August 29, 2017
August 14th, UCLA researchers Aaron Panofsky and Joan Donovan presented
findings of their study, “When Genetics Challenges a Racist’s Identity: Genetic
Ancestry Testing among White Nationalists,” at a sociology
conference in Montreal. They’d analyzed 3,070 comments organized into 70
threads publicly posted to the (sometimes difficult to access) “social movement
online community” Stormfront.
KKK Grand Wizard Don Black launched Stormfront on March 27, 1995. Posts exceed
12 million, ramping up since the 2016 election season. Panofsky and Donovan’s
report has a lot of sociology speak, such as “scholars of whiteness” and
“affiliative self-fashioning,” amid some quite alarming posts – yet also
reveals a sophisticated understanding of genetics from some contributors.
WHITE NATIONALIST ONLINE MEET-UP: STORMFRONT
“We are the voice of the new, embattled White minority!”proclaims the
bold, blood-tinged-hued message on the opening page of Stormfront, the “community
of racial realists and idealists.” It’s a site for white nationalists,
who are a little less extreme than white supremacists, who want to dominate the
world from their pinnacle of a perceived racial hierarchy. The Stormfronters
seem more concerned with establishing their white purity – defined as “non-Jewish
people of wholly European descent.”
the lines between white nationalist and supremacist blur, as Stormfront states, “If Blacks or
Mexicans become a majority, then they will not be able to maintain the White
man’s social, cultural and economic systems because they do not have to (sic)
minds needed to do so.”
idea of white rights is rather new, catalyzed by the revolts of the truly
marginalized, murdered, abused, ignored, and enslaved. In the past, whiteness
was equated to lack of race, much as I thought as a child of vanilla as a lack
of chocolate. Use of genetic ancestry testing to confirm one’s concept of pure
whiteness is also somewhat new, a subversion of technology that is disturbing
to this geneticist whose grandparents escaped the pogroms of eastern Europe.
the 153 folks on Stormfront brave enough to post their genetic ancestry test results,
53 were relieved. “Pretty much what I expected but it was good to get
it confirmed,” proclaimed one. A participant named Sloth found out he
has “pretty damn pure blood” from Scandinavia, the British
Isles, and Iceland, prompting him to plan a getaway to Iceland and get a Thor’s
hammer tattoo. Another relieved Stormfronter, worried that “Their (sic)
might be American indian or jew in the mix because I tan really easily,”
was happy to learn he’s “100% white! HURRAY!”
other 100 genetic test-takers weren’t so thrilled with their results, seeking
excuses. My favorite: “These companies are quite liberal about ensuring
every white person gets a little sprinkling of non-white DNA (we know who owns
and runs these companies).” ErikTheWhite helpfully added that the
genetic testing company 23andMe is deploying Jewish DNA to create bioweapons to
kill pure whites as if the DNA replication machinery checks in with the
religion of the person.
But an impressive 1260 posts were about the science, several debating what DNA
ancestry tests can and cannot do. I agree that the tests provide partial
information that may, in fact, be trumped by a look in the mirror or a chat
with great-grandma. Deep ancestry testing only provides partial glimpses of
parts of the world where some ancestors may have come from. I have a map of my
own roots – just what my grandmother told me.
ANCESTRY TESTING IS NOT A FINAL ANSWER
DNA-based ancestry testing, from companies such as FamilyTreeDNA, 23andMe, and Ancestry.com compare parts of the genome
that vary in DNA sequence among individuals from people living in different
geographical areas, say Charlottesville and Kenya. In addition, mapping
sequential changes in gene variant frequencies with places reveals ancient
migration routes, which often jibe with historical knowledge.
Results seem overly simplistic. A “Genetic Ethnicity Summary” from
Ancestry.com, for example, “reveals where your ancestors lived
hundreds-perhaps even thousands of years ago”to be 57% Scandinavian, 32%
British Aisles, 8% Eastern European, and 3% Uncertain. Many Stormfronters are
disturbed by the uncertainty. The Jewish sprinkles?
maps and diagrams the testing companies provide aren’t overtly racist, at least
compared to the 1890 Census categories of mulatto (half black and half white),
quadro (one-fourth black), or octaroon (one-eighth black).
genomic points of comparison include autosomal swaths, but covering only parts
of the non-sex-chromosomes – the autosomes – offers just signpoints, and are a
far cry from comparing complete genome sequences. Mitochondrial and Y
chromosome DNA sequences are considered too but must be interpreted in context,
and with the proverbial grain of salt.
Mitochondrial DNA passes only from mothers,
to all offspring, and is used to trace maternal lineage. Groups of linked genes
(haplogroups) on the dinky Y are
used to trace the paternal lineage. Mt and Y DNA can trace ancient migrations
and the echoes of history, like stretches of Genghis Khan’s Y that today are in
1 in every 200 males (~16 million!) living between Afghanistan and northeast of
China, reflecting waves of rapes by Genghis and his male descendants since the
It’s easier to see that Y and mtDNA represent only a few of
thousands of ancestors with a diagram. (DNAeXplained)
there’s a hitch: mitochondrial and Y DNA comprise <1% of a genome and are
only a tiny two of thousands of lineages contributing to the genome of a person
problems lurk behind the pretty pie charts and percentages of ancestry test
• Tests don’t include all parts of the world.
• A new mutation could place a person in the wrong population group.
• Companies compare clients’ DNA to their own proprietary databases, and so
white nationalists can shop around, seeking acceptable findings. It’s a little
like my daughter’s elementary school approach to misspelled words on
quizzes: “I just won’t ever use those words, mommy!”
• DNA ancestry testing projects current databases of population genetic
variability back in time, assuming gene variant patterns were the same.
• Databases may not include people who’ve died young from a genetic disease.
AFRICAN ORIGINS AREN’T DETECTED BECAUSE THEY DON’T VARY!
That we all came from Africa is written into our genomes, represented by
stretches of DNA so common, so much the same in all of us, that it would be
nonsensical to include them in tests meant to detect varying DNA sequences.
Even the most powerful KKK Imperial Wizard, if he understood genetics, couldn’t
whitewash the reality of our African origins. Yet a Stormfront post comforted a
man who was distraught that his Genetic Ethnic Summary included Senegal
with “… you are simply related to some White fool who left some of his
DNA with the locals in what is now Senegal.”
post revealed a bizarrely accurate take on Mendelian inheritance. AngryGoy
follows only mtDNA and Y chromosome information, despite their representation
of <1% of the genome, because they are “pure.” His reasoning: Y chromosome
DNA is transmitted entirely and unchanged from male to male and mtDNA is
transmitted entirely and unchanged from female to all offspring. But autosomal
DNA is halved at each generation as the two copies of each chromosome separate
into different eggs or sperm.
goes a step farther: a bi-racial female with a white mother or bi-racial male
with a white father are “the lesser of two evils” because at least the mtDNA
and Y DNA are untainted. This logic escaped me when I wrote the sections on
mtDNA and Y DNA in my genetics books.
considers the mtDNA and Y argument to be a version of the one-drop rule. Which
leads me to the oft-evoked metaphor of blood for genetic ancestry, which isn’t
even accurate because the red blood cells that impart the characteristic color
do not even have any DNA!
AS A SURROGATE FOR GENETICS
Claims Stormfront: “In a nutshell, the problem with humanity is not so
much one of ideology – this or that religious, political, social, or economic
doctrine – but rather one of blood. That is, that a great deal (possibly 90% or
more) of a person’s intelligence and character is determined by their DNA,
which determines the structure of their brain before they are born.”
statement reeks of genetic determinism, the idea that our traits arise
predominantly if not entirely from our genes. The 90% suggests a reference to
heritability, which for intelligence ranges from 50% to 80%, depending upon the
study consulted. But heritability isn’t the genetic contribution to a trait.
Rather, it’s the genetic contribution to the VARIABILITY of a trait.
from Nazi Germany mention “good blood” and “pure blood,” with a lone drop
enough to confer non-purity. I’m reminded of the episode of All in the Family in
which bigot Archie Bunker is horrified to learn he’s about to receive a
transfusion from a black, female, West Indian physician who shares his rare
blood type. “Not to worry,” she cautions him with a grin, “when you come out
(of) the anesthetic, you might have a strange craving for watermelon.”
Nazis quest for pure Aryan blood entailed both positive and negative eugenics.
The Lebensborn program, begun in 1935, took the children from “unwed mothers”
knocked up by the SS and placed them in good Aryan homes, and also placed
appropriately blue-eyed, blond orphans in homes, while murdering millions who
didn’t fit the Aryan definition of Nordic people from England, Germany,
Denmark, Sweden, or Norway. Excluded whites were Roma, ethnic Poles, Slavics,
and of course Jews, all deemed subhuman by the self-appointed master race.
Nazi “Law for the Prevention of Hereditarily Diseased Offspring” provided
a list. While hereditary blindness and deafness and “Hereditary chorea” are
single-gene conditions, “Congenital Mental Deficiency, Schizophrenia,
Manic-Depressive Insanity, Hereditary Epilepsy,” and “any severe hereditary
deformity” are not. Yet Genetic Health Courts ruled on who should be sterilized
to halt transmission of faulty genes.
RESTRICTING GENE POOLS IS COUNTERINTUITIVE
Some people on Stormfront ask what to do after learning their genetic ancestry
is not what they expected. Most answers are polite, but some are variations
on “If you do care about the White race, don’t breed with any White
women, therefore not polluting our gene pool.”
restricting a gene pool (a term that describes a population, not a person or family)
to promote a perceived superiority is a real headscratcher to anyone who knows
any biology whatsoever.
stems from genetic diversity – not sameness. That’s why sexual reproduction has
been so successful: A plague can’t wipe out a population if some members are
resistant to the pathogen thanks to gene variants. Conversely, a field of
genetically identical anything is vulnerable to change. So Craig Cobb, the
white nationalist who inspired Panofsky and Donovan’s project when he was
mortified onstage when confronted with genetic ancestry test results indicating
he’s 14% African, should instead be thankful that he’s not 100% white.
idea is straightforward. Members of the same ancestral population having
children together increases the chance that mutations inherited from recently
shared ancestors will show up in a child. The close relationships amplify the
distribution of mutations, and incidence of certain single-gene diseases
phrase “Jewish genetic diseases” isn’t prejudicial;
it states a biological fact. The mass murders of Jews throughout history have
strangled their genetic diversity, creating serial population bottlenecks that
have concentrated certain disease-causing mutations that made it through the
pogroms and Holocaust. And so we have Canavan disease, Tay-Sachs disease,
familial dysautonomia, and some two dozen other illnesses that strike other
families too, but us with higher frequency
The Amish and Mennonites too have much higher
incidence of several single-gene diseases that they brought in from Europe. For
example, maple syrup urine disease affects 1 in 400 newborns in these groups,
but only 1 in 225,000 in the general population.
wait! The Amish brought those bad genes
in from Switzerland and the Mennonites from the Netherlands, and they’re
certainly not Jewish. Pure white Europeans can have mutations???
cystic fibrosis. DNA in teeth discovered in a graveyard in Austria along the
Danube left there between 544 and 255 BC yielded the most common CF mutation.
(See Discovery of the Principal Cystic Fibrosis Mutation
(F508del) in Ancient DNA from Iron Age Europeans).
Austria more or less the epicenter of white purity?
from the population to the molecular level, new evidence has shown that if two
people are carriers of certain CF mutations that affect opposite ends of the
gene, the genes can complement, encoding correctly-folded proteins that
function, so that their children don’t actually face the 25% risk of inheriting
the disease. The best way to have parents carrying different mutations is for
them to have come from different population groups.
diversity can protect; genetic sameness empowers mutations. I guess the Nazi
list of Hereditarily Diseased Offspring missed the genetic diseases of European
whites. It is selective pseudoscience.
so scientifically, the white nationalists, white supremacists, and neo-Nazis
have it all wrong. For DNA doesn’t discriminate – it just assorts itself in
sync to our patterns of procreation.
WHITER SHADE OF PALE
To a geneticist, the idea of supremacy, intellectual or otherwise, based on
minimal distribution of a pigment molecule in skin is meaningless, if not
outright idiotic. Yet it has dictated so much of our history, fueled so much
senseless hatred. So I’ll end with an explanation of human skin color, from my
human genetics textbook:
definition of race based largely on skin color is more a social construct than
a biological concept, because skin color is only one of thousands of traits
whose frequencies vary in different populations. We may classify people by skin
color because it is an obvious visible way to distinguish individuals, but this
trait is not a reliable indicator of ancestry. The concept of race based on
skin color falls apart when considering many genes. That is, two people with
very dark skin may be less alike than either is to another person with very
light skin. Overall, 93% of varying inherited traits are no more common in
people of one skin color than any other.”
color arises as melanin molecules are produced and packaged into sacs called
melanosomes in cells called melanocytes. The pigment-packed melanocytes snake
between the tile-like epidermal cells, releasing melanin granules that are
broken into bits and pushed upward as the skin cells divide below. The bits of
color darken the skin, protecting it from ultraviolet radiation.
genes control melanin production and dispersal, and we vary in skin color.
Having more melanin is an adaptation, not a liability! So where did white
people come from? The prevailing hypothesis has been that white skin captures
more sunshine, making it possible to produce vitamin D and keeping bones
strong. A study from David Reich’s lab at Harvard identified 3 genes that brought white skin
who left Africa for Europe about 40,000 years ago had dark skin. Then about
8500 years ago, hunter-gatherers from Spain, Luxembourg, and Hungary brought in
variants of the genes SLC24A5 and SLC45A2, which
impair the ability to make and distribute melanin. Farther north, where the
lower light would have made white skin even more advantageous, evidence from
southern Sweden shows contribution from the third gene, HERC2/OCA2,
which conferred not only pale skin but blue eyes and blond hair too. Finally,
farmers from the Near East also brought in gene variants for white skin. Amid
all this mixing, natural selection and perhaps human behavior favored
whiteness. Completely wiping out these genes causes albinism, so if anyone
could be called mutant, it’s white people, not the brown and black.
one type of pigment molecule, controlled by just 3 of our 20,633 genes, fuel so
I applaud Panofsky and Donovan’s revelation of the twisting of genetic ancestry
testing to validate white nationalism and its slippery slope to white supremacy.
The technology has been helpful in many ways: solving crimes, reuniting
families dispersed by slavery, and finding relatives after disasters. Let’s
hope that the taking of genetic testing to the dark side of white supremacy
backfires, bringing a greater appreciation of our essential biological
The Alden March Bioethics Institute offers a Master of Science in Bioethics, a Doctorate of Professional Studies in Bioethics, and a Graduate Certificate in Clinical Ethics. For more information on AMBI's online graduate programs, please visit our website.
August 8, 2017
Charlie Gard would have turned one year old tomorrow.
Two days before the British infant died of a mitochondrial disease on July 28, a short article in MIT Technology Review teased that Shoukhrat Mtalipov and his team at Oregon Health & Science University and colleagues had used CRISPR-Cas9 to replace a mutation in human embryos, a titillating heads-up that didn’t actually name the gene or disease.
Yesterday Nature published the details of what the researchers call gene correction, not editing, because it uses natural DNA repair. I covered the news conference, with a bit of perspective, for Genetic Literacy Project.
Might gene editing enable Charlie’s parents, who might themselves develop mild symptoms as they age, to have another child free of the family’s disease? Could anything have saved the baby?
A TRAGIC CASE
The court hearing testimony on the case between Great Ormond Street Hospital (GOSH) and the family, published April 11, chronicles the sad story. The hospital had requested discontinuing life support based on the lack of tested treatment.
Charlie was born August 4, 2016, at full term and of a good weight, but by a few weeks of age, his parents noticed that he could no longer lift his head nor support any part of his body. By the October 2 pediatrician visit, Charlie hadn’t gained any weight, despite frequent breastfeeding. After an MRI and EEG, Charlie had a nasogastric tube inserted to introduce high-caloric nutrition.
By October 11, the baby was lethargic, his breathing shallow. So his parents, Connie Yates and Chris Gard, took him to GOSH. There, physicians noted Charlie’s “persistently elevated lactate.” It was an ominous sign.
Remember Bio 101? When cellular respiration in the mitochondria fails, an alternate pathway releases lactic acid – this is what causes muscle cramps in a sprinter right after a race. It’s what was happening to the thousands of mitochondria in Charlie’s muscle cells; they weren’t extracting enough ATP energy from digested nutrients, and so the baby was limp, unable to reach or react much. His brain was running out of energy too.
Lactic acid buildup in muscles when oxygen is depleted causes cramping. Charlie had persistently elevated lactic acid.
On October 25, a muscle biopsy indicated only 6% of the normal amount of mitochondrial DNA, well below the 35% that indicates a mitochondrial DNA depletion syndrome (MDDS). But which one did Charlie have? Which gene was mutant? That’s important. With a judge discussing “strains” of the syndrome, as if it is a bacterial infection and not a monogenic disease, confusion loomed.
In mid November, sequencing of Charlie’s genome found two mutations in the gene RRM2B, causing “infantile onset encephalomyopathic MDDS.” It affected the brain and muscles – that was obvious – but he was also deaf and had heart and kidney abnormalities. With these findings, the Ethics Committee at GOSH advised against a ventilator.
Charlie’s disease is a “block to the machinery in charge of supplying nucleotide building blocks for mitochondrial DNA synthesis,” Fernando Scaglia, professor of medical and human genetics at Baylor College of Medicine, told me when I picked his brain on whether gene editing might help Charlie’s parents.
(A quasi-technical aside: RRM2B encodes an enzyme [ribonucleotide reductase] that, with three other subunits, removes an oxygen from the sugar part of nucleic acid building blocks, leaving deoxyribose as the sugar rather than ribose, with two phosphates attached. This happens just outside the mitochondria. Once these precursors get into the mitochondria, a third phosphate is added, forming the DNA nucleotide building blocks of the 37 mitochondrial genes. Charlie inherited a RRM2B mutation from each parent – the gene is in the nucleus, but it is essential to supply the mitochondria with nucleotides. RRM2B’s enzyme works only in cells that aren’t dividing – hence the extreme effects on Charlie’s muscles and brain.)
Charlie’s seizures started on December 15 and never let up. Experts began weighing in, including by the end of the month Michio Hirano from Columbia University, who had experience using nucleoside bypass therapy on 18 patients with MDDS due to mutations in a different gene, TK2. A ray of hope?
(Dr. Nakeya Dewaswala, Medicowesome)
Nucleoside bypass therapy provides precursors to the DNA building blocks that have only one of the three phosphates, to circumvent the disabled enzyme, and because the full forms are too highly charged to easily enter cells. But the paper analyzing the strategy, from 2012, clearly showed that it didn’t work in an experimental system for Charlie’s disease – “myotubes,” bits of non-dividing muscle in a dish:
“First we suggest that not only myotubes (post-mitotic cells), but also myoblasts and possibly other dividing cells can show mtDNA depletion in RRM2B deficiency. Second, supplementation with dNMPs, as expected, had no beneficial effect in RRM2B deficiency. Based on the function of this protein supplementation with dNDPs could be tried as an alternative strategy in RRM2B deficiency.” (This isn’t a sentence, albeit the crucial one for the case; it means trying two phosphates instead of one.)
I’m guessing that these three sentences are what catalyzed the parents’ GoFundMe effort and desire to take their baby to the US. But “there’s never been a proper clinical trial for nucleoside therapy,” said Dr. Scaglia, although 18 patients in Spain and Italy with mutations in a different gene, TK2, have so far tolerated it. But that form only affects muscle. The treatment might not have crossed the blood-brain barrier to reach Charlie’s more extensive disease.
Justice Francis knew the limitations of what some in the media called the “pioneering treatment,” if not the difference between a microbe and a gene. “In fact, this type of treatment has not even reached the experimental stage on mice let alone been tried on humans with this particular strain of MDDS,” he wrote.
Charlie’s disease blocks the supply of DNA building blocks to the mitochondria, but his mutant gene is in the nucleus.
From January 9th until the 27th, Charlie had an unrelenting storm of seizures, his EEG erratic even when he wasn’t obviously seizing. This setback caused postponement of an ethics committee meeting and all but Dr. Hirano to give up. Perhaps he thought it a “theoretical possibility” because of that one sentence in the 2012 paper that suggested giving DNA precursors with 2 phosphates instead of one.
For a time, Columbia University considered treating Charlie, with what I don’t know. Meanwhile, nurses noted and then testified that the baby was gaining weight but making no obvious progress, countering the parents’ observations that Charlie felt pain, distress, pleasure, and subtly communicated with them.
Then an EEG from March 30 convinced even Dr. Hirano that an attempt at any treatment would be futile – a term that so dominated the court hearing that Justice Francis defined it: “for the avoidance of any doubt, the word “futile” in this context means pointless or of no effective benefit.” Goals began to focus on preventing suffering.
Yet the Pope and the President weighed in circa July 4, offering to welcome the baby for unspecified treatment to the Vatican or US. What did they know that the English doctors didn’t? And I had to wonder, where are these notables when similar things happen to many other babies born with rare genetic diseases? (See No Ice Buckets or Pink Ribbons for Very Rare Genetic Diseases)
For a time, discussion at the hearing devolved into a UK vs US scenario of the Brits taking a more reasoned approach in denying a futile therapy whereas US docs would try anything if parents could just raise enough money.
As the Pope and President were making their kind offers, pretty much all the experts were reaching agreement that Charlie should be taken off life support. Still, and understandably, the parents grabbed at any hope. “We truly believe that these medicines will work,” the father told the court, although nucleoside bypass was more an untested hypothesis than a medicine. Belief can’t alter biochemistry.
And so Charlie passed away on July 28.
COULD ANYTHING HAVED SAVED CHARLIE?
It was too soon for nucleoside bypass therapy, nor were approaches for other mitochondrial diseases such as cofactor supplementation (which I wrote about here), liver transplant, or stem cell transplant applicable. Nor can a recently-described peptide-like molecule that silences mitochondrial genes help, because Charlie’s mutant genes are in the nucleus. (A mitochondrion only houses 37 genes.)
Gene therapy or gene editing couldn’t have saved Charlie, because the intervention would have to have infiltrated his many muscle and brain cells, damaged beyond repair. But could either approach enable his parents to avoid having another child with two doses of the RRM2B mutation? (Gene therapy introduces a functioning copy of a gene; gene editing can replace it.)
Couples who are carriers of the same recessive condition already have options to avoid passing on the disease: prenatal genetic testing to identify an affected fetus and ending the pregnancy, or preimplantation genetic diagnosis (PGD) following IVF and selecting healthy embryos to continue development in the uterus.
Unfortunately, yesterday’s Nature paper about gene correction of a heart condition doesn’t apply to Charlie’s family. The researchers used CRISPR-Cas9 to snip a dominant mutation from sperm at the brink of fertilizing an egg, jumpstarting a natural DNA repair mechanism that copies a normal version of the gene from the egg to reconstitute two functioning copies — a little like me giving my husband a Women’s March tee-shirt to match mine and replace his Jets tee-shirt. The approach wouldn’t work for a sperm and an egg each bearing a recessive mutation in the same gene, the scenario for Charlie and 1 in 4 of his potential siblings, because there wouldn’t be a healthy gene to copy.
PGD tests one cell of an 8-celled embryo. If all is ok, the remainder is transferred to a woman’s uterus to continue development.
“It’s easier to do PGD and select those embryos that would not have a mutation in the particular gene, as is done for many other conditions,” Dr. Scaglia said. However, editing-out mutations can potentially help older women undergoing PGD by upping the percentage of okay embryos — both the number of eggs and their quality decline precipitously with age. A more pressing problem, Dr. Scaglia added, is controlling the cost of PGD and getting insurance to cover it, rather than pursuing gene editing.