Category: Health

{Scientists provide first evidence that carbamates can upset circadian rhythms.}

Synthetic chemicals commonly found in insecticides and garden products bind to the receptors that govern our biological clocks, University at Buffalo researchers have found. The research suggests that exposure to these insecticides adversely affects melatonin receptor signaling, creating a higher risk for metabolic diseases such as diabetes.

Published online on Dec. 27 in Chemical Research in Toxicology, the research combined a big data approach, using computer modeling on millions of chemicals, with standard wet-laboratory experiments. It was funded by a grant from the National Institute of Environmental Health Sciences, part of the National Institutes of Health.

Disruptions in human circadian rhythms are known to put people at higher risk for diabetes and other metabolic diseases but the mechanism involved is not well-understood.

“This is the first report demonstrating how environmental chemicals found in household products interact with human melatonin receptors,” said Margarita L. Dubocovich, PhD, senior author on the paper and SUNY Distinguished Professor in the Department of Pharmacology and Toxicology and senior associate dean for diversity and inclusion in the Jacobs School of Medicine and Biomedical Sciences at UB.

“No one was thinking that the melatonin system was affected by these compounds, but that’s what our research shows,” she said.

The current research focuses on two chemicals, carbaryl, the third most widely used insecticide in the U.S. but which is illegal in several countries, and carbofuran, the most toxic carbamate insecticide, which has been banned for applications on food crops for human consumption since 2009. It is still used in many countries, including Mexico and traces persist in food, plants and wildlife.

“We found that both insecticides are structurally similar to melatonin and that both showed affinity for the melatonin, MT2 receptors, that can potentially affect glucose homeostasis and insulin secretion,” said Marina Popevska-Gorevski, co-author, now a scientist with Boehringer Ingelheim Pharmaceuticals, who worked in Dubocovich’s lab while earning her master’s degree at UB. “That means that exposure to them could put people at higher risk for diabetes and also affect sleeping patterns.”

The results suggest that there is a need to assess environmental chemicals for their ability to disrupt circadian activity, something which is not currently being considered by federal regulators. The UB researchers are developing a rapid bioassay that might be able to assess environmental chemicals for this kind of activity.

The work is part of a larger effort by Dubocovich and her colleagues at UB to develop their Chem2Risk pipeline, combining UB’s expertise in computational biology and melatonin receptor pharmacology.

“Our approach seamlessly integrates the screening of environmental chemicals through computer simulation, in vitro and in vivo techniques to gauge the risk these chemicals present for various disease end points,” explained Raj Rajnarayanan, PhD, lead author and assistant professor of pharmacology and toxicology at UB.

The UB database contains about four million chemicals reported to have some level of toxicity. “From those, we identified hundreds of thousands of compounds that had readily available chemical structures so that we could study them,” Rajnarayanan explained. After grouping the chemicals in clusters according to their similarity, they found several with functional groups similar to melatonin.

Using predictive computational modeling and in vitro experiments with cells that express human melatonin receptors, they found that carbamates selectively interact with a melatonin receptor. That interaction can disrupt melatonin signaling and alter important regulatory processes in the body.

“By directly interacting with melatonin receptors in the brain and peripheral tissues, environmental chemicals, such as carbaryl, may disrupt key physiological processes leading to misaligned circadian rhythms, sleep patterns, and altered metabolic functions increasing the risk for chronic diseases such as diabetes and metabolic disorders,” said Dubocovich.

For example, she explained, there is a fine balance between the release of insulin and glucose in the pancreas at very specific times of day, but if that balance becomes disrupted over a long period of time, there is a higher risk of developing diabetes.

Dubocovich is an internationally renowned authority on the brain hormone melatonin and how melatonin receptors are regulated. Her work has significantly boosted the scientific understanding of how melatonin impacts circadian rhythms and human health in general, including sleep disorders, metabolic disease and drug addiction.

Popovska-Gorevski presented preliminary findings on this work at the 2014 Experimental Biology meeting in San Diego, receiving a Best Abstract Award from the Toxicology Division of the American Society for Pharmaceutical and Experimental Therapeutics and a Best Poster Award from the Upstate New York Pharmacology Society.

{A new Université de Montréal study in the British Medical Journal reveals that antidepressants prescribed to pregnant women could increase the chance of having a baby with birth defects.
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The risk — 6 to 10 %, versus 3 to 5 % in women who do not take the drugs — is high enough to merit caution in their use, especially since, in most cases, they are only marginally effective, the study says.

“In pregnancy, you’re treating the mother but you’re worried about the unborn child, and the benefit needs to outweigh the risk,” said the study’s senior author, Anick Bérard, a professor at UdeM’s Faculty of Pharmacy and researcher at its affiliated children’s hospital, CHU Sainte-Justine.

A well-known expert in pregnancy and depression, Bérard has previously established links between antidepressants and low birth weight, gestational hypertension, miscarriages and autism. Her new study is among the first to examine the link to birth defects among depressed women.

Every year, about 135,000 Quebec women get pregnant, and of those, about 7 % show some signs of depression, mostly mild to moderate. A much smaller percentage — less than one per cent — suffers from severe depression.

In her study, Bérard looked at 18,487 depressed women in the Quebec Pregnancy Cohort, a longitudinal, population-based grouping of 289,688 pregnancies recorded between 1998 to 2009. Of the women studied, 3,640 — about 20 per cent — took antidepressants in the first three months.

“We only looked at the first trimester, because this is where all the organ systems are developing,” said Bérard. “At 12 weeks of gestation, the baby is formed.”

Antidepressant use during this critical time-window has the potential to interfere with serotonin intake by the fetus, which can result in malformations.

“Serotonin during early pregnancy is essential for the development of all embryonic cells, and thus any insult that disturbs the serotonin signaling process has the potential to result in a wide variety of malformations,” the study says.

For example, when Celexa (the brand name for citalopram) was taken in the first trimester, the risk of major birth defects jumped from 5 per cent to 8 per cent, Bérard found. In all, 88 cases of malformations were linked to use of the drug.

Similarly, use of Paxil (paroxetine) was associated with an increased risk of heart defects; venlafaxine (Effexor), with lung defects; and tricyclic antidepressants (such as Elavil), with increased eye, ear, face and neck defects.

Depression is on the rise across the globe and is a leading cause of death, according to the World Health Organization. Depression is particularly serious during pregnancy, and doctors — especially psychiatrists, obstetricians and other specialists — are prescribing more antidepressants than ever to expectant mothers.

Over the decade or so that Bérard studied her cohort, the proportion of expectant mothers on antidepressants in Quebec doubled, from 21 users per 1,000 pregnancies in 1998 to 43 per 1,000 in 2009.

Those using the drugs tend to be older, live alone or be on welfare; they also may have other ailments such as diabetes, hypertension and asthma, the new study shows. The women generally don’t have the financial means, leisure time or support to seek other solutions, such as exercising regularly or consulting with a psychotherapist.

“There are a multitude of ways to get mild to moderate depression treated, but you need to have the time and money and also the encouragement to take advantage of them,” Bérard said.

“Given that an increasing number of women are diagnosed with depression during pregnancy, (the new) results have direct implications on their clinical management,” the study concludes. “This is even more important given that the effectiveness of antidepressants during pregnancy for the treatment of the majority of cases of depression (mild to moderate depression) have been shown to be marginal. “Hence, the need for caution with antidepressant use during pregnancy is warranted and alternative non-drug options should be considered.”

{Long-term heavy use of alcohol in adolescence alters cortical excitability and functional connectivity in the brain, according to a new study from the University of Eastern Finland and Kuopio University Hospital. These alterations were observed in physically and mentally healthy but heavy-drinking adolescents, who nevertheless did not fulfil the diagnostic criteria for a substance abuse disorder. The findings were published in Addiction Biology.}

Constituting part of the Adolescents and Alcohol Study, the study analysed the effects of heavy adolescent drinking on the electrical activity and excitability of the cortex. The study did a follow-up on 27 adolescents who had been heavy drinkers throughout their adolescence, as well as on 25 age-matched, gender-matched and education-matched controls with little or no alcohol use. The participants were 13 to 18 years old at the onset of the study.

At the age of 23-28, the participants’ brain activity was analysed using transcranial magnetic stimulation (TMS) combined with simultaneous electroencephalogram (EEG) recording. In TMS, magnetic pulses are directed at the head to activate cortical neuronal cells. These magnetic pulses pass the skull and other tissues, and they are safe and pain-free for the person undergoing TMS. The method allows for an analysis of how different regions of the cortex respond to electrical stimulation and what the functional connectivities between the different regions are. Indirectly, the method also makes it possible to analyse chemical transmission, i.e. mediator function. The effects of long-term alcohol use haven’t been studied among adolescents this way before.

The cortical response to the TMS pulse was stronger among alcohol users. They demonstrated greater overall electrical activity in the cortex as well as greater activity associated with the gamma-aminobutyric acid, GABA, neurotransmission system. There were also differences between the groups in how this activity spread into the different regions of the brain. Earlier research has shown that long-term, alcoholism-level use of alcohol alters the function of the GABA neurotransmission system. GABA is the most important neurotransmitter inhibiting brain and central nervous system function, and GABA is known to play a role in anxiety, depression and the pathogenesis of several neurological disorders.

The study found that alcohol use caused significant alterations in both electrical and chemical neurotransmission among the study participants, although none of them fulfilled the diagnostic criteria of a substance abuse disorder. Moreover, in an earlier study completed at the University of Eastern Finland, also within the Adolescents and Alcohol Study, cortical thinning was observable in young people who had been heavy drinkers throughout their adolescence. For young people whose brain is still developing, heavy alcohol use is especially detrimental. The findings of the study warrant the question of whether the diagnostic criteria for substance abuse disorders should be tighter for adolescents, and whether they should be more easily referred to treatment. The use of alcohol may be more detrimental to a developing brain than previously thought, although it takes time for alcohol-related adverse effects to manifest in a person’s life.

{Older women with low physical activity and 10 hours of daily sit time had even ‘older’ cells.}

Researchers at University of California San Diego School of Medicine report that elderly women who sit for more than 10 hours a day with low physical activity have cells that are biologically older by eight years compared to women who are less sedentary.

The study, publishing online January 18 in the American Journal of Epidemiology, found elderly women with less than 40 minutes of moderate-to-vigorous physical activity per day and who remain sedentary for more than 10 hours per day have shorter telomeres — tiny caps found on the ends of DNA strands, like the plastic tips of shoelaces, that protect chromosomes from deterioration and progressively shorten with age.

As a cell ages, its telomeres naturally shorten and fray, but health and lifestyle factors, such as obesity and smoking, may accelerate that process. Shortened telomeres are associated with cardiovascular disease, diabetes and major cancers.

“Our study found cells age faster with a sedentary lifestyle. Chronological age doesn’t always match biological age,” said Aladdin Shadyab, PhD, lead author of the study with the Department of Family Medicine and Public Health at UC San Diego School of Medicine.

Shadyab and his research team believe they are the first to objectively measure how the combination of sedentary time and exercise can impact the aging biomarker.

Nearly 1,500 women, ages 64 to 95, participated in the study. The women are part of the larger Women’s Health Initiative (WHI), a national, longitudinal study investigating the determinants of chronic diseases in postmenopausal women. The participants completed questionnaires and wore an accelerometer on their right hip for seven consecutive days during waking and sleeping hours to track their movements.

“We found that women who sat longer did not have shorter telomere length if they exercised for at least 30 minutes a day, the national recommended guideline,” said Shadyab. “Discussions about the benefits of exercise should start when we are young, and physical activity should continue to be part of our daily lives as we get older, even at 80 years old.”

Shadyab said future studies will examine how exercise relates to telomere length in younger populations and in men.

{One habit we all probably have is brushing our teeth every morning whether we wake up early or not but have you ever wondered if you are brushing your teeth properly?}

Here are 6 brushing mistakes you are probably guilty of

{{1. You brush for a very short period of time }}

Due to the hectic lifestyle in the world today, some people don’t even brush for a minute and this is so wrong. The ideal prescribed time for brushing is two to three minutes.
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2. You use a toothbrush for too long }}

It’s important you change your toothbrush regularly before the bristles of the brush begin to wear out. You shouldn’t use the same toothbrush for more than 3 months and you should also change your toothbrush if the bristles start to wear out.

{{3. You brush too much}}

I bet you are probably surprised that brushing too much is on the list. You are expected to brush at least once a day and not more than three times a day because it could result into exposure of the root of the tooth, leading to irritation.

{{4. You store your toothbrush in the bathroom }}

It’s unhygienic to store your toothbrush in the bathroom and if you must store your toothbrush in the bathroom, it’s recommended you keep the toothbrush in a covered place.

{{5. Your brushing technique is poor}}

Brushing too hard isn’t good for your teeth as it can hurt your gum and mouth. It’s also recommended you brush in a circular motion and not back and forth.

{{6. You don’t clean your tongue}}

You shouldn’t just stop at cleaning your teeth when brushing, it’s important you clean your tongue and use a dental floss.

{ATA prevents glioblastoma cells from spreading, and leave them vulnerable to chemotherapy and radiation.}

A study led by scientists at the Translational Genomics Research Institute (TGen) has identified “a potent inhibitory compound” in the elusive hunt for an improved treatment against glioblastoma, the most common and deadly type of adult brain cancer.

Aurintricarboxylic Acid (ATA) is a chemical compound that in laboratory tests was shown to block the chemical cascade that otherwise allows glioblastoma cells to invade normal brain tissue and resist both chemo and radiation therapy, according to a TGen-led report published in the scientific journal Oncotarget.

“The findings of this study could represent a breakthrough in our efforts to find an effective long-term treatment against glioblastoma multiforme (GBM),” said Dr. Harshil Dhruv, an Assistant Professor in TGen’s Cancer and Cell Biology Division, and a lead author of the study.

Initial treatment of glioblastoma consists of surgical removal of the tumor, radiation and chemotherapy using the drug temozolomide (TMZ). However, the proclivity of glioblastoma to invade adjacent brain tissue prevents the surgical removal of all tumor cells. Plus, invasive glioblastoma cells show resistance to TMZ, resulting in the cancer’s eventual return and the patient’s death, often within a year.

Despite recent advances, the median survival of glioblastoma patients is only 15 months, and survival statistics have not significantly improved over the past three decades. More than 16,000 Americans die each year of brain and other nervous system cancers.

“We simply must find a better way of treating patients with glioblastoma,” said Dr. Michael Berens, TGen Deputy Director and one of the study co-authors. “Identifying ATA could bring real hope to these patients by disrupting the cellular pathways that drive glioblastoma and make it such a formidable threat.”

Previous TGen-led studies have identified how the binding of molecules TWEAK and Fn14 stimulate glioblastoma cells to migrate, invade and survive in healthy brain tissue. The study published shows that ATA is an agent that suppresses the TWEAK-Fn14 cellular pathway. In doing so, ATA makes the cancer more vulnerable to drug and radiation therapies.

Importantly, ATA was identified by screening pharmacologically active compounds for their ability to suppress TWEAK-Fn14 signaling. And ATA provides a great starting point to develop a new therapeutic agent for the treatment of GBM.

“These data demonstrate that ATA presents a scaffold structure that could be modified in ways to improve its properties and to develop as a potential therapeutic agent to limit invasion and enhance chemotherapeutic drug efficacy in GBM,” said Dr. Nhan Tran, the senior and corresponding author of the study.

St. Joseph’s Hospital and Medical Center and the University of Maryland School of Medicine also contributed to this study.

The scientific paper, Identification of aurintricarboxylic acid as a selective inhibitor of the TWEAK-Fn14 signaling pathway in glioblastoma cells, was funded by The Ben & Catherine Ivy Foundation, and by grants from the National Institutes of Health (NIH).

“Step-by-step, TGen studies are drawing every closer to substantial improvements in how we treat glioblastoma,” said Catherine (Bracken) Ivy, founder and president of the Arizona-based Ben & Catherine Ivy Foundation. “Our aim is to help patients survive longer, and eventually find a cure.”

The study outlines goals for future investigations that will focus on identifying specific cellular signatures that indicate vulnerability to ATA, and using the ATA chemical structure to try modifications, which would become drugs to improve GBM therapy.

{After her brain cancer became resistant to chemotherapy and then to targeted treatments, 26-year-old Lisa Rosendahl’s doctors gave her only a few months to live. Now a paper published January 17 in the journal eLife describes a new drug combination that has stabilized Rosendahl’s disease and increased both the quantity and quality of her life: Adding the anti-malaria drug chloroquine to her treatment stopped an essential process that Rosendahl’s cancer cells had been using to resist therapy, re-sensitizing her cancer to the targeted treatment that had previously stopped working. Along with Rosendahl, two other brain cancer patients were treated with the combination and both showed similar, dramatic improvement.}

“When I was 21 they found a large mass in my brain and I had it resected right away. They tested it for cancer and it came back positive,” Lisa says.

“Lisa is a young adult with a very strong will to live. But it was a high-risk, aggressive glioblastoma and by the time we started this work, she had already tried everything. For that population, survival rates are dismal. Miraculously, she had a response to this combination. Four weeks later, she could stand and had improved use of her arms, legs and hands,” says paper first author Jean Mulcahy-Levy, MD, investigator at the University of Colorado Cancer Center and pediatric oncologist at Children’s Hospital Colorado.

The science behind the innovative, off-label use of this malaria drug, chloroquine, was in large part built in the lab of Andrew Thorburn, PhD, deputy director of the CU Cancer Center, where Mulcahy-Levy worked as a postdoctoral fellow, starting in 2009. Thorburn’s lab studies a cellular process called autophagy. From the Greek “to eat oneself,” autophagy is a process of cellular recycling in which cell organelles called autophagosomes encapsulate extra or dangerous material and transport it to the cell’s lysosomes for disposal. In fact, the first description of autophagy earned the 2016 Nobel Prize in Medicine or Physiology for its discoverer, Yoshinori Ohsumi.

Like tearing apart a Lego kit, autophagy breaks down unneeded cellular components into building blocks of energy or proteins for use in surviving times of low energy or staying safe from poisons and pathogens (among other uses). Unfortunately, some cancers use autophagy to keep themselves safe from treatments.

“My initial lab studies were kind of disappointing. It didn’t look like there was much effect of autophagy inhibition on pediatric brain tumors. But then we found that it wasn’t no effect across the board — there were subsets of tumors in which inhibition was highly effective,” Mulcahy-Levy says.

Mulcahy-Levy’s work with Thorburn (among others), showed that cancers with mutations in the gene BRAF, and specifically those with a mutation called BRAFV600E, were especially dependent on autophagy. In addition to melanoma, in which this mutation was first described, epithelioid glioblastomas are especially likely to carry BRAFV600E mutation.

With this new understanding, Mulcahy-Levy became an essential link between Thorburn’s basic science laboratory and the clinical practice of oncologist, Nicholas Foreman, MD, CU Cancer Center investigator and creator of the pediatric neuro-oncology at Children’s Hospital Colorado, who had been overseeing Lisa’s care.

After many surgeries, radiation treatments and chemotherapy, Lisa had started the drug vermurafenib, which was originally developed to treat BRAF+ melanoma and is now being tested in pediatric brain tumors. Lisa’s experience on the drug was typical of patients with BRAF+ cancers who are treated with BRAF inhibitors such as vemurafenib — after a period of control, cancer develops additional genetic mechanisms to drive its growth and survival and is able to progress past the initial drug.

At that point, one promising strategy is to predict and/or test for new genetic dependencies and then treat any new dependency with another targeted therapy. For example, many BRAF+ cancers treated with BRAF inhibitors develop KRAS, NRAS, EGFR or PTEN changes that drive their resistance, and treatments exist targeting many of these “escape pathways.” However, some cancers develop multiple resistance mechanisms and others evolve so quickly that it can be difficult to stay ahead of these changes with the correct, next targeted treatment.

“It’s like that story of the boy who puts his finger in the dam,” Mulcahy-Levy says. “Eventually you just can’t plug all the holes.”

Instead of this genetic whack-a-mole, the group chose to explore cellular mechanisms outside what can be a never-ending sequence of new mutations.

“Pre-clinical and clinical experience invariably shows that tumor cells rapidly evolve ways around inhibition of mutated kinase pathways like the BRAF pathway targeted here,” the paper writes. “However, based on our results, we hypothesize that by targeting an entirely different cellular process, i.e. autophagy, upon which these same tumor cells rely, it may be feasible to overcome such resistance and thus re-establish effective tumor control.”

In other words, knowing that Lisa Rosendahl’s tumor was positive for BRAFV600E mutation, and that this marked the tumor as especially dependent on autophagy — and also knowing that traditional options and even clinical trials were nonexistent — the group worked with Rosendahl and her father, Greg, to add the autophagy-inhibiting drug chloroquine to her treatment.

“In September 2015, the previous targeted drugs weren’t working anymore,” says Greg Rosendahl. “Doctors gave Lisa less than 12 months to live. We took all our cousins up to Alaska for a final trip kind of thing. Then they came up with this new combination including chloroquine.”

Vemurafenib had initially pushed Lisa’s cancer past the tipping point of survival. Then the cancer had learned to use autophagy to pull itself back from the brink. Now with chloroquine nixing autophagy, vemurafenib started working again.

“My cancer got smaller, which is awesome for me,” Lisa says.

“We have treated three patients with the combination and all three have had a clinical benefit. It’s really exciting — sometimes you don’t see that kind of response with an experimental treatment. In addition to Lisa, another patient was on the combination two-and-a-half years. She’s in college, excelling, and growing into a wonderful young adult, which wouldn’t have happened if we hadn’t put her on this combination,” Mulcahy-Levy says.

Lisa recently bought a new wheelchair so that she could spend more time at the mall. She also applied for a handicap sticker to make it easier for her to visit a nearby park with food trucks. “She wants to get out and do more. She continues to have what she feels is a good quality of life,” Mulcahy-Levy says.

Research accompanying these results in patients implies that the addition of autophagy inhibition to targeted treatments may have benefits beyond glioblastoma and beyond only BRAF+ cancers. Because chloroquine has already earned FDA approval as a safe and effective (and inexpensive) treatment for malaria, the paper points out that it should be possible to “quickly test” the effectiveness of adding autophagy inhibition to a larger sample of BRAF+ glioblastoma and other brain tumor patients, and also to possibly expand this treatment to other likely mutations and disease sites.

As Mulcahy-Levy’s early studies show, many cancers do not depend on autophagy. But at the same time, many do. Because a safe and simple drug already exists to inhibit autophagy, the time between discovering an autophagy-dependent cancer and the ability to add autophagy-inhibiting chloroquine to a treatment regimen against this cancer may be short.

“I really like being able to really tailor therapy to the patient,” Mulcahy-Levy says. “I like saying, ‘I think this is going to be really important to you,’ and not necessarily using the same treatment with another patient whose cancer is driven by different genetic alterations. This is the definition of patient-centered care — designing therapy based on that individual patient’s information. It’s not just glioblastoma, but a certain mutation and not just the mutation but a certain pattern of previous treatments and resistance.”

“It makes me feel really lucky to be a pioneer in this treatment,” says Lisa Rosendahl. “I hope it helps and I hope it helps people down the road. I want it to help.”

{With cold and dusty environment comes running nose and catarrh or outright blockage of the airways, known as sinusitis. We all experience this annoying health challenge every now and then, and some people usually feel terrible and helpless when it hits. If you suffer recurring sinus problems, then you need not worry because I know a few ways to get quick relief without going to see a doctor.}

The first one is something I have tried on a few occasions myself, and it works like magic. If you have bad sinuses, simply hold your breath and your nose together for about a minute of 30 seconds if you can. The moment you start breathing again, you’ll notice how free and smooth your breathing is again. The reason this works is because when you hold your breath, your brain feels there’s short supply of oxygen, and then opens up your airways to allow for better inflow of air.

The second trick is to push your tongue up against the roof of your mouth, and press down the space in between your eyes. Do it for a few minutes and let go, you’ll notice sputum trickling down your throat, and your breathing would be better too. Works like magic.

Please note that if your try these and they don’t work, or symptoms persist for more than 48 hours, you may have to go see a doctor for real help.

{Scientists restore long-term vision in blind mice, making a case for addressing the immune system’s role in rejecting transplanted cells.}

Stem cell therapies hold great promise for restoring function in a variety of degenerative conditions, but one of the logistical hurdles is how to ensure the cells survive in the body long enough to work. Researchers from the Buck Institute report one of the first demonstrations of long-term vision restoration in blind mice by transplanting photoreceptors derived from human stem cells and blocking the immune response that causes transplanted cells to be rejected by the recipient.

Publishing in the Cell Stem Cell, this work highlights immune system rejection as one of the key issues that needs to be addressed to improve efficiency of stem cell regeneration therapies. The findings support a path to improving clinical applications, specifically for restoring vision in humans by allowing photoreceptors derived from human stem cells to integrate and thrive in the eye.

“This turned into a nice story of long-term restoration of vision in completely blind mice,” said Buck faculty and senior author Deepak Lamba, PhD, MBBS. “We show that these mice can now perceive light as far out as 9-months following injection of these cells.”

Photoreceptors are specialized neurons in the retina that convert light into signals that the brain interprets as sight. Loss of these cells is a common endpoint in degenerative eye diseases. Human embryonic stem cells can provide a potential source for photoreceptor replacement, but despite Lamba’s prior work showing that photoreceptors derived from stem cells could function in mice, researchers hadn’t been able to show long-term sustained vision restoration. A major controversy in field, said Lamba, was whether the transplanted photoreceptors simply die off or were being actively rejected by the immune system — the eye, along with the brain, had long been thought to be “privileged” in that the cells of the immune system didn’t monitor those locations.

Lamba’s group set out to examine in detail the degree to which immune rejection contributes to disappointing outcomes in stem cell therapies for the eye, and to determine if they could find a way around the problem. If rejection was occurring and that could be suppressed, they reasoned, transplanted photoreceptors derived from stem cells might have time to integrate into the visual system and start relaying information to the brain.

The team used a specific mouse strain that is healthy but it is lacking in a specific immune cell receptor, which makes the mouse unable to reject transplanted foreign cells. Called immunodeficient IL2 receptor gamma (IL2rl) null mice, these animals lack the IL2ry receptor that humans also have as part of a functional immune system.

“This mouse strain is great model for this research because they are otherwise healthy and normal, including in their vision, so it allows us to conduct studies focused on cell integration,” said the publication’s lead author, Jie Zhu, PhD, a postdoctoral researcher who started in Lamba’s lab three years ago.

In these mice, the team showed that without the rejection process, there was a 10-fold increase of living human embryonic stem cell-derived donor retinal cells that matured and integrated into the retina.

After seeing significantly improved long-term survival and integration of the transplanted cells, the next step was to see if the cells actually functioned. The team transplanted stem cell-derived photoreceptors into another strain of mouse, called CRX null, which is congenitally blind. The team measured the pupils’ response to light and examined the brains’ visual response centers to show that signals from the eye were going to the appropriate areas of the brain. They found that even nine months to a year after photoreceptor transplantation, eyes were responding to light and transmitting sight messages to the brain.

“That finding gives us a lot of hope for patients, that we can create some sort of advantage for these stem cell therapies so it won’t be just a transient response when these cells are put in, but a sustained vision for a long time,” said Lamba. “Even though the retina is often considered to be ‘immune privileged,’ we have found that we can’t ignore cell rejection when trying to transplant stem cells into the eye.”

Dr. Lamba’s lab is dedicated to the clinical applications of human stem cells, with a special interest in restoring vision that has been compromised by degenerative eye diseases, such as macular degeneration. They are already refining the current work, said Zhu and Lamba. One direction is to use drugs already approved to prevent rejection for organ transplant that target the same receptor. “Using an antibody against this specific receptor means that the immune system might not need to be suppressed more generally, which can be very toxic,” said Zhu.

“We can also potentially identify other small molecules or recombinant proteins to reduce this interleukin 2 receptor gamma activity in the body — even eye-specific immune responses — that might reduce cell rejection,” said Lamba. “Of course it is not validated yet, but now that we have a target, that is the future of how we can apply this work to humans.”