Gene therapy | Description, Uses, Examples, & Safety Issues

Summary

gene therapy, also called gene transfer therapy, introduction of a normal gene into an individuals genome in order to repair a mutation that causes a genetic disease. When a normal gene is inserted into the nucleus of a mutant cell, the gene most likely will integrate into a chromosomal site different from the defective allele; although that may repair the mutation, a new mutation may result if the normal gene integrates into another functional gene. If the normal gene replaces the mutant allele, there is a chance that the transformed cells will proliferate and produce enough normal gene product for the entire body to be restored to the undiseased phenotype.

Human gene therapy has been attempted on somatic (body) cells for diseases such as cystic fibrosis, adenosine deaminase deficiency, familial hypercholesterolemia, cancer, and severe combined immunodeficiency (SCID) syndrome. Somatic cells cured by gene therapy may reverse the symptoms of disease in the treated individual, but the modification is not passed on to the next generation. Germline gene therapy aims to place corrected cells inside the germ line (e.g., cells of the ovary or testis). If that is achieved, those cells will undergo meiosis and provide a normal gametic contribution to the next generation. Germline gene therapy has been achieved experimentally in animals but not in humans.

Scientists have also explored the possibility of combining gene therapy with stem cell therapy. In a preliminary test of that approach, scientists collected skin cells from a patient with alpha-1 antitrypsin deficiency (an inherited disorder associated with certain types of lung and liver disease), reprogrammed the cells into stem cells, corrected the causative gene mutation, and then stimulated the cells to mature into liver cells. The reprogrammed, genetically corrected cells functioned normally.

Prerequisites for gene therapy include finding the best delivery system (often a virus, typically referred to as a viral vector) for the gene, demonstrating that the transferred gene can express itself in the host cell, and establishing that the procedure is safe. Few clinical trials of gene therapy in humans have satisfied all those conditions, often because the delivery system fails to reach cells or the genes are not expressed by cells. Improved gene therapy systems are being developed by using nanotechnology. A promising application of that research involves packaging genes into nanoparticles that are targeted to cancer cells, thereby killing cancer cells specifically and leaving healthy cells unharmed.

Some aspects of gene therapy, including genetic manipulation and selection, research on embryonic tissue, and experimentation on human subjects, have aroused ethical controversy and safety concerns. Some objections to gene therapy are based on the view that humans should not play God and interfere in the natural order. On the other hand, others have argued that genetic engineering may be justified where it is consistent with the purposes of God as creator. Some critics are particularly concerned about the safety of germline gene therapy, because any harm caused by such treatment could be passed to successive generations. Benefits, however, would also be passed on indefinitely. There also has been concern that the use of somatic gene therapy may affect germ cells.

Although the successful use of somatic gene therapy has been reported, clinical trials have revealed risks. In 1999 American teenager Jesse Gelsinger died after having taken part in a gene therapy trial. In 2000 researchers in France announced that they had successfully used gene therapy to treat infants who suffered from X-linked SCID (XSCID; an inherited disorder that affects males). The researchers treated 11 patients, two of whom later developed a leukemia-like illness. Those outcomes highlight the difficulties foreseen in the use of viral vectors in somatic gene therapy. Although the viruses that are used as vectors are disabled so that they cannot replicate, patients may suffer an immune response.

Another concern associated with gene therapy is that it represents a form of eugenics, which aims to improve future generations through the selection of desired traits. While some have argued that gene therapy is eugenic, others claim that it is a treatment that can be adopted to avoid disability. To others, such a view of gene therapy legitimates the so-called medical model of disability (in which disability is seen as an individual problem to be fixed with medicine) and raises peoples hopes for new treatments that may never materialize.

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Gene therapy | Description, Uses, Examples, & Safety Issues

History of Gene Therapy | Discovery and Evolution

References

1. Wirth T, Parker N, Yl-Hertuala. History of gene therapy. Gene. 2013;252(2):62-169.2. Food and Drug Administration. FDA continues strong support of innovation in development of gene therapy products. Press release. Accessed July 1, 2021. https://www.fda.gov/news-events/press-announcements/fda-continues-strong-support-innovation-development-gene-therapy-products3. Science History Institute. James Watson, Francis Crick, Maurice Wilkins, and Rosalind Franklin. Accessed July 1, 2021. https://www.sciencehistory.org/historical-profile/james-watson-francis-crick-maurice-wilkins-and-rosalind-franklin4. Nirenberg M. Historical review: Deciphering the genetic codea personal account. Trends Biochem Sci. 2004;29(1):46-54.5. Science History Institute. Herbert W Boyer and Stanley N Cohen. Accessed July 1, 2021. https://www.sciencehistory.org/historical-profile/herbert-w-boyer-and-stanley-n-cohen6. Sun M. Cline loses two NIH grants. Science. 1981;214(4525):1220.7. Blaese RM, Culver KW, Miller D, et al. T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science. 1995;270(5235):475-480.8. Kim YG, Cha J, Chandrasegaran S. Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain. Proc Natl Acad Sci U S A. 1996;93(3):1156-1160.9. Naldini L, Blomer U, Gallay P, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science. 1996;272(5259):263-267.10. Sibbald B. Death but one unintended consequence of gene-therapy trial. CMAJ. 2001;164(11):1612.11. Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest. 2018;118(9):3132-3142.12. Cavazzana-Calvo M, Fischer A. Gene therapy for severe combined immunodeficiency: are we there yet? J Clin Invest. 2007;117(6):1456-1465.13. Humeau L. From the bench to the clinic: story and lessons from VRX496, the first lentivector ever tested in a phase 1 clinical trial. Presented at: Beilstein Bozen Symposium; May 15-May 19, 2006; Bozen, Italy.14. Pearson S, Jia H, Kandachi K. China approves first gene therapy. Nat Biotechnol. 2004;22(1):3-4. 15. Daley J. Gene therapy arrives. Nature. 2019;576:S12-S13.16. Maguire AM, High KA, Auricchio A, et al. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009;374(9701):1597-1605.17. Luxturna (voretigene neparvovec-ryzl) [prescribing information]. Philadelphia, PA: Spark Therapeutics, Inc.; 2017.18. Christian M, Cermak T, Doyle EL, et al. Targeting DNA double-strand breaks with TAL effector nucleases. Genetics. 2010;186(2):757-761.19. Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human -thalassaemia. Nature. 2010;467(7313):318-322.20. Flemming A. Regulatory watch: Pioneering gene therapy on brink of approval. Nat Rev Drug Discov. 2012 ;11(9):664.21. Pharmaphorum. Glybera, the most expensive drug in the world, to be withdrawn after commercial flop. Accessed April 29, 2021. https://pharmaphorum.com/news/glybera-expensive-drug-world-withdrawn-commercial-flop/22. Cong L, Ran FA, Cox D, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339(6121):819-823.23. Aiuti A, Roncarolo MG, Naldini L. Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products. EMBO Mol Med. 2017;9(6):737-740.24. Strimvelis Summary of Product Characteristics, GlaxoSmithKline (GSK); 2016.25. Food and Drug Administration. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. Accessed April 27, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-car-t-cell-therapy-treat-adults-certain-types-large-b-cell-lymphoma26. European Medicines Agency. Yescarta. Accessed April 29, 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/yescarta27. Cross R. CRISPR is coming to the clinic this year. Chem Eng News. 2018;96(2):18-19.28. Food and Drug Administration. FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality. Accessed April 27, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease29. European Medicines Agency. Zolgensma. Accessed May 26, 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/zolgensma30. European Medicines Agency. Zynteglo. Accessed April 29, 2021. https://www.ema.europa.eu/en/medicines/human/referrals/zynteglo31. Regulatory Affairs Professional Society. FDA finalizes 6 gene therapy guidances, unveils a new draft. Accessed April 27, 2021. https://www.raps.org/news-and-articles/news-articles/2020/1/fda-finalizes-6-gene-therapy-guidances-unveils-a 32. PR Newswire. 4-day-old baby receives life-changing $2M gene therapy at woman's hospital in Baton Rouge. Accessed April 27, 2021. https://www.prnewswire.com/news-releases/4-day-old-baby-receives-life-changing-2m-gene-therapy-at-womans-hospital-in-baton-rouge-301233580.html

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History of Gene Therapy | Discovery and Evolution

Gene therapy: The Potential for Treating Type 1 Diabetes – Healthline

Many people whove recently received a diagnosis of type 1 diabetes (T1D) immediately think, When will there be a cure?

While the potential for a cure has been dangling in front of people with T1D for what seems like forever, more researchers currently believe that gene therapy could finally one day soon, even be the so-called cure thats been so elusive.

This article will explain what gene therapy is, how its similar to gene editing, and how gene therapy could potentially be the cure for T1D, helping millions of people around the world.

Gene therapy is a medical field of study that focuses on the genetic modification of human cells to treat or sometimes even cure a particular disease. This happens by reconstructing or repairing defective or damaged genetic material in your body.

This advanced technology is only in the early research phases of clinical trials for treating diabetes in the United States. Yet, it has the potential to treat and cure a wide range of other conditions beyond just T1D, including AIDS, cancer, cystic fibrosis (a disorder that damages your lungs, digestive tract, and other organs), heart disease, and hemophilia (a disorder in which your blood has trouble clotting).

For T1D, gene therapy could look like the reprogramming of alternative cells, making those reprogrammed cells perform the functions your original insulin-producing beta cells would otherwise perform. If you have with diabetes, that includes producing insulin.

But the reprogrammed cells would be different enough from beta cells so that your own immune system wouldnt recognize them as new cells and attack them, which is what happens in the development of T1D.

While gene therapy is still in its infancy and available only in clinical trials, the evidence so far is becoming clearer about the potential benefits of this treatment.

In a 2018 study, researchers engineered alpha cells to function just like beta cells. They created an adeno-associated viral (AAV) vector to deliver two proteins, pancreatic and duodenal homeobox 1 and MAF basic leucine zipper transcription factor A, to a mouses pancreas. These two proteins help with beta cell proliferation, maturation, and function.

Alpha cells are the ideal type of cell to transform into beta-like cells because not only are they also located within the pancreas, but theyre abundant in your body and similar enough to beta cells that the transformation is possible. Beta cells produce insulin to lower your blood sugar levels while alpha cells produce glucagon, which increases your blood sugar levels.

In the study, mouse blood sugar levels were normal for 4 months with gene therapy, all without immunosuppressant drugs, which inhibit or prevent the activity of your immune system. The newly created alpha cells, performing just like beta cells, were resistant to the bodys immune attacks.

But the normal glucose levels observed in the mice werent permanent. This could potentially translate into several years of normal glucose levels in humans rather than a longtime cure.

In this Wisconsin study from 2013 (updated as of 2017), researchers found that when a small sequence of DNA was injected into the veins of rats with diabetes, it created insulin-producing cells that normalized blood glucose levels for up to 6 weeks. That was all from a single injection.

This is a landmark clinical trial, as it was the first research study to validate a DNA-based insulin gene therapy that could potentially one day treat T1D in humans.

This was how the study worked:

The researchers are now working on increasing the time interval between therapy DNA injections from 6 weeks to 6 months to provide more relief for people with T1D in the future.

While this is all very exciting, more research is needed to determine how practical the therapy is for people. Eventually, the hope is that the AAV vectors could eventually be delivered to the pancreas through a nonsurgical, endoscopic procedure, in which a doctor uses a medical device with a light attached to look inside your body.

These kinds of gene therapy wouldnt be a one-and-done cure. But it would provide a lot of relief to people with diabetes to perhaps enjoy several years of nondiabetes glucose numbers without taking insulin.

If subsequent trials in other nonhuman primates are successful, human trials may soon begin for the T1D treatment.

Does that count as a cure?

It all depends on who you ask because the definition of a cure for T1D varies.

Some people believe that a cure is a one-and-done endeavor. They see a cure as meaning youd never have to think about taking insulin, checking blood sugars, or the highs and lows of diabetes ever again. This even means you wouldnt have to ever go back to a hospital for a gene therapy follow-up treatment.

Other people think that a once-in-a-few-years treatment of gene editing may be enough of a therapy plan to count as a cure.

Many others believe that you need to fix the underlying autoimmune response to truly be cured, and some people dont really care one way or another, as long as their blood sugars are normal, and the mental tax of diabetes is relieved.

One potential one-and-done therapy could be gene editing, which is slightly different from gene therapy.

The idea behind gene editing is to reprogram your bodys DNA, and if you have type 1 diabetes, the idea is to get at the underlying cause of the autoimmune attack that destroyed your beta cells and caused T1D to begin with.

Two well-known companies, CRISPR Therapeutics and regenerative med-tech company ViaCyte, have been collaborating for a few years to use gene editing to create islet cells, encapsulate them, and then implant them into your body. These protected, transplanted islet cells would be safe from an immune system attack, which would otherwise be the typical response if you have T1D.

The focus of gene editing is to simply cut out the bad parts of our DNA in order to avoid conditions such as diabetes altogether and to stop the continuous immune response (beta cell attack) that people who already have diabetes experience daily (without their conscious awareness).

The gene editing done by CRISPR in their partnership with ViaCyte is creating insulin-producing islet cells that can evade an autoimmune response. These technology and research are ever evolving and hold a lot of promise.

Additionally, a 2017 study shows that a T1Dcure may one day be possible by using gene-editing technology.

Both gene therapy and gene editing hold a lot of promise for people living with T1D who are hoping for an eventual future without needing to take insulin or immunosuppressant therapy.

Gene therapy research continues, looking at how certain cells in the body could be reprogrammed to start making insulin and not experience an immune system response, such as those who develop T1D.

While gene therapy and gene-editing therapy are still in their early stages (and much has been held up by the coronavirus disease 19 [COVID-19] pandemic), theres a lot of hope for a T1D cure in our near future.

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Gene therapy: The Potential for Treating Type 1 Diabetes - Healthline

Cell and gene therapy: Biopharma portfolio strategy | McKinsey

The potential importance of cell and gene therapy (CGT) to healthcare and the biopharma industry seems clear. CGT accounts for just 1 percent of launched products in major markets, with treatment of the vast majority of diseases still using small-molecule drugs. Yet those productswhich include cell therapies, such as chimeric antigen receptor (CAR) T-cell therapy for aggressive B-cell lymphomas, and gene therapiesto treat a range of monogenic rare diseaseshave proved transformative for patients. And there are many more in development. As of February 2020, CGT products account for 12 percent of the industrys clinical pipeline and at least 16 percent of the preclinical pipeline, but as most manufacturers do not disclose their preclinical assets, the true figure may be considerably higher (Exhibit 1).

Exhibit 1

New CGT products will surely emerge from this pipeline upon the continuing discovery of indications that CGT can address and the growing industry understanding of the genetic drivers and determinants of more complex, multifactorial diseases. Indeed, the pace of CGT-asset development is similar to that of monoclonal-antibody (mAb) assets in that modalitys early years, and mAb therapy went on to transform the biopharma market (see sidebar, Cell and gene therapy: Mirroring monoclonal-antibody therapy).

Exciting clinical results are helping to propel this pace. Success rates for CGT products are higher than those for small-molecule products, probably because CGT tends to target specific disease drivers rather than the broad targets (with potential for off-target effects) of small-molecule therapy. The sample size of launched CGTs is small, so comparisons may change as the market evolves. Nevertheless, there is a marked difference thus far. Between 2008 and 2018, the R&D success rate from Phase I to launch for small-molecule products was 8.2 percent; for CGT products, it was 11 percent.

Recognizing CGTs potential, 16 of the worlds largest (by revenue) 20 biopharmacos now have CGT assets in their product portfolios. Yet most companies are moving cautiouslyonly two of the top 20 have CGT assets making up more than 20 percent of their pipelines. They are still considering whether, when, and how to reposition their portfolios. In the meantime, biotech companies remain leaders in CGT innovation.

As of February 2020, only a small percentage of launched CGT assets either originated from or are owned by a top 20 biopharmacoin both cases, only 15 percent of launched assetsindicating how much opportunity there is for such companies to increase their exposure to CGT assets (Exhibit 2).

Exhibit 2

The figures are not altogether surprising, given that biopharmacos expertise often lies in disease areas, not in the development of the technology platforms that generate CGT products. More often than not, the original research behind new platforms is conducted by academics (who go on to set up their own biotech companies) and investors (whose models include company origination because of the potential financial gains and the concentrated technical risk that platform investments carry). Venture-capital firms are more comfortable than established biopharmacos with such risks.

Nevertheless, given the growth potential of CGT and the promise it holds for patients, most large biopharmacos are considering increasing their presence in the market. This article is intended to help guide their decisions, describing the key considerations when assessing investment opportunities and the various entry strategiesas well as the trade-offs to be made when choosing among them.

There are many technology platforms in development that seek to address different challengesassociated with CGT. In cell therapy, work is afoot to improve the manufacture of autologous therapies to reduce the cost of goods sold or vein-to-vein time, enable breakthrough efficacy in solid tumors, and improve the patient or customer experience. In gene therapy, there are investment opportunities in platforms that aim to overcome the limitations of current vectors (such as the size of the transgene, suboptimal tropism, or the triggering of an immune response) that enable nonviral delivery methods, reduce manufacturing costs, and expand manufacturing capacity.

The decision, therefore, is about not only whether to increase investment in CGT but also which technology platforms or assets to back. Companies should thus assess each investment opportunity by both strategic fit and technology attractiveness. Strategic considerations on a CGT platform or asset include whether it complements a companys disease areas of focus, the internal pipeline would benefit from diversification with new modalities, and the company has the required capabilities, capital, and conviction.

A host of questions need to be asked to gauge the attractiveness of the technology. Has it demonstrated proof of concept? What risks remain? Does the company have enough understanding of the underlying mechanisms? Does the technology enable first-mover advantage? What are the intellectual-property considerations? Is the platform differentiated from competing platforms? And given the rapid pace of innovation in CGT, what is the risk that the technology platform quickly becomes obsolete?

CAR T-cell therapy, whereby a patients T cells are genetically engineered to express a chimeric antigen receptor that targets a specific tumor antigen, illustrates the potential risk. In a relatively short time, the field has progressed from an initial set of constructs to a second generation that has given rise to two FDA-approved products, YESCARTA and KYMRIAH, even as third- and fourth-generation products are in development.

Investment opportunities that have a strong strategic fit and high-potential technologythose that fall into the top-right quadrant shown in Exhibit 3will be attractive. For example, a CAR T-cell or T-cell-receptor platform would fall in the top right for many oncology-focused companies. In the absence of such opportunities, those in the top-left or bottom-right quadrants may still be worthwhile as a means of gaining exposure to CGT, perhaps through an early-stage investment. For example, next-generation, unproven gene-editing technologies may fall in the bottom-right quadrant for companies focused on rare diseases with known genetic drivers. Companies would have to be prepared to tolerate the associated risks, however, and not all will conclude that now is the time to make a move.

Exhibit 3

Once a manufacturer has decided that it makes strategic sense to invest in CGT and has identified an attractive technology, it must choose an entry strategy. There are three main options: build a proprietary platform, buy an existing platform or one or more of its assets, or form a partnership to gain access to assets on platforms developed by others (Exhibit 4). The three options have different profiles in the capital required, changes to the operational model needed, and risk (as measured by the degree of diversification offered across different technologies).

Exhibit 4

Companies that build a platform or platforms from scratch enjoy full control over development efforts and retain all the financial rewards of successful assets. They also get the chance to build their own CGT capabilitiesscientific, clinical, and commercialand have the freedom to adapt as the technology evolves. In return, they have to commit significant resources to internal R&D and will, in effect, be placing big, early bets on a single or very limited number of platforms. Additionally, they may need to make significant changes to operating models designed for traditional modalities.

Buying a developed platform or late-stage asset carries less technical risk (assuming robust early data), though invariably a price premium too. This means that few, if any, companies will be able to acquire a large number of them, so companies continue to bet on a single or limited number of platforms.

The third optionforming a partnership to gain access to assets on platforms that others have developedlies between these two extremes in investment cost and risk. Because partnerships in the still-nascent CGT sector are relatively cheap, biopharmacos can afford to spread their bets on where future success might lie through establishing several partnerships.

Accordingly, most biopharmacos to date have followed the partnership route when placing a stake in CGT. Between 2010 and 2014, there were a total of 16 M&A deals in the CGT space. That rose to more than 60 between 2015 and 2019. However, even in 2019, when M&A activity was strongest, partnerships accounted for more than 80 percent of total transaction activity (Exhibit 5).

Exhibit 5

Nearly all of the top 20 biopharmacos have formed at least one partnership, while ten have made an acquisition. Just one has built its own platform. Exhibit 6 details this, along with the impact that the deals have had on the composition of company pipelines.

Exhibit 6

Partnerships come in three main varieties: those that give a biopharmaco access to a single asset, those that give it access to all assets in selected therapeutic areas that might emerge from a platform, and those that give it access to all platform assets, regardless of the therapeutic area or indication.

Partnerships structured to give a biopharmaco access to a single asset are the simplest way to enter the CGT market and are often chosen by companies that have a strong focus on certain indications and believe that their competitive advantage lies in owning multiple therapies across modalities in that space. A single-asset partnership also minimizes the investment required. However, this kind of partnership may leave a biopharmaco having to introduce a new operating model for a single asset.

Partnerships structured to give a biopharmaco access to all assets from a platform in certain therapeutic areas can help companies with a strong strategic focus on a given therapeutic area strengthen their portfolios and build more expertise in that area. In addition, more assets in a new modality means more opportunity to build the relevant development and commercial expertise.

The third option, partnering to win access to all the assets in a particular modality generated by a platform, tends to be the partnership of choice for biopharmacos that believe future competitive advantage lies in access to the best technology, no matter what may be the associated indication or therapeutic area. Through such a partnership, a company can follow the science, developing the technology for the indications in which it can provide the most clinical benefit. Such a strategy requires more investment than other forms of partnership, however, and so carries more concentrated technology risk. Companies may also find themselves developing products for therapeutic areas in which they have no expertise and thus are at a competitive disadvantage.

In addition to these three kinds of partnerships with biotech companies, some biopharmacos are considering more innovative ways to allocate their limited resources across multiple CGT technologies in a manner that also boosts their chances of keeping pace with rapid innovation. By partnering with venture-capital firms or biotech originators to launch new assets, new platforms, or even new companies or by collaborating with large academic institutions to license multiple new technologies, they are making much earlier-stage bets on where future success might lie.

The CGT era is an exciting one for healthcare, and all biopharmacos will want to reassess their portfolio strategies to decide whether and to what extent to diversify their pipelines. Most big biopharmacos have chosen partnerships to explore CGT initially, though the likelihood is that many will use a combination of strategies to increase their exposure and access to several technologies as the market evolves. Yet whether a company is still testing the water or is ready to commit, it will need to think carefully about how it builds its exposure to the CGT market and be fully aware of how to assess each investment opportunity, the range of possible entry strategies, and the different advantages and risks that each carries.

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Cell and gene therapy: Biopharma portfolio strategy | McKinsey

Difference Between Ex Vivo and In Vivo Gene Therapy

Key Difference Ex Vivo vs In Vivo Gene Therapy

Gene therapy is an important technique which is used to treat or prevent genetic diseases by introducing genes for missing or defective genes. Certain diseases can be cured by inserting the healthy genes in place of mutated or missing genes responsible for the disease. Gene therapy is mostly applied for somatic cells than germline cells, and it can be categorized into two major types named Ex vivo gene therapy and In vivo gene therapy. The key difference between Ex vivo and In vivo gene therapy is that therapeutic genes are transferred to in vitro cell cultures and reintroduced into a patient in ex vivo gene therapy while genes are delivered directly to patients tissues or cells without culturing the cells in vitro in in vivo gene therapy.

CONTENTS1. Overview and Key Difference2. What is Ex Vivo Gene Therapy3. What is In Vivo Gene Therapy4. Side by Side Comparison Ex Vivo vs In Vivo Gene Therapy5. Summary

Ex vivo gene therapy is a type of gene therapy which involves exterior modification of a patients cell and reintroduction of it to the patient. The cells are cultured in the labs (outside the patients body), and genes are inserted. Then the stable transformants are selected and reintroduced into the patient to treat the disease. Ex vivo gene therapy can be applied only to certain cell types or selected tissues. Bone marrow cells are the cells frequently used for ex vivo gene therapy.

There are several major steps involved in Ex vivo gene therapy as follows;

In ex vivo gene therapy, carriers or vectors are used to deliver genes into target cells. Successful gene delivery is dependent on the carrier system, and the important vectors used in ex vivo gene therapy are viruses, bone marrow cells, human artificial chromosome, etc. Compared to the in vivo gene therapy, ex vivo gene therapy does not involve adverse immunological reactions in the patients body since the genetic correction is done in vitro. However, the success depends on stable incorporation and expression of the remedial gene within the patient body.

Figure 01: Ex vivo gene therapy

In vivo gene therapy is a technique which involves direct delivery of genes into the cells of a particular tissue inside the patients body to treat genetic diseases. It can be applied to many tissues of the human body including liver, muscle, skin, lung, spleen, brain, blood cells, etc. The therapeutic genes are introduced by the viral or nonviral-based vectors into the patient. However, the success depends on several factors such as efficient uptake of the therapeutic gene carrying vectors by the target cells, intracellular degradation of the genes within the target cells and gene uptake by the nucleus, expression ability of the gene, etc.

Figure 02: In vivo gene therapy

Therapeutic genes are introduced into patients body as a treatment for certain diseases. It is known as gene therapy and can be done in two ways namely ex vivo gene therapy and in vivo gene therapy. The difference between ex vivo and in vivo gene therapy is that gene insertion in ex vivo gene therapy is done in the cell cultures exterior to patients body and the corrected cells are reintroduced to the patient while in in vivo gene therapy genes are introduced directly into the interior target tissues without isolating the cells. The success of the both processes depends on the stable insertion and transformation of the therapeutic genes into the patient cells.

Reference:1.What is gene therapy? Genetics Home Reference. U.S. National Library of Medicine. National Institutes of Health, n.d. Web. 24 Apr. 2017.2.Evaluation of the Clinical Success of Ex Vivo and In Vivo Gene Therapy | JYI The Undergraduate Research Journal. JYI The Undergraduate Research Journal. N.p., n.d. Web. 24 Apr. 20173. Crystal, Ronald G. In vivo and ex vivo gene therapy strategies to treat tumors using adenovirus gene transfer vectors. SpringerLink. Springer-Verlag, n.d. Web. 24 Apr. 2017

Image Courtesy:1. ExVivoGeneTherapy plBy Pisum na podstawie pracy Lizanne Koch Own work (CC BY-SA 3.0) via Commons Wikimedia2. In vivo gene therapy pl By Pisum na podstawie pracy Lizanne Koch Own work (CC BY-SA 3.0) via Commons Wikimedia

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Difference Between Ex Vivo and In Vivo Gene Therapy

Gene Therapy Gel Offers New Hope Against Rare Blistering Disease

THURSDAY, Dec. 15, 2022 (HealthDay News) -- An experimental gene therapy that's applied as a skin gel appears to heal wounds caused by a rare and severe genetic skin disease.

Experts called the findings "remarkable," and said they bring hope of a better quality of life to children and young adults living with the condition, called dystrophic epidermolysis bullosa (DEB).

The disease affects about 3 out of every 1 million people. It's caused by a flawed gene that renders the body unable to produce a particular collagen -- a "glue" between the skin layers that is essential to its strength and integrity.

Kids born with DEB are sometimes called "butterfly children" because their skin is so fragile, even an ordinary bump or friction can cause blistering that progresses to painful open wounds.

In the most severe cases, infants have blisters or missing skin at birth, or soon after. Those children typically develop widespread scarring over their bodies and can have eye inflammation that impairs their vision. Blisters and scarring also arise along the lining of the mouth, throat and digestive tract -- which can interfere with eating and cause malnutrition.

As young adults, people with DEB face a high risk of squamous cell carcinoma, a form of skin cancer that is normally highly curable, but in a person with DEB often proves deadly.

There has never been any specific treatment for DEB. Managing it is all about wound care, preventing infections, trying to relieve pain and other "supportive" therapies, said Dr. Peter Marinkovich, the senior researcher on the new study.

"We're helplessly watching blisters and wounds form, without any way to stop them," said Marinkovich, who directs Stanford University's Blistering Disease Clinic.

The new gene therapy, delivered by a skin gel applied directly to wounds, could become the first treatment for the rare disease. Krystal Biotech, the product's developer, has submitted an application for approval to the U.S. Food and Drug Administration, and said the agency granted it "priority review" designation.

The therapy does not correct the genetic flaw causing DEB, or cure the disease.

Instead, the gel contains a modified herpes virus that delivers two functioning copies of the gene, called COL7A1, to patients' skin cells. The cells are then able to produce the missing collagen protein -- with the goal of healing wounds.

In the new trial, published Dec. 15 in the New England Journal of Medicine, Marinkovich and his team found the approach did just that.

The study involved 31 children and adults with DEB. Each patient had one wound treated with the gene therapy gel, and a second, similar wound treated with a placebo (inactive) gel. In all cases, it was applied during weekly bandage changes.

After six months, 67% of wounds treated with the gene therapy were completely closed, versus 22% of those treated with the placebo gel. That included healing of longstanding -- even 10-year-old -- wounds, according to Marinkovich.

Other experts called the trial "pivotal," and said that if the therapy continues to have such benefits over the long term, it could have a "transformational" impact on patients' quality of life.

"This is a devastating disease," said Dr. Aimee Payne, a professor of dermatology at the University of Pennsylvania.

Payne, who wrote an editorial published with the study, said that various high-tech treatments for DEB have been attempted -- including stem cell therapies and skin grafts.

"And now this comes along, and it's a salve that you put on the skin," Payne said. "It almost seems magical."

The notion of topical treatments is new to the gene therapy field, said David Schaffer, a professor of chemical and biomolecular engineering at the University of California, Berkeley.

A limitation of the approach is that it's transient, explained Schaffer, who wrote a separate editorial published with the study. As skin cells naturally die, the functioning COL7A1 gene is lost, too.

So the topical therapy will likely need to be repeated indefinitely. In addition, it does not penetrate the skin, Schaffer said. That means while it can be applied as needed to new wounds, it cannot prevent them.

That said, a gel capable of closing wounds could transform patients' lives, according to Schaffer. And if that healing is ultimately shown to prevent squamous cell carcinoma, he said, "that would be huge."

As for safety, the trial found no serious side effects. A theoretical concern, the experts said, is that the immune system could react against the herpes simplex virus used in the gel, or the newly produced collagen protein.

The herpes virus is genetically modified so that it cannot replicate or spread in the body. But because the virus is naturally adept at evading the immune system, Marinkovich explained, it's a good vehicle for delivering the COL7A1 gene to cells without sparking an immune response.

The skin gel does not address the internal lesions that DEB causes. But, Marinkovich said, it's possible the same gene therapy could be delivered to those areas of the body by other means -- drops for the eyes, an oral "swish" for the mouth, or suppositories for anal lesions.

Among the ongoing research steps, he said, is to treat skin lesions in younger children, as early as 6 months of age, to see if that can prevent extensive skin scarring.

Schaffer pointed to the bigger picture. Gene therapy, he said, has long been "held back" by a lack of good delivery systems. But that's changing. Just last month, Schaffer noted, the first gene therapy for hemophilia B -- delivered by a single IV infusion -- was approved by the FDA.

"Gene therapy is beginning to work," he said.

More information

The nonprofit DEBRA has more on the different forms of epidermolysis bullosa.

SOURCES: M. Peter Marinkovich, MD, associate professor, dermatology, and director, Blistering Disease Clinic, Stanford University School of Medicine; Aimee S. Payne, MD, PhD, professor, dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia; David V. Schaffer, PhD, professor, chemical and biomolecular engineering, bioengineering, molecular and cell biology, University of California, Berkeley; New England Journal of Medicine, Dec. 15, 2022

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Gene Therapy Gel Offers New Hope Against Rare Blistering Disease

What is Gene Therapy? | FDA – U.S. Food and Drug Administration

Human gene therapy seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use 1.

Gene therapy is a technique that modifies a persons genes to treat or cure disease. Gene therapies can work by several mechanisms:

Gene therapy products are being studied to treat diseases including cancer, genetic diseases, and infectious diseases.

There are a variety of types of gene therapy products, including:

Gene therapy products are biological products regulated by the FDAs Center for Biologics Evaluation and Research (CBER). Clinical studies in humans require the submission of an investigational new drug application (IND) prior to initiating clinical studies in the United States. Marketing a gene therapy product requires submission and approval of a biologics license application (BLA).

Long Term Follow-Up After Administration of Human Gene Therapy Products; Guidance for Industry, January 2020

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What is Gene Therapy? | FDA - U.S. Food and Drug Administration

New Treatments for Retinitis Pigmentosa – American Academy of …

Hope may be on the horizon for people with retinitis pigmentosa, a rare inherited eye disease with no cure. Existing treatments only help a fraction of the estimated 100,000 Americans with this condition. But advances in gene therapy may soon help restore vision to a greater number of people.

Retinitis pigmentosa causes light-detecting cells in the retina to break down over time, destroying vision. Mutations in more than 60 different genes can contribute to this condition.

If you are diagnosed with retinitis pigmentosa, its vital to undergo genetic testing to identify your underlying mutation," says Ninel Gregori, M.D., an Academy member and a professor of clinical ophthalmology at Bascom Palmer Eye Institute.

That's because people with certain genetic mutations may qualify to participate in a clinical trial of a new treatment before it's widely available.

"Knowing which gene causes your disease and asking your ophthalmologist about options to join a clinical trial may help save your vision, Gregori says.

Two treatments are currently available for patients with retinitis pigmentosa.

The gene therapy Luxturna is only for patients with a mutation in both copies of the RPE65 gene. Because of this mutation, the retina doesn't respond properly to light. A single injection of Luxturna delivers a healthy copy of the RPE65 gene directly to the retina. This restores the retina's ability to respond to light.

If patients receive the treatment early enough after diagnosis, Luxturna can improve night vision and help patients better navigate in low-light conditions.

Luxturna was developed by Spark Therapeutics and approved in 2017 by the U.S. Food and Drug Administration. It costs $850,000 for both eyes, which may be covered by insurance.

Patients with advanced retinitis pigmentosa may experience some minor improvements in vision using the Argus II bionic eye. Patients who benefit from this treatment often have very low visual acuity, and may only be able to perceive light. A surgery is required to place a small electronic device on the retina. Patients must also wear a special pair of glasses mounted with a video processing technology. The glasses send images to the device, which stimulates light-sensing cells in the retina and transmits these images to the brain.

Earlier this year, Second Sight Medical Products announced a redesigned set of glasses for use with previously implanted Argus II systems, but the glasses are not yet commercially available. Although new Argus II implants are no longer available, a different implant is in early development in Australia.

Several new treatments on the horizon aim to benefit people with retinitis pigmentosa. Many of these therapies are still being tested, and it will likely be several years before they become available to patients. But the results so far are promising. Ask your ophthalmologist whether you qualify for a clinical trial.

GenSight Therapeutics is testing a treatment that has the potential to help people with retinitis pigmentosa regardless of their genetic mutation. Treatments that use light as a tool to control cells are known as optogenetic therapies.

The optogenetic therapy from GenSight combines an eye injection with the use of high-tech goggles. The injection delivers a gene that helps retinal cells respond to light. The goggles allow these cells to send electrical signals to the brain. Together, the injection and goggles attempt to replicate the work of light-sensing cells called photoreceptors, which don't work well in people with retinitis pigmentosa.

Patients must train for several months to learn how to use the goggles. So far, five patients have had the treatment. Some have gained the ability to distinguish high-contrast objects on a table and identify crosswalk lines on the street. They are still not able to read, recognize faces or drive. Other companies pursuing optogenetic therapies include Retrosense Therapeutics (Allergan), Nanoscope Therapeutics, and Vedere Bio, Inc. (Novartis).

People with an aggressive form called X-linked retinitis pigmentosa may benefit from experimental gene therapies in development by three companies: Meira GTX, Applied Genetic Technologies and BioGen. This condition is caused by a mutation in the RPGR gene and typically affects men.

All three treatments involve a procedure called vitrectomy and an eye injection that delivers healthy copies of the RPGR gene to a part of the retina called the macula. Some patients in the clinical trials who received treatment in one eye experienced improvements in their field of vision, light sensitivity and ability to navigate in a dark room. A company called 4D Molecular Therapeutics is testing another type of gene therapy that does not require a vitrectomy.

ProQR Therapeutics is developing a gene therapy that could stop vision loss in people with retinitis pigmentosa and Usher syndrome caused by a mutation in the USH2Agene. This mutation prevents patients from making the USH2A protein, which is essential for vision. The therapy, called QR-421a, is injected into the retina and allows cells to produce a healthier version of the USH2A protein. So far, patients with both advanced and early-moderate disease experienced improvements in both visual acuity and field of vision. ProQR Therapeutics expects to test the therapy in a phase 2-3 clinical trial in the fall of 2021.

Another study by ProQR Therapeutics is testing a treatment for people who have retinitis pigmentosa due to a mutation in the RHOgene. This is also known as RP4. This mutation causes patients to produce a faulty version of the rhodopsin protein, which normally converts light into an electrical signal. The faulty protein becomes toxic to the retina over time. The new treatment, QR-1123, is delivered by an eye injection and prevents the faulty protein from being made. This allows the normal version of the protein to rule the retina again. This therapy is currently being studied in a phase 1-2 clinical trial.

Leber congenital amaurosis is a form of retinitis pigmentosa that affects infants. This disease destroys light-sensing cells in the retina. Type 10 disease is caused by a defect in the CEP290 gene that leads to progressive vision loss and, in many cases, legal blindness.

There are two promising treatments in development for this treatment.

Scientists have developed a gene-editing tool called CRISPR to try to remove the genetic defect. The treatment is delivered to the retina during an eye injection. Researchers hope the tool will help the retina produce a protein that keeps cells from dying and also revives some dead cells. This could help patients regain some vision. Allergan and Editas Medicine are leading the phase 1-2 BRILLIANCE clinical trial with 18 patients to test this treatment.

ProQR Therapeutics is testing a type of gene therapy known as RNA antisense oligonucleotide therapy. This treatment is delivered via an eye injection, and it allows production of a protein needed for vision. Patients in an ongoing phase 2-3 clinical trial are experiencing significant improvements in vision and retinal structure several months after injection.

These treatments could help patients avoid debilitating vision loss due to retinitis pigmentosa.

Gene therapy for some forms of retinitis pigmentosa offer the potential of halting the otherwise relentless progressive loss of vision and visual field. In some patients, it may actually improve vision, light sensitivity, and ability to see and navigate in the dark, says Christine Kay, MD, director of retinal genetics at Vitreoretinal Associates in Gainesville, FL.

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New Treatments for Retinitis Pigmentosa - American Academy of ...

Fact Check-mRNA vaccines are distinct from gene therapy … – Reuters

Vaccines that use mRNA technology are not gene therapy because they do not alter your genes, experts have told Reuters after contrary claims were posted online.

Thousands of social media users have shared such posts since the rollout of COVID-19 vaccines began (here) and have continued to do so through August.

Its not a vaccine. Its gene therapy! wrote one Facebook user on Aug. 9, noting that gene therapy manipulates genetic code (here and here).

Pfizer/BioNTech and Moderna have both developed shots that use a piece of genetic code from SARS-CoV-2, the coronavirus that causes COVID-19, to prompt an immune response in recipients (here). However, experts told Reuters that this is not the same as gene therapy.

As mRNA is genetic material, mRNA vaccines can be looked at as a genetic-based therapy, but they are classified as vaccines and are not designed to alter your genes, said Dr Adam Taylor, a virologist and research fellow at the Menzies Health Institute, Queensland, Griffith University.

Gene therapy, in the classical sense, involves making deliberate changes to a patients DNA in order to treat or cure them. mRNA vaccines will not enter a cells nucleus that houses your DNA genome. There is zero risk of these vaccines integrating into our own genome or altering our genetic makeup.

Taylor explained that mRNA enters cells shortly after vaccination and instructs them to create a SARS-CoV-2 spike protein, prompting the immune response.

He added that unlike gene therapy, mRNA vaccines are then rapidly degraded by the body.

In fact, because mRNA is degraded so quickly chemical modifications can be made to mRNA vaccines to make them a little more stable than regular mRNA.

Gene therapy, on the other hand, involves a process whereby an individuals genetic makeup is deliberately modified to cure or treat a specific genetic condition (here).

It can be done in several ways, such as replacing a disease-causing gene with a healthy alternative, disabling a disease-causing gene or introducing a new gene to help treat a disease, according to the U.S. Food and Drug Administration (FDA) (here).

If we suffer from an inherited blood disease then the defect in our genes can be corrected in blood cells and then we can be cured, said David Schaffer, professor of Chemical and Biomolecular Engineering and Director of the Berkeley Stem Cell Center at the University of California, Berkeley, in an email to Reuters.

In most cases, the DNA is therapeutic because it encodes a mRNA, which encodes a protein that has a beneficial effect on a patient. So, if someone has a disease where the gene encoding an important protein is mutated - such as hemophilia, cystic fibrosis, retinitis pigments - then it can be possible to deliver the DNA encoding the correct copy of that protein in order to treat the disease.

He added: Because DNA has the potential to persist in the cells of a patient for years, this raises the possibility of a single gene therapy treatment resulting in years of therapeutic benefit.

Moderna, which has developed one of the mRNA COVID-19 vaccines used across the world, explained in a fact sheet that mRNA and gene therapy take fundamentally different approaches.

Gene therapy and gene editing alter the original genetic information each cell carries, the company writes. The goal is to produce a permanent fix to the underlying genetic problem by changing the defective gene. Moderna is taking a different approach to address the underlying cause of MMA and other diseases. mRNA transfers the instructions stored in DNA to make the proteins required in every living cell. Our approach aims to help the body make its own missing or defective protein (www.modernatx.com/about-mrna).

Reuters has in the past debunked claims that COVID-19 vaccines can genetically modify humans here and here .

Missing context. Scientists told Reuters that while mRNA vaccines can be considered genetic-based therapy because they use genetic code from COVID-19, they are not technically gene therapy. This is because the mRNA does not change the bodys genetic makeup.

This article was produced by the Reuters Fact Check team. Read more about our work to fact-check social media postshere .

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Fact Check-mRNA vaccines are distinct from gene therapy ... - Reuters

The Era of One-Shot, Multimillion-Dollar Genetic Cures Is Here – WIRED

  1. The Era of One-Shot, Multimillion-Dollar Genetic Cures Is Here  WIRED
  2. Despite Eye-Popping $3.5 Million Price Tag For Gene Therapy Hemgenix, Budget Impact For Most Payers Will Be Relatively Small  Forbes
  3. FDA approves first haemophilia B gene therapy  Nature.com
  4. FDA Approves $3.5 Million Hemophilia B Gene Therapy  BioPharm International
  5. A $3.5M 'bargain'? CSL's hemophilia B drug sets new pricing benchmark, as gene therapy costs mount  MM+M Online
  6. View Full Coverage on Google News

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The Era of One-Shot, Multimillion-Dollar Genetic Cures Is Here - WIRED

Manslaughter Case Has a Strange Twist: Tesla That Killed Couple Was on Autopilot

A court case is about to kick off in Los Angeles later this month, involving a fatal crash caused by a Tesla vehicle, which was on Autopilot.

A provocative manslaughter case is about to kick off in Los Angeles later this month, involving a fatal crash caused by a Tesla vehicle that had the company's controversial Autopilot feature turned on.

It's the first case of its kind, and one that could set a precedent for future crashes involving cars and driver-assistance software, Reuters reports.

We won't know the exact defense until the case gets under way, but the crux is that the man who was behind the wheel of the Tesla is facing manslaughter charges — but has pleaded not guilty, setting up potentially novel legal arguments about culpability in a deadly collision when, technically speaking, it wasn't a human driving the car.

"Who's at fault, man or machine?" asked Edward Walters, an adjunct professor at the Georgetown University, in an interview with Reuters. "The state will have a hard time proving the guilt of the human driver because some parts of the task are being handled by Tesla."

The upcoming trial is about a fatal collision that took place in 2019. The crash involved Kevin George Aziz Riad, who ran a red light in his Tesla Model S, and collided with a Honda Civic, killing a couple who were reportedly on their first date.

According to vehicle data, Riad did not apply the brakes but had a hand on the steering wheel. Perhaps most critically, though, the Tesla's Autopilot feature was turned on in the moments leading up to the crash.

Riad is facing manslaughter charges, with prosecutors arguing his actions were reckless.

Meanwhile, Riad's lawyers have argued that he shouldn't be charged with a crime, but have so far stopped short of publicly placing blame on Tesla's Autopilot software.

Tesla is not directly implicated in the upcoming trial and isn't facing charges in the case, according to Reuters.

A separate trial, however, involving the family of one of the deceased is already scheduled for next year — but this time, Tesla is the defendant.

"I can't say that the driver was not at fault, but the Tesla system, Autopilot, and Tesla spokespeople encourage drivers to be less attentive," the family's attorney Donald Slavik told Reuters.

"Tesla knows people are going to use Autopilot and use it in dangerous situations," he added.

Tesla is already under heavy scrutiny over its Autopilot and so-called Full Self-Driving software, despite conceding that the features "do not make the vehicle autonomous" and that drivers must remain attentive of the road at all times.

Critics argue that Tesla's marketing is misleading and that it's only leading to more accidents — not making the roads safer, as Tesla CEO Elon Musk has argued in the past.

In fact, a recent survey found that 42 percent of Tesla Autopilot said they feel "comfortable treating their vehicles as fully self-driving."

Regulators are certainly already paying attention. The news comes a week after Reuters revealed that the Department of Justice is investigating Tesla over Autopilot.

Last year, the National Highway Traffic Safety Administration (NHTSA) announced an investigation of accidents in which Teslas have smashed into emergency response vehicles that were pulled over with sirens or flares.

This month's trial certainly stands the chance of setting a precedent. Was Riad fully at fault or was Tesla's Autopilot at least partially to blame as well?

The answer now lies in the hands of a jury.

READ MORE: Tesla crash trial in California hinges on question of 'man vs machine' [Reuters]

More on Autopilot: Survey: 42% of Tesla Autopilot Drivers Think Their Cars Can Drive Themselves

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Manslaughter Case Has a Strange Twist: Tesla That Killed Couple Was on Autopilot

There’s Something Strange About How These Stars Are Moving, Scientists Say

Astronomers are puzzled by the strange behavior of a crooked cluster of stars, which appears to be following an alternative theory of gravity.

Astronomers are puzzled by the strange behavior of certain crooked clusters of stars, which appear to be violating our conventional understanding of gravity.

Massive clusters of stars usually are bound together in spirals at the center of galaxies. Some of these clusters fall under a category astrophysicists call open star clusters, which are created in a relatively short period of time as they ignite in a huge cloud of gas.

During this process, loose stars accumulate in a pair of "tidal tails," one of which is being pulled behind, while the other moves ahead.

"According to Newton’s laws of gravity, it’s a matter of chance in which of the tails a lost star ends up," Jan Pflamm-Altenburg of the University of Bonn in Germany, co-author of a new paper published in the Monthly Notices of the Royal Astronomical Society, in a statement. "So both tails should contain about the same number of stars."

But some of their recent observations seemingly defy conventional physics.

"However, in our work we were able to prove for the first time that this is not true," Pflamm-Altenburg added. "In the clusters we studied, the front tail always contains significantly more stars nearby to the cluster than the rear tail."

In fact, their new findings are far more in line with a different theory called "Modified Newtonian Dynamics" (MOND).

"Put simply, according to MOND, stars can leave a cluster through two different doors," Pavel Kroupa, Pflamm-Altenburg's colleague at the University of Bonn and lead author, explained in the statement. "One leads to the rear tidal tail, the other to the front."

"However, the first is much narrower than the second — so it’s less likely that a star will leave the cluster through it," he added. "Newton’s theory of gravity, on the other hand, predicts that both doors should be the same width."

The researchers' simulations, taking MOND into consideration, could explain a lot. For one, they suggest that open star clusters survive a much shorter period of time than what is expected from Newton's laws of physics.

"This explains a mystery that has been known for a long time," Kroupa explained. "Namely, star clusters in nearby galaxies seem to be disappearing faster than they should."

But not everybody agrees that Newton's laws should be replaced with MOND, something that could shake the foundations of physics.

"It’s somewhat promising, but it does not provide completely definitive evidence for MOND," University of Saint Andrews research fellow Indranil Banik told New Scientist. "This asymmetry does make more sense in MOND, but in any individual cluster there could be other effects that are causing it — it’s a bit unlikely that would happen in all of them, though."

The researchers are now trying to hone in on an even more accurate picture by stepping up the accuracy of their simulations, which could either support their MOND theory — or conclude that Newton was, in fact, correct the first time around.

More on star clusters: Something Is Ripping Apart the Nearest Star Cluster to Earth

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There's Something Strange About How These Stars Are Moving, Scientists Say

Greta Thunberg Says UN Climate Conference Is a Scam and She’s Not Attending

The UN's upcoming COP27 climate conference in Egypt is basically a

COP Out

Ever since she lambasted world leaders at a UN conference in 2018 when she was only 15 years old, Swedish environmental activist Greta Thunberg has had the ear of the international community.

Now, Thunberg says she's skipping out on next week's COP27 UN climate summit in Egypt. Why? Because it's rife with "greenwashing."

"I'm not going to COP27 for many reasons, but the space for civil society this year is extremely limited," Thunberg said at a press event for her book, "The Climate Book," as quoted by The Guardian. "The COPs are mainly used as an opportunity for leaders and people in power to get attention, using many different kinds of greenwashing."

Ultimately, in Thunberg's view, the COP conferences "are not really meant to change the whole system" and instead only promote incremental change. Bluntly put, they're feel-good events that don't accomplish much, so she's bowing out.

Wasted Breath

It's not an unfair assessment. For all the pledges made to drastically cut back emissions and achieve net carbon zero by 2050, very few nations have followed through in the short term. And in Europe, the energy crisis in the wake of the war in Ukraine has further sidelined those climate commitments.

So we can't blame her for not going. But it's a bit disheartening that even a tenacious young spokesperson like Thunberg has given up on convincing world leaders at the biggest climate summit in the world.

Maybe it's indicative of the frustrations of her generation at large. When Thunberg was asked what she thought about the recent wave of Just Stop Oil protests that included activists throwing soup on a Van Gogh painting, she said that she viewed what many detractors perceived as a dumb stunt to be symptomatic of the world's failure to effect meaningful environmental change.

"People are trying to find new methods because we realize that what we have been doing up until now has not done the trick," she replied, as quoted by Reuters. "It's only reasonable to expect these kinds of different actions."

Maybe the real question is: if even a UN climate conference isn't the place to get the message out and change hearts, where's the right place, and what's the right way? If the headlines are any indication, zoomers are struggling to figure that out.

More on Greta Thunberg: Greta Thunberg Thinks Germany Shutting Down Its Nuclear Plants Is a Bad Idea

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Greta Thunberg Says UN Climate Conference Is a Scam and She's Not Attending

Twitter Working on Plan to Charge Users to Watch Videos

According to an internal email obtained by The Washington Post, Musk wants to have Twitter charge users to view videos posted by content creators.

Now that Tesla CEO Elon Musk has taken over Twitter, the billionaire has been frantically shuffling through ambitious plans to turn the ailing social media platform into a revenue-driving business.

Case in point, according to internal email obtained by The Washington Post, Musk is plotting for Twitter to charge users to view videos posted by content creators and take a cut of the proceeds — a highly controversial idea that's already been met with internal skepticism.

The team of Twitter engineers has "identified the risk as high" in the email, citing "risks related to copyrighted content, creator/user trust issues, and legal compliance."

In short, Musk is blazing ahead with his infamously ambitious timelines — a "move fast and break things" approach that could signify a tidal change for Twitter's historically sluggish approach to launching new features.

Musk has already made some big structural changes to Twitter, having fired high-up positions at the company and dissolved its board of directors.

The company will also likely be facing mass layoffs, according to The Washington Post.

The new feature detailed in the new email, which is being referred to as "Paywalled Video," allows creators to "enable the paywall once a video has been added to the tweet" and chose from a preset list of prices, ranging from $1 to $10.

"This will also give Twitter a revenue stream to reward content creators," Musk tweeted on Tuesday, adding that "creators need to make a living!"

But whether Twitter users will be willing to pay for stuff that was previously free remains anything but certain.

Musk has already announced that he is planning to charge $8 a month for Twitter users to stay verified, which has been met with derision.

The billionaire CEO is facing an uphill battle. Now that the company is private, he has to pay around $1 billion in annual interest payments, a result from his $44 buyout, according to the WaPo.

Compounding the trouble, Reuters reported last week that Twitter is bleeding some of its most active users.

Meanwhile, Musk's chaotic moves are likely to alienate advertisers, with the Interpublic Group, a massive inter-agency advertising group, recommending that its clients suspend all paid advertising for at least the week.

That doesn't bode well. It's not out of the question that a paywalled video feature may facilitate the monetization of pornographic content, which may end up scaring off advertisers even further — but Twitter's exact intentions for the feature are still unclear.

According to Reuters, around 13 percent of the site's content is currently marked not safe for work (NSFW).

It's part of Musk's attempt to shift revenue away from advertising on the platform. In a tweet last week, he promised advertisers that Twitter wouldn't become a "free-for-all hellscape."

But that hasn't stopped advertisers from already leaving in droves.

All in all, a paywalled video feature could mark a significant departure for Twitter, a platform still primarily known for short snippets of text.

For now, all we can do is watch.

READ MORE: Elon Musk’s Twitter is working on paid-video feature with ‘high’ risk [The Washington Post]

More on Twitter: Elon Musk Pleads With Stephen King to Pay for Blue Checkmark

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Twitter Working on Plan to Charge Users to Watch Videos

This Deepfake AI Singing Dolly Parton’s "Jolene" Is Worryingly Good

Holly Herndon uses her AI twin Holly+ to sing a cover of Dolly Parton's

AI-lands in the Stream

Sorry, but not even Dolly Parton is sacred amid the encroachment of AI into art.

Holly Herndon, an avant garde pop musician, has released a cover of Dolly Parton's beloved and frequently covered hit single, "Jolene." Except it's not really Herndon singing, but her digital deepfake twin known as Holly+.

The music video features a 3D avatar of Holly+ frolicking in what looks like a decaying digital world.

And honestly, it's not bad — dare we say, almost kind of good? Herndon's rendition croons with a big, round sound, soaked in reverb and backed by a bouncy, acoustic riff and a chorus of plaintive wailing. And she has a nice voice. Or, well, Holly+ does. Maybe predictably indie-folk, but it's certainly an effective demonstration of AI with a hint of creative flair, or at least effective curation.

Checking the Boxes

But the performance is also a little unsettling. For one, the giant inhales between verses are too long to be real and are almost cajolingly dramatic. The vocals themselves are strangely even and, despite the somber tone affected by the AI, lack Parton's iconic vulnerability.

Overall, it feels like the AI is simply checking the boxes of what makes a good, swooning cover after listening to Jeff Buckley's "Hallelujah" a million times — which, to be fair, is a pretty good starting point.

Still, it'd be remiss to downplay what Herndon has managed to pull off here, and the criticisms mostly reflect the AI's limited capabilities more than her chops as a musician. The AI's seams are likely intentional, if her previous work is anything to go off of.

Either way, if you didn't know you were listening to an AI from the get-go, you'd probably be fooled. And that alone is striking.

The Digital Self

Despite AI's usually ominous implications for art, Herndon views her experiment as a "way for artists to take control of their digital selves," according to a statement on her website.

"Vocal deepfakes are here to stay," Herndon was quoted saying. "A balance needs to be found between protecting artists, and encouraging people to experiment with a new and exciting technology."

Whether Herndon's views are fatalistic or prudently pragmatic remains to be seen. But even if her intentions are meant to be good for artists, it's still worrying that an AI could pull off such a convincing performance.

More on AI music: AI That Generates Music from Prompts Should Probably Scare Musicians

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This Deepfake AI Singing Dolly Parton's "Jolene" Is Worryingly Good

Scientists Found a Way to Control How High Mice Got on Cocaine

A team of neuroscientists at the University of Wisconsin claim to have found a way to control how high mice can get on cocaine.

A team of neuroscientists at the University of Wisconsin claim to have found a way to control how high mice can get on a given amount of cocaine.

And don't worry — while that may sound like a particularly frivolous plot concocted by a team of evil scientists, the goal of the research is well-meaning.

The team, led by University of Wisconsin neuroscientist Santiago Cuesta, was investigating how the gut microbiome can influence how mice and humans react to ingesting the drug.

The research, detailed in a new paper published this week in the journal Cell Host & Microbe, sheds light on a vicious feedback loop that could explain cases of substance abuse disorders — and possibly lay the groundwork for future therapeutic treatments.

In a number of experiments on mice, the researchers found that cocaine was linked to the growth of common gut bacteria, which feed on glycine, a chemical that facilitates basic brain functions.

The lower the levels of glycine in the brain, the more the mice reacted to the cocaine, exhibiting abnormal behaviors.

To test the theory, the scientists injected the mice with a genetically modified amino acid which cannot break down glycine. As a result, the behavior of mice returned to normal levels.

In other words, the amino acid could curb cocaine addiction-like behaviors — at least in animal models.

"The gut bacteria are consuming all of the glycine and the levels are decreasing systemically and in the brain," said Vanessa Sperandio, senior author, and microbiologist from the University of Wisconsin, in a statement. "It seems changing glycine overall is impacting the glutamatergic synapses that make the animals more prone to develop addiction."

It's an unorthodox approach to treating addiction, but could be intriguing — if it works in people, that is.

"Usually, for neuroscience behaviors, people are not thinking about controlling the microbiota, and microbiota studies usually don't measure behaviors, but here we show they’re connected," Cuesta added. "Our microbiome can actually modulate psychiatric or brain-related behaviors."

In short, their research could lead to new ways of treating various psychiatric disorders such as substance use by adjusting the gut microbiome and not making changes to the brain chemistry.

"I think the bridging of these communities is what's going to move the field forward, advancing beyond correlations towards causations for the different types of psychiatric disorders," Sperandio argued.

READ MORE: How gut bacteria influence the effects of cocaine in mice [Cell Press]

More on addiction: Study: Magic Mushrooms Helped 83% of People Cut Excessive Drinking

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Scientists Found a Way to Control How High Mice Got on Cocaine

Cats May Be Tampering With Crime Scenes, Scientists Say

Cats, ever the mischievous and frisky pets, may be harboring a lot more human DNA than once thought, possibly tampering crime scenes, a new study says.

Cat Burglar

Cats are known for not really minding their own business, getting their furry paws on just about anything they can.

And it turns out, this makes them effective vectors for DNA evidence, according to a study published last month in the journal Forensic Science International: Genetic Supplement Series.

Researchers collaborating with the Victoria Police Forensic Services Department in Australia found detectable human DNA in 80 percent of the samples collected from 20 pet cats, with 70 percent of the samples strong enough that they could be linked to a person of interest in a crime scene investigation.

"Collection of human DNA needs to become very important in crime scene investigations, but there is a lack of data on companion animals such as cats and dogs in their relationship to human DNA transfer," said study lead author Heidi Monkman, a forensic scientist at Flinders University, in a statement.

"These companion animals can be highly relevant in assessing the presence and activities of the inhabitants of the household, or any recent visitors to the scene."

Here Kitty

One possible takeaway is that cats — and other companion pets like dogs — could be harboring DNA that could help solve a case.

The bigger issue, though, is that pets could introduce foreign DNA that muddles a crime scene, possibly leading to an innocent person being implicated. A pet could be carrying the DNA of a complete stranger, or it might bring the DNA of its owner into a crime scene that they had nothing to do with.

Monkman's colleague and co-author of the paper, Maria Goray, is an experienced crime scene investigator and an expert in DNA transfer. She believes their findings could help clear up how pets might tamper a crime scene by carrying outside DNA.

"Are these DNA findings a result of a criminal activity or could they have been transferred and deposited at the scene via a pet?" Goray asked.

It's a question worth asking — especially because innocent people have been jailed off botched DNA science far too often.

More on DNA evidence: Cops Upload Image of Suspect Generated From DNA, Then Delete After Mass Criticism

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Cats May Be Tampering With Crime Scenes, Scientists Say

China Plans to Send Monkeys to Space Station to Have Sex With Each Other

Chinese astronauts are reportedly planning to let monkeys loose on their brand-new space station to have them have sex with each other.

Chinese scientists are reportedly planning to send monkeys to its new Tiangong space station for experiments that will involve the animals mating and potentially reproducing, the South China Morning Post reports.

It's a fascinating and potentially controversial experiment that could have major implications for our efforts to colonize space: can mammals, let alone humans, successfully reproduce beyond the Earth?

According to the report, the experiment would take place in the station's largest capsule, called Wentian, inside two biological test cabinets that can be expanded.

After examining the behavior of smaller creatures, "some studies involving mice and macaques will be carried out to see how they grow or even reproduce in space," Zhang Lu, a researcher at the Chinese Academy of Sciences in Beijing, said during a speech posted to social media earlier this week, as quoted by the SCMP.

"These experiments will help improve our understanding of an organism’s adaptation to microgravity and other space environments," he added.

Some simpler organisms, including nematodes and Japanese rice fish, have been observed reproducing in space.

But more complex life forms have struggled. In 2014, a Russian experiment to see whether geckos could produce offspring in space failed when all the critters died.

And the failure rate for mammals, so far, has been total. Soviet Union scientists got mice to mate during a space flight in 1979, but none of them gave birth after being returned to Earth.

In other words, getting monkeys to reproduce on board a space station will be anything but easy. For one, just dealing with living creatures in space can pose immense challenges. The astronauts will "need to feed them and deal with the waste," Kehkooi Kee, a professor with the school of medicine at Tsinghua University, told the SCMP.

Then there's the fact that astronauts will have to keep the macaques happy and comfortable, something that experts say will be challenging since long term confinement in the spartan environments of space habitats could cause immense stress for the simians.

And even if astronauts successfully set the mood for the monkeys, the physics of sex in space are predicted to be challenging.

"Firstly, just staying in close contact with each other under zero gravity is hard," Adam Watkins, an associate professor of reproductive physiology at University of Nottingham, wrote in a 2020 open letter highlighted by the SCMP. "Secondly, as astronauts experience lower blood pressure while in space, maintaining erections and arousal are more problematic than here on Earth."

With its new space station in nearly full operation, China isn't shying away from asking some big questions — but whether these experiments will play out as expected is anything but certain.

READ MORE: Chinese scientists plan monkey reproduction experiment in space station [South China Morning Post]

More on sex in space: Scientists Say We Really Have to Talk About Boning in Space

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China Plans to Send Monkeys to Space Station to Have Sex With Each Other

NASA Sets Launch Date for Mission to $10 Quintillion Asteroid

After disappointing setbacks and delays, NASA has finally got its mission to an invaluable asteroid made of precious metals back on track.

Rock of Riches

After disappointing setbacks and a delay over the summer, NASA says it's finally reviving its mission to explore a tantalizing and giant space rock lurking deep in the Asteroid Belt.

Known as 16 Psyche, the NASA-targeted asteroid comprises a full one percent of the mass of the Asteroid Bet, and is speculated to be the core of an ancient planet. But Psyche's size isn't what intrigues scientists so much as its metal-rich composition, believed to be harboring a wealth of iron, nickel, and gold worth an estimated $10 quintillion — easily exceeding the worth of the Earth's entire economy. Although, to be clear, they're not interested in the metals' monetary value but rather its possibly planetary origins.

Back On Track

Initially slated to launch in August 2022, NASA's aptly named Psyche spacecraft became plagued with a persistent flight software issue that led the space agency to miss its launch window that closed on October 11.

But after surviving an independent review determining whether the mission should be scrapped or not, NASA has formally announced that its spacecraft's journey to Psyche will be going ahead, planned to launch aboard a SpaceX Falcon Heavy rocket as early as October 10, 2023.

"I'm extremely proud of the Psyche team," said Laurie Leshin, director of NASA's Jet Propulsion Laboratory, in a statement. "During this review, they have demonstrated significant progress already made toward the future launch date. I am confident in the plan moving forward and excited by the unique and important science this mission will return."

Although the new launch date is only a little over a year late, the expected arrival at the asteroid Psyche is set back by over three years — 2029 instead of 2026 — due to having to wait for another opportunity to slingshot off of Mars' gravity.

Peering Into a Planet

Once it arrives, the NASA spacecraft will orbit around the asteroid and probe it with an array of instruments, including a multispectral imager, gamma ray and neutron spectrometers, and a magnetometer, according to the agency.

In doing so, scientists hope to determine if the asteroid is indeed the core of a nascent planet known as a planetesimal. If it is, it could prove to be an invaluable opportunity to understand the interior of terrestrial planets like our own.

More on NASA: NASA Announces Plan to Fix Moon Rocket, and Maybe Launch It Eventually

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NASA Sets Launch Date for Mission to $10 Quintillion Asteroid

Scientists Use Actual Lunar Soil Sample to Create Rocket Fuel

A team of Chinese researchers claim to have turned lunar regolith samples brought back by the country's Chang'e 5 mission into a source of fuel.

Fill 'Er Up

A team of Chinese researchers say they managed to convert actual lunar regolith samples into a source of rocket fuel and oxygen — a potential gamechanger for future space explorers hoping to make use of in-situ resources to fuel up for their return journey.

The researchers found that the lunar soil samples can act as a catalyst to convert carbon dioxide and water from astronauts' bodies and environment into methane and oxygen, as detailed in a paper published in the National Science Review.

"In situ resource utilization of lunar soil to achieve extraterrestrial fuel and oxygen production is vital for the human to carry out Moon exploitation missions," lead author Yujie Xiong said in a new statement about the work. "Considering that there are limited human resources at extraterrestrial sites, we proposed to employ the robotic system to perform the whole electrocatalytic CO2 conversion system setup."

That means we could have a much better shot at carrying out longer duration explorations of the lunar surface in the near future.

Set It, Forget It

According to the paper, which builds on previous research suggesting lunar soil can generate oxygen and fuel, this process can be completed using uncrewed systems, even in the absence of astronauts.

In an experiment, the team used samples from China's Chang'e-5 mission, which landed in Inner Mongolia back in December 2020 — the first lunar soil returned to Earth since 1976.

The Moon soil effectively acted as a catalyst, enabling the electrocatalytic conversion of carbon dioxide into methane and oxygen.

"No significant difference can be observed between the manned and unmanned systems, which further suggests the high possibility of imitating our proposed system in extraterrestrial sites and proves the feasibility of further optimizing catalyst recipes on the Moon," the researchers conclude in their paper.

Liquified

But there's one big hurdle to still overcome: liquifying carbon dioxide is anything but easy given the Moon's frosty atmosphere, as condensing the gas requires a significant amount of heat, as New Scientist reported earlier this year.

Still, it's a tantalizing prospect: an autonomous machine chugging away, pumping out oxygen and fuel for future visitors. But for now, it's not much more than a proof of concept.

READ MORE: Scientists investigate using lunar soils to sustainably supply oxygen and fuels on the moon [Science China Press]

More on lunar soil: Bad News! The Plants Grown in Moon Soil Turned Out Wretched

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Scientists Use Actual Lunar Soil Sample to Create Rocket Fuel