Reading the internal clock


The Conversation



September 10, 2018

By Rosemary Braun: Assistant Professor of Biostatistics, Preventive Medicine and Engineering Sciences and Applied Mathematics, Northwestern University. Disclosure statement: Receives funding from NIH, NSF, DARPA, the Simons Foundation, and the James S. McDonnell Foundation.

Your body’s internal clock – the circadian rhythm – regulates an enormous variety of processes: when you sleep and wake, when you’re hungry, when you’re most productive. Given its palpable effect on so much of our lives, it’s not surprising that it has an enormous impact on our health as well. Researchers have linked circadian health to the risk of diabetes, cardiovascular disease and neurodegeneration. It’s also known that the timing of meals and medicines can influence how they’re metabolized.

The ability to measure one’s internal clock is vital to improving health and personalizing medicine. It could be used to predict who is at risk for disease and track recovery from injuries. It can also be used to time the delivery of chemotherapy and blood pressure and other drugs so that they have the optimum effect at lower doses, minimizing the risk of side effects.

However, reading one’s internal clock precisely enough remains a major challenge in sleep and circadian health. The current approach requires taking hourly samples of blood melatonin – the hormone that controls sleep – during day and night, which is expensive and extremely burdensome for the patient. This makes it impossible to incorporate into routine clinical evaluations.

My colleagues and I wanted to obtain precise measurements of internal time without the need for burdensome serial sampling. I’m a computational biologist with a passion for using mathematical and computational algorithms to make sense of complex data. My collaborators, Phyllis Zee and Ravi Allada, are world-renowned experts in sleep medicine and circadian biology. Working together, we designed a simple blood test to read a person’s internal clock.

Listening to the music of cells

The circadian rhythm is present in every single cell of your body, guided by the central clock that resides in the suprachiasmatic nucleus region of the brain. Like the secondary clocks in an old factory, these so-called “peripheral” clocks are synchronized to the master clock in your brain, but also tick forward on their own – even in petri dishes!

Your cells keep time through a network of core clock genes that interact in a feedback loop: When one gene turns on, its activity causes another molecule to turn it back down, and this competition results in an ebb and flow of gene activation within a 24-hour cycle. These genes in turn regulate the activity of other genes, which also oscillate over the course of the day. This mechanism of periodic gene activation orchestrates biological processes across cells and tissues, allowing them to take place in synchrony at specific times of day.

The discovery of the core clock genes is so fundamental to our understanding of how biological functions are orchestrated that it was recognized by the Nobel Committee last year. Jeffrey C. Hall, Michael Rosbash and Michael W. Young together won the 2017 Nobel Prize in Physiology or Medicine “for their discoveries of molecular mechanisms controlling the circadian rhythm.” Other researchers have noted that as many as 40 percent of all other genes respond to the circadian rhythm, changing their activity over the course of the day as well.

This gave us an idea: Perhaps we could use the activity levels of a set of genes in the blood to deduce a person’s internal time – the time your body thinks it is, regardless of what the clock on the wall says. Many of us have had the experience of feeling “out of sync” with our environments – of feeling like it’s 5:00 a.m. even though our alarm insists it’s already 7:00. That can be a result of our activities being out of sync with our internal clock – the clock on the wall isn’t always a good indication of what time it is for you personally. Knowing what a profound impact one’s internal clock can have on biology and health, we were inspired to try to gauge gene activity to measure the precise internal time in an individual’s body. We developed TimeSignature: a sophisticated computational algorithm that could measure a person’s internal clock from gene expression using two simple blood draws.

Designing a robust test

To achieve our goals, TimeSignature had to be easy (measuring a minimal number of genes in just a couple blood draws), highly accurate and – most importantly – robust. That is, it should provide just as accurate a measure of your intrinsic physiological time regardless of whether you’d gotten a good night’s sleep, recently returned from an overseas vacation or were up all night with a new baby. And it needed to work not just in our labs but in labs across the country and around the world.

To develop the gene signature biomarker, we collected tens of thousands of measurements every two hours from a group of healthy adult volunteers. These measurements indicated how active each gene was in the blood of each person during the course of the day. We also used published data from three other studies that had collected similar measurements. We then developed a new machine learning algorithm, called TimeSignature, that could computationally search through this data to pull out a small set of biomarkers that would reveal the time of day. A set of 41 genes was identified as being the best markers.

Surprisingly, not all the TimeSignature genes are part of the known “core clock” circuit – many of them are genes for other biological functions, such as your immune system, that are driven by the clock to fluctuate over the day. This underscores how important circadian control is – its effect on other biological processes is so strong that we can use those processes to monitor the clock!

Using data from a small subset of the patients from one of the public studies, we trained the TimeSignature machine to predict the time of day based on the activity of those 41 genes. (Data from the other patients was kept separate for testing our method.) Based on the training data, TimeSignature was able to “learn” how different patterns of gene activity correlate with different times of day. Having learned those patterns, TimeSignature can then analyze the activity of these genes in combination to work out the time that your body thinks it is. For example, although it might be 7:00 a.m. outside, the gene activity in your blood might correspond to the 5:00 a.m. pattern, indicating that it’s still 5:00 a.m. in your body.

We then tested our TimeSignature algorithm by applying it to the remaining data, and demonstrated that it was highly accurate: We were able to deduce a person’s internal time to within 1.5 hours. We also demonstrated our algorithm works on data collected in different labs around the world, suggesting it could be easily adopted. We were also able to demonstrate that our TimeSignature test could detect a person’s intrinsic circadian rhythm with high accuracy, even if they were sleep-deprived or jet-lagged.

Harmonizing health with TimeSignature

By making circadian rhythms easy to measure, TimeSignature opens up a wide range of possibilities for integrating time into personalized medicine. Although the importance of circadian rhythms to health has been noted, we have really only scratched the surface when it comes to understanding how they work. With TimeSignature, researchers can now easily include highly accurate measures of internal time in their studies, incorporating this vital measurement using just two simple blood draws. TimeSignature enables scientists to investigate how the physiological clock impacts the risk of various diseases, the efficacy of new drugs, the best times to study or exercise and more.

Of course, there’s still a lot of work to be done. While we know that circadian misalignment is a risk factor for disease, we don’t yet know how much misalignment is bad for you. TimeSignature enables further research to quantify the precise relationships between circadian rhythms and disease. By comparing the TimeSignatures of people with and without disease, we can investigate how a disrupted clock correlates with disease and predict who is at risk.

Down the road, we envision that TimeSignature will make its way into your doctor’s office, where your circadian health could be monitored just as quickly, easily and accurately as a cholesterol test. Many drugs, for example, have optimal times for dosing, but the best time for you to take your blood pressure medicine or chemotherapy may differ from somebody else.

Previously there was no clinically feasible way to measure this, but TimeSignature makes it possible for your doctor to do a simple blood test, analyze the activity of 41 genes and recommend the time that would give you the most effective benefits. We also know that circadian misalignment – when your body’s clock is out of sync with the external time – is a treatable risk factor for cognitive decline; with TimeSignature, we could predict who is at risk, and potentially intervene to align their clocks.

We need more swamps!

September 12, 2018

Authors

William Moomaw

Professor Emeritus of International Environmental Policy, Tufts University

Gillian Davies

Visiting Scholar, Global Development and Environment Institute, Tufts University

Max Finlayson

Director, Institute for Land, Water and Society, Charles Sturt University

Disclosure statement

William Moomaw receives funding from Rockefeller Brothers Foundation William Moomaw is affiliated with and serves as board chair of Woods Hole Research Center and The Climate Group North America. He is a board member of Earthwatch Institute, The Consensus Building Institute and The Nature Conservancy of Massachusetts. He also serves as a consultant to the Sustainability Advisory Board of Caterpillar Corporation.

Gillian Davies works for BSC Group, Inc. She receives funding from the Massachusetts Association of Conservation Commissions and the Massachusetts Environmental Trust. She has served on the Executive Boards of the international Society of Wetland Scientists, the New England Chapter of the Society of Wetland Scientists, and the Association of Massachusetts Wetland Scientists and is a member of these organizations. She is currently the chair of the Waters of the United States ad hoc Committee for the Society of Wetland Scientists. She also is a member of the Association of State Wetland Managers, the Society for Ecological Restoration and the Society of Soil Scientists of Southern New England.

Max Finlayson receives funding from the Australian Centre for Agricultural Research. He is the President-elect of the Society of Wetland Scientists, a member of the Ramsar Convention on Wetland’s Scientific and Technical Review Panel (STRP) from 1993 to 2018 with input on wetland assessments and climate change, and in 2018 joined the Science Committee of the International Lake Environment Committee (ILEC).

Partners

Tufts provides funding as a founding partner of The Conversation US. Charles Sturt provides funding as a member of The Conversation AU.

“Drain the swamp” has long meant getting rid of something distasteful. Actually, the world needs more swamps – and bogs, fens, marshes and other types of wetlands.

These are some of the most diverse and productive ecosystems on Earth. They also are underrated but irreplaceable tools for slowing the pace of climate change and protecting our communities from storms and flooding.

Scientists widely recognize that wetlands are extremely efficient at pulling carbon dioxide out of the atmosphere and converting it into living plants and carbon-rich soil. As part of a transdisciplinary team of nine wetland and climate scientists, we published a paper earlier this year that documents the multiple climate benefits provided by all types of wetlands, and their need for protection.

A vanishing resource

For centuries human societies have viewed wetlands as wastelands to be “reclaimed” for higher uses. China began large-scale alteration of rivers and wetlands in 486 B.C. when it started constructing the Grand Canal, still the longest canal in the world. The Dutch drained wetlands on a large scale beginning about 1,000 years ago, but more recently have restored many of them. As a surveyor and land developer, George Washington led failed efforts to drain the Great Dismal Swamp on the border between Virginia and North Carolina.

Today many modern cities around the world are built on filled wetlands. Large-scale drainage continues, particularly in parts of Asia. Based on available data, total cumulative loss of natural wetlands is estimated to be 54 to 57 percent – an astounding transformation of our natural endowment.

Vast stores of carbon have accumulated in wetlands, in some cases over thousands of years. This has reduced atmospheric levels of carbon dioxide and methane – two key greenhouse gases that are changing Earth’s climate. If ecosystems, particularly forests and wetlands, did not remove atmospheric carbon, concentrations of carbon dioxide from human activities would increase by 28 percent more each year.

From carbon sinks to carbon sources

Wetlands continuously remove and store atmospheric carbon. Plants take it out of the atmosphere and convert it into plant tissue, and ultimately into soil when they die and decompose. At the same time, microbes in wetland soils release greenhouse gases into the atmosphere as they consume organic matter.

Natural wetlands typically absorb more carbon than they release. But as the climate warms wetland soils, microbial metabolism increases, releasing additional greenhouse gases. In addition, draining or disturbing wetlands can release soil carbon very rapidly.

For these reasons, it is essential to protect natural, undisturbed wetlands. Wetland soil carbon, accumulated over millennia and now being released to the atmosphere at an accelerating pace, cannot be regained within the next few decades, which are a critical window for addressing climate change. In some types of wetlands, it can take decades to millennia to develop soil conditions that support net carbon accumulation. Other types, such as new saltwater wetlands, can rapidly start accumulating carbon.

Arctic permafrost, which is wetland soil that remains frozen for two consecutive years, stores nearly twice as much carbon as the current amount in the atmosphere. Because it is frozen, microbes cannot consume it. But today, permafrost is thawing rapidly, and Arctic regions that removed large amounts of carbon from the atmosphere as recently as 40 years ago are now releasing significant quantities of greenhouse gases. If current trends continue, thawing permafrost will release as much carbon by 2100 as all U.S. sources, including power plants, industry and transportation.

Climate services from wetlands

In addition to capturing greenhouse gases, wetlands make ecosystems and human communities more resilient in the face of climate change. For example, they store flood waters from increasingly intense rainstorms. Freshwater wetlands provide water during droughts and help cool surrounding areas when temperatures are elevated.

Salt marshes and mangrove forests protect coasts from hurricanes and storms. Coastal wetlands can even grow in height as sea level rises, protecting communities further inland.

But wetlands have received little attention from climate scientists and policymakers. Moreover, climate considerations are often not integrated into wetland management. This is a critical omission, as we pointed out in a recent paper with 6 colleagues that places wetlands within the context of the Scientists’ Second Warning to Humanity, a statement endorsed by an unprecedented 20,000 scientists.

The most important international treaty for the protection of wetlands is the Ramsar Convention, which does not include provisions to conserve wetlands as a climate change strategy. While some national and subnational governments effectively protect wetlands, few do this within the context of climate change.

Forests rate their own section (Article 5) in the Paris climate agreement that calls for protecting and restoring tropical forests in developing countries. A United Nations process called Reducing Emissions from Deforestation and Degraded Forests, or REDD+ promises funding for developing countries to protect existing forests, avoid deforestation and restore degraded forests. While this covers forested wetlands and mangroves, it was not until 2016 that a voluntary provision for reporting emissions from wetlands was introduced into the U.N. climate accounting system, and only a small number of governments have taken advantage of it.

Models for wetland protection

Although global climate agreements have been slow to protect wetland carbon, promising steps are starting to occur at lower levels.

Ontario, Canada has passed legislation that is among the most protective of undeveloped lands by any government. Some of the province’s most northern peatlands, which contain minerals and potential hydroelectric resources, are underlain by permafrost that could release greenhouse gases if disturbed. The Ontario Far North Act specifically states that more than 50 percent of the land north of 51 degrees latitude is to be protected from development, and the remainder can only be developed if the cultural, ecological (diversity and carbon sequestration) and social values are not degraded.

Also in Canada, a recent study reports large increases in carbon storage from a project that restored tidal flooding to a saltmarsh near Aulac, New Brunswick, on Canada’s Bay of Fundy. The marsh had been drained by a dike for 300 years, causing loss of soil and carbon. But just six years after the dike was breached, rates of carbon accumulation in the restored marsh averaged more than five times the rate reported for a nearby mature marsh.

Ten feet (3 meters) of carbon-rich soil accumulation along Dipper Harbour, Bay of Fundy, New Brunswick, Canada, has been radiocarbon dated to have accumulated over 3,000 years. Gail Chmura, McGill University, CC BY-ND

In our view, instead of draining swamps and weakening protections, governments at all levels should take action immediately to conserve and restore wetlands as a climate strategy. Protecting the climate and avoiding climate-associated damage from storms, flooding and drought is a much higher use for wetlands than altering them for short-term economic gains.

This article has been updated to add a link to the Scientists’ Second Warning to Humanity.

Author, civil rights leader Carol Anderson to speak at The Ohio State University

Distinguished historian, author and civil rights thought leader Carol Anderson will make an appearance at Ohio State on September 26 to discuss the impact of voter suppression on democracy.

Carol Anderson, who earned her Ph.D. in history from The Ohio State University, is the Charles Howard Candler Professor of African American Studies at Emory University and author of the New York Times bestseller, White Rage: The Unspoken Truth of Our Nation’s Divide.

Her latest book, One Person, No Vote: How Voter Suppression is Destroying Our Democracy, released September 11, and will be the focus of her discussions in Columbus. One Person, No Vote follows the story of government-dictated racial discrimination through the adoption of state voter suppression laws and explains how voter suppression works, from photo ID requirements to gerrymandering to poll closures.

All Voting is Local fights for the right to vote through a unique combination of data-driven organizing, advocacy and communications. It is a collaborative campaign housed at The Leadership Conference Education Fund, in conjunction with Access Democracy; the American Civil Liberties Union Foundation; the American Constitution Society; the Campaign Legal Center; and the Lawyers’ Committee for Civil Rights Under Law.

Hey! Democracy! Choices!

by Tom H. Hastings

What, we wonder, can we do about it?

What is there to do about a lack of funding for our public schools and education in general? Just looking at the federal level, despite an economy that is doing very well at the moment, Trump’s proposed 2019 education budgetchops it from $68 billion in 2016 to $63 billion in 2019, cheating children while at the same time spending more and more on war profiteers like Lockheed and Boeing.

Indeed, the daily contracts for the war department are staggering. Just today, 10 September 2018,Boeing is awarded $2.85 billion, $51 million to Lockheed, $19 million to Northrup Grumman, an additional contract of $14 million more to Boeing, and $12 million to BAE Technology Solutions.

Those are just the Air Force contracts for one random day. The Navy’s, Army’s, and Defense Logistics Agency list other contracts for the day, each one in the $millions, even more than $200 million for L-3 Communications Vertex Aerospace.

But, I hear you snort, that’s how Trump is creating jobs!

Nope. That’s how he’s losing them, once the new budgets kick in.

Economists figure it by jobs created per $million spent. The military contractors produce far fewer jobs/$million than does education. Nationwide, the average is 17 jobs per $million(or 17,000 jobs/$billion), and if you just consider the government workers, including all members of all branches of the military and all agency workers, that sector actually creates 21 jobs per $million spent, more than any other sector. Therefore, the private sector profits are obscenely high in Pentagon budgets.

To create more jobs, to create more educational opportunities for our young people, vote for candidates who will cut military spending and increase education. Ask your candidates for federal office very specifically about their intentions, ask incumbents about their actual voting records, and choose accordingly. Our future is at stake more than ever in this midterm election season. From an environment under attack, to foreign influence on our elections, to a drive toward the US as less and less free, our opportunity to fix this starts right now.

No, I am not a registered Democrat. But it seems to me, as an analyst, that Democrats, in general, are looking out for the welfare, education, good health, and breathable air for all, while Republicans are—at least at the leadership level—mired in dirty tricks, identity politics, elite enrichment, obeisance to Putin, and craven corruption. Or, as Thomas Friedman has written, “Donald Trump is either an asset of Russian intelligence or really enjoys playing one on TV.”

I want to be proud of my country and right now, bluntly, I am not. I have hope, but it revolves around regular folks rising up in rejection of Trump and his agenda in November. Our enlightened self-interest is at stake, the well-being of our children and grandchildren is in the balance. Let’s do right.

Dr. Tom H. Hastings is PeaceVoice Director and on occasion an expert witness for the defense in court.

The Conversation

Immigrant detention in the US: 4 essential reads

September 14, 2018

Author

Danielle Douez

Associate Editor, Politics + Society

More children are being held in immigrant detention centers in the U.S. than ever previously recorded, according to The New York Times.

The number of immigrant children in detention has risen to about 12,800, the Times reports, a significant increase from 2,400 in 2017. Here are 4 stories from our archive that will help readers understand some central issues around immigrant detention:

1. Legal challenges

Since President Donald Trump took office, there have been numerous legal challenges to his administration’s policies on immigration, including on immigrant and child detention. In July, a federal court ruled that detention centers could no longer give drugs to treat psychiatric symptoms to children without the consent of a parent or guardian.

Immigration scholar Kevin Johnson writes about several cases in U.S. history that set legal precedents in disputes over detaining immigrants and protecting their rights. For example, a class action lawsuit filed by immigrants in detention in the 1980s argued that moving detainees away from major urban areas deprived them of a right to counsel. The court agreed and ruled in their favor.

Johnson writes: “The long history of detention has an equally long history of legal challenges. These are likely to continue in the Trump administration, which has made detention a cornerstone of its immigration enforcement plan.”

2. Standards for children and families

One case in particular stands out as more relevant to today’s debate about detaining children and families. The Flores case was filed in 1985 and led to what’s known as the “Flores settlement.” This contract between the government and the plaintiffs set standards for holding children and families in detention, which courts continue to use today.

For example, the agreement says that the government must release immigrant children after 20 days of detention.

In a separate analysis, Johnson explains the case and why it has had such a lasting impact.

3. Who’s to blame?

Critics have blamed the Trump administration for the inhumane detention of immigrant children. However, public policy professor Susan M. Sterett argues that the contractors who provide the detention facilities are also to blame for suffering children.

Although government contracting is not new, the contracts themselves rarely garner attention from the public. There are many reasons why the government uses contracting services. In this case, it is likely because the contractors can act more quickly than the government to provide housing for detained children, Sterett writes.

“[The government] hands nonprofit groups, for-profit businesses and local governments US$1 billion a year or more to house nearly 12,000 children. This money is dispensed through government contracts that do not always gain much public attention,” Sterett writes.

4. Echoes from the past

This episode in U.S. history is not unique. In the 1990s, thousands of Haitians fleeing violence started the journey toward the U.S. to seek safety. Presidents George H.W. Bush and Bill Clinton responded by authorizing their capture and indefinite detention at a military base at Guantanamo Bay in Cuba.

Scholar A. Naomi Paik writes about conditions on the base: “Under the stress of imprisonment with no end in sight, some refugees fell into despair. The most dire cases purposely hurt themselves or attempted suicide. Children also endured the camp conditions that nearly broke grown adults.”

As information emerges about conditions in today’s detention centers, the parallels to the past may be instructive.

Editor’s note: This story is a roundup of articles from The Conversation’s archives.

The Conversation

Can Jeff Bezos help the homeless? 4 essential reads

September 14, 2018

Author

Aviva Rutkin

Big Data + Applied Mathematics Editor

Tonight, some 554,000 people in the U.S. will be homeless.

Many of them live on the West Coast, where Amazon CEO Jeff Bezos is launching a new fund that plans to fight the problem. Part of the US$2 billion donated by Bezos will be spent “to provide shelter and hunger support to address the immediate needs of young families.”

With such an enormous challenge, where would it make sense to start? We looked into our archives for stories on what it would take to eradicate homelessness in the U.S. today.

1. How the homeless population is changing

“The common perception of homelessness is that it is a problem that afflicts only those with mental health and substance use problems,” writes Margot Kushel, a professor of medicine at University of California, San Francisco. But a diverse array of Americans are affected.

In fact, the U.S. homeless population is getting older and sicker. Today, half is over the age of 50. Many of these older homeless adults are the victims of circumstance. “Their lives became derailed by job loss, illness, a new disability, the death of a loved one or an interaction with the criminal justice system,” writes Kushel.

2. Homeless high school students

Another group that struggles with homelessness: American teens. One in 30 high school students in the U.S. have experienced homelessness in the past year.

Research from Stacey Havlik at Villanova University shows “that school counselors often lack knowledge about students who are homeless, and have limited training to support their needs.” These students may need not only basic support like food and clothing, but extra attention to their mental health and planning for the future.

3. Better places to stay

About a quarter of homeless Americans are unsheltered. But even when there are shelters, people may choose not to go to them. Many are run-down and dirty, offer little privacy or feel unsafe.

Jill Pable at Florida State University suggests rethinking shelter design. Her team upgraded a local shelter with new features, like better lighting, privacy curtains and room to store possessions. “This small, only partially controlled study is not the final word in shelter design,” she writes, but the feedback from families who tried the new space was very positive.

4. Integrating homeless people into their communities

Another team in Connecticut helps people with mental illness and criminal histories, many of whom have experienced homelessness, by teaching them about citizenship. The Citizens Project in New Haven is an intervention program that teaches people how to participate in their community, with classes on topics like conflict resolution and public speaking. Afterwards, participants report better quality of life, less substance abuse and fewer criminal charges.

“The people we worked with needed to see themselves – and be seen as – full members of their neighborhoods and communities,” write program creators Michael Rowe of Yale University and Charles Barber of Wesleyan University. “They needed, in other words, to be citizens.”

Editor’s note: This story is a roundup of articles from The Conversation’s archives.

The Conversation

Study shows BPA substitutes may cause same health issues as the original

September 13, 2018

Authors

Patricia Hunt

Professor of Molecular Biosciences, Washington State University

Tegan Horan

Washington State University

Disclosure statement

Patricia Hunt receives funding from grants R01 HD083177 and R56 ES13527 from the National Institutes of Health.

Tegan Horan does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

The credibility of scientific findings hinges on their reproducibility. As a scientist, it is therefore disastrous when you are unable to replicate your own findings. Our laboratory has found itself in just this situation several times; in each instance, unintended environmental exposure distorted our data. Our first accidental foray into toxicology 20 years ago convinced us of the need to understand the reproductive effects of environmental chemical contaminants. The latest twist in our journey down that road adds a new dimension to an old concern, BPA.

Bisphenol A, or BPA, is a man-made chemical that has become a household word. It is a plasticizer used in such a wide range of consumer products that daily exposure is inevitable. People absorb BPA through our skin – from receipts and contamination of personal care products and water. We ingest it via contamination from plastic food containers, and food and beverage liners. We even inhale it as a contaminant in dust. Studies of this chemical number in the thousands, but whether BPA is hazardous to our health remains “controversial.” Here’s why: Although data from traditional toxicology testing provide little or no evidence of harm, independent investigators like us have reported effects induced by very low doses thought to be in the realm of human exposure.

The implications of these low-dose effects for human health and reproduction captured media attention and increased consumer unease. In response, manufacturers introduced BPA replacements by producing structurally similar bisphenols. As a result, it no longer is simply BPA contaminating our environment but an ever-increasing array of bisphenols. Our recent studies of several replacements suggest effects on the production of eggs and sperm similar to those induced by BPA.

BPA substitutes

We stumbled into the BPA world 20 years ago when cages housing mice for our studies were damaged when inadvertently washed with a detergent intended for the floor. Unbeknownst to us the detergent caused BPA to leach out of the cages. We happened to be studying eggs from young females and saw an immediate increase in eggs with scrambled chromosomes that would give rise to chromosomally abnormal embryos. In the intervening 20 years, our studies and those of colleagues have described the effects of BPA exposure on the developing brain, heart, lung, prostate, mammary gland and other tissues, and our studies have described serious effects on the production of both eggs and sperm. Together these findings inflamed debate about the safety of BPA and resulted in the rapid appearance of “BPA free” products.

Bisphenol S looks similar to BPA and also causes problems in the production of both eggs and sperm.

Remarkably, almost exactly 20 years after the BPA exposure of our mice, we recently found ourselves, once again, victim of an environmental contamination that halted our research. We were working to pinpoint the critical windows of BPA exposure when we noticed that something was interfering with our experiments. This time the effect was harder to run to ground: Again, it appeared to be due to cage damage, but the damage was milder, limited to a subset of cages, and the effect on our results was evident in some animals and not others.

The major culprit this time was not BPA but the replacement bisphenol, BPS, leaching from damaged polysulfone caging. Knowing what it was didn’t make eliminating it easy. We tried several less expensive methods to solve the problem, but ultimately had to replace all the cages and water bottles in the facility. When we could resume our studies, we experimentally tested four common replacement bisphenols and found effects on sperm and egg production in our mice analogous to those that result from BPA exposure.

The possibility that exposure effects may span generations has been a growing concern. Our recent experience with accidental exposure allowed us to ask if BPS exposure effects persisted across generations, and if so, for how long. Our data suggest persistence of effects for up to three generations, with full recovery evident in great-grandsons.

Widespread use of BPA-like chemicals

Do we simply have bad lab karma? No, we think we have supersensory powers. The process of making eggs and sperm is tightly controlled by complex hormone signals. This makes it vulnerable to endocrine-disrupting chemicals like bisphenols – chemicals that can interfere with our body’s hormones. Bisphenol contaminants cause a seismic shift in our data, but it’s not that the research of others isn’t also affected, but most remain blissfully ignorant.

Importantly, our laboratory knew what data from unexposed animals should look like. What if we hadn’t? We would have misinterpreted our results. If we had been asking if BPA had an effect, background bisphenol contamination would have diminished it, causing us to conclude that BPA had little or no effect.

This isn’t merely hypothetical. BPA use is so prevalent in consumer products and routine laboratory materials (like mouse caging materials or culture flasks) that low-level contamination of unexposed control groups is increasingly difficult to avert. Data and conclusions from CLARITY-BPA, a large, ambitious collaborative study conducted by three U.S. agencies, are coming out now. CLARITY was launched to understand why findings from traditional toxicology studies of BPA and those of independent investigators differ. Animal contamination was evident in a pilot study, but the source could not be determined, and the CLARITY initiative proceeded.

Given our experience, we have great concern about drawing any conclusions from CLARITY data because there is no way to determine the impact of low-level contamination.

The bisphenol story details the evolution of only one class of the endocrine-disrupting chemicals that are common contaminants in our lives. The ability of manufacturers to rapidly modify chemicals to produce structurally similar replacements undermines the ability of consumers to protect themselves from hazardous chemicals and federal efforts to regulate them.

As a canary whose research has been twice derailed by bisphenols, we feel the need to chirp loudly: These contaminants may not only affect our health, but also our ability to conduct meaningful studies of chemicals to determine if and how they impact on our health and the environment.

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