The Future of Fertility Technology, From Technosemen to Uterine … – The MIT Press Reader

How will future generations come to be? There is no straightforward answer.

Fertility technology is an area of intense interest, in which scientists continue to push the boundaries of a human bodys capability to generate the matter that will produce a healthy, living child. It is, unsurprisingly, an area of rapid scientific and technological research so much so that regulatory bodies across the world have difficulty keeping up-to-date with the latest developments in order to regulate their use properly.

The following excerpt from the conclusion of Fertility Technology describes some of the methods that scientists and for-profit companies are testing and offering to patients and clients who are willing to try (and to fund, often at great expense) cutting-edge but unproven techniques to raise their chances of having a baby. This excerpt also draws attention to individuals who need extra assistance with conceiving but for financial, health, or ethical reasons do not want to engage with the latest techniques. Some techniques that were available in the 19th century, like artificial insemination, still can work backed by updated forms of medical technologies. There is no lack of attention to this area of scientific and technological development, from prospective parents, from scientists, from sperm and egg banks, from international transit companies, from potential donors, from ethicists and indeed from anyone engaged in questions of how humans will appear in the future.

The health of sperm remains an important area of diagnostic concern. Among a host of other issues, low sperm count, low motility, and sperm antibodies (proteins that damage or kill sperm) are all sources of infertility. Sperm health is difficult to treat, but some workarounds for those with at least some healthy sperm do exist. These include testicular sperm extraction and testicular sperm aspiration, using high-powered needles and delicate microsurgical instruments. Physicians can also perform testicular mapping, where they use fine-needle aspiration to try to find pockets of sperm production in the testes.

In addition to technologies that can help manifest pregnancy, the gametes, or reproductive cells, themselves can be thought of as technologies. This is true of technosemen, or semen that has undergone laboratory manipulation to be suited especially for intra-cytoplasmic sperm injection (ICSI), where a single healthy sperm is injected directly into each mature egg, and IVF, where an egg is combined with sperm in vitro. Researchers Matthew Schmidt and Lisa Jean Moore have called it the new and improved bodily product that semen banks advertise to clients. The methods for technosemen manipulation are various. The swim-up method, for example, involves centrifuging the semen sample, removing the seminal fluid, and placing the remaining sperm pellet in an artificial insemination medium, and then collecting the most active semen, which swim to the top of the solution. Another method is Percoll washing, which involves layering the semen with a cleansing solution and centrifuging it for half an hour.

Washed technosemen is perceived as healthier and more potent than natural, unmanipulated semen.

The ability to manipulate and to choose the best semen affects how clinics view their donors, their donations, and the children who might result from them. For example, in advertising materials for the Danish company Cryos, semen is solely described in light of the technology involved, writes researcher Charlotte Krolkke. Traces of the matter are reworked into sophisticated technology, beautiful children and indeed and not surprisingly happy, healthy, potent donors. This view that semen is a technoscientific product, not a body product, likewise manifests in China, where the countrys Ministry of Health established specific requirements for technosemen under national law from 2001 to 2003. The Ministry requires a concentration standard of 60 million sperm cells per milliliter, which is four times higher than the World Health Organizations criteria for normal male fertility, according to anthropologist Ayo Wahlberg, who published a detailed study of sperm-banking in China. A range of technologies of assurance quantify spermatic quality not only according to sperm per milliliter, but also motility grades, percentages of normal morphology, and milligrams of fructose per milliliter. Then, only the best sperm is used to make the best quality children.

The ability to test spermatic health is a means of managing the effects of environmental pollution on the next generation as well. In cities like Wuhan, one study found, semen donated on days with high levels of air pollution showed lower sperm count and concentration than semen donated on days with lower levels of air pollution. Washed technosemen is perceived as healthier and more potent than natural, unmanipulated semen. (Whether it leads to healthier children is much harder to discern.) Sperm banks can then make claims about the potency of their products, while at the same time making claims as to the naturalness of new reproductive technologies, writes Lisa Jean Moore in her book Sperm Counts. These constructions suggest that new reproductive technologies are not unnatural but rather an improvement upon the inherent unpredictability of natural procreation. In other words, the best semen is not natural; it is processed and refined through technology.

Like many areas of medicine, reproductive medicine attracts inventors and entrepreneurs. Some of their solutions may provide valid diagnostic information or improve chances of pregnancy but are not yet tested or approved by medical regulatory bodies. Some can be added to standard IVF treatments or are offered as part of comprehensive fertility medicine packages that may not be necessary for all patients. These add-ons can be problematic, as IVF patients may not be adequately informed about the benefits and risk of IVF add-ons or may not be aware of the paucity of supportive evidence for safety and effectiveness, according to findings from a recent survey. As navigating the world of add-ons may be confusing even for knowledgeable clients, some countries regulatory bodies provide guidance. The UKs Human Fertilisation and Embryology Authority (HFEA) publishes a traffic-light system, which rates add-ons according to available cost implications, risks, and evidence. A green light indicates that a treatment has shown positive results according to at least one randomized control study, an amber light indicates mixed results, and a red light indicates no positive results. Reviews of add-ons available since 2015 show their overall limited benefit and potential unknown harms to patients.

A survey taken in June and July 2020 showed that up to 24 add-ons were available at clinics across Australia, many of which mirrored those available in the UK. They ranged from mild and complementary (aspirin, acupuncture) to loosely linked (melatonin) to highly technological (assisted hatching). Another review of 10 add-ons, from screening hysteroscopy (examination of the uterus under anesthesia) to androgen supplements, found either that they had no effect on implantation or live birth rates or that there was insufficient data to support such a claim. A third review of five add-ons solely for the endometrium (mucus membrane lining the uterus) showed that their effects ranged from unclear (vasodilators such as sildenafil [Viagra] to thicken the endometrium) to harmful (endometrial scratching, which inflames the endometrium and might make the embryo more likely to implant). These reviews caution that profit may motivate clinics to provide costly IVF add-ons with no evidence base.

One of the add-ons that has received the most attention from scholars and fertility medicine specialists is time-lapse imaging, and as such, it is valuable to examine its implications in detail. Time-lapse imaging of embryos from fertilization to three days afterward (for double embryo transfer) to five days afterward (for single embryo transfer) is designed to help embryologists choose the healthiest possible embryo for implantation. Time-lapse imaging technologies, explains Lucy van de Wiel in her exploration of the world of egg freezing, allow for continuous observation by taking photographs every 5 to 20 minutes while the embryos remain in the incubator. . . . By matching the videos with growth patterns of embryos that developed into healthy fetuses, the time-lapse system suggests which embryos are most likely to grow into a baby. The time-lapse systems film the developing embryos and quantify the visual information onto grids, and then clinicians must have specialized training in algorithmic analysis to predict each ones likelihood of turning into a blastocyst, or a fertilized egg. These systems, called EmbryoScope (manufactured by Vitrolife) and Eeva (short for Early Embryo Viability Assessment, manufactured by Merck), depend on past selections to predict future embryo viability. In a May 2019 survey of fertility clinic websites in the United Kingdom, time-lapse imaging costs an average of 478 as a stand-alone treatment and an average of 4,020 as part of a treatment package. The systems themselves cost clinics 75,00080,000.

Reviews caution that profit may motivate clinics to provide costly IVF add-ons with no evidence base.

Time-lapse imaging alters more than just the process of embryo selection. As van de Wiel writes, by matching the embryos cellular growth patterns to previous embryonic populations recorded developmental rhythms, time-lapse technology brings embryonic aging to the forefront in embryo selection. Time-lapse imaging turns embryo selection into a new, data-driven way of seeing using automated pattern recognition and algorithmic predictive analysis. This process not only changes how laboratory technicians and embryologists see and choose embryos for implantation, but it also changes how a prospective parent or parents see their embryos: Ranking means that the woman or couple has a quantified sense of the blastocysts potential for development, researcher Catherine Waldby points out.

HFEA gives time-lapse imaging an amber light, as being undisturbed while they grow may improve the quality of the embryos but theres certainly not enough evidence to show that time-lapse incubation and imaging is effective at improving your chance of having a baby. Before getting a green light from HFEA and other national regulatory agencies, time-lapse imaging needs more proof to support Vitrolifes and Mercks claims that their products improve embryo selection. In general, inventors and suppliers of new add-ons may be pursuing not only patient satisfaction and profit but also the satisfaction of developing an IVF breakthrough technology to improve implantation and live-birth success rates markedly.

Another high-technology method currently being developed involves obtaining functional gametes from either human embryonic stem cells or induced pluripotent stem cells, which are derived from skin or blood cells, and the use of mitochondrial DNA from a donor egg to manifest so-called three-parent embryos. For the latter, women with healthy mitochondrial histories are asked to donate their eggs to women with family histories of disease, and the recipients nuclear genetic material is transferred to the healthy egg, explains Waldby. This enables the recipient to conceive a child who is genetically her own, if the terms of genetics are limited to nuclear DNA. The embryo is then the product of three peoples gametes, containing the nuclear DNA of the intending parents and the mitochondrial DNA of an egg donor. The UKs Human Fertilisation and Embryology Act (1990) was amended in 2015 to legalize this procedure, called MDNA transplantation; the United Kingdom is the only country that permits it.

The procedure is intended to help women with mitochondrial disorders often undetectable in preimplantation genetic testing (PGT) avoid passing those disorders onto potential children, and to ensure that those children are their genetic offspring. Unfortunately for the further acceptance of this procedure, one study found, most maternally inherited mitochondrial disorders only develop in adulthood, whereas mitochondrial disorders that severely affect babies are caused, in approximately 80% of cases, by nuclear defects that are inherited from both parents. In other words, replacing mitochondrial DNA alone cannot prevent diseases inherited from both parents, and the procedure helps only in the 20 percent of diseases that are only inherited maternally. The procedure also carries further risks:

[1] the potential side-effects caused by the co-existence of two different types of mitochondria within the embryos cytoplasm, including the possible carry-over of pathogenic mtDNA; [2] the possible defects caused by mismatching the nuclear and mitochondrial genomes, such as metabolic dysfunction and epigenetics effects; and [3] the social and psychological consequences of having been conceived using genetic material from three people.

Access to the procedure is heavily restricted, and disorders can often be found in gametes more easily and cost-efficiently using an older diagnosis method, PGT. The ethical considerations of procedures like IVM and MDNA leave many open questions about their use, especially if more problems with them are identified and more countries legalize them.

Another significant technological step is IVF in persons with transplanted uteri. The first modern attempt at a uterine transplant alone took place in Saudi Arabia in 2000. The first IVF procedure in a transplanted uterus from a live donor that resulted in a live birth happened 14 years later in Gothenburg, Sweden. The first live birth via IVF in a uterine transplant in the United States occurred in 2017, and the IVF-transplant procedure has resulted in 70 uterine transfers with 14 live births worldwide as of June 2021. Uterine transplants have been a focus of reproductive medical attention in the last two decades. If the transplant is successful, the donated uterus is removed after a certain period of time and number of successful IVF pregnancies a number that the patient would determine.

The IVF-transplant procedure has resulted in 70 uterine transfers with 14 live births worldwide as of June 2021.

Uterine transplantation is an intricate procedure, involving immunosuppressant drug regimens, the risk of organ rejection, the possible development of a thrombosis, and other complications. Connecting the blood vessels of the donated uterus to those in the recipients body is particularly tricky. But there are many other steps before the transplant and IVF can begin. On the practical side, there is no uterine donation registry, so in the case of live donation, the person without a uterus must ask a prospective donor for theirs (or the prospective donor must offer). Transplantation from a nondirected (anonymous) living donor or a deceased donor is also possible, though familial donors with identical blood types lower the risk of rejection. For some studies, prospective transplant recipients must secure their own donor. Interviews with 10 uterus-seekers in Sweden described how they reached out to their mothers as well as older sisters or aunts, raising the possibility that they could gestate a child using the same uterus in which they themselves were gestated. The emotional intricacy of asking (and possibly receiving) an organ donation in this situation is obvious.

Familial complexities aside, IVF in uterine transplants sparks the possibility of gestating pregnancies outside the human body completely in artificial wombs (ectogenesis). Research on human ectogenesis is still illegal in the United Kingdom, but animal research has been in progress there since the early 1960s. For humans, writes legal scholar Amel Alghrani, technology that can mimic the functions of the maternal uterus can help save the lives of extremely premature babies born on the cusp of viability. . . . Such technology can also help women who suffer from uterus factor infertility and thus are unable to gestate their own child. Research is underway in Sweden (by the same team that facilitated the first uterine transplant) to create a viable bioengineered uterus, including artificial amniotic fluid and an artificial endometrium. A bioengineered uterus could also be used for part of a pregnancy; for example, gestation could begin in the human womb, with the fetus transferred later to the artificial one. Successful human ectogenesis, whether wholly or partially gestated in an artificial uterus, could open up a new world of possibilities of reproduction.

Farther in the future is in vitro gametogenesis (IVG), the creation of gametes using pluripotent stem cells (cells that can differentiate into many cell types). If a patient cannot provide gametes for an assisted reproduction treatment, IVG could create gametes from their skin cells. Artificial gametes, writes Alghrani in her book on regulating assisted reproductive technologies, raise one of the most dramatic possibilities that two men (and maybe also two women) could create a baby that is genetically related [to] both of them, in the same way as men and women. Artificial gametes widen procreative possibilities for those unable to reproduce via traditional methods of sexual reproduction. As a result, a couple of any gender could provide all the gametes needed to produce an embryo that is genetically related to both of them.

Of course, child-seekers will continue to use less advanced technologies alongside technologies that require advanced medical assistance and infrastructures. Technologies and methods with historical longevity, such as fertility calendars and home-based insemination, will coexist alongside advances in high-technology methods. Home-based insemination persists especially in countries where access to assisted reproductive technologies is restricted or illegal for some identity groups (usually gay, trans, non-binary, and lesbian individuals). They may find assistance in printed or Internet guides to doing so, which originate in the feminist womens health movements of the 1970s. Lesbian insemination guidebooks have been in print since 1979, and syringes, cannulas, cervical caps or diaphragms, eye droppers, and jars are available to anyone who purchases them from a medical supply store or online.

People who want fertility assistance, but on their own terms, choose methods that do not violate their own boundaries. They develop hybrid-technology practices, as Laura Mamo of the Health Equity Institute calls them, or practices of borrowing from both high- and low-tech methods according to their own health and preferences. Whether its through ovulation timing, smartphone apps, or smart jewelry, individuals and couples have a range of options for charting their own journeys through the fertility landscape as long as they have the time, patience, finances, and good health to do so.

A history of fertility technologies can only hint at the vastly complex ways that the desire for children affects the lives of individuals, couples, communities, and nations. The technologies that make pregnancy possible for some people are a source of disappointment for others. They are means of giving certain embryos a chance to develop as persons in the world, but also a means of keeping other embryos and potential persons out of the world. Fertility technologies are much more than a way to address reproductive health problems or simply a medical procedure to cure a medically described condition, as Sandra P. Gonzlez-Santos reminds us. They are a tool through which people create people. How they will develop next and what kinds of human life will emerge as a result of using them remains to be seen.

Donna J. Drucker is Assistant Director of Scholarship and Research Development at the Columbia University School of Nursing. She is the author of The Classification of Sex: Alfred Kinsey and the Organization of Knowledge, The Machines of Sex Research: Technology and the Politics of Identity, 19451985, Contraception: A Concise History, and Fertility Technology, from which this article is adapted.

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Recent advances in CRISPR-based genome editing technology and … – Military Medical Research

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Iron & the brain: Where and when neurodevelopmental disabilities … – URMC

Study finds possible cellular origin for impairments associated with gestational iron deficiency

The cells that make up the human brain begin developing long before the physical shape of the brain has formed. This early organizing of a network of cells plays a major role in brain health throughout the course of a lifetime. Numerous studies have found that mothers with low iron levels during pregnancy have a higher risk of giving birth to a child that develops cognitive impairments like autism, attention deficit syndrome, and learning disabilities. However, iron deficiency is still prevalent in pregnant mothers and young children.

The mechanisms by which gestational iron deficiency (GID) contributes to cognitive impairment are not fully understood.The laboratory of Margot Mayer- Proschel, PhD, a professor ofBiomedical GeneticsandNeuroscienceat theUniversity of Rochester Medical Center, was the first todemonstrated that the brains of animals born to iron-deficient mice react abnormally to excitatory brain stimuli, and that iron supplements giving at birth does not restore functional impairment that appears later in life. Most recently, her lab has made a significant progress in the quest to find the cellular origin of the impairment and have identified a new embryonic neuronal progenitor cell target for GID. This study was recently published in the journalDevelopment.

We are very excited by this finding, Mayer-Proschel said, who was awarded a$2 million grant from the National Institute of Child Health & Human Development in 2018to do this work. This could connect gestational iron deficiency to these very complex disorders. Understanding that connection could lead to changes to healthcare recommendations and potential targets for future therapies.

Michael Rudy, PhD, and Garrick Salois, who were both graduate students in the lab and co-first authors of the study, worked backward to make this connection. By looking at the brains of adults and young mice born with known GID, they found disruption of interneurons, cells that control the balance of excitation and inhibition and ensure that the mature brain can respond appropriately to incoming signals. These interneurons are known to develop in a specific region of the embryonic brain called the medial ganglionic eminencewhere specific factors define the fate of early neuronal progenitor cells that then divide, migrate, and mature into neurons that populate the developing cerebral cortex. The researchers found that this specific progenitor cell pool was disrupted in embryonic brains exposed to GID. These findings provide evidence that GID affects the behavior of embryonic progenitor cells causing the creation of a suboptimal network of specialized neurons later in life.

As we looked back, we could identify when the progenitor cells started acting differently in the iron-deficient animals compared to iron normal controls, Mayer-Proschel said. This confirms that the correlation between the cellular change and GID happens in early utero. Translating the timeline to humans would put it in the first three months of gestation before many women know they are pregnant.

Margot Mayer-Proschel

Having identified cellular targets in a mouse model of GID, Neuroscience graduate student Salois in the Mayer-Proschel lab is now establishing a human model of iron deficiency using brain organoidsa mass of cells, in this case that represent a brain. These mini brains that look more like tiny balls that need a microscope to be studied, can be instructed to form specific regions of the ganglionic eminences of the embryonic human brain. With these researchers can mimic the development of the neuronal progenitor cells that are targeted by GID in the mouse.

We believe this model will not only allow us to determine the relevance of our finding in the mouse model for the human system but will also enable us to find new cellular targets for GID that are not even present in mouse models, said Mayer-Proschel. Understanding such cellular targets of this prevalent nutritional deficiency will be imperative to take the steps necessary to make changes to how we think of maternal health. Iron is an important part of that, and the limited impact of iron supplementation after birth makes it necessary to identify alternative approaches,

Additional authors include Janine Cubello, PhD, and Robert Newell at the University of Rochester. This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institute of Health, the Toxicology training grant of the Environmental Health Department at the University of Rochester, the New York Stem Cell Training Grant, and the Kilian J. and Caroline F. Schmitt Foundation through the Del Monte Institute for Neuroscience Pilot Program.

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Solnica-Krezel honored for contributions to developmental biology … – Washington University School of Medicine in St. Louis

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Scientist to receive Conklin Medal for work in vertebrate embryonic development

Solnica-Krezel

Lilianna Solnica-Krezel, PhD, the Alan A. and Edith L. Wolff Distinguished Professor and head of the Department of Developmental Biology at Washington University School of Medicine in St. Louis, is to receive the 2023 Edwin G. Conklin Medal from the Society for Developmental Biology. She is being recognized for her significant contributions to the understanding of early embryonic development in vertebrates, with a particular focus on zebrafish as a model organism.

The society awards the Edwin G. Conklin Medal in Developmental Biology annually to recognize developmental biologists who have made extraordinary research contributions to the field and are excellent mentors helping to train the next generation of scientists. Solnica-Krezel will receive the honor in July at the societys annual meeting in Chicago, where she will deliver a lecture.

Studying zebrafish, Solnica-Krezel and her team are focused on understanding the earliest stages of development, when different tissues first arise and are arranged into the body plan. Her team also works with human stem cells to test whether the same processes are relevant in people. The research has implications for understanding miscarriage, birth defects and cancer.

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Solnica-Krezel honored for contributions to developmental biology ... - Washington University School of Medicine in St. Louis

Umbilical Cord Keepsakes Are Going Viral: OB-GYNs Weigh In On … – Scary Mommy

Among the many treasured keepsakes out there to celebrate your little one coming into the world, youre probably aware of the classics: memory books, photo albums, framed hand- and footprints. But if youve been on TikTok lately, you may have noticed a decidedly different kind of keepsake flooding your feed some parents are preserving their umbilical cords as a way to cherish the connection between themselves and their babies, creating a memory they can hold onto for years to come.

If this is the first youre hearing of umbilical cord keepsakes, you likely have some questions. Namely, how does one ask for their umbilical cord? Is it even safe and sanitary to handle it? And how do you transform it into something special, like a heart or a star, especially if youre not particularly crafty or handy?

Granted, if youre being honest, the idea might even make your stomach turn a little especially if youre not a mom whos crunchy enough to have ever considered preserving placental parts for any reason. Thats understandable. But in learning a little more about why certain parents opt for this very intimate art form, you might be surprised to find that you sort of see the appeal. Or, at the very least, you understand why they see the appeal.

The first thing that might pop into your head is, Huh, I didnt even really know people were allowed to keep their umbilical cord. But yep, thats a thing people can (and often) do. Scary Mommy asked two OB-GYNs about the protocol here, and they explained you can certainly ask your obstetrician or someone on your delivery care team to hold onto the umbilical cord. If youre adopting or working with a surrogate, you can also ask the birth mom or gestational carrier for it as well. Most hospitals have policies and processes for patients to request to keep their placentas, which would include the umbilical cord. Its not a very common request, but it does happen, explains Staci Tanouye, MD FACOG.

Still, its not exactly the type of thing you can handle willy-nilly, as caring for an umbilical cord requires some pretty measured safety precautions you will not want to skimp on. Wearing gloves is essential, and Kim Langdon, MD, an OB-GYN with Medzino, explains that parents can request a section of the umbilical cord, placed in a plastic bag, rinsed clear of blood and debris, and refrigerated or have it placed in a desiccator, a specialized sealable container or package that prevents moisture from developing within.

Hospital staff can help ensure that all safety measures are adhered to, with Tanouye adding, As long as its not being ingested and it can be fully dehydrated so it doesnt grow mold, I dont see a safety problem with keeping a portion of the umbilical cord. The biggest precaution is ensuring it is fully dehydrated and dried to minimize the risk of it developing mold.

Bringing it home is only half the adventure, and youre likely also wondering how the heck to transform it into a work of art. Thats where artists like Casey Merrell of uCord Keepsakes can help. Merrell has created umbilical cord keepsakes for parents for more than seven years, working closely with families every step of the way.

Merrell recommends asking someone you trust (dads, doula, birth partners, or another family member) to keep track of the umbilical cord, as things can get chaotic in the hustle and bustle of labor and delivery. She adds that legally, your healthcare provider or birth facility cannot prevent you from taking home the placenta (which includes the umbilical cord), and it is your right to keep it. Depending on the policies of your provider/facility, you may be required to sign a release form or liability form in order to keep your umbilical cord, she adds.

Working with a placenta specialist like Merrell is your best bet for a seamless, stress-free, and safe process: A trained professional is going to be trained/certified in bloodborne pathogens, storage, and sanitation guidelines. Merrell only works with one cord at a time to prevent cross-contamination or any other mix-ups. A professional will also wear all needed PPE and all safety procedures are followed, including supplies sanitized and disposed of between each client, she says. Giving it to a friend or family member might mean theyre dehydrating your cord in a personal kitchen near foodborne items, pets and kids, or other non-trained people, leading to a host of potential mishaps.

Merrell notes that each cord is unique, requiring different preservation methods, and the amount of equipment required often means its cheaper and easier to work with a trained professional. At UCord Keepsakes, it costs $149 total, so by the time you gather a dehydrator, payment paper, finishing/sealing materials, gloves/other PPEs, cutting supplies, sanitation supplies, display box, etc., youll likely be over that price point, she says.

A trained placenta specialist can also create a truly unique work of art, with Merrell noting that some cords are long enough to spell out words like love or the babys name or initials. Metallic gold and rose gold options are most popular for finishing, but some moms like to leave them with a clear coating so you can visibly see the vessels that attach mom/baby.

If youre easily grossed out by bodily fluids and the like, your initial reaction might still be, well, grossed out. But before you brand umbilical cord keepsakes as a ridiculous idea, consider this: It helps some people cope with the grief of losing a child.

Merrell, a mom of four living children and a sleeping little boy, is passionate about providing the service, especially to those who have experienced a stillbirth or infant loss and would like a tangible memory of their angel baby. Most cords do work, but both doctors note some instances in which a parent will not be able to keep the umbilical cord after delivery.

If the cord or placenta is abnormal in any way or was the cause of fetal distress, if there was suspicion of an infection, then you probably wouldn't be allowed to have a section until it had been analyzed by the lab or pathologist, says Langdon, with Tanouye adding that some complications during pregnancy or childbirth (like an infection) might prevent parents from taking it home. In Merrells experience, this is rare, and most parents are able to bring it home without issue.

One final tip, per Langdon: Make sure you collect the cord blood before you cut a section of the cord for future storage as embryonic stem cells, if that is something you plan to do. Otherwise, youll likely get the green light to preserve such this link between you and your little one if thats something that speaks to you. If not, just remember before you bash it... it is very meaningful to some parents.

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Umbilical Cord Keepsakes Are Going Viral: OB-GYNs Weigh In On ... - Scary Mommy

An old model with new insights: endogenous retroviruses drive the … – Nature.com

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Vertex heads to the clinic with a next-gen stem cell candidate for … – Endpoints News

Vertex will start human testing of a new-and-improved version of its stem cell therapy for type 1 diabetes.

Regulators cleared Vertexs IND for its stem cell-derived pancreatic islet cell therapy VX-264 in type 1 diabetes, the company announced Thursday.

While the new candidate uses the same islet cells as VX-880, Vertexs original stem cell program for diabetes, it also makes use of an immunoprotective device that potentially eliminates the need for immunosuppression. Patients who take immunosuppressants may face a range of side effects, including an increased risk of infection. The device used in this program was invented by Semma Therapeutics, which was acquired by Vertex in 2019, and further developed at Vertex, according to a spokesperson.

The news comes several months after Vertex struck a $320 million deal to acquire ViaCyte and its other stem cell program for diabetes. The deal was intended to accelerate Vertexs overall diabetes pipeline, but did not play into the development of either VX-880 or VX-264, according to the company.

Both companies had been attempting to rejuvenate patients abilities to produce their own insulin using stem cell transplants. ViaCyte was going for an off-the-shelf gene-edited approach encapsulated in immune-evading devices that researchers thought could prevent rejection.

VX-880 has successfully demonstrated clinical proof of concept in T1D, and the acquisition of ViaCyte will accelerate our goal of transforming, if not curing T1D by expanding our capabilities and bringing additional tools, CEO Reshma Kewalramani said in a statement at the time.

Vertex plans to launch a Phase I/II trial in the first half of this year and is already conducting a Phase I/II in Canada, it said on Thursday.

Editors Note: This story has been updated throughout to reflect that ViaCytes technology was not used in the development of VX-880 or VX-264. A previous version of this story incorrectly stated that VX-264 was developed using technology from the ViaCyte acquisition. The story has been corrected to reflect that the device used in this program was invented by Semma Therapeutics, which was acquired by Vertex in 2019, and further developed at Vertex.

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Remarks as Prepared for Delivery by First Lady Jill Biden at the … – The White House

New Orleans, LA

Thank you, Senator Cassidy.

Its so nice to be back in New Orleans!

Dr. Ramos, Im grateful for this opportunity to see the exciting work youre doing and the progress being made. And Mayor Cantrell, Representative Boyd, Congressman Carter, thank you for the warm welcome back to this city.

Years ago, my sister Jan was diagnosed with lymphoma. Like every family that faces cancer, my sisters and I were stunned when we heard her diagnosis, terrified of losing her. But even as I held her hand, and my breath, through doctor visit after doctor visit, one thing gave me hope: that researchers like you were working tirelessly to find the best, most effective treatments for people like my sister.

For six weeks, Jan underwent stem cell transplant therapy. I visited her whenever I could. It was painful at times. But it worked. Today, thanks to her treatment and the strength she found to fight, she is a survivor.

Cancer changes everyone it touches. And in some ways, it touches us all.

This community knows that more than most. So many families here in Louisiana have lost loved ones to this disease. I know thats probably why many of you are here, why you do this work. Because you know that the breakthroughs and discoveries that you make here, every cancer-causing virus we learn how to defeat, every clinical trial that ends in success, become the miracles that our families are praying for.

Your work changes lives. And it saves them.

Thats why the Louisiana Cancer Research Center was created: because your state legislature understood that the only way we can end the devastation of this disease is by bringing researchers, and doctors, and nurses, and patients together. We see the power of that collaboration here, where LSU, Tulane, Xavier University, and Ochsner are working together under one roof and in communities throughout the state.

Today, we met nurses who are part of an incredible pilot program funded by the National Cancer Institute, revolutionizing clinical trial enrollment in remote areas throughout the southern gulf. And we saw the lab where researchers are looking for ways to stop viruses from turning healthy cells into tumors.

This work is possible because the state of Louisiana has come together. Your congressional and state representatives from both sides of the aisle, the private sector, non-profits, and academia. And one of your strongest advocates has been Senator Cassidy.

Bill, you and Dr. Cassidy have fought for patients for so long. From opening a free clinic for those most in need, to treating the uninsured, to making breast cancer screenings more accessible in this community, youve served the people of this state as doctors, and now, as public servants dedicated to investing in research to end cancer.

You understand that cancer doesnt care who someone votes for. It isnt a red or a blue issue. Its a human one. And it takes all of us, working together and sharing ideas, to stop it.

My husband, President Biden, knows that too. His Cancer Moonshot is bringing to the table the brightest minds and fiercest hearts to learn, and collaborate, and discover.

Were investing in new ways to prevent, detect, and treat cancer, and expanding access to routine screenings. That means right here, with millions of dollars from the federal government to support member institutions and scientists of the LCRC.

Today at the White House, were convening patients, survivors, companies, academic institutions, and health care providers to collaborate on efforts that will save lives from colorectal cancer.

And, in the 2024 budget that Joe released just yesterday, he is reducing the deficit and building the economy from the bottom up and the middle out, as well as investing in cancer research and prevention.

Together, across party lines and state lines were building a world where cancer is not a death sentence, where treatments are less toxic and people live longer, healthier, happier lives. Its ambitious. But its also within our reach.

For Joe and me, this is the mission of our lives. And we are ready and proud to work beside you.

Thank you.

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Remarks as Prepared for Delivery by First Lady Jill Biden at the ... - The White House

4 Big Things You Should Know About Primary Immunodeficiency Diseases – Self

As humans, weve been living alongside viruses, bacteria, fungi, and other pathogens for as long as weve existedand weve developed pretty hardy immune systems to deal with them. Unfortunately, in rare cases, some people are born with genetic errors in their immune systems that might make even the mildest bug a serious foe. Many of the symptoms of these conditions first start to appear in childhoodeven in infantsbut others dont present themselves until well into adulthood.

Primary immunodeficiency diseases (PIDDs)now commonly referred to as inborn errors of immunity (IEIs)1is a group of genetic diseases that cause the immune system to malfunction,Dusan Bogunovic, PhD, a professor at the Precision Immunology, Mindich Child Health and Development, and Icahn Genomics institutes in New York City, tells SELF.

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For some people, the immune system malfunctions by not mounting enough of a defense against harmful pathogens, which can result in stubborn infections that lead to frequent illnesses. For others, genetic errors can actually cause the immune system tooverfunction, or put up a fight when its not necessary, which can harm the bodys healthy tissues in the process. Some PIDD conditions, such asWiskott-Aldrich syndrome, are characterized by an underperformingand an overperforming immune system, according toXiao Peng, MD, PhD, an assistant professor of genetic medicine and the director of the Genetics of Blood and Immunity Clinic at Johns Hopkins University School of Medicine. So not only is the immune system insufficiently capable of attacking the things that it should be, sometimes it likes to go rogue and attack the things that it shouldnt be, she tells SELF.

All of this is to say that the immune system is undeniably complex, and experts are still learning about all of the genes involved in PIDDs. Heres what you should know about this umbrella of diseasesincluding the kinds of symptoms that might be worth exploring further.

Most PIDDs are caused by an erroror several errorsin a persons genes, Dr. Peng says. For example, they may have inherited damage to a variant in a single gene.1 In turn, they may experience frequent infections or chronic inflammation, and this can set the stage for serious health problems, Dr. Bogunovic saysall because the immune system isnt quite working right.

These diseases also run on a spectrum, Dr. Peng says. On the most severe end, there are cases likeDavid Vetter, a young boy from Texas who had severe combined immunodeficiency (SCID); he made national news because he had to live in a plastic bubble to protect himself from a number of infectious pathogens until he died at age 12. (Newborns are routinely screened for SCID, among a few other PIDDs.2) Other PIDDs, however, may only make a person more likely to experience complications to a very specific type of pathogen that they dont get exposed to until much later in life, if at all.

It really depends on the person. Even if two people are diagnosed with the same PIDD, one person may end up getting very sick, while another lives a generally healthy life. Some people might have antibody deficiencies that you can measure on a lab test, but [they] never get super sick, Dr. Peng says. That speaks to the fact that what your cells are doing is not necessarily what your body and your environment are putting you at risk for.

That said, one potential indicator that you have an inborn error of immunityis that youre getting severely sick on a regular basiswhich well talk more about in a second.

There are nearly 500 different PIDDs that experts are aware of, and that number is growingmore than 100 new gene errors that contribute to these diseases are discovered every year, according to Dr. Peng.3

When you look at each PIDD individually, each type is relatively rare; collectively, however, these conditions are estimated to affect up to 5 in every 1,000 peopleand certain PIDDs are more frequently diagnosed than others.3 The most common PIDDs affect the bodys ability to produce antibodies, protective proteins that attach to harmful pathogens and remove them from your body. For example, common variable immunodeficiency (CVID), one of the most common PIDDs diagnosed, causes people to have low levels of blood immunoglobulins (another name for antibodies), which can increase their risk of infection, according to theImmune Deficiency Foundation (IDF). Its estimated to affect about 1 in 25,000 people.

Another common PIDD is selective IgA deficiencyas many as 1 in 500 white people have it, but research is lacking to determine the prevalence in people of color. IgA deficiency means an important type of immunoglobulin, immunoglobulin A (IgA), is undetectable in the blood, even though other types of immunoglobulin in the body are detected at normal levels.4 People with IgA deficiency often complain of frequent ear infections, sinusitis, bronchitis, and pneumonia that might not resolve with regular treatment, the IDF notes. They may also have issues with their gut health (including gastrointestinal infections or chronic diarrhea), or have autoimmune conditions, Dr. Peng says, like celiac disease, lupus, or rheumatoid arthritis.

Remember: Not everyone who is diagnosed with PIDDs gets sick a lotplenty of people who have the selective IgA deficiency dont end up seeing the doctor any more often than other folks, while others end up severely ill. Doctors arent sure why that is yet.

When it comes to PIDDs, the biggest red flags include:

Other possible symptoms of PIDDs include digestive issues, delayed growth or development, or inflammation of the internal organs, according to the Mayo Clinic.

Unfortunately, identifying a PIDD can take a while. On average, it takes people more than six years to get an accurate diagnosis, which can be fatal in some cases, Dr. Bogunovic says.5 There are lots of reasons a diagnosis can be delayed, he says, including that primary immunodeficiency diseases sometimes dont appear until later in a persons life, primary care doctors arent always aware of the vast range of PIDDs or their unique symptoms, and it might be difficult for some people to access the right experts (like an immunologist) or credible institutions for both geographic and socioeconomic reasons.

The good news is, thats not always the case. Dr. Peng has been on care teams that provided patients with a diagnosis within a week, thanks to experts working together on several fronts and diving into the persons genetics and medical history.

When it comes to PIDD treatments, there are a few options, and each has potential pros and cons. They fall into the following three broad categories.

This is often the most accessible avenue, and lots of people diagnosed with PIDDs do well by managing infections for years and years, Dr. Peng says. For example, according to theMayo Clinic, if you have frequent bacterial infections, longer courses of antibiotics or intravenous antibiotics may be recommended. Long-term antibiotic use may help to ward off an infection before it starts too. If a person is lacking certain antibodies, immunoglobulin therapytypically an IV treatmentcan help replace the lacking proteins.

This can be done via a bone marrow or stem cell transplant.6 For astem cell transplant, a doctor takes stem cells (a.k.a. blood-forming cells) from a donor with a healthy immune system. The doctor also wipes out the patients immune system (essentially erasing the genetic errors in question). Then, healthy stem cells from a donor are put into the blood of the patient. These new stem cells replicate over time, completely replacing the persons formerly malfunctioning immune system. Unlike with managing symptoms, if all goes well, the patient is cured.

Unfortunately, Dr. Peng says, moving forward with a stem cell transplant is not a simple decision for the doctor or the patient. Youre basically knocking out all of the persons immune defenses, putting them at incredible risk for infection before you give them back someone elses stem cells, she says. Even after the cells have been transferred to the person receiving the transplant, it takes time for whats essentially a brand-new immune system to reach fighting capacity. Unfortunately, theres also a risk that the donors new cells will view the recipients body as a threat and start attacking otherwise healthy tissues, Dr. Peng says. Genetic testing is critically important when screening candidates for a stem cell transplant, she adds, because some genetic errors live elsewhere in the body, not just the stem cells.

Unlike a stem cell transplant, in gene therapy, technology is used to extract a patients own stem cells, edit the PIDD-related genetic error out of a persons stem cells, then deliver the corrected stem cells back into their body intravenously, per the Mayo Clinic. Most gene therapy is in its early stages and not ready for patient use yet, Dr. Peng says, but there are severalclinicaltrials that are currently testing these therapies on humans. According to theImmune Deficiency Foundation, there are only a few current use cases for gene therapy outside of these trials, including for children with certain types of SCID.

Finally, many people reduce their risk of infection with the basic protective protocols youre probably already familiar with: practicing good hygiene like handwashing, eating well, exercising regularly, and avoiding people who are actively sick, the Mayo Clinic notes.

I think a lot of it is just providing families with information about the nature of that particular immune disease and what their risks are and what situations they need to be a little bit more vigilant [about], Dr. Peng says. Its crucial to find balance too, to make sure their lives dont become entirely about avoidance. Some of the most common sense, simple things are also the most useful things.

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4 Big Things You Should Know About Primary Immunodeficiency Diseases - Self

Caribou Biosciences Reports Fourth Quarter and Full Year 2022 … – Yahoo Finance

Caribou Biosciences, Inc.

-- CB-010 ANTLER Phase 1 trial in r/r B-NHL ongoing with update planned for H2 2023 --

-- CB-011 CaMMouflage Phase 1 trial in r/r MM recruiting patients at dose level 1 --

-- CB-012 IND-enabling studies initiated; IND submission in r/r AML planned for H2 2023 --

-- $317.0 million in cash, cash equivalents, and marketable securities as of December 31, 2022; cash runway to fund the current operating plan into 2025 --

BERKELEY, Calif., March 09, 2023 (GLOBE NEWSWIRE) -- Caribou Biosciences, Inc. (Nasdaq: CRBU), a leading clinical-stage CRISPR genome-editing biopharmaceutical company, today reported financial results for the fourth quarter and full year 2022 and reviewed recent pipeline progress.

We successfully demonstrated the potential of our chRDNA genome-editing technology with promising clinical data from CB-010, our lead allogeneic cell therapy, said Rachel Haurwitz, PhD, Caribous president and chief executive officer. The initial dose level of CB-010 demonstrated 6-month complete response rates that have the potential to rival the responses seen with approved autologous CAR-T cell therapies. We are excited that the FDA granted the CB-010 program RMAT and Fast Track designations last year. Our team drove additional pipeline progress with an IND clearance for CB-011, enabling us to activate clinical sites for our CaMMouflage Phase 1 trial. In 2023, Caribou plans to maintain this momentum by advancing two ongoing clinical trials for our off-the-shelf cell therapies in patients with hematologic malignancies and preparing an IND submission for our third program, CB-012.

Accomplishments and Highlights

Pipeline and Technology

CB-010: Caribou reported promising data at dose level 1 (40x106 CAR-T cells) from its ongoing ANTLER Phase 1 clinical trial of CB-010 in patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL).

Following a single infusion of CB-010 at dose level 1, all 6 patients in cohort 1 achieved complete responses as their best response. 3 of 6 patients maintained complete responses at 6 months, with 2 of 6 maintaining complete responses at 12 months. Caribou plans to provide an update from the ongoing ANTLER Phase 1 trial for CB-010 in H2 2023.

Clinical data presentations are available on Caribous website under Scientific Publications.

Following demonstration of an encouraging safety profile at dose level 2 (80x106 CAR-T cells), with no dose-limiting toxicities (DLTs) in the 3 patients treated, Caribou continues to enroll patients at dose level 3 (120x106 CAR-T cells).

The U.S. Food and Drug Administration (FDA) has granted CB-010 Regenerative Medicine Advanced Therapy (RMAT), Fast Track, and Orphan Drug designations. These designations provide important benefits in the drug development process and are designed to facilitate and expedite development and regulatory review, including providing eligibility for priority and rolling reviews and accelerated approval, if relevant criteria are satisfied.

CB-010 is the first allogeneic anti-CD19 CAR-T cell therapy in the clinic, to Caribous knowledge, with a PD-1 knockout (KO), a genome-editing strategy designed to improve antitumor activity by limiting premature CAR-T cell exhaustion.

Additional information on the ANTLER trial (NCT04637763) can be found at clinicaltrials.gov.

CB-011: Caribou recently activated clinical sites for the recruitment of patients at dose level 1 (50x106 CAR-T cells) of CB-011 in the CaMMouflage Phase 1 trial for relapsed or refractory multiple myeloma (r/r MM).

CB-011 is the first allogeneic CAR-T cell therapy in the clinic, to Caribous knowledge, that is engineered to improve antitumor activity through an immune cloaking strategy with a B2M KO and insertion of a B2MHLA-E fusion protein to blunt immune-mediated rejection.

Preclinical data for CB-011 were presented in a poster at the 2023 Tandem Meeting: Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, February 15-19, 2023, in Orlando, Florida. The poster presentation is available on Caribous website under Scientific Publications.

Additional information on the CaMMouflage trial (NCT05722418) can be found at clinicaltrials.gov.

CB-012: Caribou has initiated IND-enabling studies for CB-012, an allogeneic anti-CLL-1 CAR-T cell therapy, to support a planned IND application submission for relapsed or refractory acute myeloid leukemia (r/r AML).

CB-012 is the first allogeneic CAR-T cell therapy, to Caribous knowledge, with both checkpoint disruption, through a PD-1 KO, and immune cloaking, through a B2M KO and B2MHLA-E fusion protein insertion; both armoring strategies are designed to improve antitumor activity. CB-012 is engineered with 5 genome edits, enabled by Caribous next-generation CRISPR technology platform, which uses Cas12a chRDNA genome editing to significantly improve the specificity of genome edits.

In preclinical AML models, CB-012 significantly reduced tumor burden and increased overall survival compared to controls.

CB-020: Caribous first induced pluripotent stem cell (iPSC)-derived allogeneic CAR-NK cell therapy, CB-020, is designed to target solid tumors expressing the tumor antigen ROR1.

Preclinical data supporting the selection of the ROR1 CAR construct and armoring strategies for the companys CAR-NK cell platform were presented at the 12th American Association for Cancer Research and Japanese Cancer Association (AACR-JCA) Joint Conference in December 2022. The poster presentation is available on Caribous website under Scientific Publications.

Story continues

Anticipated 2023 Milestones

CB-010: Caribou plans to provide an update from the ongoing ANTLER Phase 1 trial for CB-010 in H2 2023.

CB-011: Caribou recently activated clinical sites for the recruitment of patients at dose level 1 and plans to provide an update on the clearance of dose levels as appropriate from the CaMMouflage Phase 1 trial for CB-011.

CB-012: Caribou plans to submit an IND application for CB-012 in H2 2023.

Upcoming Investor Conferences

Fourth Quarter and Full Year 2022 Financial Results

Cash, cash equivalents, and marketable securities:Caribou had $317.0 million in cash, cash equivalents, and marketable securities as of December 31, 2022, compared to $413.5 million as of December 31, 2021. Caribou expects these cash, cash equivalents, and marketable securities will be sufficient to fund its current operating plan into 2025.

Licensing and collaboration revenue: Revenue from Caribous licensing and collaboration agreements was $3.7 million for the three months ended December 31, 2022 and $13.9 million for the full year 2022, compared to $2.6 and $9.6 million, respectively, for the same periods in 2021. The increases were primarily due to revenue recognized under the AbbVie Agreement.

R&D expenses:Research and development expenses were $25.7 million for the three months ended December 31, 2022 and $82.2 million for the full year 2022, compared to $15.1 and $52.3 million, respectively, for the same periods in 2021. The increases were primarily due to costs to advance pipeline programs; increased headcount, including stock-based compensation; facilities and other allocated expenses; and increased external manufacturing and clinical activities.

G&A expenses:General and administrative expenses were $8.5 million for the three months ended December 31, 2022 and $38.0 million for the full year 2022, compared to $7.9 and $24.3 million, respectively, for the same periods in 2021. The increases were primarily due to increased headcount, including stock-based compensation; legal, accounting, insurance, and other expenses necessary to support the growth and operation of a clinical-stage public company; and facilities and other allocated expenses.

Net loss: Caribou reported a net loss of $27.0 million for the three months ended December 31, 2022 and $99.4 million for the full year 2022, compared to $18.5 and $66.9 million, respectively, for the same periods in 2021.

About Caribous Novel Next-Generation CRISPR Platform CRISPR genome editing uses easily designed, modular biological tools to make DNA changes in living cells. There are two basic components of Class 2 CRISPR systems: the nuclease protein that cuts DNA and the RNA molecule(s) that guide the nuclease to generate a site-specific, double-stranded break, leading to an edit at the targeted genomic site. CRISPR systems are capable of editing unintended genomic sites, known as off-target editing, which may lead to harmful effects on cellular function and phenotype. In response to this challenge, Caribou has developed CRISPR hybrid RNA-DNA guides (chRDNAs; pronounced chardonnays) that direct substantially more precise genome editing compared to all-RNA guides. Caribou is deploying the power of its Cas12a chRDNA technology to carry out high efficiency multiple edits, including multiplex gene insertions, to develop CRISPR-edited therapies.

About Caribou Biosciences, Inc.Caribou Biosciences is a clinical-stage CRISPR genome-editing biopharmaceutical company dedicated to developing transformative therapies for patients with devastating diseases. The companys genome-editing platform, including its proprietary Cas12a chRDNA technology, enables superior precision to develop cell therapies that are armored to potentially improve antitumor activity. Caribou is advancing a pipeline of off-the-shelf cell therapies from its CAR-T and CAR-NK platforms as readily available treatments for patients with hematologic malignancies and solid tumors.

Follow us @CaribouBio and visit http://www.cariboubio.com.

Caribou Biosciences and the Caribou logo are registered trademarks of Caribou Biosciences, Inc.

Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, without limitation, statements related to Caribous strategy, plans, and objectives, and expectations regarding its clinical and preclinical development programs, including its expectations relating to the timing of updates from its ANTLER Phase 1 clinical trial for CB-010 as well as the status and updates from its CaMMouflage Phase 1 clinical trial for CB-011, expectations about product developments in 2023, and the submission of an IND application for CB-012. Management believes that these forward-looking statements are reasonable as and when made. However, such forward-looking statements are subject to risks and uncertainties, and actual results may differ materially from any future results expressed or implied by the forward-looking statements. Risks and uncertainties include, without limitation, risks inherent in the development of cell therapy products; uncertainties related to the initiation, cost, timing, progress, and results of Caribous current and future research and development programs, preclinical studies, and clinical trials; and the risk that initial or interim clinical trial data will not ultimately be predictive of the safety and efficacy of Caribous product candidates or that clinical outcomes may differ as more patient data becomes available; the risk that preclinical study results we observed will not be borne out in human patients; as well as other risk factors described from time to time in Caribous filings with the Securities and Exchange Commission, including its Annual Report on Form 10-K for the year ended December 31, 2022 and subsequent filings. In light of the significant uncertainties in these forward-looking statements, you should not rely upon forward-looking statements as predictions of future events. Except as required by law, Caribou undertakes no obligation to update publicly any forward-looking statements for any reason.

Caribou Biosciences, Inc.Condensed Consolidated Balance Sheet Data(in thousands) (unaudited)

December 31,2022

December 31,2021

Cash, cash equivalents, and marketable securities

$

317,036

$

413,508

Total assets

373,765

442,356

Total liabilities

72,894

54,531

Total stockholders' equity

300,871

387,825

Total liabilities and stockholders' equity

$

373,765

$

442,356

Caribou Biosciences, Inc.Condensed Consolidated Statement of Operations(in thousands, except share and per share data)(unaudited)

Three Months EndedDecember 31,

Year EndedDecember 31,

2022

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Caribou Biosciences Reports Fourth Quarter and Full Year 2022 ... - Yahoo Finance