‘The Biggest Challenge Is To Find Out How 98% of DNA Regulates … – Kashmir Life

A young geneticist, Dr Rais A Gania was surprised to see his takeaways from his PhD were part of the text well before he entered the classroom as a teacher. Credited for identifying a particular enzyme that helps in crucial DNA copying, he is serving the IUSTs molecular medicine centre. In a freewheeling interview, he opens up about his research and future plans

KASHMIR LIFE (KL): You studied in Kashmir and worked in different universities all over the world. How was your learning curve and what were the challenges you faced?

DR RAIS A GANAI (DRAG): I was born and brought up in the Posh-Kirri village of Anantnag. I did my primary schooling at Government Primary School in the same village. Later, I went to the Government Middle in the nearby Hugam village. Later, my father suggested me to complete further studies in Srinagar, as he was working at the University of Kashmir. Then, I went to the Starland High School Zakura and completed my matriculation there.

In Srinagar, I found it very difficult to compete with students because of the language barrier, as the medium of instruction was different. It was a challenging task to learn English and Urdu languages. It took me a lot of time to cope with the level of the students.

Then I completed my 10+2 from Soura Higher Secondary School. Afterwards, I went to the Islamia College of Science and Commerce, where from I completed my graduation. Even though there was not an ample structure at that time but the laboratories were well established. Attendance of labs was mandatory, due to which my scientific temper got developed.

After that, I was selected at the University of Kashmir for a couple of courses but I chose to study Biotechnology. After completing the Masters degree in Biotechnology, I went to the Indian Institute of Science (IISc), Bangalore, where I worked under the mentorship of Prof Umesh Varshney and worked intensely on various Biotechnological challenges. He invested a lot of money, time and effort and taught me many new things due to which my interest in the research further deepened. During this time a few of my research papers were published.

Then I went to Sweden in 2009 for my PhD and completed it in 2015 and later got an international Postdoc fellowship offer in Sweden amounting to Rs 2.5 crore. I used that fellowship and immigrated to the USA. There I joined the NewYork based Howard Huges Medical Institute. I did research there for almost 2-3 years under the well-known researcher Danny Reinberg.

Then I came back to Kashmir as a Ramanujan Fellow. Initially, I joined the Central University of Kashmir and later moved to the IUSTs Watson-Crick Centre for Molecular Medicine in 2020.

KL: The work on genetics has been going on in all major universities throughout the world. However, we still have not understood the gene fully. What are the various challenges in understanding the gene, and what are the different goalposts we still have to reach?

DRAG: The gene is actually a small DNA sequence made of sugar bases like Adenine, Guanine, Thymine, and Cytosine (A, G, T, C). They are about 3 billion sugar bases called Nucleotides (made of Deoxyribose sugar, the Phosphate group, and the Nitrogen base) in a DNA molecule arranged in a chain structure. All the Nucleotides in a DNA molecule do not constitute genes, but only 1-2 per cent makes the genes and the rest 98-99 per cent of the base pairs do not attribute to the genes.

Scientists have identified most of the genes in our body and their functioning but the functioning of the rest 98 per cent of the non-genomic sequences (regulatory sequences) is still not known. We only know that these contain non-genomic sequences that regulate the genes, but the biggest challenge is to find out how 98 per cent of DNA regulates the 1 per cent of DNA.

The other major challenge was to understand the three-dimensional structure of DNA and its arrangement inside the cell. The chromosomes are arranged in compartmental structures. How and when these compartments are formed is yet to be discovered. How these genes are activated and repressed in the cells is still a challenge.

The actual structure of a DNA molecule has a three-dimensional chromatin architecture. These DNA molecules are present on the chromosomes. Our body contains 46 chromosomes in each cell that are intertwined inside the cell. The intertwined structure of chromosomes helps in the better expression of genes during cell division and cell formation. All the required genes express together and activate simultaneously in order to form a complete cell.

KL: What was your PhD all about and what were the major takeaways from your research?

DRAG: As I mentioned that DNA is a small molecule contained in a cell. A cell contains two meters of intertwined DNA, which if stretched is equivalent to at least four times the distance between the sun and the earth. During cell division and cell multiplication, this DNA is replicated/ duplicated which has to be very accurate. Genetic defects during cell division cause mutations/errors, which lead to genetic diseases, metabolic disorders, or even cancer.

During my PhD, my research was about the role of an enzyme called DNA polymerase in DNA replication. This enzyme reads, copies, and then makes the exact copy of a parent DNA molecule. The three billion nucleotides of a DNA molecule in a cell are copied accurately without any error or defect with the help of this enzyme. Besides, it also rectifies the errors, which are caused during cell division and helps in errorless duplication. Thus, the DNA polymerase enzyme not only plays a role in DNA replication but also fixes the errors caused during DNA replication, if any.

I also studied the functioning of various other enzymes but the pivotal research was about DNA polymerase. The majority of DNA polymerase enzymes look like, if I can say, a right-hand structure, containing a thumb, a palm, and fingers. The DNA polymerase, we studied has an additional domain called the P-domain, unlike the other DNA-Polymerase enzymes which only have three domains. The majority of DNA-Polymerase enzymes require a scaffold or support (called PCNA) for DNA copy and replication, but the DNA-polymerase we studied does not require PCNA rather it has the inbuilt P-domain that helps in DNA synthesis and thus does not require an outside scaffold. This was the biggest takeaway from my PhD research.

To my surprise, I later found when I was at the Central University of Kashmir, that our work and findings were published in textbooks, and are being taught to students in different Universities all over the world. It was a very difficult project to work on because nobody prior to us had worked on this. Our work was then published in the Journal Nature Structural and Molecular Biology, which now is a part of the textbooks and is being taught.

KL: What was your Post-doctorate research about, and what were your accomplishments and learnings during that period?

DRAG: I mostly studied two things during my Postdoc research, the role of epigenetic factors in the development, and the development of stem cells into the cardiomyocyte.

I actually wanted to expand and diversify my expertise, so I shifted to the field of epigenetics.

Under epigenetics, we study how the genes present in the DNA are regulated. Let us understand it this way if we have two monozygotic twins and one of them is raised by the adopted parents and the other by the natural parents. Technically, after 30 years of age, both should be identical because of the principle of monozygotic nature, but because of the environmental effects, they would have developed variations over time. It is because the influence of environmental conditions affects the development of an individual and that regulates the body. Thus, the effect of an environment on the development over time, beyond the genetic basis and beyond DNA is called epigenetics.

There are thousands of genes on a DNA molecule and there are specific factors that actually regulate the functioning of these genes. I also worked on these factors.

DNA is wrapped around by the histone proteins. These proteins contain chemical modifications or tags that determine the function of the DNA sequence. I worked on early embryonic development, particularly on stem cells. I studied how differentiated development takes place from a single cell into different kinds of complex organs i.e., how a stem cell is transformed into a cardiomyocyte.

KL: How could you make lawmen understand this differentiation of a stem cell into different complex organs? What really controls this differentiation of cells? Is this also part of epigenetics?

DRAG: Nobody really knows how embryonic development occurs as it is not easy to study this field. People have now started research on it.

During embryonic development, the fusion of egg and sperm results in the formation of a Zygote, which later undergoes the 2-cell stage and the 4-cell stage, and so on. From day one of development certain genes are activated which stimulates the Zygote division and this division activates other genes, which then cause muscle cell formation. More and more genes get activated that guide the muscle cells to transform into different complex organs. It is mostly like this, but there is still ambiguity on how embryonic development takes place through different stages of development.

KL: What is your role at the IUSTs Watson-Crick Centre for Molecular Medicine and what are the different domains you are working on?

DRAG: I am establishing my lab here for research purposes. Besides, I am also the coordinator of the B Voc course on the Medical Lab and Molecular Diagnostic Technology. I teach students also. I guide students on how to do diagnostic tests and the process of opening diagnostic clinics.

The primary part of my job at the Watson-Crick Centre is to do research along with my students who work with me on the continuation of my PhD research work. We are studying the role of DNA polymerase enzyme other than the role of DNA synthesis.

Secondarily, we are also studying epigenetics. Epigenetic marks at different positions of a DNA molecule, other than the normal positions cause diseases like cancer, and developmental and neurodegenerative diseases, among others. Therefore, our aim is to research epigenetics in detail in order to develop drugs for the treatment of these diseases.

Mujtaba Hussain processed the interview

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'The Biggest Challenge Is To Find Out How 98% of DNA Regulates ... - Kashmir Life

What a startups woolly mammoth meatball tells us about the future of meat – The Indian Express

While this will be a one-off creation, perhaps garner publicity for the food-tech company, founder Tim Noakesmith told the AP that through the mammoth meatball, the company hoped to start a conversation around global meat consumption.

Cultivated meat also called cultured or cell-based meat is made from animal cells but livestock does not need to be killed in order to produce it. Notably, it is different from plant-based meat substitutes in that it actually uses animal DNA to recreate in a lab the taste and texture of meat. Plant-based substitutes, on the other hand, try and mimic the taste and texture of meat using other plant-based alternatives.

For the woolly mammoth project, Vow worked with Prof Ernst Wolvetang, at the University of Queenslands Australian Institute for Bioengineering, The Guardian reported. The aim was to create the mammoth muscle protein from available DNA. Prof Wolvetangs team took the DNA sequence for mammoth myoglobin, a key muscle protein in giving the meat its flavour, and filled in any gaps using the DNA of the African elephant, the closest living relative of the extinct woolly mammoth.

The prepared DNA sequence was then placed in myoblast (embryonic precursor to muscle cells) stem cells from a sheep, which soon replicated in the right lab conditions to grow to the nearly 20 billion cells subsequently used by the company to create the mammoth meatball.

It was ridiculously easy and fast, Prof Wolvetang told The Guardian. We did this in a couple of weeks. Initially, the idea was to produce dodo meat. However, the DNA sequences required for that do not exist.

The mammoth meatball has not been tasted by anyone, even its creators. Nor does Vow plan to put it into commercial production. Instead, the idea has been to use the meatball to start a much-needed conversation.

We wanted to get people excited about the future of food being different to potentially what we had before. That there are things that are unique and better than the meats that were necessarily eating now, and we thought the mammoth would be a conversation starter and get people excited about this new future, Noakesmith told the AP.

But also the woolly mammoth has been traditionally a symbol of loss. We know now that it died from climate change. And so what we wanted to do was see if we could create something that was a symbol of a more exciting future thats not only better for us, but also better for the planet, he added.

Multiple studies have pointed out the massive impact that the global meat industry has on the environment. According to the Food and Agriculture Organization of the United Nations (FAO), global meat consumption has increased significantly in recent decades, with per capita consumption almost doubling since the early 1960s.

This means that roughly 14.5 per cent of global emissions of greenhouse gases are attributable to livestock farming. This includes not just carbon dioxide but also methane and nitrous oxide, which scientists say have a climate warming potential of anywhere between 25 times and 300 times higher than that of carbon dioxide.

Most greenhouse gas emissions from plant-based foods are lower than those linked to animal-based foods.

Experts say that if cultivated/cultured meat is widely adopted, it could vastly reduce the environmental impact of global meat production in the future.

By cultivating beef, pork, chicken, and seafood, we can have the most impact in terms of reducing emissions from conventional animal agriculture and satisfying growing global demand for meat while meeting our climate targets, Seren Kell, science and technology manager at Good Food Institute, a nonprofit that promotes plant- and cell-based alternatives to animal products, told the AP.

This is because cultivated meat uses much less land and water than livestock, and produces no methane emissions. The industry can run on energy produced purely from renewable sources. While the woolly mammoth meatball is, as was planned, an unconventional idea, most of the industry has been focussing on commonly consumed meats like pork, chicken and beef.

However, there is a long way to go before cultivated meat becomes mainstream across the world. Currently, Singapore is the only country to have approved cell-based meat for consumption. Vow hopes to enter the market later this year, with its quail-based meat product.

More than getting regulatory approvals, for cultivated meat to really take off, there has to be a massive, global-scale behavioural and cultural change. We have a behaviour change problem when it comes to meat consumption, George Peppou, CEO of Vow, told The Guardian.

Projects such as Vows woolly mammoth meatball help draw attention and start conversations on the possibilities of cultivated meat. (This) will open up new conversations about cultivated meats extraordinary potential to produce more sustainable foods, Kell told the media.

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What a startups woolly mammoth meatball tells us about the future of meat - The Indian Express

First-of-its-kind stem cell study sheds light on Klinefelter syndrome – Medical Xpress

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The impact of X overdosage on the global transcriptomes of Saudi and ENA KS-iPSCs. A) Venn diagram showing the DEGs shared in the contrast 47,XXY Vs. 46,XY in iPSCs generated from ENA and Saudi KS patients. B) Gene Ontology analysis on common DEGs using the GO enriched for Biological Processes (BP), Molecular Functions (MF), and Cellular components (CC). C) KEGG enrichment analysis and D) MGI Mammalian phenotype disease pathway analysis on Saudi and ENA common DEGs. Credit: Endocrine Connections (2023). DOI: 10.1530/EC-22-0515

In a research partnership between King Abdullah University of Science and Technology (KAUST), King Abdulaziz University, Jeddah (KAU), and King Abdulaziz University Hospital, Jeddah (KAUH), scientists have conducted a first-of-its-kind study in the Kingdom that compares stem cells derived from a unique cohort of Saudi Klinefelter patients with a group of North American and European descent.

Klinefelter is a chromosomal disease characterized by an extra chromosome X in the cells of males. Frequent clinical features of the syndrome are infertility, intellectual disability, metabolic syndrome and type 2 diabetes among others, and one out of every six hundred Saudi males are affected.

However, the MENA population is largely underrepresented when it comes to studying the impact of the genomic background on disease susceptibility and prognosis. The majority of studies involving the use of iPSCs have been performed using North American and European patients.

The KAUST-KAU-HAUH study addresses this gap using a "patient-derived induced pluripotent stem cells" (iPSC)-based disease modeling study aimed at understanding the molecular basis of Klinefelter syndrome. By using skin, blood, hair or urine-derived cell samples with the iPSC approach, it is possible to bring the patient's cells back to the embryonic state in which they developed, and use them to model the onset and progression of diseases "in a dish."

"The Kingdom is benefitting from the world-class collaboration between our three leading research entities," said Vice President for Research Pierre Magistretti, Distinguished Professor and director of the KAUST Smart-Health Initiative. "The iPSC technology is revolutionizing the study of the molecular mechanisms of diseases as it provides a way to work on human cells derived from patients."

Magistretti added that the platform for iPSC that KAUST scientists have developed allow for unique collaborations with clinical centers such as KAU KAUH and with the support of KAUST Smart-Health Initiative.

The results from this first joint Saudi study demonstrate the existence of a subset of genes residing on the X chromosome, whose dysregulation specifically characterizes Klinefelter syndrome, regardless of the geographical area of origin, ethnicity and genetic makeup.

"This Saudi iPSC cohort will serve as an ideal cellular platform to explore further work into chromosomal diseases," said Antonio Adamo, assistant professor and principal investigator in the Stem Cell and Diseases Laboratory at KAUST. "For example, it would be particularly interesting modeling neurodevelopment and anatomical changes affecting gray and white matters, features typically observed in Klinefelter Syndrome."

This cellular platform will be used to generate the so-called "mini-brains," three-dimensional cultures of patient-derived cells resembling the human brain that can be used to study the molecular mechanisms underlying the neurodevelopmental features of the disease. The findings yield an in vitro model suitable for the development of personalized medicine applications.

The findings are published in the journal Endocrine Connections.

More information: Veronica Astro et al, A transcriptomic signature of X chromosome overdosage in Saudi Klinefelter syndrome induced pluripotent stem cells, Endocrine Connections (2023). DOI: 10.1530/EC-22-0515

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First-of-its-kind stem cell study sheds light on Klinefelter syndrome - Medical Xpress

Scientists inject stem cells into the brain of Parkinsons patient – Freethink

A new stem cell therapy for Parkinsons disease has just been administered to a person for the first time and if it works as hoped, it could revolutionize how doctors treat the disease.

[W]e maybe have a treatment that we can offer to patientsin the beginning of the disease, like a one time treatment, and that will last for the rest of the patients life and make it possible to reduce the medication that patients otherwise need, said principal investigator Gesine Paul-Visse from Swedens Lund University.

The challenge: An estimated 8.5 million people are living with Parkinsons, a progressive neurodegenerative disorder caused by the loss of the brain neurons that produce the chemical dopamine, which helps coordinate movement.

The shortage of dopamine leads to the hallmark symptoms of Parkinsons, including tremors, stiffness, and impaired coordination. Medications can increase dopamine levels, but they can also cause side effects, interfere with other meds, and become less effective over time.

The use of stem cells will, in theory, enable us to make unlimited amounts of dopamine neurons.

The idea: Rather than relying on meds, Paul-Visse and her collaborators in Sweden and the UK hope to actually replace dopamine-producing nerve cells in the brains of Parkinsons patients using embryonic stem cells, which can develop into almost any type of cell in the body.

For their therapy, STEM-PD, the researchers programmed stem cells sourced from donated embryos to turn into dopamine nerve cells. When transplanted into the brains of rodent models of Parkinsons, the cells developed as hoped, and the animals motor symptoms were reversed.

The researchers have now administered the treatment to a person for the first time, and by the end of their newly launched STEM-PD trial, eight people with moderate Parkinsons will undergo the therapy.

Looking ahead: The trials primary goal is to assess the safety of STEM-PD, but the researchers will also be looking to see if the therapy improves symptoms, reduces the need for medication, or leads to the development of new dopamine-producing neurons in the brain.

The efficacy of the treatment wont be apparent right away, though.

These cells that we are transplanting are actually immature, so they need some time to mature in the adult brain, and that will take at least a year, maybe even longer, said Paul-Visse. So we wont expect to see any changes before in one years time.

The big picture: Treatments that work in animals often dont translate to people, but if STEM-PD proves safe and effective, the impact could be huge, given that stem cells can be duplicated an unlimited number of times.

The use of stem cells will, in theory, enable us to make unlimited amounts of dopamine neurons and thus opens the prospect of producing this therapy to a wide patient population, said clinical lead Roger Barker from the University of Cambridge. This could transform the way we treat Parkinsons disease.

Wed love to hear from you! If you have a comment about this article or if you have a tip for a future Freethink story, please email us at tips@freethink.com.

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How organoids are advancing the understanding of chronic kidney … – Nature.com

Kidney-like structures called organoids can be grown from stem cells.Credit: Xia Lab

Ryuichi Nishinakamuras quest to build a transplantable kidney began in the 1990s, when the nephrologist found he had little to offer his patients. At times he was ridiculed for setting such an unrealistic goal, but I was very naive and young, so I just went forward, recalls Nishinakamura, who is now a stem-cell biologist at Kumamoto University in Japan.

But the discoveries of human embryonic stem cells in 1998 and of a way to create induced pluripotent stem (iPS) cells in 2006 made the task of growing fresh kidneys seem more achievable. Many investigators differentiated various types of kidney cell from iPS cells and grew kidney organoids tiny, organ-like structures with multiple types of kidney cell that partly mimic kidney structure and function. In 2013, Nishinakamuras lab achieved one of the early milestones, demonstrating both mouse and human kidney organoids1. Many labs are now producing ever-more functional organoids that are proving useful in modelling kidney development and disease.

Part of Nature Outlook: Chronic kidney disease

But Nishinakamuras goal of a transplantable human kidney is still many years away. We do have kidney in a dish, says Melissa Little, a developmental biologist at the Murdoch Childrens Research Institute in Melbourne, Australia. But will it be useful if we transplant it? Thats a much bigger question.

We are at a bottleneck, says Yun Xia, a stem-cell biologist at Nanyang Technological University in Singapore, who sees an enormous gap between todays research and what people need. Like many of her colleagues, Xia worries that to keep its credibility with funders and the public, organoid research needs to show progress towards treatments. Some groups are working towards auxiliary kidneys, which would be a fraction of the size of a normal kidney but could still stabilize a persons health.

The kidney is an exceptionally tricky organ to replicate in a lab. Youve got 2530 distinct cell types with functional roles that have to be anatomically placed in the right position for the organ to work, says Little. By contrast, the heart is thought to have only nine major cell types2.

The kidneys functional unit for removing waste from the blood, the nephron, is an intricate and precisely organized structure. The first step in filtering the blood takes place in networks of small blood vessels called glomeruli. The resulting filtrate then passes through a series of tubes, in which various solutes are exchanged with blood vessels, before ending up in a branching tree of collecting ducts that funnels the waste to the ureter and out towards the bladder. For a kidney to function, it is not enough to simply have the right cells they must also be arranged correctly.

A number of daunting obstacles remain on the road to a transplantable kidney. One of the biggest is immaturity of the cells, which typically resemble progenitor cells from the first or second trimester of human development, limiting their functionality.

There has been steady progress on this front. In 2022, for instance, Little and her colleagues demonstrated more functional human proximal tubule cells, which she calls the powerhouses of the kidney3. The lab of nephrologist Joseph Bonventre at Brigham and Womens Hospital in Boston, Massachusetts, did the same that year for the collecting ducts two main functional cell types4.

Researchers have also worked out how to boost their ability to create kidney organoids in volume, another key requirement for potential treatments. For example, researchers in the Netherlands have grown sheets of iPS-cell-derived nephrons at a large scale5.

Like other forms of tissue derived from pluripotent stem cells, kidney organoids can include undesired off-target cells such as muscle neurons, and researchers need to follow precise protocols to guard against the appearance of tumour cells. General advances in the stem-cell field are minimizing these challenges.

Forming a vasculature, however, is a much greater hurdle. A fully developed and precisely structured blood system is needed to keep the flows of blood and urine exchanging correctly throughout the nephron. This has not been achieved in experimental systems, says Jamie Davies, a developmental biologist and tissue engineer at the University of Edinburgh, UK. Instead, the vasculature generally remains in a primitive state and soon dies out.

Organoids transplanted into immunodeficient mice do attract blood vessels from the host animal, allowing nephrons to start filtering the blood and generating urine, says Nishinakamura. However, the urine has nowhere to go, so transplants typically fail at that stage, he says.

The push to build better organoids based on iPS cells has vastly increased researchers understanding of kidney development and disease. Compared with cell cultures, organoids already offer enhanced models of kidney disease particularly for genetic illnesses in children. For example, the crucial cells that wrap around glomerulus capillaries and begin the filtering process, called podocytes, are rubbish in 2D cell cultures but much better representations in 3D organoids, Little says.

Organoid models also readily display the characteristic cysts of autosomal dominant polycystic kidney disease the most prevalent genetic kidney disease and one subject to intense research. One 2022 study reported a scalable human kidney organoid platform that enabled the testing of hundreds of small-molecule drugs against this condition6.

Researchers are now able to grow kidney organoids with more-functional cells.Credit: J. M. Vanslambrouck et al. Nature Commun. 13, 5943 (2022).

Diabetes is the largest driver of chronic disease in adults but a formidable task to model, because the condition impairs the blood vessels that are difficult to reproduce in organoids. Moreover, says Xia, kidney organoids, like many cell cultures, are generally bathed in high levels of glucose, making it hard to pick out the effects of the raised blood glucose levels generated in diabetes.

Kidney organoids show great promise in drug testing. Many drug candidates fail testing because they cause kidney damage, but this is not picked up in 2D cell cultures because they often lose their sensitivity, says Bonventre. For example, he says, the protein KIM-1 is a strong biomarker for damage to proximal tubule cells in vivo but not in 2D cell culture. If kidney organoids can display the same KIM-1 gene-expression patterns that are seen in vivo, they will provide excellent toxicity models, he says. His lab is studying such organoid-based models.

Using organoids based on iPS cells as a treatment for kidney disease is far from the first cell-based therapy to be proposed. Many clinical trials have tested the effect of mesenchymal stem cells (multipotent stem cells found in tissue, such as bone marrow), with mixed results. Most researchers agree that although these cells might secrete factors that help with kidney repair, they dont structurally improve the kidney. One long-studied alternative technique that selects, enhances and reinserts kidney cells from people with kidney disease is being examined in a phase III clinical trial sponsored by the biotechnology company ProKidney in Winston-Salem, North Carolina.

But injecting iPS-cell-based organoid-derived cells alone into kidneys doesnt seem to be a promising strategy, says Nishinakamura. Such cells might secrete factors that improve kidney function, much as mesenchymal stem cells are thought to do, he says. But these progenitor cells are unlikely to stay and play happily within the kidney; its not clear where the cells might go, or if and how they then mature.

Organoid-derived cells might help when it comes to improving transplants of donated kidneys, says Nria Montserrat, a stem-cell biologist at the Institute for Bioengineering of Catalonia in Barcelona, Spain. She is testing that hypothesis in collaboration with Cyril Moers, a transplant surgeon at the University of Groningen in the Netherlands. Donated organs are often maintained before transplant by being perfused in a liquid bath rather than frozen. Moers hopes that adding organoid-derived cells to these baths will allow these organs to be preserved better, evaluated more accurately and (eventually) made healthier before transplant. Montserrats lab is running pilot experiments with human organoid cells released into perfused pig kidneys.

More broadly, a number of groups are studying the potential for transplanting a more substantial set of organoid tissues into people with kidney disease. Little wants to create what she calls an auxiliary kidney, designed to connect to a persons failing kidney.

In her labs unpublished experiments, human kidney organoids transplanted into immunocompromised mice successfully gather blood vessels and start filtering urine. Getting all those nephrons to connect to the underlying kidney will be the challenge, she says. If the nephrons connect into the existing kidney itself, then the urine will go out the way all of the urine goes. Youre essentially freeloading on the anatomy of the existing patient kidney, even though that patients kidney is pretty sick.

More from Nature Outlooks

Biotechnology company Trestle Biotherapeutics in San Diego, California, is also developing a transplantable auxiliary kidney. Co-founder and developmental biologist Alice Chen says that this tissue might end up in another location, such as below the existing kidney near the bladder. Trestle is growing organoids about 100 times the size of those commonly reported in the scientific literature, she says, and is seeing encouraging progress in how these tissues engraft in mice, connect to the host circulation and continue to mature.

The start-up was launched with the view that a bioengineered kidney will demand industrial-scale expertise in many fast-evolving disciplines, including stem-cell science and 3D bioprinting. We had to pull all of that brainpower, those technologies and those ideas together, says Chen.

Most people with kidney disease are hoping for treatments that let them live their lives replacing or minimizing dialysis, or postponing the immediate need for a donated kidney rather than for a complete bioengineered organ. Were not creating an entire organ, we need to create some sort of tissue that can return 1020% function to these patients, Chen says. And that is achievable.

Some research groups are using organoids as potential sources of cells for hybrid external devices with bioengineered 3D scaffolds, designed to act like improved dialysis systems.

In one such effort, Bonventre hopes to make a device with a sub-population of just two types of cell: proximal tubule cells and collecting duct cells. Other types of kidney cells remain important, he says, but achieving every function of a normal kidney seems like a distant goal. Lets not shoot for a galaxy thats three billion light years away, he says. Lets try to get to the Moon first, and maybe Mars.

But Nishinakamura remains fixed on his original dream of a complete kidney, which he thinks is needed more than ever for the millions of people whose chronic kidney disease steadily progresses towards end-stage renal disease. Im always telling my graduate students, Dont say it is impossible.

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How organoids are advancing the understanding of chronic kidney ... - Nature.com

Why CRISPR babies are still too risky embryo studies highlight … – Nature.com

A human embryo at the 16-cell stage sits on the tip of a pin. Researchers say genome-editing techniques are still not safe enough to be used in embryos destined for reproduction.Credit: Dr Yorgos Nikas/Science Photo Library

More than four years after the first children with edited genomes were born, genome-editing techniques are still not safe enough to be used in human embryos that are destined for reproduction, organizers of the Third International Summit on Human Genome Editing announced at the conclusion of the meeting.

Heritable human genome editing remains unacceptable at this time, they said in a statement issued on 8 March. Preclinical evidence for the safety and efficacy of heritable human genome editing has not been established, nor has societal discussion and policy debate been concluded.

Beyond CRISPR babies: how human genome editing is moving on after scandal

The statement came at the end of a day of discussion and debate in London about the potential of altering the genomes of either embryos or reproductive cells, called gametes, in ways that would be passed down to future generations. Many of the talks at the meeting were focused on technical and scientific challenges, such as the uncertain consequences of breaking both strands of the DNA double helix a necessary step in some forms of genome editing in embryos.

In addition to those challenges, society must grapple with questions about whether the technology should be deployed, organisers said: Governance frameworks and ethical principles for the responsible use of heritable human genome editing are not in place.

Some researchers have argued that heritable genome editing could help people who carry genetic diseases to avoid passing those conditions on to their children. In many cases, this can already be done by combining in vitro fertilization (IVF) with testing of the resulting embryos for a given genetic disorder. But that is not always an option, such as when all a couples embryos will inevitably inherit the genetic disorder, or when all available embryos happen to carry the responsible genes.

In addition to broader concerns about ethics and social justice, editing embryos would require a safe and effective genome-editing platform to minimize the chances of harming the embryo, the resulting child, and that childs descendants. Most research on genome editing in embryos, however, has been done using animal models such as mice, which might not accurately reflect what happens in human embryos. And although potential genome-editing therapies have been widely studied in adult human cells, embryos might respond differently than adult cells to the DNA damage caused by some genome editing tools.

Only a handful of laboratories have directly tried to edit the genomes of human embryos using the popular editing system CRISPR-Cas9, and several of these presented concerning results at the summit.

CRISPR gene editing in human embryos wreaks chromosomal mayhem

The Cas9 enzyme works by breaking both strands of DNA at a site designated by a guiding piece of RNA. The cell then repairs that DNA break, either by using an error-prone mechanism that stitches the two ends together but sometimes deletes or inserts a few DNA letters in the process, or by replacing the missing DNA with a sequence copied from a template provided by the researcher. DNA breaks created by Cas9 in embryos are usually repaired using the error-prone pathway, rather than using the template DNA, said Deitrich Egli, a stem cell biologist at Columbia University in New York City, at the conference.

Egli and other researchers also reported on the consequences of the double-strand breaks made by Cas9. Developmental biologist Kathy Niakan at the University of Cambridge, UK, recounted her labs experience with the apparent loss of large regions of chromosomes that occurred when using CRISPR-Cas9 to edit human embryos1. Shoukhrat Mitalipov, a reproductive biologist at Oregon Health & Science University in Portland, also said that his laboratory had found large DNA deletions at the editing site in human embryos, and that these deletions might not be detected using standard tests2.

Can human embryos at this stage really tolerate this kind of intervention? asked Dagan Wells, a reproductive geneticist at the University of Oxford, UK, who also reported concerning responses to DNA breaks in human embryos. About 40% of the embryos in one of his genome-editing studies failed to repair broken DNA. Over one-third of those embryos continued to develop, he said, resulting in the loss or gain of pieces of chromosomes in some cells. That could risk the health of offspring if such embryos were allowed to develop further. These results are really a warning, he said.

There are newer variations on CRISPR-Cas9 editing that do not break both strands of the DNA helix. Base editing, for example, can convert one single DNA letter to another, and a technique called prime editing allows researchers to insert DNA sequences more predictably than CRISPR-Cas9 editing. Neither of these methods cause double-strand breaks, but they have not been as thoroughly studied and optimized as CRISPR-Cas9. At the summit, developmental biologist Yuyu Niu at the Kunming University of Science and Technology in China reported that one kind of base editor did not cause off-target DNA mutations in rhesus macaque (Macaca mulatta) embryos, but it did cause unwanted RNA mutations3.

Super-precise CRISPR tool enhanced by enzyme engineering

An alternative to editing embryos would be to instead edit gametes, such as eggs and sperm, or the stem cells that give rise to them. This would also sidestep concerns that efforts to edit embryos might not succeed in all cells of the embryo, resulting in offspring that contain a mixture of edited and unedited cells. Several researchers at the summit reported progress towards generating gametes in the laboratory, but doing this with human cells destined for reproductive uses still poses challenges.

The summit organizers urged that researchers continue to explore each of these options, even as policy makers and the public grapple with what restrictions should be placed on heritable genome editing.. We are still keen that the research goes ahead, said developmental biologist Robin Lovell-Badge of the Francis Crick Institute in London, who chaired the organizing committee for the summit. In parallel, there has to be more debate about whether the technique is ever used.

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Why CRISPR babies are still too risky embryo studies highlight ... - Nature.com

Study reveals limitations in evaluating gene editing technology in … – OHSU News

Gene editing technologies hold promise in preventing and treating debilitating inherited diseases, however new research from Oregon Health & Science University reveals limitations that must be overcome before gene-editing to establish a pregnancy can be deemed safe or effective. (OHSU/Sara Hottman)

A commonly used scientific method to analyze a tiny amount of DNA in early human embryos fails to accurately reflect gene edits, according to new research led by scientists at Oregon Health & Science University.

The study, published today in the journal Nature Communications, involved sequencing the genomes of early human embryos that had undergone genome editing using the gene-editing tool CRISPR. The work calls into question the accuracy of a DNA-reading procedure that relies on amplifying a small amount of DNA for purposes of genetic testing.

In addition, the study reveals that gene editing to correct disease-causing mutations in early human embryos can also lead to unintended and potentially harmful changes in the genome.

Together, the findings raise a new scientific basis for caution for any scientist who may be poised to use genetically edited embryos to establish pregnancies. Although gene editing technologies hold promise in preventing and treating debilitating inherited diseases, the new study reveals limitations that must be overcome before gene-editing to establish a pregnancy can be deemed safe or effective.

Shoukhrat Mitalipov, Ph.D. (OHSU)

It tells you how little we know about editing the genome, and particularly how cells respond to the DNA damage that CRISPR induces, said senior author Shoukhrat Mitalipov, Ph.D., director of the OHSU Center for Embryonic Cell and Gene Therapyand, professor of obstetrics and gynecology, molecular and cellular biosciences, OHSU School of Medicine, OHSU Oregon National Primate Research Center. Gene repair has great potential, but these new results show that we have a lot of work to do.

The findings come during the Third International Summit on Human Genome Editing in London. On the eve of the last international summit, held in Hong Kong in November 2018, a Chinese scientist revealed the birth of the worlds first babies resulting from gene-edited embryos through an experiment that generated global condemnation.

Interview with Shoukhrat Mitalipov, Ph.D., in the Mitalipovlab at OHSU. (OHSU/Sara Hottman)

Before an edited embryo can be transferred to establish a pregnancy, it is important to make sure the procedure worked as intended.

Because early human embryos consist of just a few cells, its not possible to collect enough genetic material to effectively analyze them. Instead, scientists interpret data from a small sample of DNA taken from a few or even a single cell, which then must be multiplied millions of times during a process known as whole genome amplification.

The same process known as preimplantation genetic testing, or PGT is often used to screen human embryos for various genetic conditions in patients undergoing in vitro fertilization.

Paula Amato, M.D.,(OHSU)

Whole genome amplification has limitations that reduce the accuracy of genetic testing, said senior co-author Paula Amato, M.D., professor of obstetrics and gynecology in the OHSU School of Medicine.

The concern is that we might be misdiagnosing embryos, Amato said.

Amato, who uses in vitro fertilization to treat patients struggling with infertility as well as to prevent the transmission of inherited diseases, said PGT using more advanced technology is still clinically useful for detecting chromosomal abnormalities and genetic disorders caused by a single gene mutation transmitted from parent to child.

The study highlights the challenges of establishing the safety of gene-editing techniques.

We may not be able to reliably predict that this embryo will result in a healthy baby, Mitalipov said. Thats a major problem.

To overcome these issues, OHSU researchers, along with collaborators with research institutions in South Korea and China, established embryonic stem cell lines from gene-edited embryos. Embryonic stem cells grow indefinitely and provide ample DNA material that does not require whole genome amplification to analyze.

Researchers say the discovery highlights the error-prone nature of whole genome amplification and the need to verify edits in embryos by establishing embryonic stem cell lines.

Using embryonic stem cells, the new study verifies the process of gene repair that Mitalipovs lab developed; the findings were published in the journal Naturein 2017 and verifiedin 2018.

In that study, scientists cut a specific target sequence on a mutant gene known to be carried by a sperm donor.

Researchers found that human embryos repair these breaks, using the normal copy of the gene from the other parent as a template. Mitalipov and co-authors confirmed that this process, known as gene conversion, occurs regularly in early human embryos following a double-strand break in their DNA. Such a repair, if used to establish a pregnancy through in vitro fertilization and embryo transfer, could theoretically prevent a known familial disease from being passed on to the child, as well as all future generations of the family.

In the study published in 2017, the OHSU researchers targeted a gene known to cause a deadly heart disease.

In this new publication, researchers targeted other discrete mutations using donated sperm and eggs, including one mutation known to cause hypertrophic cardiomyopathy, a condition in which the heart muscle becomes abnormally thick, and a different one associated with high cholesterol. In each case an enzyme known as Cas9, used in tandem with CRISPR, induced a double-strand break in DNA at the precise site of the mutation.

In addition to replicating and confirming the gene-repair mechanism reported in 2017, the new study examines what happens in the genome beyond the specific site where the mutant gene is repaired. And thats where a problem can occur.

In this paper we asked, how extensive is that gene conversion repair mechanism? Amato said. It turns out that it can be very lengthy.

Extensive copying of the genome, from one parent to the other, creates a scenario known as loss of heterozygosity.

Every human being shares two versions, or alleles, of every gene on the human genome one contributed from each parent. Most of the time, the alleles are identical, given 99.9% of any individuals DNA sequence is shared with the rest of humanity. In some cases, however, one parent will carry a recessive disease-causing mutation thats normally canceled out by the other parents dominant healthy version of the same gene.

These polymorphisms in the genetic code can be critically important. For example, a gene may encode a protein that protects against specific types of cancer.

If you have one abnormal copy of a recessive mutation, that may pose no risk, Amato said. But if you have loss of heterozygosity leading to two mutant copies of the same tumor suppressor gene, now youre at significantly increased risk for cancer.

The more genetic code thats copied, the greater the risk of dangerous genetic changes. In the new study, scientists measured gene conversion tracts ranging from a relatively small segment to as large as 18,600 base pairs of DNA.

In effect, the repair of one known mutation may create more problems than it solves.

If youre cutting in the middle of a chromosome, there could be 2,000 genes there, Mitalipov said. Youre fixing one tiny spot, but all these thousands of genes upstream and downstream may be affected.

The finding suggests that much more research is needed to understand the mechanism at work in gene-editing before using it clinically to establish a pregnancy.

Studies conducted at the OHSU Center for Embryonic Cell and Gene Therapy were supported by OHSU institutional funds and a grant from the Burroughs Wellcome Fund.

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Study reveals limitations in evaluating gene editing technology in ... - OHSU News

Stem Cell Assay Market :How the Market will perform in Upcoming … – Digital Journal

The Stem Cell Assay Market Industry research projection to 2023-2030 offers thorough industry data to help companies create growth plans and make smarter business choices based on predictions and market trends. The dynamic market structure, the product offerings of major players, their challenges, technical innovation, impediments and barriers, data on communication and sales, sales by country, risk, prospects, the competitive environment, growth strategy, and others are among the marketing variables covered in the study. It goes into great detail regarding the present and future conditions of the market. The report examines a range of elements, such as technology advancements, technological levels, and the various business models employed by the markets leading competitors at the moment.

Stem cells are the most fundamental type of biological cells. They have the ability to develop into multiple cell types and can multiply into more of the same type of stem cell. Adult stem cells and embryonic stem cells are the two different kinds of stem cells. These cells can be found in the bone marrow, adipose tissue, and blood, among other body parts. Also harvested from umbilical cord blood are stem cells. Two processesobligatory asymmetric replication and stochastic differentiationare used to maintain the bodys stem cell population. The introduction of stem cells has demonstrated promising outcomes in the treatment of numerous disorders, including cancer. Stem cells play a significant role in the bodys natural healing process.

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List of Key players in the global Stem Cell Assay Market: Merck & Co., Thermo Fisher Scientific, GE Healthcare, Agilent Technologies, Bio-Rad Laboratories, Promega Corporation, Cell Biolabs, PerkinElmer, Miltenyi Biotec, HemoGenix, Bio-Techne Corporation, STEMCELL Technologies, and Cellular Dynamics International.

SWOT Analysis of Global Stem Cell Assay Market

The report focuses on revenue analysis and SWOT analysis in addition to market share analysis of businesses, detailed profiles, product/service overviews, and business overviews to better correlate market competitiveness.

Information source and Research Methodology:

Using both primary (surveys and interviews) and secondary (industry body databases, dependable paid sources, and trade periodicals) data collection techniques, our researchers put the study together. A complete qualitative and quantitative analysis is included in the report. The research covers growth trends, micro- and macroeconomic indicators, as well as legislation and governmental programmes.

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The study looks at new market trends as well as the chance that different trends will have an impact on growth.The report also covers the elements, difficulties, and chances that will significantly affect the worldwide Stem Cell Assay market.Standards and technological instruments that take the Stem Cell Assay industrys predicted expansion into account.To forecast future growth rates, the research comprises a thorough analysis of market information as well as past and present growth trends.In order to produce forecasts for the future growth, the research comprises a thorough review of market statistics as well as historical and present growth conditions.

What are the goals of the report?

This market report displays the estimated market size for the Stem Cell Assay Market Industry at the end of the projected period.The research also examines historical and contemporary market sizes.The graphs display the compound annual growth rate (CAGR) and year-over-year growth (percent) for the specified forecast time.The study includes a market overview, geographic scope, segmentation, and financial results of the major rivals.The research evaluates the current situation of the industry inNorth America, Asia Pacific, Europe, Latin America, the Middle East, and Africa,as well as future growth opportunities.The study examines the future periods growth rate, market size, and market worth.

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Table of Content

Chapter 1 Industry Overview1.1 Definition1.2 Assumptions1.3 Research Scope1.4 Market Analysis by Regions1.5 Market Size Analysis from 2023 to 203011.6 COVID-19 Outbreak: Stem Cell Assay Industry Impact

Chapter 2 Stem Cell Assay Competition by Types, Applications, and Top Regions and Countries2.1Market (Volume and Value) by Type2.3Market (Volume and Value) by Regions

Chapter 3 Production Market Analysis3.1 Global Production Market Analysis3.2 Regional Production Market Analysis

Chapter 4 Stem Cell Assay Sales, Consumption, Export, Import by Regions (2016-2022)Chapter 5 North AmericaIndustry Market AnalysisChapter 6 East Asia Stem Cell Assay Market AnalysisChapter 7 EuropeIndustry Market AnalysisChapter 8 South Asia Stem Cell Assay Market AnalysisChapter 9 Southeast Asia Market AnalysisChapter 10 Middle East Stem Cell Assay Market AnalysisChapter 11 Africa Market AnalysisChapter 12 Oceania Market AnalysisChapter 13 South America Stem Cell Assay Market AnalysisChapter 14 Company Profiles and Key Figures in Stem Cell Assay BusinessChapter 15 Stem Cell Assay Market Forecast (2023-2030)Chapter 16 ConclusionsResearch MethodologyContinued.

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Finally, the report majorly enlightens the key growth and limiting factors which majorly targets at the center of the market affecting the growth and its development in either positive or negative extent. The report also specifies the impact of regulations and policies implemented by the administration over the current growth and upcoming opportunities that may lead to the market development escalation. The Stem Cell Assay Market report offers a superior vision of the global market, which will help clients to manage the business precisely with better growth and expansion compared to its contenders in the market.

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Stem Cell Assay Market :How the Market will perform in Upcoming ... - Digital Journal

Leading innovators in cell therapy for ocular disorders for the … – Pharmaceutical Technology

The pharmaceutical industry continues to be a hotbed of innovation, with activity driven by the evolution of new treatment paradigms, and the gravity of unmet needs, as well as the growing importance of technologies such as pharmacogenomics, digital therapeutics, and artificial intelligence. In the last three years alone, there have been over 633,000 patents filed and granted in the pharmaceutical industry, according to GlobalDatas report on Innovation in Pharmaceuticals: Cell therapy for ocular disorders.

However, not all innovations are equal and nor do they follow a constant upward trend. Instead, their evolution takes the form of an S-shaped curve that reflects their typical lifecycle from early emergence to accelerating adoption, before finally stabilising and reaching maturity.

Identifying where a particular innovation is on this journey, especially those that are in the emerging and accelerating stages, is essential for understanding their current level of adoption and the likely future trajectory and impact they will have.

110 innovations will shape the pharmaceutical industry

According to GlobalDatas Technology Foresights, which plots the S-curve for the pharmaceutical industry using innovation intensity models built on over 756,000 patents, there are 110 innovation areas that will shape the future of the industry.

Within the emerging innovation stage, cell therapy for ocular disorders, coronavirus vaccine components, and DNA polymerase compositions are disruptive technologies that are in the early stages of application and should be tracked closely. Adeno-associated virus vectors, alcohol dehydrogenase compositions, and antibody serum stabilisers are some of the accelerating innovation areas, where adoption has been steadily increasing. Among maturing innovation areas are anti-influenza antibody compositions and anti-interleukin-1, which are now well established in the industry.

Innovation S-curve for the pharmaceutical industry

Cell therapy for ocular disorders is a key innovation area in pharmaceuticals

Stem cells have the capacity to revive degenerated cells or replace cells. Various cell types have been used as the source of therapeutic cells, including human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs), and human umbilical tissue-derived cells (hUTCs). The regeneration, proliferation and differentiation potential of stem cells result in therapeutic intervention in different kinds of eye disease, including age-related macular degeneration (AMD), inherited retinal diseases (IRDs), glaucoma, and corneal diseases.

GlobalDatas analysis also uncovers the companies at the forefront of each innovation area and assesses the potential reach and impact of their patenting activity across different applications and geographies. According to GlobalData, there are 30+ companies, spanning technology vendors, established pharmaceutical companies, and up-and-coming start-ups engaged in the development and application of cell therapy for ocular disorders.

Key players in cell therapy for ocular disorders a disruptive innovation in the pharmaceutical industry

Application diversity measures the number of different applications identified for each relevant patent and broadly splits companies into either niche or diversified innovators.

Geographic reach refers to the number of different countries each relevant patent is registered in and reflects the breadth of geographic application intended, ranging from global to local.

Senju Pharmaceutical is the leading patent holder of cell therapies for ocular disorders. The company has filed a number of patents covering various cell therapies for the treatment of ophthalmic disorders. One notable patent is a miR-203 inhibitor for corneal epithelial disorder.

In terms of application diversity, Acro Biomedical is the top company, followed by Daiichi Sankyo, and Mayo Clinic. By means of geographic reach, Intellia Therapeutics holds the top position, while HLB Co Ltd, and Mayo Clinic stand in second and third positions, respectively.

To further understand the key themes and technologies disrupting the pharmaceutical industry, access GlobalDatas latest thematic research report on Pharmaceutical.

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GlobalData, the leading provider of industry intelligence, provided the underlying data, research, and analysis used to produce this article.

GlobalDatas Patent Analytics tracks patent filings and grants from official offices around the world. Textual analysis and official patent classifications are used to group patents into key thematic areas and link them to specific companies across the worlds largest industries.

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Leading innovators in cell therapy for ocular disorders for the ... - Pharmaceutical Technology

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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