Lymphoid Cancer Risk Linked to Long Telomeres and POT1 Mutations

Researchers at the Johns Hopkins Kimmel Cancer Center and the Telomere Clinic at Johns Hopkins have identified an inherited cancer predisposition syndrome that results in unusually long telomeres that allow lymphocytes to stay in a biologically more youthful state for extended periods, increasing the risk of lymphoid malignancies. The findings, published the journal Blood, showed that inherited loss-of-function mutations in the POT1 gene disrupt normal telomere regulation and alter the aging dynamics of immune cells. The investigators found that because of this longer cellular lifespan cancer-associated mutations are persistent and expand over time, creating favorable conditions for the development of lymphoma and related blood cancers.

“The spectrum of lymphoid cancers was striking,” said senior author Mary Armanios, MD, a professor of medicine at Johns Hopkins. “Family members developed childhood leukemia, multiple forms of lymphoma, and adult-onset chronic lymphocytic leukemia—cancers often considered biologically distinct and associated with different inherited risks. Yet within the same families, multiple lymphoid malignancies appeared across generations. Some individuals developed melanoma before lymphoma, while others developed as many as five cancers over a lifetime. The good news is the cancers tended to be slow-growing and usually curable.”

Telomeres are protective caps at the ends of chromosomes that normally shorten with age and as a result of cell division, which limits the lifespan of cells that accumulate damage. POT1, or protection of telomeres 1, normally regulates telomere length by binding single-stranded telomeric DNA and restricting telomerase-mediated elongation. The researchers said that  “POT1 binds single-stranded telomeric DNA and is essential for telomere protection, but POT1 heterozygous loss of function is permissive of telomerase elongation in the absence of a detectable DNA damage response.”

For their initial research the investigators focused on 51 people from 24 families that were know to carry mutant POT1 variants. The surveyed the participants to evaluate family cancer histories and collected biological samples to define the range of cancers associated with the mutations with the aim of examining how telomeres influenced lymphocyte aging. The data showed that among this small cohort, hematologic malignancies were the second most common cancers after melanoma, occurring in 27% of participants, with lymphoid cancers accounting for approximately three-quarters of blood malignancies found.

As a result, the researchers noted that “our data identify extended cellular longevity due to long TL as an inherited risk factor for lymphoma, explaining its syndromic association with solid tumors and, in some cases, myeloproliferative neoplasms.”

The investigators also found that telomeres responded differently that is typically observed as people aga. In those people with the POT1 mutation telomere length remained stable over time and in some cases lengthened rather than shortening with age. The findings indicated that lymphocytes retained prolonged replicative capacity, allowing cells with oncogenic mutations to survive instead of being eliminated through senescence.

To find out whether these findings extended beyond the studied families, the researchers then analyzed data from 210 adults with POT1 variants enrolled in the UK Biobank and found that people carrying pathogenic POT1 variants had an eightfold increased risk of lymphoma, and 45% developed lymphoid malignancies by age 80.

The research also examined asymptomatic POT1 mutation carriers to understand how lymphoma develops before clinical diagnosis. Among carriers without lymphoma, 12 of 20 had evidence of B-cell or T-cell clonality, a precursor state associated with lymphoma development. After age 65, all studied carriers showed detectable clonality. Sequencing and cytogenetic analyses revealed lymphoma-associated mutations in nearly all mutation carriers older than 60 years.

The study was prompted by earlier research which has shown evidence linking long telomeres to tumor development. Work in animal models had shown that long telomere length can bypass cellular senescence checkpoints and increase tumor incidence. Other  research had also found POT1 mutations in melanoma, papillary thyroid cancer, glioma, sarcoma, and chronic lymphocytic leukemia. But, the prevalence and natural history of these mutations across hematologic malignancies had remained uncertain.

The findings may influence future approaches to cancer surveillance and genetic evaluation in individuals with POT1 variants. The researchers said that ultralong lymphocyte telomere length could help identify pathogenic variants and distinguish variants of uncertain significance. They noted, however, that telomere length testing may have limitations because advanced clonality can interview with the ability to accurately measure baseline telomeres.

“Our data suggest that, for now, telomere length clinical testing should be reserved for individuals with variants in the gene that have unclear significance,” Armanios said.

The post Lymphoid Cancer Risk Linked to Long Telomeres and <i>POT1</i> Mutations appeared first on Inside Precision Medicine.

What Is Traumatic Separation?

You may have a memory of being separated from a parent when you were a child, even just for a few minutes. Maybe you lost them in a crowd or wandered a little too far at the store and felt panicked and afraid.

A moment like this might be among your earliest memories because the feeling was so intense, says Caitlyn Downie, LCSW, the Director of Trauma and Resilience at the Child Mind Institute. That offers some insight into the fear of a child of any age who is separated from a parent or caregiver in a more serious way. The effects of this stress are so powerful they can actually change the way a child develops.

A toddler whose mother goes to prison. A kindergartener whose father is detained and deported. A teen who is placed in foster care. These are a few examples of what experts call traumatic separation, a clinical concept based on the importance of the parent-child bond and the profound effects that can result from breaking it.

What is traumatic separation?

Traumatic separation isn’t a clinical diagnosis, but research shows that it can be profoundly harmful to kids. What makes it traumatic (as opposed to routine partings, like when an adult regularly leaves their child to go to work) is the character of the separation: ones that are sudden, unexpected, or confusing, or those that come about through larger distressing events, like a natural disaster or war. It’s not defined by the time spent apart — both short and long-term separations can be harmful.

Some common examples of separation that can become traumatic include:

  • Parental deportation
  • Immigration (e.g., forced separation at the border)
  • Parental military deployment
  • Parental incarceration
  • Termination of parental rights

Separating from a parent or primary caregiver can be distressing to a child even when it’s deemed necessary for their safety, as in cases where the parent they have been separated from has abused them, says Kimberly Alexander, PsyD, a psychologist at the Child Mind Institute. “There’s still a natural attachment that occurs. And the separation disrupts that relationship, even if it’s for the support and care of the child.”

Why is traumatic separation harmful?

More than eight decades of research has shown the profound developmental importance of the parent-child bond. This is the guiding principle of attachment theory, which was pioneered by a British psychologist who studied children who were evacuated during the Blitz, the aerial bombardment of London in World War II.

Here’s what the research tells us about the harms of traumatic separation:

It can disrupt secure attachment

Think of secure attachment as a “fundamental sense of security and safety” that a child feels with a parent or caregiver, says Dylan Gee, PhD, a psychologist at Yale University who studies how early-life stress affects children’s development.

“Attachment is the lens through which children come to know what they can expect from the world around them,” she explains. “Is this going to be a safe place or a dangerous place? This is foundational to a child’s sense of their ability to navigate the world. Traumatic separation can shatter that sense of safety.”

It can affect neurobiological development

Children’s brains are especially plastic, says Dr. Gee, constantly learning to understand their environment and how to deal with stress. “Trauma that occurs in childhood can be even more consequential than trauma that occurs later in life,” she says, and experiencing these disruptions in childhood can affect the way your brain and body are primed to react to stress later on.

But heightened plasticity is a paradox, she adds. “It confers more vulnerability, but it also confers more potential for resilience — children have heightened potential for supportive intervention and for healing and recovery.”

What do the effects of traumatic separation look like?

There are acute and short-term effects that are common across kids of all ages:

Sleep problems: “It’s often one of the first things that we see: nightmares, trouble falling asleep, or a lot of crying as kids are trying to fall asleep,” Dr. Gee says.

Separation anxiety: This might look like distraction, withdrawal, or clinginess because of fear of being separated from their new caregivers, Dr. Alexander says.

But signs may take weeks or months to show up. Dr. Alexander advises caregivers to consider the child’s baseline — their typical patterns of eating, sleeping, or engaging with others. “If they’re having more trouble with sleep, they’re eating more, eating less, they’re withdrawing or expressing a lot of worried thoughts three or four months later — that’s something worth getting looked at by a clinician,” she says.

Signs of traumatic separation at different ages

“Sometimes people ask, ‘Well, when is separation the most harmful?’ It can be extremely harmful at any age,” Dr. Gee emphasizes. But there are specific signs at different developmental stages:

Infants

Babies may not be as consciously aware of being separated from a parent as older children, “but they’re fundamentally aware that their primary source of regulation and safety is missing,” Dr. Gee says. Because infants are so reliant on caregivers for nurturing and sustenance, the separation “can be experienced as a threat to their survival.” That might look like “crying a lot or becoming withdrawn,” she says. “And at any age we can see intense fear.”

Toddlers and young children (3–6)

Toddlers and young children might become extra clingy with new caregivers or show regressive behaviors like bedwetting or baby talk. Regressive behaviors happen when kids are overwhelmed by stress and can’t express themselves another way, Downie says. “It’s like your nervous system goes kind of haywire,” she explains, “so it uses the body to signal that something is wrong.”

Similarly, kids at this age might act out more, throwing more tantrums, or withdraw. They might develop selective mutism, a condition where kids are too anxious or distressed to speak, even when they want to, in certain situations or with certain people.

School-age children

School-age children might act out or experience separation anxiety. They may also struggle to understand the meaning of the separation, why it happened, or who is at fault for it. Thus, kids at this age are more prone to magical or distorted thinking and feelings of guilt, thinking or saying things like, “I’m the one that caused this” or “This is my fault.”

The weight of these distorted thoughts or other worries, Dr. Alexander says, might make it appear as though a child is struggling to concentrate or that they’re disengaged or distracted. They might withdraw in a group or be averse to stepping outside of their comfort zone.

Children who are school age or older can also experience emotional desensitization — a kind of emptiness of feeling — Downie says, which can look like spikes in irritability, a lack of empathy, not smiling or expressing positive emotions, or an inability to relate to others.

Preteens and teenagers

“I’ve seen teenagers have a lot of mistrust with systems and be very oppositional,” says Downie. “Like, ‘I don’t trust you. I don’t trust my teacher. I don’t trust this child services worker.’” It might make sense that, say, a teen in foster care would be wary of the foster care system. But Downie says it’s often a larger instinct for anger and mistrust, one that extends beyond any specific entity or person.

The teenage years are also when kids are forming their identity, and traumatic separation can fundamentally alter that process. For example, a teen with younger siblings may step into a parent role, taking on new worries and responsibilities. Conversely, teens may become more reckless in a caregiver’s absence, putting them at risk for substance abuse or incarceration.

How to help kids separated from a parent

Adults caring for a child who has been separated from a parent — family members, foster parents, teachers — “can play a profound role in supporting their mental health and resilience,” says Dr. Gee.

Validate feelings

One of the most important things caregivers can do is be present as a child reacts to their experiences, especially if and when scary feelings come up. But be careful not to lead kids or assume they feel a certain way. “You don’t want to make something more distressing to a child if it’s not presenting itself,” says Downie.

If a child expresses guilt, or says something like, “This is my fault,” there are still ways to validate the feeling without endorsing the statement, says Dr. Alexander. You might say something like: “I can understand why that thought comes to mind and how difficult it is to feel that way. When you’re ready, let’s think about other possibilities to this situation.”

Create consistency and stability

One of the hardest things about traumatic separation is the uncertainty — Where did they go? When will they come back? What is happening? Giving kids some sense of consistency and stability can help them feel safe despite the unknowns. So as much as possible, help them stick to any routines: going to school, seeing friends, doing activities they enjoy.

Dr. Alexander advises focusing on things you can control — for example, shielding kids from potentially worrying discussions in a family where a parent has been deported.

“There would likely be a lot of conversations in the home about the situation, maybe a lot of watching the news, maybe making a lot of phone calls to attorneys,” she explains. “So where are you having those conversations, and can you have them in an area or at a time of day where your kid isn’t overhearing the discussions out of context?”

For young kids, it might be as simple as asking them to play in their room. For teens, it might be better to have certain conversations when they are out of the house and invite them to participate directly in others.

Be honest but reassuring

Caregivers might not have all the answers — like knowing when a child’s parent is coming back — but they can create a sense of consistency and stability in how they respond to kids’ questions, too.

Avoid undue reassurance (“Everything is going to be fine”) or over-promising (“They’ll be back in two weeks”) by focusing on what kids can expect, says Dr. Gee. For example: “What I can tell you is that I’m here for you, and I’m going to be with you until he’s back,” or “You’re safe with me, and I’m going to stay with you through this really hard time.”

Model handling stress

Children are sensitive to tone, Dr. Alexander says. “So, if you’re having really big emotions that are out of context for a child, the child is looking at these emotions and trying to understand what’s happening. ‘Am I in danger in this specific moment?’”

She says it helps to have conversations about these moments, especially with younger kids. “Like, ‘I know you noticed mommy crying. We’re feeling really big feelings, and this is how we’re going to deal with those big feelings. I’m going to take a break. I’m going to get a sip of water. Whenever you’re having big feelings, I want you to let me know so that I can help you try doing the same things,’” Dr. Alexander says, explaining the importance of naming the emotion and then teaching kids that there are ways of dealing with it.

Long-term risks of traumatic separation

The effects of traumatic separation can persist even after a child and their caregiver are reunited. Traumatic separation, like other adverse childhood experiences, puts kids at risk for a host of long-term medical and mental health conditions, including depression, anxiety, attention issues, and post-traumatic stress disorder (PTSD).

But Downie notes that not everyone who experiences traumatic separation develops PTSD. “Just because someone’s experiencing trauma now doesn’t mean that it’s going to become a PTSD diagnosis,” she says. “A lot of the behaviors that we’re talking about are normal and expected. There’s an adjustment period when a separation happens.” But if symptoms persist or escalate over several months, a child may need more serious support.

Treatment for a trauma diagnosis

While not every child who experiences a separation may receive a trauma diagnosis or require treatment, cognitive behavioral therapy (CBT) — and the more specific trauma-focused cognitive behavioral therapy (TF-CBT) — is the “gold standard,” says Downie. TF-CBT is specifically for children experiencing trauma-related symptoms. An important component of TF-CBT is creating a trauma narrative, where kids create a story about what happened to help them process it. “But if you have a child who is not ready to process and integrate that trauma, you can’t force the pacing of the treatment,” she says.

In short, a good clinician will follow a child’s lead — even if that means just sitting in the same room with them to build trust. “People really need to feel like they’re being heard and that they can trust someone,” Downie says. Which is why a supportive caregiver or trusted adult can make a big difference.

“If people can take anything away from this, it’s that you want to make kids understand that that they’re not responsible for what’s happened and that people do care about them,” Downie says. “Kids are really resilient, and they can adapt in a good-enough environment. They don’t have to have everything to be successful.”

The post What Is Traumatic Separation? appeared first on Child Mind Institute.

ASGCT CEO David Barrett Previews the Upcoming Conference in Boston

The 29th American Society of Gene & Cell Therapy (ASGCT) meeting kicks off in Boston next week. The annual event will be a whirlwind of sessions, keynotes, fireside chats, posters, and exhibitors.

For the second year in a row, GEN spoke with David Barrett, JD, who has been the CEO of ASGCT since 2016. In this interview, we discuss his perspective on the event, if there is anything new that attendees should be looking out for, and what he, personally, is most looking forward to.

This interview has been edited for length and clarity.

LeMieux: The ASGCT meeting is an annual event. What are some of the things that will make this year’s meeting special?

Barrett: There is a lot that is special this year. First and foremost, it feels like a bit of a homecoming which is really exciting. The last time we were in Boston was in 2008. And Boston is a city and community where gene therapy, biotech, and research are all located. You can feel it when you’re in Cambridge and I think you are absolutely going to feel that when you’re inside the convention center.

The fact that the meeting is in Boston this year is also special for me because one of the very first things I did when I joined ASGCT in 2016, was to source the location for the 2020 annual meeting at the Hynes Convention Center in Boston. I was very excited and it was the first time we were going to take up an entire convention center. But that meeting, of course, did not happen; it had to be canceled because of COVID. So that makes this meeting in Boston particularly special. We finally get to have the meeting in Boston that I’ve been hoping for since 2016!

And we are growing. We are at the bigger of the two convention centers in Boston. We are going to surpass the total number of people that we had last year and I have every expectation that we’ll see significant growth year over year.

As far as other things that are that are new and interesting this year… I said this last year, but it’s worth adding it again—the science is always different. It is very consistent that we will have great science every year, and it is a wonderfully fun question mark of what exactly that science is going to look like. It’s always exciting because the science is always different year after year. So, by its very nature, it will be an exciting new conference this year.

Also, we’ll have a puppy park in the exhibit hall, so that’s really fun!

LeMieux: What are some things that will be highlighted at the meeting that ASGCT has been working on over the past year?

Barrett: ASGCT has done a lot this year. There is a lot that we have been very vocal about so far, and there is a lot that we’ll be sharing during the annual meeting.

Number one is that we partnered with Orphan Therapeutics Accelerator (OTXL) to found CGTxchange—the first and only clearing house and marketplace of its kind for cell and gene therapy assets. It is being built as we speak and we’ll have some exciting announcements during the annual meeting about assets that will hopefully be in the CGTxchange by that point. It is the culmination of a lot of work on what to do about commercially pre-viable (not non-viable) cell and gene therapies and the work that we’re doing to make those more commercially possible.

Also, ASGCT is hosting its Momentum Gala—the first formal gala at our annual meeting. That event has resonated really well with sponsors and donors. In fact, it is sold out! That event is going to be used to celebrate the launch of ASGCT Foundation, which is a separately incorporated 501C3 charitable foundation to support ASGCT’s mission to advance early career researchers and enable the development of cell and gene therapies. Also at the gala, we’ll be announcing some new initiatives to support patient access and reduce barriers to diagnosis, clinical trial participation, and treatment with cell and gene therapies.

Another major thing that’s going on is a considerable expansion of our educational activities. We recently launched a new e-learning tool and platform—the ASGCT Learning Center—a really fun project that we’ve been working on to expand how we we are getting new content to our new and expanding audiences.

We recognize that we have a really broad audience at ASGCT that is made up of cell and gene therapy basic science researchers, translational researchers, physician scientists and others in the ecosystem of drug development and administration for cell and gene therapies. And we’re looking at new ways to provide content that can help satisfy the learning needs of that really broad audience. The learning center is a big tool in our quiver to be able to do that.

LeMieux: What do you hope people take away from the meeting?

Barrett: I hope they take away a couple of things… number one, I hope they take knowledge, education, and awareness of what’s going on in the space and what has been happening over the course of the last 12 months. I hope that they take that back to their individual place of work. And I hope that, generally speaking, we fulfill our mission by expanding that knowledge base among all of the stakeholders in cell and gene therapy. Another thing that I hope people take away from this is that, after a lot of ups and downs and undulations in this field over the course of the past two to three years, that there is an extraordinary sense of excitement about the next phases in the development of cell and gene therapy drugs.

We have some really exciting new regulatory pathways. We have a lot of development of personalized gene editing technologies and techniques that can bring gene therapies much more quickly and effectively to patients who need them. We have seen significant advancements in more traditional or classic AAV gene therapies that are allowing these to be safer and more efficacious. And we’re seeing an expansion of cell-based gene therapies through an ever-expanding portfolio of indications that are reached by CAR Ts, primarily in cancer, but in an expanding outlook for the use of CAR Ts outside of cancer as well. So, I am hopeful that attendees come away with a renewed energy and vigor for the development of satellite gene therapies.

LeMieux: Is there anything specific planned at the meeting to touch on the concerns of the challenges that the scientific community is facing right now—with funding or other barriers?

Barrett: We are very excited to have Katherine Szarama, PhD—who was recently named acting director of FDA’s Center for Biologics Evaluation and Research (CBER)—participating in a fireside chat, addressing regulatory uncertainties. [Szarama replaced Vinay Prasad, MD, MPH, on May 1st.]

We have two other fireside chats focused on regulation, as well. The three fireside chats will offer attendees an opportunity to learn a little more, ask some questions, and hear from some of the individuals in those sessions specifically.

But I think that people will also see, more broadly, the ongoing work that ASGCT is doing to continue to create a partnership and a positive working relationship with the FDA to support those regulatory concerns.

LeMieux: What are you most looking forward to?

Barrett: I think I said this last year, but it really is one of my favorite components of the annual meeting. Every year, I look forward to taking some time to watch the exhibit hall being built. When the rope drops and people enter the exhibit hall for that very first reception, the hall is in pristine condition. And one of my favorite parts is watching it get to that pristine condition because it is just so exciting to see everything being built and come to a head, to have the whole field enter all at one space, and to be able to see an industry live and in person. Because so much of what we do is at our computer screens—and what we read about, hear about, or listen to people talk about. But when you actually see the field of gene and cell therapy on display, it is really exciting and satisfying.

Lastly, I will add that I’m looking forward to eating too much clam chowder while in Boston (chuckling).

The post ASGCT CEO David Barrett Previews the Upcoming Conference in Boston appeared first on GEN – Genetic Engineering and Biotechnology News.

Barriers and Facilitators in the Implementation of the Systematic Medical Appraisal, Referral, and Treatment (SMART) Mental Health Digital Intervention in Rural India: Mixed Methods Process Evaluation Study

<strong>Background:</strong> An estimated 150 million people have mental health care needs in India, but only 15% are able to access care. Depression and anxiety contribute to a large proportion of mental morbidity. The Systematic Medical Appraisal, Referral, and Treatment (SMART) Mental Health trial used a mobile-based clinical decision support system for primary care doctors and community health workers (CHWs) to identify and treat people at risk of depression, anxiety disorders, and self-harm. A community-based antistigma campaign was also delivered. The intervention led to improved remission rates for depression and anxiety and lower stigma scores. <strong>Objective:</strong> A process evaluation assessed (1) implementation fidelity, barriers, and facilitators; (2) perceptions of doctors and CHWs on the use of SMART Mental Health; and (3) the causal pathways that led to trial outcomes. <strong>Methods:</strong> A mixed methods evaluation combining backend program data and qualitative data was conducted. A total of 38 focus group discussions and 37 key informant interviews were conducted with primary doctors, CHWs, government officials, local community leaders, and research project staff. The data were coded and analyzed using a framework analysis approach based on the UK Medical Research Council guidance on process evaluations and the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework. <strong>Results:</strong> The intervention had high implementation fidelity. Across clusters, the median proportion of participants with at least 1 CHW follow-up was 98% (IQR 96.6%-100%). The referral rate for a psychiatrist was low (224/1697, 13.2%), and only 23.6% (53/224) of those referred visited the psychiatrist. The median exposure to antistigma audiovisual content was 84% (IQR 65.7%-95.9%). At the community level, key implementation barriers included cultural inhibitions in seeking mental health care and the unavailability of patients due to competing demands. Proximity and tight social connections between CHWs and their communities were important facilitators in seeking medical help. Doctor and CHW training, mentoring, and feedback provided by program staff were important facilitators to support the use of the digital health components by the health workforce. <strong>Conclusions:</strong> A complex intervention that included both community-based antistigma and clinical digital health interventions achieved high implementation fidelity. Key areas to consider for maintenance of such interventions include (1) the need for sustained community-based strategies to address stigma and other cultural barriers; (2) health workforce strengthening policies, including supportive supervision for CHWs and doctors to increase capability in the use of mental health digital health tools; and (3) strategies to improve access to specialist care for those with more complex care needs. <strong>Trial Registration:</strong> Clinical Trial Registry India CTRI/2018/08/015355; https://tinyurl.com/5r63suxp

Immune Mapping Links Sex-Specific Genetics to Autoimmune Disease

The largest study to date to examine immune differences between sexes at single-cell resolution has identified over 1,000 genetic switches that operate in distinct ways when comparing immune cells from men and women. Published today in The American Journal of Human Genetics, these findings could explain why women are much more likely to be affected by autoimmune conditions than men. 

“Our findings show that the immune system needs to be studied with sex in mind,” says Seyhan Yazar, PhD, group leader of the precision immunology program at the Garvan Institute of Medical Research in Australia. “Even though we know men’s and women’s immune systems differ, many studies still overlook these differences, which can limit how well we understand disease, and in turn bias treatment options.”

Yazar’s team analyzed single-cell RNA sequencing data from over 1.25 million circulating immune cells from nearly 1,000 healthy individuals who participated in the OneK1K cohort. This Australian research program maps how individual immune cells respond to disease and pathogens to determine why some individuals respond to treatment but others don’t. 

Results revealed distinct genetic and cellular profiles between both sexes. While men were found to have a higher proportion of monocytes, women showed higher levels of B cells and regulatory T cells. In men, genetic activity seemed to focus on basic cellular maintenance processes, but in women genetic activity heavily skewed towards the activation of inflammatory pathways. 

“While this highly reactive immune profile gives females an advantage in fighting viral infections, it comes with a biological trade-off: a greater predisposition to autoimmune diseases,” says Sara Ballouz, PhD, senior lecturer at the University of New South Wales (UNSW). “On the other hand, male immune cells are less primed for inflammation, making men generally more susceptible to infections and non-reproductive cancers.”

Interestingly, most of the genetic switches found to be active in individuals of one sex but not the other were not found to be located in sex chromosomes. More than 1,000 sex-specific genetic switches were identified on autosomes, with many of them being directly linked to autoimmune conditions. 

“This is the first time we have shown that these differences occur at the genetic control level, providing a new layer of insight into human immunity,” Ballouz says. “Having shown that female-biased genes are heavily enriched in inflammatory pathways, we now have another biological rationale for why the immune system can more easily mistakenly attack the body’s own tissues in women.”

The analysis found female-specific genetic variants that affected the expression of two genes linked to systemic lupus erythematosus (SLE), an autoimmune condition that is nine times more likely to affect women than men. Although conditions like SLE are multifactorial, uncovering the contribution of genetic variants to their development is an important step forward towards better understanding disease susceptibility between sexes. 

“Our findings add strong evidence that female and male autoimmune diseases may not be the same, and the way we should treat them may not necessarily be the same,” says Yazar. “Currently, clinicians rely on a one-size-fits-all management approach for most autoimmune diseases—a more inclusive approach is needed.”

Currently, autoimmune conditions are often treated with broad immunosuppressants that reduce the activity of the entire immune system. Research is striving to move towards treatments that more precisely target each person’s unique needs, which is only possible through the identification of distinct genetic pathways driving autoimmune disease. 

“If we want to realize the potential of precision medicine, we have to understand these fundamental biological variables,” says Joseph E. Powell, PhD, director of the translational genomics program at the Garvan Institute. “Treatments need to be tailored not just to the disease, but to how a patient’s immune system operates at a baseline genetic level.”

The post Immune Mapping Links Sex-Specific Genetics to Autoimmune Disease appeared first on Inside Precision Medicine.

What’s next for IVF

MIT Technology Review’s What’s Next series looks across industries, trends, and technologies to give you a first look at the future. You can read the rest of them here.

Forty-eight years ago this July, Louise Joy Brown became the world’s first person born with the help of in vitro fertilization. Millions more IVF babies have entered the world since then. And that’s partly thanks to advances in technology that have made IVF safer and more effective.

But it’s still not perfect. The process can be slow, painful, and expensive—and that’s for the lucky people who are able to access it in the first place. And by at least one measure, IVF success rates have been declining in recent years.

Reproduction is complex, and there’s a lot that embryologists and gynecologists still don’t know and can’t control. They don’t know why many healthy-looking embryos don’t “stick” in the uterus, for example. They don’t always have an explanation for why their patients can’t get pregnant. And they can’t always account for vast differences in IVF success rates between individuals and between fertility clinics.

Scientists are working on all those questions and more. They’re wrestling with complex ethical questions about how new genetic tools will be used to analyze or even alter embryos. Meanwhile, technologies designed to standardize treatment, eliminate human error, boost success rates, and make IVF more accessible are already beginning to usher in a new era for assisted reproduction—one aided by AI and robots.

1. Helping embryos stick

Some of those technologies are being developed at the Carlos Simon Foundation in Valencia, Spain. When I visited in March, researchers gave me a tour of the labs and showed me a device that had been used to keep a human uterus alive outside the body for the first time.

While some members of the team dream of building artificial uteruses that might one day be able to carry a fetus to term, they first want to use such devices to learn more about implantation—the moment at which a fertilized egg makes contact with the lining of the uterus, burrows inside, and essentially “hatches,” triggering the start of a pregnancy.

Despite decades of advances in IVF, that process is still poorly understood. Even healthy-looking embryos stick no more than 40% to 60% of the time.

In IVF techniques used today, clinics can create early-stage embryos and wait until the uterus is deemed most receptive, but once they insert the embryo into the uterus, it’s on its own. Xavier Santamaria, senior clinical scientist at the Carlos Simon Foundation, and his colleagues are trialing a different approach. They’ve developed a device that, at the press of a button, injects the embryo into the uterine lining.

Scientists in Valencia showcase Transfer Direct.

JESS HAMZELOU / MITTR

In a demonstration I watched with a prototype, Santamaria picked up his speculum and turned to face the vaginal opening of his “patient,” which in this case was just a model of the real thing—a plastic bottom with labia, a vagina, a uterus, and ovaries, two short stumps representing what would normally be a pair of legs held in stirrups.

He hunched over and peered inside. “Embryo,” he called. His colleague Maria Pardo, an embryologist, passed him a thin needle containing a mouse embryo she had recently collected from a petri dish.

Santamaria’s device allows for the embryo-containing needle to be connected to a delivery tube. This tube also has a camera, a light, and a sensor that lets the doctor know when the needle reaches the uterine lining. Once it has been fed into the uterus, the gynecologist can see the inside of the organ and direct the tube to the lining.

Scientists in Valencia showcase Transfer Direct.

JESS HAMZELOU / MITTR

“When everything is ready, you just press the button,” Santamaria said as he activated it using a foot pedal, allowing the embryo to be injected. “There it goes.”

The team has just started a trial of the device; so far, fewer than 10 women have undergone the procedure, and none of those have become pregnant. But foundation director Carlos Simon is hopeful, noting that the inventors of IVF had to perform over 160 cycles before Louise Brown was born (between 1969 and 1978, that team performed 457 cycles in 250 people, resulting in only two live births). “The trial is ongoing,” he says.

2. Picking the “best” eggs, sperm, and embryos

One long-running challenge of IVF has been selection. Say you manage to collect 10 eggs from one partner and a decent-looking semen sample from the other. How do you choose which cells to use? The same question comes up once the resulting embryos have been cultured in a dish for a few days: Which should you transfer to the uterus?

Traditionally, these judgments have been made by eye. Embryologists literally pick the ones that look the best in terms of their shape or, in the case of sperm, how they move. But scientists have been working on alternatives. And over the last decade or so, many have turned to genetic testing to hint at which embryos have the best chances of creating a healthy baby.

The most commonly used test is called PGT-A, which stands for preimplantation genetic testing for aneuploidy. Aneuploidy essentially means having an “incorrect” number of chromosomes, and it is thought that embryos with such characteristics are more likely to be lost through miscarriage or potentially develop into babies with genetic conditions.

Once embryologists have created embryos in the lab, they can pinch off a few cells and test them for aneuploidies. The tests are especially beneficial for women over the age of 38, says Alan Penzias, a reproductive endocrinologist at Boston IVF. “You start to see an improvement: more babies and fewer miscarriages,” he says. The tests can shorten the time to pregnancy.

This type of genetic testing is possible thanks to multiple advances in technology—not just in genomics, but also in the ability to keep embryos alive in a dish for five to six days and the technique of freezing embryos while the cells undergo testing and thawing them once the results are in. And it has become hugely popular—some clinics do PGT-A tests on all their embryos.

But PGT-A won’t give you a perfect readout of a future baby’s genetics, says Sonia Gayete-Lafuente, a reproductive endocrinologist at the Center for Human Reproduction in New York City. And some of the abnormalities might be able to self-correct with time. Gayete-Lafuente and her colleagues have transferred some of those “abnormal” embryos into patients’ uteruses and seen them develop into perfectly healthy children, she says.

Other forms of PGT are even more controversial. PGT-P tests are designed to predict an embryo’s chances of developing complex traits that rely on multiple genes, including medical disorders but also physical characteristics like height or cognitive factors like IQ. These tests are new, and they are illegal in some countries, including the UK. But they are gaining ground in the US. Nucleus Genomics—a company that invites customers to “have [their] best baby”—promises to predict traits running the gamut from eye color and intelligence to left-handedness and risk of Alzheimer’s.

When I asked IVF practitioners how they might respond if a patient asked for this service, most dodged the question and told me there’s not enough evidence that any of these tests actually work. They also cautioned that selecting for one trait might inadvertently introduce new risks. None seemed especially keen on the idea of using genetic testing for anything other than preventing serious disease.

3. Speeding things up with AI

Some seemed more excited about the potential for AI. After all, AI tools are generally good at recognizing patterns. Many researchers have attempted to train tools to spot healthy sperm, eggs, and embryos.

And they’ve had some success. A team at Columbia University Medical Center in New York has developed a device that uses AI to examine semen samples from men who have only tiny numbers of healthy sperm. An embryologist might struggle to find a single healthy sperm in such a sample. But the Sperm Tracking and Recovery (STAR) system can analyze over a million microscope images in an hour. It has already been used to create healthy embryos. The team behind the work announced the first pregnancy resulting from the treatment in November last year.

Other teams are using AI tools to advance IVF in more dramatic ways. Around a decade ago, a reproductive endocrinologist named Alejandro Chavez-Badiola began developing an AI tool trained to rank embryos, another to rank eggs, and another to select sperm. He recalls being struck by a realization that these tools were “the brains that have the potential to drive robots in the future,” he says.

4. Using robots to standardize IVF

In the early 2020s, Chavez-Badiola and his colleagues decided to combine technologies and develop an automated system for IVF. In theory, a robotic system loaded up with AI tools could undertake most of the steps required in the IVF process: selecting the eggs and sperm, fertilizing eggs to create embryos, culturing those embryos in a dish, and selecting the “best” one for transfer. Such a system could “do everything in a standard way” without ever getting tired, he says.

Chavez-Badiola, who is now founder and chief medical officer at Conceivable, started building prototypes by motorizing regular IVF equipment and connecting it to computers. He and his colleagues started testing their system with animal cells before eventually moving on to human ones. “We were able to prove that integrating robots to automate different steps in IVF is doable,” he says.

The device is now being used to prepare sperm and eggs and create embryos. At least 19 children have been born following the automated IVF. It is early days, but Chavez-Badiola is hoping that future iterations of the machine could each process thousands of IVF cycles in a year, potentially making the procedure more affordable and accessible.

Many in the field are excited about the potential for automated devices like Conceivable’s. “This is all time saved for the embryologists,” says Laura Rienzi, a clinical embryologist and scientific director of the IVIRMA network of fertility centers in Italy. She also hopes it will help standardize IVF treatments. “Automation [will allow for] every patient to be treated in the same way in every single lab in the world,” she says.

5. Controversial edits are on the table

There’s a catch, however: All these technologies rely on the availability of at least some healthy sperm, eggs, and embryos at the outset. Embryologists and IVF patients have to work with what they’ve got. And sometimes, what they’ve got won’t result in a healthy baby. 

That’s why some scientists are proposing a controversial idea: using gene-editing technologies like CRISPR to tinker with the genome of an IVF embryo before it is implanted. The biophysicist He Jiankui infamously took this approach to create embryos that resulted in the births of three children in the late 2010s. He was widely condemned by the scientific community and ultimately spent three years in a Chinese prison

His former romantic partner Cathy Tie, who now leads startup Origin Genomics, is pursuing the technology as a potential way to prevent serious disease in children. At a recent event held at the Hastings Center for Bioethics, Tie made the case for using embryo editing to prevent diseases like cystic fibrosis, Huntington’s, and sickle-cell.

It won’t be straightforward from a technical, legal, or ethical perspective. Diseases that are known to be caused by single-gene mutations are good first candidates, but as the Center for Human Reproduction’s Gayete-Lafuente points out, most diseases are much more complicated than that. “I wish we could understand the genetic basis of every disease to be able to prevent it,” she says. So far, we can’t. Besides, most diseases can be influenced by our diets, behaviors, and environments as well as our genes.

As things stand, no one knows if editing a human embryo to eliminate the risk of one disease might increase a future child’s risk of some other disorder. And some scientists worry that such edits might be a slippery slope to genetic enhancement or eugenics.

Rienzi hopes that the technology might be developed in a safe way with regulatory oversight, and only for a specific list of diseases. “It has to be within a legal context,” she says. “But to me, it’s a dream.”

In the meantime, the field looks set to keep transforming with the development of new technologies that are already creating healthy babies. Watch this space.