Second Letter to FDA Requesting Response to Citizens Petition to Withdraw Approval for Pregnancy Drug 17-OHPC ("Makena") Pending Fetal Germline Impact Assessment
Note: Sometimes I need to pinch my arm to remind myself that it's 2017. You know, it's easy to forget! Because so much of our world is lost in a time warp. Take, for example, the FDA, which seems to be completely — and I mean completely — oblivious to the fact (1) that fetuses have germ cells, and (2) that fetal germ cells are tissues of interest for pharmaceutical toxicology. Basic high school biology stuff. Oh, people of the United States, I weep for all of you, and for all our successive generations. —JE
Escher Fund for Autism
Division of Dockets Management
Food and Drug Administration
Department of Health and Human Services
5630 Fishers Lane, rm. 1061
Rockville, MD 20852
February 8, 2017
Re: Docket Number FDA-2015-P-0876—Re Citizen Petition to Withdraw Approval for 17α-Hydroxyprogesterone Caproate (“17-OHPC,” Including Brand “Makena”) as a Drug Used in Pregnancy, Pending Fetal Germline Impact Assessment
To the Commissioner of the Food and Drug Administration:
The FDA received the undersigned’s above-referenced petition on March 19, 2015. Nearly two years later, the agency has taken no action on the petition, which seeks immediate action to withdraw approval for the pregnancy drug 17-OHPC, pending fetal germline impact assessment. The synthetic compound at issue is an endocrine disrupting chemical (“EDC”) widely administered to pregnant women, exposing simultaneously their fetuses and those fetuses’ early germ cells to that chemical and/or its metabolites, as the chemicals easily pass the placenta and enter fetal tissues, including gonadal tissues. EDCs are documented to interfere with healthy germ cell development.
By sitting on the petition, the FDA is acting in reckless disregard for the gametic health of countless exposed offspring, and risking the developmental integrity of their offspring, and in so doing, continuing its indefensible and outdated policy of ignoring outright the pharmaceutical risks to vulnerable fetal germline. The petitioner asks that the FDA act expeditiously to grant the petition.
• There is little question that germ cells are direct targets of endocrine disruptors from the very early stages of fetal gonad formation. Epigenetic pathways are crucial for germline development and EDCs can interfere with epigenetic mechanisms, including DNA methylation, histone modifications, changes of chromatin structure and microRNA expression, resulting in the transmission of deranged genetic information to the following generation.
• In genes subject to fine dosage control such as imprinted genes, for example, geno-affective exposures such as EDCs may easily cause small molecular glitches with catastrophic, life-long neurodevelopmental consequences.
• In June 2015, the world’s most esteemed hormone biologists, the Endocrine Society, issued a public statement that EDCs must be assessed for fetal germline impacts. Petitioner is not presenting a “fringe” or novel question, but rather a fundamentally critical issue for drug toxicology and generational public health.
• The drug at issue has only a most minimal impact on preterm birth, and patients can receive natural progesterone analogues instead of 17-OHPC where preterm birth is a consideration, while the drug is undergoing safety review.
• As an alternative to removing the drug from the market, the FDA can require the vendors of this drug to warn all consumers of the possibility for germline damage to their babies, and to their eventual grandchildren.
• In the event that adequate safety assessments reveal no adverse molecular effects on fetal germline, the vendors of 17-OHPC may resume marketing and selling the drug.
It is tragedy that the FDA, which is commissioned with the duty to assess damaging effects of pregnancy drugs, seems to possess neither the ability nor interest to contemplate the manifest, unequivocal drug vulnerabilities of fetal germline, even to intentional, high-dose persistent EDC exposures such as 17-OHPC. Given the potential germline consequences of the drug as outlined in the petition, the petitioner implores the agency to act responsibly and grant the petition without further delay.
The petitioner wishes again to thank FDA staff for its consideration.
Very truly yours,
Escher Fund for Autism
A Modern Biology Lesson for President Trump, and a Plea for Smarter Directions in Autism Causation Research
Since vaccines have clearly not contributed to the increase in autism, what questions should we should be asking instead?
President Donald Trump
The White House
1600 Pennsylvania Avenue NW
Washington, DC 20500
January 23, 2017
Dear President Trump,
As the mother of two children with severe, nonverbal autism, I must give you credit. While most politicians ignore the devastating and costly autism crisis that has swept our country, you have been unafraid to voice your concern. The tremendous surge in serious neurodevelopmental pathology over the past three decades has led to what is now one of our nation’s greatest public health and social services predicaments. And yet we still have few explanations for what lies behind this grim phenomenon.
Given the persistent vacuum of information and people’s rather understandable desire to make sense of inexplicable tragedies and hardships playing out in more than a million homes across the states, it’s not terribly surprising that attractive, if superficial, theories have taken root, even in the face of overwhelming evidence against them.
One hypothesis, with which you may be flirting, is the idea that vaccines cause autism. Another idea posits that we are all essentially delusional—that autism is perfectly natural, and rising rates are simply an artifact of awareness, broader diagnostics and re-labeling of conditions that once bore other names, such as childhood schizophrenia. The collective data from epidemiological and basic research show emphatically that neither of these views is correct. Vaccines do not cause autism. And the majority of the autism surge cannot be explained by heightened awareness and diagnostic shifts. Nevertheless, in their respective and somewhat diametrically opposed corners, these fictions stubbornly persist.
I’m writing this letter because we must move past this dead-end false dichotomy and approach the autism question with both the urgency and biological rationalism it deserves. You and your staff seem to have the urgency, now let’s nail the biological rationalism.
Research is increasingly demonstrating that the impairments we call autism are disorders of brain development and function, particularly with respect to circuits that underlie learning, and that the dysfunctions begin to show their hands in early fetal development. While some direct somatic prenatal impacts raise the risk for autism, such as fetal exposure to certain anti-seizure medications, some infections, and prematurity, those factors appear to explain only a fraction of the overall cases.
Many researchers are quick to call the unaccounted-for remainder “genetic” mainly because autism is without doubt strongly heritable, meaning in most cases it likely stems from glitches within the egg and/or sperm of the parents, and not from proximal blows to the developing brain (as is the case with Zika microcephaly).
Many counter, however, that autism can’t be genetic because genes don’t change that quickly or easily, and moreover we can’t seem to find genetic causes for more than about 10% of autism cases. And that is true—our millenia-old human genes can’t explain the increase in autism, and the DNA-scouring approach has largely come up empty-handed.
The problem is this “genes or environment” view of autism is premised on a faulty, incomplete and outdated view of biology, and is therefore misguiding our federal approach to the issue. The past ten years have seen a sea change in how biologists think about heritability, moving away from simple genetic determinism, which still regrettably dominates autism research, and toward a multifactorial systems view embracing the importance of many aspects of genome and gamete biology, in addition to other developmental factors. If we want to understand autism, our research must flow from biological realities, not outmoded hyper-simplistic notions.
Here’s a quick biology lesson. DNA is but a single piece of an extraordinarily complex molecular apparatus within gametes that holds sway over later neurodevelopment. Normal brain growth and function depends on a galaxy of itty-bitty on-off switches lying between genes, several “epigenetic” processes, which include chemical tags within and atop DNA helping control gene expression, and cytoplasmic molecules such as tiny RNAs that help define final protein products, among other factors. As the field of genomic toxicology has discovered, these crucial molecular processes can be vulnerable to disruption.
With this vulnerability in mind, I seed-fund pilot projects investigating generational impacts of fetal exposure to certain toxicants, including tobacco (via maternal smoking pervasive in the second half of the 20th century), certain pregnancy drugs, and other surprising exposures such as maternal general anesthesia. This work is based in part on my experience discovering I had been exposed in utero to acute doses of powerful synthetic steroid hormone administered to my mother when pregnant with me (and my eggs). I believe my two children’s catastrophically abnormal neurodevelopment likely stems from unforeseen errors laid down by aberrant hormonal signaling in my vulnerable egg precursor cells. I have found many other autism parents with this same exposure story, and many other autism parents with stories of prenatal exposures to other toxicants of interest. This concept has come to be known as the “Time Bomb” hypothesis of autism because it links forgotten gamete exposures in the parents to mystifying pathology in children some decades later. If we accelerate autism research as we should, I believe this hypothesis warrants attention.
Another important and related field for research relates to exposures in the pre-conception window. Taken as a whole, studies suggest that subtle impairments in sperm or in the conceptus (perhaps precipitated through certain forms of assisted reproductive technology) may contribute to autism risk. In one study, for example, abnormal epigenomic marks were found in the sperm of fathers of children with autism. It’s critical to better understand what exposures or manipulations may perturb the late-stage gametes and elevate the risk for dysregulated neurodevelopment.
A third area for improved research involves direct effects on central nervous system development. Some studies suggest that early exposure to certain chemicals, including endocrine-disrupting compounds, may have adverse and persistent effects on healthy brain development. Though some work is being done in this field already, there are many chemicals that warrant more thorough review for developmental safety.
While vaccines—like all pharmaceutical drugs—carry some risks, there is no reason to attribute the stunning surge in autism to them. Allow me to offer a few of the reasons:
Mr. President, you are an expert businessman. You do not waste time and you do not waste money. But further inquiry into the autism/vaccine connection is a waste of time and money at exactly the moment we should be urgently hunting down more promising theories, some of which are described above. Americans deserve answers, and this is no time for either complacency (autism is all “natural diversity”) or unscientific dead-ends (vaccine blaming). I believe considerable progress on autism is firmly within our grasp.
Thank you for your sincere concern about the autism crisis, which deserves a place as one of America’s top policy priorities, and your consideration of these ideas.
Very truly yours,
Jill Escher is founder of the Escher Fund for Autism, the mother of two children with nonverbal forms of autism, an active advocate for autism causes in the San Francisco Bay Area, and a housing provider to adults with autism and developmental disabilities. Learn more about her hypothesis at the Escher Fund’s science education website, www.GermlineExposures.org.
Latest Expert Interviews: Fetal Germ Cell Vulnerability, Non-Genetic Transmission of Traits, and the "Hidden History" of Prenatal Drugs
We are pleased to announce the addition of five fascinating new expert interviews at GermlineExposures.org.
Toshi Shioda, MD, PhD, Harvard University:
A Revolution in Germline Toxicology: Primordial Germ Cell-Like Cells (PGC-LCs)
One of the barriers to understanding germline exposure risk is the lack of effective and reliable models for mechanistic studies. Dr. Shioda’s lab has taken advantage of cutting edge tools from stem cell biology and deep sequencing technology to develop germ cell models on which new toxicological tests could be run.
"If epigenetic errors occur in the germline genome during the reprogramming process during pregnancy of a woman, her sons or daughters appear normal, but their germline cells carry a potential bomb."
Piroska Szabó, PhD, Van Andel Institute:
Chemicals Can Exert Direct Epigenetic Effects on Exposed Fetal Germ Cells
Dr. Szabó's recent paper in Genome Biology reported that endocrine disruptors affected the global transcription and DNA methylation state of exposed fetal mouse germ cells, but these aberrations were not passed on to the germ cells of the subsequent generation.
"I am concerned about harming the exposed germ cells by the chemicals we have tested. I also feel very concerned about potentially harming the germ cells by the many thousands of additional man-made chemicals that humans or wildlife can’t avoid being exposed to."
Miklos Toth, PhD, Cornell Medical Center:
Non-DNA Mediated Transmission of Behavior Across Generations
Maternal factors during sensitive periods of development produce persistent effects in the offspring, including effects on brain development and behavior. Dr. Toth's latest paper looks beyond fetal effects to successive generations, looking at altered methylation and gene expression in genes whose functions can be linked to behavioral traits, and ultimately, changes in neuronal function and behavior in generations of mice.
"We believe that iterative somatic transmission (through bioactive compounds via the placenta and breast milk) of behavioral traits is a prominent intergenerational and multigenerational mechanism."
June Reinisch, PhD, Prenatal Development Project, and former director, The Kinsey Institute:
The "Hidden History" of Pregnancy Drugs in the Postwar Era
Prenatal Exposures Oral History Project
Dr. Reinisch is renowned for her pioneering investigations of adverse impacts of various post-war pregnancy drugs, including once-common synthetic steroid hormones and barbiturates, on fetal development. In the 1970s Jill Escher, who had been exposed in utero to large quantities of synthetic steroid hormones, was one of her study subjects.
"There was a gigantic growth in all kinds of pharmaceuticals after World War II. Since there was this idea of the fetal placental barrier, there was the notion you could treat the mother without interfering with the baby. That went on for much longer than it should have."
Mark Klebanoff, MD, MPH, University of Ohio:
Postwar Obstetric Practices
Prenatal Exposures Oral History Project
Dr. Klebanoff has examined a variety of outcomes in cohorts of pregnancies from the post-war decades, during which some myth-driven obstetric practices were the norm.
"It gave me a good healthy dose of humility because the between-the-lines message was let's wait another 40 years to find out how many things we do today do more harm than good."
See all 35 expert interviews:
[This post was written by my friend, a DES victim named Marcia Love. It was written for her blog IWantAnApology.com. While I was not a DES daughter, I was exposed in utero to heavy amounts of other synthetic steroid hormones, and I identify with her plight and outrage at the lack of accountability in the medical and regulatory systems regarding this violently toxic pregnancy drug that was given recklessly to millions of gestating women. I'm proud to say I am now sponsoring a study on grandchild (germline) effects of DES on development of those offspring of exposed gametes. -Jill Escher]
They Made Us Freaks And Gave Us Cancer!
The True Story Of The Largest Disaster In Pharmaceutical History
by Marcia Love
This page is about the drug Diethylstilbestrol.
When you think about the largest or greatest drug disaster most people think of Thalidomide which was certainly a devastating catastrophe. The heartbreaking pictures of those born without limbs or those with deformed limbs can never be forgotten by those who have seen them.
In terms of the number of people affected Diethylstilbestrol was far worse. Th CDC estimates that over ten million people were exposed.
There are a few very profound differences between the two drugs.
First, the physical defects from Thalidomide were very apparent and immediate. A baby born with no limbs draws attention. One born with a 40x increased risk of cancer 20 years down the road not so much.
Next we have the fact that Thalidomide was not distributed worldwide so the number of people exposed was far less. The number of people exposed to Thalidomide is in the tens of thousands.
Then there is the fact that Thalidomide is still being sold and in fact many studies have for instance shown it to be effective in the treatment of multiple myeloma, especially when used with other drugs.
And of course Thalidomide was never sold in the U.S.
For these reasons every scientist on the planet and most lay men as well know about Thalidomide but very few know about Diethylstilbestrol.
Know that the pharmaceutical industry here in America operates the same way the tobacco companies did foryears. Deny responsibility, Deny your product kills and pay shills to promote your product in the face of increasing evidence which says that it indeed kills.
In 2012 Gruenenthal Group (The company which sold Thalidomide) to mothers and their children for the tragedy.
No such apology has ever been offered for Diethylstilbestrol.
In 2010 then senators John Kerry and Scott Brown sent a letter asking for an apology from the FDA. The response they got was something like “we are making sure that doesn’t happen again.”
They never got their apology…
Diethylstilbestrol was discovered in England at Oxford University in 1938 by Sir Charles Dodds.
It was found to have have estrogen like effects and was marketed as a cheap synthetic replacement for estrogen. The supposed premise that it was sold on was that since it behaved like estrogen it could be used as a cheap synthetic estrogen.
As it turns out Diethylstilbestrol is not a synthetic estrogen but an endocrine disruptor.
Dodds warned of intersex and cancerous outcomes and the FDA initially denied approval of the drug.
This did not stop the pharmaceutical companies from aggressively campaigning to get the drug approved. The reason? It was a free drug that anyone could manufacture and sell. English lay at the time forbade money to be made on anything discovered with public funds.
The drug companies pooled their resources and formed what was known as the Small Committee, hiring former Eli Lilly CEO Don Carlos Hines to represent them.
Soon there was an article in the Readers Digest stating that a new wonder drug for treating post-menopausal symptoms was available and was just awaiting the approval of the FDA.
Such articles asked readers to send letters to their congressmen and even the president. The aggressive campaign worked and by 1940 the FDA had approved it for use in treating gonorrheal vaginitis, menopausal symptoms, atrophic vaginitis and lactation suppression. The gonorrheal vaginitis indication was removed when penicillin was discovered.
At the behest of their pharmaceutical representatives doctors also began prescribing Diethylstilbestrol off label for the purpose of preventing miscarriages. As with the other four approved indications no proof was ever provided as to the efficacy of the drug for this purpose.
Scientific method was not widely used at this point in history because the FDA did not yet require it even though it was standard practice as early as the late 1930’s. So the MD was easily convinced by the affable drug rep to prescribe it for his at risk patients without any proof that it actually worked.
Off label prescription of Diethylstilbestrol for preventing miscarriage ended in 1947 when the FDA approved it for that use after years of pressure from the pharmaceutical companies. They convinced doctors and patients alike to write letters attesting to the safety and effectiveness of the drug.
Then came George and Olive Smith two “researchers” from Harvard who began advocating for an increasing regimen ending at 125 mg/day during the final month of pregnancy. At the time Eli Lilly was selling it in doses of .1,.5 and 5 mg. The most outrageous thing is that there was absolutely no proof of efficacy of these large doses because the scientific method had yet to be employed on the drug!
So then Bristol-Myers Squibb sought and and was granted permission to market and sell Diethylstilbestrol in doses of 25 mg and 100 mg.
As a fetus develops it’s hormonal needs vary by the micro-second and it is impossible for anyone to know what those exact needs are. DES is a powerful endocrine disruptor and introducing it into the womb at random times leads to arbitrary results.
Some women ended up with a T-Shaped uterus, some did not. Some sons became transgender, some did not. There are commonalities in mothers, sons and daughters however.
Finally in 1951 a double blind study was conducted at the University of Chicago and Diethylstilbestrol was proven to have to no effect on the prevention of miscarriages.
This fact did not slow down sales however. Coming from someone who was born in 1956 and exposed to the Smith & Smith regimen you can imagine how heartbreaking that fact is.
The person I was meant to be was never born and my body was permanently altered before I was born for no reason other than profit.
Study after study proved that Diethylstilbestrol did absolutely nothing to prevent miscarriages but yet the FDA still allowed it to be sold.
By the late 1960’s six of the seven leading textbooks on Obstetrics and Gynecology said Diethylstilbestrol had no value in preventing miscarriages but it wasn’t until 1971 when the New England Journal of Medicine published a study which found an astounding link between vaginal clear cell adenocarcinoma and in utero exposure to Diethylstilbestrol in women and young girls. Prior to this that type of cancer was only found in older women and even then only rarely.
Even after it was proven to cause cancer the FDA only removed prevention of miscarriage as in indication for Diethylstilbestrol use and added pregnancy as a contraindication for Diethylstilbestrol use.
The FDA never banned DES outright and other indications were allowed to stand but as evidence mounted the FDA started taking more action against it and in 1975 ordered 25mg and 100mg tablets withdrawn from the market.
In 1978 the FDA removed postpartum lactation suppression from their approved indications and by the 1990’s the only approved indications were for advanced breast cancer in postmenopausal women and for the treatment of advanced prostate cancer.
Finally in 1997 the last U.S. manufacturer Eli Lilly stopped making and marketing Diethylstilbestrol.
For 60 years Diethylstilbestrol was prescribed for made up reasons without any scientific data whatsoever to warrant it’s prescription. If it wasn’t so heartbreaking it might be laughable some of the reasons it was prescribed.
Starting in the 1950’s and continuing through the 1970’s Diethylstilbestrol was prescribed for “excessive height” in prepubescent girls, particularly in Australia.
The CDC estimates that 10 million people were exposed between 1938 and 1971 the vast majority for the prevention of miscarriage ruse. That means 5 million DES mothers gave birth to 2.5 million DES sons and 2.5 million DES daughters.
From the CDC’s website:
“More than 30 years of research have confirmed that health risks are associated with DES exposure. However, not all exposed persons will experience the following DES-related health problems.
In addition to causing cancer Diethylstilbestrol is a known teratogen, that is it is capable of causing physical malformations to those exposed in utero.
DES exposed daughters have a higher risk of reproductive tract abnormalities including epithelial cell changes known as vaginal adenosis, an increased cervical transformation zone and uterine abnormalities such as a T-shaped uterus.
In 2005 Dr Scott Kerlin published the results of an on-line survey of DES sons.
Out of 500 surveyed 150 men reported gender identity issues. Looking at the math:
150/500 x 2.5 million = 750,000 male to female transexuals were artificially created by the pharmaceutical industry.
Estimates of the natural occurrence of transexualism was somewhere between 1 in 5,000 to 1 in 70,000 depending on who you believe. Sill noting compared to the 3 in 10 you get when administering DES into the womb.
I am a DES son and there is virtually no help out there for me. I have a microphallus, ovaries, intermittent gender dysphoria and a whole lot more.
I am demanding an apology from the FDA, Eli Lilly and Bristol-Meyers Squibb and Harvard University.
Because of their blind pursuit of profit, ignoring all scientific proof of the harm their products do to developing fetuses and refusing to take responsibility I and millions of others have suffered greatly and have led miserable lives.
Their greed has caused me life-long pain and humiliation and ensured I would never find the happiness our constitution allows us to pursue.
It is time to fight back…
Letter to FDA's Center for Tobacco Products Regarding Study of Tobacco Smoking Impacts on Germ Cells
Escher Fund for Autism
Director, Center for Tobacco Products
FDA Document Control Center
10903 New Hampshire Avenue
Building 71, Room G335
Silver Spring, MD 20993-0002
October 17, 2016
Re: Center for Tobacco Products Efforts to Address Tobacco-Induced Human Germ Cell Damage
Dear Mr. Zeller,
I am a science philanthropist primarily concerned about adverse mutagenic and epimutagenic effects of various drugs, pharmaceuticals and tobacco on the human germline.
Based on my admittedly partial review of CTP activities, it appears that the CTP limits its concern for adverse outcomes of tobacco exposure to the somatic level. While questions of somatic pathology such as lung cancer, addiction, and heart disease are clearly of utmost importance in safeguarding public health, they also miss an entire dimension of risk.
Owing to its various toxic components, tobacco smoke has been shown to cause adverse impacts on germ cells. It has been shown to induce mutation in germ cells in human studies and animal models, as well as somatic mosaicism in animal models. At least one study points to transgenerational neurodevelopmental effects of nicotine, most likely via epigenetic mechanisms. The mutagenic and epimutagenic properties of tobacco smoke are now well known.
It is therefore surprising that the FDA’s CTP does not seem to include human germ cells, both male (sperm and precursors) and female (eggs and precursors), as a potential endpoint for tobacco toxicity. If in fact the high pregnancy smoking rates of the past decades increased risk for germline mutation and/or epimutation, developmental abnormalities in resulting offspring may be significant, and may include neurodevelopmental disorders such as autism and ADHD.
I am writing to inquire about what you think could be done at the CTP to ensure the FDA expeditiously addresses tobacco-induced risks to germ cells, particularly the highly vulnerable early germ cells that lie within fetuses. Health Canada, for example, has an admirable program on the gametic genetic toxicology of tobacco. What can we do to ensure a vigorous response here in the United States at the FDA as well?
Thank you for your consideration.
Very truly yours,
Escher Fund for Autism
My name is Jill Escher. I'm a science philanthropist who kickstarts pioneering research projects investigating the generational toxicity of certain potent exposures, including DES, tobacco and other drugs. While I'm not a DES daughter, I was exposed to a multitude of other synthetic steroid hormones in utero as part of a then-popular, if ineffective, "anti-miscarriage" practice. You can read my story here. You can see my science website at GermlineExposures.org.
Based on human, animal, and in vitro studies, as well as family interviews, I hypothesize that DES, along with several other toxic substances, can damage the genomic information in early fetal-stage gametes. For a variety of reasons, the early gamete is probably the single most vulnerable stage of the human lifecycle. Damage during that phase, which could be genetic or epigenetic in nature, can manifest as abnormal development in the subsequent offspring.
For example, I hypothesize that the intensive synthetic steroid hormone drug regimen to which I was subjected as a fetus subtly deranged the molecular programming of my early eggs. This derangement I believe resulted in the starkly abnormal neurodevelopment — autism — of my children. I have met many other families with the same story.
I am pleased to announce that I am funding the world's first research study into the grandchild effects of DES (3d gen), looking specifically at neurodevelopment and behavioral impacts. This work will be done in collaboration with Harvard University, based on the Nurses' Health Study II. If you can support this work, please contact us.
Thank you for your support! If you have any questions, please do not hesitate to reach me at: email@example.com
I was pleased to be featured on the Autism Speaks blog earlier this month with this post. —JE
Autism’s missing link? Study family history alongside genetics
Can exposures during our own prenatal development affect our children? This mom and autism advocate is funding research to find out
By Jill Escher, founder of the Escher Fund for Autism. Jill has two children with autism and is a longtime supporter and collaborator with Autism Speaks.
The dominant idea in autism research today is that the causes of autism are largely genetic. As a result, funding for autism research has emphasized hunting around DNA for clues.
I agree this is essential. However, to my mind, it’s also incomplete. It's not enough to draw blood and sequence our genes. We should put equal effort into investigating family histories.
Why our histories? To be blunt, our histories are not just about us, they’re also about our sperm and eggs – our gametes – the raw material that give rise to our children. Remember learning in biology class that “a girl is born with all her eggs?” Our gamete-producing cells, in both males and females, didn’t develop in a vacuum: They tangoed with environmental exposures, starting in our mothers’ wombs.
Looking beyond DNA
You probably know of obvious exposures that can affect genes. Examples include carcinogens such as tobacco smoke and mutagens such as X-rays. Both can directly damage DNA. In addition, emerging research shows that some drugs and other chemicals (including so-called “endocrine disruptors”) can modify how our genes operate without altering their underlying DNA code. This is the science of epigenetics, the study of mechanisms that control how genes turn on and off at the proper time and place.
Our gametes are vulnerable to a variety of environmental influences, and their vulnerability can set the stage for disorders and diseases.
Let me offer a hypothetical illustration about how this might work. Say a medical treatment for children involved repeated X-rays of the abdomen. That radiation could cause genetic errors in the children’s egg- or sperm-progenitor cells. As a result, their offspring, born decades later and conceived of those cells, might have higher rates of certain genetic disorders.
Now, I will argue that other, perhaps less obvious, gene-environment interactions may be tinkering with our genes. Take my family history as an example. My husband and I have two autistic children, ages 17 and 10. We have no family history of autism or mental disorders. The conceptions, pregnancies and deliveries were entirely normal with no notable risk factors. The kids are robustly healthy, and genetic tests have failed to show anything amiss. But their brains clearly did not wire up in the typical fashion. They remain severely challenged and nonverbal to this day. Are their genes alone to blame, or is there something more?
I believe that autism research is entering a new era
where we no longer look at genes and environment in isolation.
Our family stories will be instrumental in breaking new ground
and solving some of autism's deepest mysteries.
Exploring my own prenatal exposures
Several years ago, I discovered some troubling news about my own history. I obtained detailed medical records showing that during my mother’s pregnancy, I was prenatally exposed to heavy and continuous doses of powerful synthetic steroid hormone drugs. At that time, some doctors used many of these drugs (these were endocrine disruptors, or hormone mimics) to prevent miscarriage – though it turns out they were ineffective, and in many cases, profoundly damaging.
Now you might be thinking, what a weird idea that medications that my mother took during pregnancy with me in 1965 could cause developmental problems in my children decades later.
It might make sense if you consider that my early egg cells were already present when I was developing in my mother’s womb. Could the fake hormones given to my mother have disrupted the normal process of reprogramming in my budding egg cells? If so, molecular glitches in my eggs might manifest as dysregulations of development decades later, after my children were conceived and then missed their early milestones.
Some researchers have termed this the "time bomb" hypothesis, because of the proposed delayed effect of gamete, or germline, exposures that occurred decades before.
In recent years, I’ve met many autism parents with similar in utero exposure histories – some involving pharmaceuticals, tobacco or illegal drugs. I’ve grown particularly concerned about the fetal germline impacts of all the heavy pregnancy smoking of the 1950s through 1970s. Though pregnancy drugs and smoking were rampant in those decades, few people have asked about the health and development consequences to the generation exposed as gametes. There are plausible connections to dysregulation of neurodevelopment.
However, a plausible connection is not enough. It's just a place to start. Now we must move forward with serious research investigating the possibility of such gene-environment interactions. To kick-start this area of research, I support pilot projects through a grant program, in addition to my education and advocacy work.
Collaborating with Autism Speaks
I've also found a wonderful collaborator in Autism Speaks. Already, Autism Speaks and the Escher Fund for Autism have sponsored, with the UC Davis MIND Institute, the first scientific symposium on Environmental Epigenetics in Autism.
Now Autism Speaks, the Escher Fund and the Autism Science Foundation are sponsoring an ongoing, free webinar series probing epigenetics and gene-environment interactions in autism. Autism Speaks also funds a number of innovative research projects exploring the epigenetics of autism.
I believe that autism research is entering a new era where we no longer look at genes and environment in isolation. Our family stories will be instrumental in breaking new ground and solving some of autism's deepest mysteries.
To learn more, also see:
“What is epigenetics and what does it have to do with autism,” in the Autism Speaks “Got Questions?” advice column.
Environmental Epigenetics Webinars co-sponsored by Autism Speaks, Autism Science Foundation and Escher Fund for Autism
By Jill Escher
There is increasing appreciation that a subset of ASDs may be driven by heterogenous de novo errors in the germline (egg or sperm leading to the conceptus) or early conceptus, and also that epigenetic errors might be at play in some forms of autism. It seems reasonable to ask the next question, if there exist such molecular glitches in the germline, might they have been precipitated by certain mutagenic or epimutagenic exposures? As evidence mounts that autism is strongly heritable but not strongly genetic in the Mendellian sense, these questions appear to be increasingly reasonable.
My work promoting gene-environment investigation in autism etiology is based in part on my own story. As an embryo and fetus was heavily exposed to a variety of synthetic steroid hormone drugs that were part of a popular, yet ineffective, "anti-miscarriage" protocol of the 1960s. I hypothesize these acute exposures induced subtle molecular errors, likely of an epigenetic nature, during reprogramming in my vulnerable early oocyctes, resulting in the delayed phenotypic consequence of my children's severe yet idiopathic dysregulated neurodevelopment (labeled as autism), decades after the exposure itself. I have found numerous autism families with strikingly similar evolutionarily novel exposures and strikingly similar unexplained pathologies in their offspring.
But as I interviewed autism parents to investigate their prenatal histories, another exposure kept popping up. Over and over I would hear comments like: "No I don't think my mom took any drugs when she was pregnant with me, but she smoked like a chimney," or "My mother chain-smoked, so did my dad, and my mom kept smoking all the way through labor." At first I paid little attention to these anecdotes as I considered cigarette smoking to be mundane and harmless relative to the potent geno-affective chemicals to which I had been exposed. But in my interviews, stories of "grandma's smoking" and often grandpa's too, began to display an strong pattern, even though I started my interview project not remotely interested in this exposure.
Grandmaternal cigarette smoking makes scientific sense in relation to de novo germline errors
When one considers the well-established mutagenic effects of tobacco smoke, in combination with the critical developmental window of fetal germline synthesis, when the germline is stripped of methylation and dynamically remodeled, the biological plausibility of the hypothesis begins to add up.
High toxicity. Tobacco smoke has many toxic and mutagenic components. There is also growing appreciation for its epimutagenic effects. Components of concern include BaP, nicotine, tar, formaldehyde, and benzene, not to mention additives and even pesticide and radiation residues.
Research has shown that tobacco smoke and/or its constituents cause increased rates of mutation in gametes. DeMarini, in "Declaring the existence of human germ-cell mutagens," Environmental and Molecular Mutagenesis 2012, states that many studies have shown cigarette smoke to be a somatic-cell mutagen, and is genotoxic to oocytes and sperm of smokers. Marchetti et al, in "Sidestream tobacco smoke is a male germ cell mutagen," PNAS 2011, reflected that cigarette smoking increases oxidative damage, DNA adducts, DNA strand breaks, chromosomal aberrations, and heritable mutations in sperm. The study showed that short-term exposure to mainstream tobacco smoke or sidestream tobacco smoke (STS), the main component of second-hand smoke, induces mutations at an expanded simple tandem repeat locus (Ms6-hm) in mouse sperm. Passive exposure to cigarette smoke can cause tandem repeat mutations in sperm under conditions that may not induce genetic damage in somatic cells. Recent work by Yauk et al (unpublished) in a mouse model suggests increased rates of somatic mosaicism as a result of male germline exposure to benzo(a)pyrene, a mutagenic component of cigarette smoke, exposure.
A recent study from the NIEHS, "DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis," http://www.cell.com/ajhg/fulltext/S0002-9297%2816%2900070-7, found more than 6,000 differentially methylated CpG sites in newborns of mothers who smoked during pregnancy.
Germline damage demonstrated. With respect to F1 paternal smoking, studies have shown reduction of quantity and quality of sperm in tobacco-using males, including a mouse study by Yauk finding changes in the DNA sequence of sperm cells. See Yauk et al, Mainstream tobacco smoke causes paternal germ-line DNA mutation, Cancer Res. 2007.
Why examine early germline exposure instead of closer to the time of conception?
As autism researchers increasing turn attention to gene-environment interactions in autism etiology, there have been efforts to seek "pre-conception" exposure data in certain cohorts. While this is a positive development, it ignores the biological reality that the most vulnerable period of germline development is the earliest phase (ie, in the embryo, fetus, and neonate) in which the dynamic rearrangement of germline epigenetic reprogramming, including the laying of imprints, occurs. As with somatic development, the germline, too, has "critical windows" in which vulnerability to exposures is more acute than in other phases.
With respect to proximal exposure of the fetal brain, as opposed to germline, though fetal smoking exposure is associated with a wide variety of adverse outcomes and birth defects, there appears to be no evidence to support a measurable association between maternal prenatal smoking and ASD in offspring. See Rosen et al, "Maternal Smoking and Autism Spectrum Disorder: A Meta-analysis," Journal of Autism and Developmental Disorders 2015. However, germline exposure effects have not been probed.
This could be a "smoking gun"
In the big picture of potential mutagenic and epimutagenic agents, why focus on F0 cigarette smoking, instead of, say, synthetic sex steroid drugs or general anesthesia, which are two of the other potent prenatal exposures which repeatedly came up in the autism family interviews? Here are two reasons, aside from the known mutagenicity aspect:
High prevalence. F0 maternal smoking appears to have been one of the most prevalent and acute toxic exposures during the timeframe in which the new generation of autism parents—and their germ cells—were in utero. Up to 40% of women smoked at the peak of the late 1960s. Furthermore, the exposure was often heavy—5,400 cigarettes through gestation for a pack-a-day smoker.
Ease of ascertainment. It is easier to ascertain F0 smoking than use of other medications or medical interventions, simply because smoking would remain in the recollections of family members. (For example, I would not have known anything about my in utero exposures were it not for the exceptionally rare circumstance of having obtained detailed records of pharmaceuticals given to my mother while pregnant with me. My mother never told me about the medications, and did not smoke.)
Let's get this research party started
Sensing that high rates of maternal smoking in the second half of the 20th century may have unanticipated but lasting genomic consequences, Escher Fund for Autism seed funded a number of small pilot studies (for example, Denmark Prenatal Development Project cohort, CHDS cohort, UK ALSPAC cohort) that can begin to probe potential grandchild (F2) neurodevelopmental sequelae of grandmaternal (F0) smoking, via child (F1) prenatal smoking exposure. It will likely take years for pilot data to be sorted out. In addition, none of these projects are based on cohorts of autism subjects for whom we have genomic data.
Escher Fund is also communicating with other researchers in an attempt to persuade them to examine F0 smoking as a variable in their autism cohorts, including:
Australia Autism Biobank
MSSNG (University of Toronto, Autism Speaks)
Kaiser Autism Family Genetics Study (Kaiser)
Korean Autism Cohort study (UCSF)
African American autism cohort (UCLA)
CHARGE study (UC Davis)
Some observations from my interviews with autism families
Based on my many interviews with autism families in which at least one biological grandmother had smoked heavily during pregnancy, I'd like to offer some preliminary observations:
--The families had no prior history of autism
--ASD cases where grandmother was a heavy smoker tend to be severe and nonverbal--perhaps there is a dose-response effect
--The ASD is usually sporadic among siblings, but often siblings have other pathologies such as ADHD or learning disabilities
--Sometimes F2 cousins descended from the same F0 grandmother who smoked have ASD
--The grandfather was often a smoker too, meaning second-hand smoke could be a factor
--There seem to be more multiplex F2 ASD children in African American families where a grandmother had smoked
--Where F0 paternal grandmother had smoked, F1 father had smoked, and F1 father was of an older age, the risk for ASD in the F2 offspring seems to be markedly higher
I hope more and more autism research can focus on this question of germline exposure to cigarette smoke, rather than continuing down the path of "genetics in a vacuum." My hunch, after conducting about 200 autism family interviews and reviewing many studies probing germline toxicity of cigarette smoke, is that heavy maternal smoking of the 1950s-70s could be the single greatest contributor to the heritably-driven surge in idiopathic abnormal neurodevelopment we see today.
"Josh Would Have Loved This": Is the Autism Surge a "Genetic Emergency" Foreseen by Geneticists in the 1960s?
A scientific disconnect may be one reason the autism epidemic remains such a mystery
By Jill Escher
In 2011, much to my shock and horror, I discovered that as a fetus I had been exposed to regular infusions of potent synthetic steroid hormone drugs deployed as part of a then-popular, if ineffective, anti-miscarriage protocol. Knowing a little bit about the chemical mutilation caused by the fake hormone drug DES (diethylstilbestrol), and a bit about epigenetics as well, I immediately began to question whether my acute exposures—specifically, possible errors they may have induced in my nascent eggs—led to the wildly abnormal neurodevelopmental outcomes in two of my children, both of whom have autism, a "genetic" condition completely without precedent in my or my husbands' families.
Shortly after my discovery/hypothesis-conjuring I called my oldest friend to share the news. Her response was immediate: "Josh would have loved this!"
By Josh, she was referring to her late stepfather-in-law, the legendary geneticist and Nobel laureate Joshua Lederberg. Among his many accomplishments, Lederberg was a leader in developing the field of "environmental mutagenesis." According to Brown University sociologist Scott Frickel, the environmental mutagenesis movement grew out of the revelation that new synthetic and toxic chemicals could have lasting consequences for the human genome, amounting to a future "genetic emergency".
Dr. Lederberg was gravely concerned about the possibility the chemical revolution was creating a silent, hidden human genetic emergency that might not be fully realized for decades. As early as 1950, he remarked, "I have the feeling that, in our ignorance, chemical mutagenesis poses a problem of the same magnitude as the indiscriminate use of radiation." (Frickel, Chemical Consequences, p. 51) Five years later, his concerns continued unabated: "more extensive studies are needed to establish, for example, whether the germ cells of man are physiologically insulated against such chemical insults from the environment." (Id.) His colleague James Crow, in "Concern for Environmental Mutagens," summed up their beliefs like this: "The bottom line is human germinal mutation and the translation of this into effects on human welfare. We still have no reliable way to move from DNA damage, however precisely measured, to human well-being n generations from now.... Lowering the mutation rate or preventing its increase is good, even if we don't know how good." (Id. p 135)
Decades before I had an inkling about my prenatal chemical exposures—I was probably about 20 at the time and on a trip with my old friend who was soon to marry into his family—I met Dr. Lederberg in his home on the campus of Rockefeller University, where he served as president. Youth is truly wasted on the young because I can only imagine the lively discussion he and I would have today, three decades later. "Why is DNA particularly vulnerable to artificial steroids and their abnormal molecular structures?" "Why is the FDA refusing to require fetal germline effects of pregnancy drugs, and what can be done to change that?" "What is the interplay between epigenetic alterations and predisposition to mutation?" "What components of cigarette smoke might interfere with DNA repair in fetal germ cells?" And the list could go on and on.
How regrettable that Dr. Lederberg has passed, because it's my impression that the field of genetics today is largely unconcerned with questions like these. Autism genetics, for example, is focused almost exclusively on gene-hunting with scant curiosity about factors that may have actually caused the wide variety of autism-associated errors in the first place. For the past few months I have been actively pushing a variety of autism cohorts to ascertain grandmaternal smoking habits, and while I've had some success I can't help but sense how completely uninterested nearly all leading autism geneticists are in these sort of questions, questions which strike me as obvious and urgent, given what we know about tobacco-induced mutagenesis and the high rates of maternal smoking in the 1950s-70s.
But science has a culture, and presently that culture is divided fairly neatly into scientific silos that tend not to easily intermix. Genetics, mutagenesis, epimutagenesis and chemical/pharmaceutical history tend to be their own worlds. This disconnect may be one of the reasons we're still head-scratching about the colossal surge in autism cases—it seems genetic, but we can't have a "genetic epidemic," right? Or, perhaps, taking a cue from Dr. Lederberg and colleagues, we can. If we're perturbing our germline via novel chemical agents, we most certainly can have a genetic/epigenetic epidemic, what the environmental mutagenesis leaders had called a "genetic emergency" back in the 1960s. It will take a lot more work and creative thinking to probe these questions.
I am now a card-carrying member of the Environmental Mutagenesis and Genomics Society, which Dr. Lederberg co-founded in the 1960s, and now work to further scientific investigation into both genetic and epigenetic consequences of exposures. I hope to continually push for multidisciplinary thinking in autism causation, knowing all the while that "Josh would have loved this."
Jill Escher is the founder of the Escher Fund for Autism, president of Autism Society San Francisco Bay Area, and the mother of two children with nonverbal autism. You can learn more about her story here.
Links to articles and presentations featuring Jill's story and the germline disruption hypothesis of autism:
April 2016, Florida State University Symposium on the Developing Mind keynote: "Out of the Past: Old Exposures, Heritable Effects, and Emerging Concepts for Autism Research." (Slides)
November 2015, Bay Area Autism Consortium Conference, "The Germline Disruption Hypothesis of Autism." (Poster presentation)
September 2015, Environmental Mutagenesis and Genomics Society Conference, "Germline Disruption Hypothesis of Autism, in a Nutshell." (6-minute video)
August 2014, Ancestral Health Symposium: Epigenetics and the Multigenerational Effects of Nutrition, Chemicals and Drugs (40-minute video)
November 2013, University of Illinois School of Pharmacy guest lecture, "Are Grandma's Pregnancy Drugs (from the 1950s, 60s and 70s) Partly to Blame for Today's Autism Epidemic?" (Slides)
September 2013, Pittsburgh Post Gazette: Can Autism Be Triggered in Future Generations?
September 2013, Environmental Mutagenesis and Genomics Society Conference, Epigenetics Special Interest Group keynote, "20th C. Prenatal Pharmaceuticals & Smoking (& More), Fetal Germline Epigenetics, and Today's Autism Epidemic: Any Connections?" (Slides)
August 2013, San Francisco Chronicle: Mother's Quest Could Help Solve Autism Mystery
August 2013, Autism Speaks Blog: A Grandmotherly Clue in One Family's Autism Mystery
July 2013, Environmental Health News: Onslaught of autism: A mom's crusade could help unravel scientific mystery
July 2013, NIH Interagency Autism Coordinating Committee, National Institutes of Health: Autism: Germline Disruption in Personal and Historical Context (15-minute video)
March 2013, presentation at the symposium Environmental Epigenetics: New Frontiers in Autism Research (scroll down for 10-minute video)
Newest Presentation: "Out of the Past: Old Exposures, Heritable Effects, and Emerging Concepts for Autism Research"
This spring and summer I'll be giving a number of talks on the germline disruption hypothesis of autism and the important role for "citizen science" in improving autism research. You can see the slides from my upcoming talk, "Out of the Past: Old Exposures, Heritable Effects, and Emerging Concepts for Autism Research," April 8 at Florida State University here.
Jill Escher, Escher Fund for Autism, is a California-based science philanthropist and mother of two children with severe autism, focused on the question of how environmentally induced germline disruptions may be contributing to today's epidemics of neurodevelopmental impairment. You can read about her discovery of her intensive prenatal exposure to synthetic hormone drugs here. Jill is also president of Autism Society San Francisco Bay Area.