaminants or fillers.
  • Nearly 60% of the herbal products contained plant species not listed on the label.
  • Product substitution was detected in 32% of the samples.
  • More than 20% of the products included fillers such as rice, soybeans and wheat not listed on the label.

This graphical summary of the results taken from the NY Times speaks for itself.

1105-HERBAL-FOR-FRONT-popup

In a follow-up press release from the University of Guelf, Dr. Newmaster said that “[c]ontamination and substitution in herbal products present considerable health risks for consumers.” He added that “[w]e found contamination in several products with plants that have known toxicity, side effects and/or negatively interact with other herbs, supplements and medications.” The statement added that one product labeled as St. John’s Wort contained Senna alexandrina, a plant with laxative properties—not intended for prolonged use, as it can cause chronic diarrhea and liver damage, and negatively interacts with immune cells in the colon. Also, several herbal products contained Parthenium hysterophorus (feverfew), which can cause swelling and numbness in the mouth, oral ulcers and nausea. It also reacts with medications metabolized by the liver.

Furthermore, one ginkgo product was contaminated with Juglans nigra (black walnut), which could endanger people with nut allergies. Unlabeled fillers such as wheat, soybeans and rice are also a concern for people with allergies or who are seeking gluten-free products, Newmaster said. “It’s common practice in natural products to use fillers such as these, which are mixed with the active ingredients. But a consumer has a right to see all of the plant species used in producing a natural product on the list of ingredients.”

Dietary Supplements Account for ~20% of Drug-related Liver Injuries

Consumer safety is not a theoretical concern. According to Anahad O’Connor’s follow-on and lengthier Dec 22nd 2013 NYTimes article entitled Spike in Harm to Liver is Tied to Dietary Aids, “[d]ietary supplements account for nearly 20 percent of drug-related liver injuries that turn up in hospitals, up from 7 percent a decade ago, [that] according to an analysis by a national network of liver specialists. The research included only the most severe cases of liver damage referred to a representative group of hospitals around the country, and the investigators said they were undercounting the actual number of cases.” The article features a 17 year-old male who suffered severe liver damage after using a concentrated green tea extract he bought at a nutrition store as a “fat burning” supplement. The damage was so extensive that he was put on the waiting list for a liver transplant. Fortunately he recovered and the transplant wasn’t necessary.

This NYTimes article is well worth reading, and provided further evidence that tighter regulations are needed.

Conclusions

Given the sobering significance of the above study by Newmaster and coworkers, I thought it was better to directly quote concluding remarks by these authors, rather than selectively paraphrase and oversimplify the situation:

“Currently there are no standards for authentication of herbal products. Although there is considerable evidence of the health benefits of herbal medicine, the industry suffers from unethical activities by some of the manufacturers, which includes false advertising, product substitution, contamination and use of fillers. This practice constitutes not only food fraud, but according to the WHO, serious health risks for consumers. A study of health claims made by herbal product manufacturers on the internet found that 55% of manufacturers illegally claimed to treat, prevent, diagnose or cure specific diseases. Regulators such as the FDA and Canadian Food Inspection Agency (CFIA) may not have the resources to adequately monitor the dietary supplement manufacturers and their advertising claims, and there are concerns that the current regulatory system is not effective in protecting consumers from the risks associated with certain herbal products. Chemical research studies have documented poor quality control and high content variability of active ingredients among products from a variety of manufacturers of herbal supplements. This is partly because herbs contain complicated mixtures of organic chemicals, the levels of which may vary substantially depending upon many factors related to the growth, production and processing of each specific herbal product. Although many manufacturers provide products with consistent levels of active ingredients through a process known as chemical standardization, this technique has uncertain effects on the safety and efficacy of the final product.”

“Many of the dangers of commercial plant medicine have been brought to light by DNA technology based studies that have identified contamination of herbal products with poisonous plants. Eroding consumer confidence is driving the demand for a product authentication service that utilizes molecular biotechnology. One approach to vetting herbal product substitution and contamination is product authentication using DNA barcoding. Research studies such as ours and others reinforce the importance of using DNA barcoding in the authentication of socioeconomically important herbal species. We suggest that the herbal industry should voluntarily embrace DNA barcoding for authenticating herbal products through testing of raw materials used in manufacturing products, which would support sovereign business interests and protect consumers. This would be a minor cost to industry with a limited amount of bulk product testing, which would certify a high quality, authentic product. If the herb is known to have health benefits and it is in the product, then this would provide a measure of quality assurance in addition to consistent levels of active ingredients. Currently we are building an SRM DNA barcode library for commercial herbal species and standard testing procedures that could be integrated into cost effective ‘best practices’ in the manufacturing of herbal products. This would provide industry with a competitive advantage as they could advertise that they produce an authentic, high quality product, which has been tested using DNA-based species identification biotechnology, therefore gaining consumer confidence and preference. This approach would support the need to address considerable health risks to consumers who expect to have access to high quality herbal products that promote good health.”

I for one would gladly pay a premium for herbal products that are “DNA Barcode Certified”.

Wouldn’t you?

As always, your comments are welcomed.

Postscript

After I finished writing this post, I went back to the aforementioned BMC Medicine article by Newmaster and coworkers to use its Google-based link to blogs citing this publication. While most were recaps of the report, one entitled It’s Now Herbal Products’ Turn to (Unfairly) Wear the Scarlet Letter caught my attention. I won’t provide a synopsis here, but you may want to read the blogger’s rather different, über critical commentary that seems (unfairly) biased to me.

If you’re interested in all facets of DNA barcoding, I highly recommend visiting the DNA Barcoding blog by Dirk Steinke at Guelf University that has new posts daily.

For those of you who are educators, the BioBelize website provides an example of how secondary education programs in New York City and Belize came together to define and implement DNA Barcoding curricula to encourage young student interest and involvement in this aspect of science.

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.