Monthly Archives: March 2017

Thuy Truong thought her aching back was just a pulled muscle from working out. But then came a high fever that wouldn't go away during a visit to Vietnam. When a friend insisted Truong, 30, go to an emergency room, doctors told her the last thing she expected to hear: She had lung cancer. Back in Los Angeles, Truong learned the cancer was at stage 4 and she had about eight months to live.

"My whole world was flipped upside down," says Truong, who had been splitting her time between the San Francisco Bay Area and Asia for a new project after selling her startup. "I've been a successful entrepreneur, but I'm not married. I don't have kids yet. [The diagnosis] was devastating."

Doctors at the University of Southern California took a blood sample for genetic testing. The "liquid biopsy" was able to detect tumor cells in her blood, sparing her the risky procedure of collecting cells in her lungs.

Genetic sequencing allowed the lab to isolate the mutation that caused her cancer to produce too much of the EGFR (epidermal growth factor receptor) protein, triggering cancer cells to grow and proliferate. Fortunately, her type of mutation responds to EGFR-targeting drugs, such as Tarceva or Iressa, slowing tumor growth.

Personalized medicine uses genetic information to design treatments targeted to individual patients.

Unlike chemotherapy, which blasts all fast-growing cells in its wake, targeted treatments go after specific molecules. That makes them more effective at fighting particular types of cancers, including breast, colorectal and lung cancers. Now the approach is being expanded to fight an even broader range of cancers. It's all part of a new wave in health care called personalized, or precision, medicine.

"This is the future of medicine," says Dr. Massimo Cristofanilli, associate director for translational research and precision medicine at Northwestern University. "There is no turning back. The technology is available and there are already so many targeted therapies."

Most medical treatments have been designed for the average patient, leading to a one-size-fits-all approach. But with vast amounts of data at their disposal, researchers now can analyze information about our genes, our family histories and other health conditions to better understand which types of treatments work best for which segments of the population.

This is a big deal. But it requires the know-how of geneticists, biologists, experts in artificial intelligence and computer scientists who understand big-data analytics. Several startups have already begun this work.

Deep Genomics, founded by researchers at the University of Toronto, uses AI to predict how genetic mutations will change our cells and the impact those changes will have on the human body. Epinomics, co-founded by scientists and physicians from Stanford University, is building a map of what turns our genes on and off, giving physicians a guide they could use to craft personalized therapies. And Vitagene, a small San Francisco startup, provides personalized advice on nutrition and wellness based on your DNA.

Dr. Massimo Cristofanilli

Just like Facebook learns to automatically recognize Aunt Martha in your family photos, Deep Genomics finds and categorizes patterns in genetic data. Once it's found those patterns, the company's deep learning system can infer if and how changes to your DNA affect your body.

That's a big step forward compared with current genetic tests. Most can only give a probability of, say, getting breast cancer based on data from an entire population. Other tests can't even tell you if the genetic changes they've detected mean anything.

The work is personal for Brendan Frey, CEO and co-founder of Deep Genomics and a professor at the University of Toronto. Fourteen years ago, he and his wife discovered their unborn baby had a genetic condition.

"We knew there was a genetic problem, but our counselor couldn't tell us if it was serious or if it was going to turn out to be nothing," Frey says. "We were plunged into this very difficult, emotional situation."

The experience made Frey want to bridge the divide between identifying genetic anomalies and understanding what they mean.

Deep learning or machine learning -- when computers teach themselves as they see more data -- can also help doctors know which drugs will most effectively treat a patient's illness and whether that person is more likely to experience side effects.

It can also help predict how cancer cells will mutate. And that can help drug companies come up with new treatments as tumor cells change and patients no longer respond to the drugs that worked.

That could help turn a disease like cancer into a manageable chronic ailment, says Cristofanilli.

Where Deep Genomics analyzes patterns in genetic data to predict when mutations will make you sick, Epinomics looks at epigenomics, or the study of what turns our genes on and off.

The company describes it like this: If your genome, which shows what genes we have, is the hardware of our bodies, then the epigenome is its software programming. Epinomics aims to decode that programming.

Every cell in the body carries the same genetic code. But cells in the heart, brain, bone and skin function differently based on this programming. It happens because chemical markers attach to DNA to activate or silence genes. These markers, known as the epigenome, vary from one cell type to another and are affected by both nature (inheritance) and nurture, which can include the air we breathe and the food we eat.

Researchers think a disruption to the epigenome can cause illnesses such as Alzheimer's disease, diabetes or cancer. Understanding it could give physicians a guide to the best options for each patient, like having a GPS for treatments at the molecular level.

"We are focusing on what is happening at the programming level of each cell," says Epinomics co-founder Fergus Chan. "Once we understand how genes are being turned on and off, we'll be able to better predict which treatments will work or whether changes to lifestyle will have an impact on health."

When Vitagene co-founder and CEO Mehdi Maghsoodnia asked a doctor what vitamins he should be taking, he was handed a bottle of pills and told to hope for the best.

Fergus Chan

That was the beginning of Vitagene, which uses genetic data and other health information culled from a detailed questionnaire to deliver a personalized nutritional supplement plan that lists which vitamins you need and in what doses, as well as what to avoid.

Maghsoodnia offers an alternative to the one-size-fits-all $27 billion US dietary supplement industry. Customers pay $99 to have their DNA tested and blood analyzed. And for $69 a month, Vitagene will package and ship supplements in dosages tailored to your individual needs.

The Food and Drug Administration estimates there are more than 85,000 dietary supplements on the US market, most of which are unregulated. Nearly all are "promising everything from anti-aging to weight loss, and no science behind it to tell you what works for you," says Maghsoodnia. "We help filter through the noise."

Vitagene's algorithm has been tested on patients who've had bariatric surgery for weight loss, which often leaves them deprived of key nutrients. Vitagene helped develop a supplement regimen to get these patients the nutrition they need after surgery.

Precision medicine is in its early days.

This is especially true for psychiatry and its exploration of how the brain responds to the environment, stress and genetic disorders. Now several companies are selling tests to help psychiatrists select drug treatments by looking at patients' DNA mutations and their metabolizing rate.

See more from CNET Magazine.

But critics caution that these genetic tests may be overselling their capabilities.

"Precision medicine has been very promising in oncology," says Jose de Leon, a professor of psychiatry at the University of Kentucky who specializes in psychopharmacology. "But we know a lot more about cancer and how it works. In psychiatry, it's much harder because we don't know enough about how the brain works."

Yes, precision medicine holds enormous promise.

Even so, Northwestern's Cristofanilli cautions clinicians to stay grounded in reality. "It can be difficult to understand where reality becomes imagination," he says. "We want to make sure we are protecting patients from claims that we may not deliver."

For her part, Truong is grateful to benefit from the work that's already been done. "I'm an engineer," she says.

"I don't believe in miracles. I believe in science."

This story appears in the spring 2017 edition of CNET Magazine. For other magazine stories, click here.

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Life, disrupted: In Europe, millions of refugees are still searching for a safe place to settle. Tech should be part of the solution. But is it? CNET investigates.

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Gene therapy: What personalized medicine means for you - CNET - CNET

From left, Dr. Teresa Sim, Dr. Magdalena Walkiewicz and Dr. Jason Heaney discuss their recent paper in the American Journal of Human Genetics.

An international team of researchers from institutions around the world, including Baylor College of Medicine, has discovered that mutations of the OTUD6B gene result in a spectrum of physical and intellectual deficits. This is the first time that this gene, whose functions are beginning to be explored, has been linked to a human disease. The study appears in the American Journal of Human Genetics.

Our interest in this gene began when we carried out whole exome sequencing the analysis of all the protein-coding genes of one of our patients who had not received a genetic diagnosis for his condition that includes a number of intellectual and physical disabilities, said co-first author Dr. Teresa Sim, a postdoctoral associate of molecular and human genetics and a fellow in Clinical Molecular Genetics and Genomics. We identified OTUD6B, a gene that until now had not been linked to a health condition.

We identified a presumed loss-of-function mutation in the OTUD6B gene in our first patient, said co-senior author Dr. Magdalena Walkiewicz, assistant professor of molecular and human genetics at Baylor and assistant laboratory director at Baylor Genetics. We discovered that this gene seemed to be highly involved in human development; when the gene cannot fulfill its function, the individual presents with severe intellectual disability, a brain that does not develop as expected and poor muscular tone that limits the ability to walk, as well as cardiovascular problems.

Making a convincing case for OTUD6B

However, one case does not represent sufficient evidence to support the involvement of OTUD6B in the medical condition.

To make a convincing case that this gene is essential for human development we needed to find more individuals carrying mutations in OTUD6B, Walkiewicz said.

Mutations in OTUD6B are rare so the researchers had to look into the exomes all the protein-coding genes of a large number of individuals to find others carrying mutations in this gene. Walkiewicz and her colleagues first looked into their clinical exome database at Baylor Genetics labs, specifically into the data of nearly 9,000 unrelated, mostly pediatric-age individuals, many of which carrying neurologic conditions, and found an additional individual carrying genetic changes in the same gene. The clinical characteristics of this individual were strikingly similar to those of the first patient, which led the team to expand their search for more patients.

When we study very rare disorders we rely on collaborations with scientists around the world to find other families affected by mutations in one gene, said Walkiewicz.

One of the strategies that helps researchers find more cases is running the gene of interest through GeneMatcher, a web-tool developed as part of the Baylor-Hopkins Center for Mendelian Genomics for rare disease researchers. Similar to online dating websites that match couples, GeneMatcher allows researchers to find others that are interested in the same genes they are working on.

Without this type of collaborations it would be very difficult to make a convincing case. Between GeneMatcher and our database we found a total of 12 individuals carrying mutations in OTUD6B and presenting with similar clinical characteristics, Walkiewicz said.

An animal model corroborates the human findings

Animal models are one way to determine whether a change in this gene is actually causing the condition, said co-senior author Dr. Jason Heaney, assistant professor of molecular and human genetics and director of the Mouse Embryonic Stem Cell Core at Baylor. Having a similar change in an animal model gene that results in similar characteristics in a mouse can show us whether the gene is causing the condition.

Baylor is part of the International Mouse Phenotyping Consortium. Its goal is to generate a knockout model for every gene in the mouse genome, about 20,000 protein-coding genes, and determine what each gene is involved with.

In this case we learned in the animal model lacking the OTUD6B gene that the gene is highly expressed in the brain and we knew that the patients had reduced intellectual capacities. The animals had cardiovascular defects very similar to those in the patient population. The animal models allowed us to see that having this mutation of this gene causes the clinical characteristics observed in the patients. It highlights how useful animal models can be for understanding human disease, Heaney said.

Through multiple lines of evidence the researchers have established that mutations in OTUD6B can cause a range of neurological and physical conditions and highlight the role of this gene in human development.

In addition, our collaborators in Germany performed functional analysis for this gene on blood cells from patients, Walkiewicz said. Their findings suggest that the OTUD6B protein contributes to the function of proteasomes, large molecular complexes that are at the center of the cellular process that degrades proteins that are damaged or are not needed by the cell. This discovery strengthens the notion that disturbances of the proteasome can cause human disease.

There is interest in better understanding the mechanisms of the disorder at the cellular and molecular level. By understanding the processes that lead to the disease, we can then hope to develop therapies for those patients, said Walkiewicz. One of the highlights of this project is the tremendous collaboration with a number of different centers and labs and putting this tremendous effort together resulted in a publication that is very strong.

Another important contribution of this project is that we provided some answers for the families, and brought them together which offers the opportunity of mutual support, said Sim.

For a complete list of the authors and their affiliations and financial support for this project click here.

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OTUD6B gene mutations cause intellectual, physical disability - Baylor College of Medicine News (press release)

BOSTON (January 27, 2010) Researchers at Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts have developed a new tool for gene therapy that significantly increases gene delivery to cells in the retina compared to other carriers and DNA alone, according to a study published in the January issue of The Journal of Gene Medicine. The tool, a peptide called PEG-POD, provides a vehicle for therapeutic genes and may help researchers develop therapies for degenerative eye disorders such as retinitis pigmentosa and age-related macular degeneration.

For the first time, we have demonstrated an efficient way to transfer DNA into cells without using a virus, currently the most common means of DNA delivery. Many non-viral vectors for gene therapy have been developed but few, if any, work in post-mitotic tissues such as the retina and brain. Identifying effective carriers like PEG-POD brings us closer to gene therapy to protect the retinal cells from degeneration, said senior author Rajendra Kumar-Singh, PhD, associate professor of ophthalmology and adjunct associate professor of neuroscience at Tufts University School of Medicine (TUSM) and member of the genetics; neuroscience; and cell, molecular, and developmental biology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

Safe and effective delivery of therapeutic genes has been a major obstacle in gene therapy research. Deactivated viruses have frequently been used, but concerns about the safety of this method have left scientists seeking new ways to get therapeutic genes into cells.

We think the level of gene expression seen with PEG-POD may be enough to protect the retina from degeneration, slowing the progression of eye disorders and we have preliminary evidence that this is indeed the case, said co-author Siobhan Cashman, PhD, research assistant professor in the department of ophthalmology at TUSM and member of Kumar-Singhs lab.

What makes PEG-POD especially promising is that it will likely have applications beyond the retina. Because PEG-POD protects DNA from damage in the bloodstream, it may pave the way for gene therapy treatments that can be administered through an IV and directed to many other parts of the body, said Kumar-Singh.

Kumar-Singh and colleagues used an in vivo model to compare the effectiveness of PEG-POD with two other carriers (PEG-TAT and PEG-CK30) and a control (injections of DNA alone).

Gene expression in specimens injected with PEG-POD was 215 times greater than the control. While all three carriers delivered DNA to the retinal cells, PEG-POD was by far the most effective, said first author Sarah Parker Read, an MD/PhD candidate at TUSM and Sackler and member of Kumar-Singhs lab.

Age-related macular degeneration, which results in a loss of sharp, central vision, is the number one cause of vision loss in Americans age 60 and older. Retinitis pigmentosa, an inherited condition resulting in retinal damage, affects approximately 1 in 4,000 individuals in the United States.

This study was supported by grants from the National Eye Institute of the National Institutes of Health, the Foundation for Fighting Blindness, The Ellison Foundation, The Virginia B. Smith Trust, the Lions Eye Foundation, and Research to Prevent Blindness. Sarah Parker Read is part of the Sackler/TUSM Medical Scientist Training Program, which is funded by the National Institute of General Medical Sciences, part of the National Institutes of Health.

Read SP, Cashman SM, Kumar-Singh R. The Journal of Gene Medicine. 2010 (January). 12(1): 86-96. A poly(ethylene) glycolylated peptide for ocular delivery compacts DNA into nanoparticles for gene delivery to post-mitotic tissues in vivo. Doi: 10.1002/jgm.1415

About Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences

Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University are international leaders in innovative medical education and advanced research. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, biomedical sciences, special combined degree programs in business, health management, public health, bioengineering and international relations, as well as basic and clinical research at the cellular and molecular level. Ranked among the top in the nation, the School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. Tufts University School of Medicine and the Sackler School undertake research that is consistently rated among the highest in the nation for its impact on the advancement of medical science.

If you are a member of the media interested in learning more about this topic, or speaking with a faculty member at the Tufts University School of Medicine, the Sackler School of Graduate Biomedical Sciences, or another Tufts health sciences researcher, please contact Siobhan Gallagher at 617-636-6586 or, for this study, Lindsay Peterson at 617-636-2789.

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Researchers develop new tool for gene delivery - ScienceBlog.com (blog)

Leon Csernohlavek

In September 2015, Elizabeth Parrish flew from Seattle to Colombia to receive an experimental treatment.

She had spent more than two years studying literature, talking to experts, and had decided to undergo gene therapy a treatment for genetic disorders that adds genes into cells to replace those that are faulty or absent. She ordered the therapeutic cells months in advance and arranged for a technician to administer the therapy in a clean room within a short distance of a hospital, in case she suffered a bad immune response. The gene therapy was shipped in a closed container and administered via an IV over approximately five hours. Parrish remained under observation for a few days and then flew home.

Was I anxious afterwards? Yes, Parrish says. I was definitely looking for indications that anything was wrong with my body. I was acutely aware of every ache and pain. She had become the first person to subject herself to gene therapy for the disease that affected her. Her condition? Ageing.

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In January 2013, Liz Parrish son was diagnosed with Type 1 diabetes. Every few days, he would have some devastatingly low blood sugar levels, Parrish says. I was continually reminded that we as humans spend a lot of time trying to pretend as if our death is not eminent. She remembers being told that her son was lucky because diabetes was treatable. I was really hit hard by the time I spent in children's' hospitals, Parrish says. She had read about the promises of modern medicine, in particular, gene therapy. I began trying to figure out why nothing was translating to hospitals where kids were dying.

Parrish began attending medical conferences on her own. I found this conference in Cambridge that looked to be about genetics, Parrish says. It turned out to be about longevity. There she learned how gene modifications had already extended the normal lifespan of worms up to 11 times and of mice by five times. It made me realise that if ageing was a disease and everyone was suffering from an illness, the fastest way to fund this research would be to essentially educate the world that was the case and get them to put money behind finding a cure, Parrish says.

At that point, Parrish, who up until then had been working part-time for software companies, started her own company, BioViva, to expedite therapeutics and give access to patients. Why did so many patients have to wait, suffer and die? Parrish asks. We became so risk adverse that patients die waiting for treatment. We have to change that drastically. We have millions of terminally ill patients on the planet right now. These patients should have access to the most promising therapeutics that don't have a myriad of off-target effects. There is no artificial intelligence or meta analysis of these therapies that is going to replace what happens in the human body. And we let people die because we're so concerned that a therapy might kill them. This is lawyering at its absolute worst.

Parrish then made another decision: she was going to try the first therapy on herself. I believed it was the most responsible and ethical thing to do. I believed the company should take its own medicine first before moving onto patients.

Parrish tried two therapies. One was a myostatin inhibitor, a drug designed to increase muscle mass, and the second was telomerase therapy, which lengthens the telomeres, a part of the chromosomes that protect genetic material from damage and allows the replication of DNA. Lengthening the telomeres can, at least in theory, extend cellular lifespan and make cells more resilient to damage.

The telomerase therapy had reversed ageing and extended lifespan in mice, Parrish says. I assumed this was the most promising therapy ever, and it was just sitting in research and wasn't moving forward as a viable option due to what appeared to be patenting issues and a lot of academics sitting on the fence bickering. We will never know unless we get it in humans. It's almost a moot point to try to continue to argue whether it works or not if we never use it. Its just like lemmings walking off the cliff, waiting for someone else to solve the problems.

A few weeks after the treatment, Parrish undertook follow-up exams, conducted by independent third parties. Her telomeres in her white blood cells had lengthened by more than 600 base pairs which, according to Parrish, implies they had extended by the equivalent of 20 years. A full-body MRI imaging revealed an increase in muscle mass and reduction in intramuscular fat. Other tests indicate Parrish now has improved insulin sensitivity and reduced inflammation levels.

The company was built essentially to prove these therapies work or not, Parrish says. Remember BioViva is not a research organisation. We are taking things like gene therapies and using them like technology. We would like to create an open market where people have access to acquiring these technologies, much like you would acquire a cellphone or a computer.

Further tests are being conducted at George Churchs lab in Harvard. Parrish and her team are currently working with other hospital clinics around the world to conduct more safety and feasibility studies in human subjects. I had already put things into perspective that without medicine, my son would be dead and he really was the meaning of my life, Parrish says. I was a person who quite honestly felt I had not really contributed that much to society and this was my opportunity to do so.

More here:
Ageing is a disease. Gene therapy could be the 'cure' - Wired.co.uk

A UC San Diego-led research team has put the hot gene-editing technology CRISPR/Cas9 to a novel use, finding more than 120 new leads for cancer drugs.

The team inactivated targeted genes in lab-cultured kidney, lung and cervical cancer cancer cells to pinpoint those that kill these cells but leave normal cells unharmed.

With the gene editing technology, large numbers of genes can be tested simultaneously for their effect on cancer, said John Paul Shen, one of the studys lead authors.

The study also found that the weak spots where inactivation kills malignant cells varies according to the cell type.

CRISPR has made the once cumbersome process of gene editing, faster and more precise, leading to comparisons with the impact of the word processor. But in this study, Shen and colleagues turned CRISPR on its head to selectively introduce disabling errors.

Human testing with already approved drugs identified through the research could begin in as little as a year, said Shen, postdoctoral researcher at UC San Diego School of Medicine. Further down the road, new drugs precisely targeted to vulnerable spots in various types of cancer could be developed.

Doctors could rework their cancer therapies to take the findings into account. But more validation of the study findings is needed before that can be done.

This discovery is still preliminary, Shen said. Before you would change what youre doing for a patient, you would need to see that interaction reproduces in other cell types. Ideally, youd like to see it in a mouse model, not just a cell culture.

Each cancer is unique, Shen said, so it would theoretically be possible to develop drugs personalized toward each individual cancer. Of course, this isnt practical. But the next best thing is to identify subtypes of cancers with common vulnerabilities. Patients can be treated with drugs or combinations of drugs that target those vulnerabilities.

The study was published March 20 in Nature Methods. Other co-first authors along with Shen are Dongxin Zhao and Roman Sasik. The senior authors are Trey Ideker and Prashant Mali. It can be found at j.mp/cancercr.

Ideker has developed a model of cancer circuits that link apparently randomly placed cancer-causing mutations into patterns of molecular activity. So a cancer driven by a mutation in one circuit might be stopped by interrupting the downstream effects of that mutation.

In this study, researchers looked for gene pairs that exhibit synthetic lethality. This is when inactivating both genes kills the cells, but if one gene in the pair is active, the cells survive. So cancers driven by a synthetic lethal mutation can be killed by inactivating the other gene in the pair, leaving normal cells unharmed.

Some existing drugs work this way, such as the ovarian cancer drug olaparib, Shen said. Sold under the brand name Lynparza, the drug was approved for in December 2014 for cancers with disabling mutations in the BRCA1 or BRCA2 genes.

And there are many other synthetic-lethal gene combinations yet to be discovered, Shen said, perhaps triggered by existing drugs that werent developed with that effect in mind. Even if only a small fraction can form the base of new drugs, they would greatly expand the range of cancers that can be treated in this way.

To this model, CRISPR brings the ability to test potential synthetic lethal combinations much more quickly and efficiently than disabling genes one at a time.

The CRISPR technology is often used by researchers to repair genetic defects. It allows cutting a precise location in the gene to allow a corrected DNA sequence to be inserted. But in this study, the goal was to break the DNA without supplying a correction. The natural DNA repair mechanisms rejoined the broken ends, introducing errors in the process.

UCSDs Mali and others have adapted CRISPR to rapidly inactivate pairs of genes.

Researchers developed a new way to guide the Cas9 enzyme, which cleaves DNA, to target both a tumor suppressor gene thats often mutated in cancer along with a gene that could be targeted with a cancer drug.

Thats never been done before, in a high throughput, in human cells, Shen said.

After sorting through more than 2,500 gene combinations the scientists found more than 120 new synthetic-lethal interactions.

However, many of these synthetic-lethal interactions occurred in just one of the three cell types tested, the study found. This means the source of the cancer must also be considered in developing drugs by this method.

Finding that this difference in interactions varied by cell types was probably the studys biggest discovery, Shen said.

Now that weve shown that this technology works, we want to move forward and test many more cell types and see what are the synthetic lethal interactions that are conserved (among different cell types), because those are the ones that well want to take into the clinic, he said.

Additional study co-authors include: Jens Luebeck, Amanda Birmingham, Ana Bojorquez-Gomez, Katherine Licon, Kristin Klepper, Daniel Pekin, Alex Beckett, Kyle Sanchez, Alex Thomas, Chih-Chung Kuo, Nathan E Lewis, Aaron N Chang, Jason F Kreisberg, all of UC San Diego; Dan Du, Assen Roguev, Nevan Krogan, all of UC San Francisco; and Lei Qi, Stanford University.

This research was funded in part, by the National Institutes of Health, Burroughs Wellcome Fund, March of Dimes Foundation, Sidney Kimmel Foundation, California Institute for Regenerative Medicine, UC San Diego Clinical and Translational Research Institute Grant, and Novo Nordisk Foundation Center for Biosustainability.

bradley.fikes@sduniontribune.com

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Gene editing used to find cancer's genetic weak spots - The San Diego Union-Tribune

March 21, 2017 by Jeannette Jimenez Credit: CC0 Public Domain

Researchers at Baylor College of Medicine, Texas Children's Hospital and Rice University have uncovered a gene mutation that may provide answers to unexplained female infertility. The study appears in Scientific Reports, a member of the Nature family of journals.

"Experts cannot identify the cause of the problem in an estimated 10 to 15 percent of couples with infertility and 50 percent of women with recurrent pregnancy loss," said senior author Dr. Ignatia B. Van den Veyver, professor of obstetrics and gynecology and molecular and human genetics at Baylor, and director of clinical prenatal genetics at Baylor and Texas Children's Hospital. "Researchers have found that women with mutations that lead to loss-of-function of some of the genes of the NLRP family can fail to reproduce for reasons that may include recurrent loss of pregnancies with abnormally developing placentas, loss of the embryo before implantation, or, more rarely, having a baby with developmental disabilities."

"Women carrying these mutations are healthy in all other physical aspects, so they are unaware that they have these mutations that do not allow them to carry a pregnancy," said first author Dr. Sangeetha Mahadevan, a graduate of the Translational Biology and Molecular Medicine program and currently a postdoctoral fellow in the Van den Veyver lab. "To investigate the mechanisms by which the inactivation of the human NLRP2 and NLRP7 genes might affect reproductive success and fertility, we developed a mouse model."

Mice, however, only carry the Nlrp2 gene, and the researchers hypothesized that it might assume the role of both NLRP2 and NLRP7 in humans.

A closer look at the role of Nlrp2

"When we genetically engineered mice to lack the Nlrp2 gene, the animals looked completely normal. However, when the females mated, we observed three different types of outcomes: some did not get pregnant, others had stillborn pups with abnormalities and a third group of females gave birth to live pups of normal appearance, but fewer per litter. Some of the pups were smaller or larger than expected," Mahadevan said. "Thus, there was a spectrum of reproductive outcomes when the females lacked the Nlrp2 gene. However, when male mice lacked the gene, there was no impact on fertility or offspring."

"From prior studies by us and others, we knew that DNA methylation of genes that are normally methylated when the mother passes them on, was absent in pregnancies of women with mutations in the NLRP7 gene," Van den Veyver said. "Methylation is a small chemical modification on DNA that controls which genes are expressed and which are not."

In the mouse model lacking the Nlrp2 gene, the scientists also observed abnormal DNA methylation in the offspring, which allowed them to draw stronger parallels between the human and the mouse systems.

Connecting NLRP2, the subcortical maternal complex and fertility

"We were very interested in learning how NLRP2 aids in passing on DNA methylation marks to the next generation," Van den Veyver said. "Initially we thought we had to focus on the nucleus of the cell and the proteins that carry out methylation there, but instead we discovered that NLRP2 proteins are mostly outside the nucleus. They are part of a large protein complex inside the egg called the subcortical maternal complex."

The subcortical maternal complex is part of the proteins and other molecules packed inside the egg as it prepares for fertilization. After the egg is fertilized and begins to divide, there is a period of time during which the fertilized cell and early embryo relies heavily on the proteins and other compounds that the egg has stored to carry on essential functions - including DNA methylation - until the embryo can switch on its own genes. These stored compounds are all of maternal origin.

"We also found that when the Nlrp2 gene is absent or inactive in the mother, the subcortical maternal complex does not form properly anymore in the egg and that, in addition, one of the proteins that plays a role in DNA methylation seems not to be in the right place in early embryos," said Mahadevan. "This might help explain the disturbances in DNA methylation observed in offspring of female mice lacking Nlrp2."

"Finding NLRP2 proteins in the subcortical maternal complex was not unexpected but this is the first time scientific evidence shows that NLRP2 proteins are part of this important cellular complex, providing more support to the idea that the complex is critical for fertility and embryonic development," Van den Veyver said.

Implications for in vitro fertilization

The researchers also investigated whether lack of the Nlrp2 gene in mouse eggs would affect their survival when cultured in the lab. This is relevant to in vitro fertilization, a procedure in which eggs are collected and cultured in special conditions in the lab in preparation for fertilization.

"When we attempted to grow the eggs of a female mouse carrying the mutation in the Nlrp2 gene in an artificial environment in the lab, they did not develop," said Mahadevan. "This finding has implications for in vitro fertilization. It is important to recognize that there will be women who may not be candidates for this procedure because their embryos would likely be unable to grow in culture as a result of the females carrying these mutations in NLRP genes."

"I think that in addition to establishing a connection with fertility and pregnancy loss, understanding these basic early mechanisms associated with NLRP genes is very important for developmental disorders in general, and particularly for those with DNA methylation abnormalities," Van den Veyver said. "It is a very rare human condition with a very unique mutation that teaches a lot about different aspects of development."

Explore further: Scientists show NLRP2 protein's role in maintaining fertility later in life

More information: Sangeetha Mahadevan et al, Maternally expressed NLRP2 links the subcortical maternal complex (SCMC) to fertility, embryogenesis and epigenetic reprogramming, Scientific Reports (2017). DOI: 10.1038/srep44667

Led by Prof. Mohamed Lamkanfi (VIBGhent University), researchers have demonstrated in animal models that a protein called NLRP2 plays an important role in early embryogenesis, the process of cell division in fertilized ...

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For the first time, researchers have shown that poorly controlled maternal diabetes has an adverse effect on methylation of the maternal imprinting gene Peg3, contributing to impaired development in offspring.

Families struggling with infertility or a genetic predisposition for debilitating mitochondrial diseases may someday benefit from a new breakthrough led by scientists at OHSU and the Salk Institute for Biological Studies.

In a first-of-its-kind study published in the March 1, 2017 edition of Molecular Therapy, researchers from the National Institute on Deafness and Other Communication Disorders (NIDCD) and Johns Hopkins University School of ...

A person carrying variants of two particular genes could be almost three times more likely to develop multiple sclerosis, according to the latest findings from scientists at The University of Texas Medical Branch at Galveston ...

Researchers at Baylor College of Medicine, Texas Children's Hospital and Rice University have uncovered a gene mutation that may provide answers to unexplained female infertility. The study appears in Scientific Reports, ...

A group of researchers has found that three siblings born with cleft lip and palate share a common gene mutation associated with the birth defect.

Chronic lung infections can be devastating for patients with cystic fibrosis (CF), and infection by Burkholderia cenocepacia, one of the most common species found in cystic fibrosis patients, is often antibiotic resistant. ...

Einstein researchers have developed and validated a method for accurately identifying mutations in the genomes of single cells. The new method, which can help predict whether cancer will develop in seemingly healthy tissue, ...

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Gene mutation may be linked to unexplained female infertility - Medical Xpress