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Asbestos Awareness and Education – Mesothelioma.net Blog

September 26th, 2020 6:00 am

This page has been fact checked by an experienced mesothelioma Patient Advocate. Sources of information are listed at the bottom of the article.

We make every attempt to keep our information accurate and up-to-date.

Please Contact Us with any questions or comments.

Asbestos use is in decline, but exposure to this harmful material is still possible, especially in occupational settings. Many victims of exposure have developed mesothelioma, but experts in abatement, prevention, medicine, and advocacy are helping these people and preventing future exposure.

Asbestos is a group of minerals made of silicon and oxygen and with a fibrous structure. People have mined and used asbestos for hundreds of years because of its unique properties:

Asbestos use in the U.S. took off in the late 1800s, but peak asbestos use occurred from the 1930s through the 1970s. Many industries used asbestos in materials, mostly for fireproofing and insulating. Some of the most significant users of asbestos historically were companies that made construction materials and components for ships.

Asbestos did not come under scrutiny until a connection was finally made between exposure to the fibers and poor respiratory health. The first regulations on asbestos use came in the 1970s.

The Environmental Protection Agency banned asbestos completely in 1989, but the Fifth Circuit Court of Appeals overturned it. Today, asbestos use is limited. It still lingers in older materials.

Mesothelioma is a cancer of the mesothelium, the tissue lining organs in the body. Asbestos is the leading cause and risk factor, although the link has not always been understood. Mesothelioma can occur around the lungs, in the abdomen, around the heart, or very rarely in the testicles.

Pleural mesothelioma, around the lungs, is the most common type. This is because asbestos exposure typically occurs through inhalation of the fibers. Peritoneal, the abdominal type, is the second most common.

Mesothelioma is aggressive, spreads rapidly, is difficult to treat, and is almost always terminal. Survival rates are relatively low for this cancer.

Doctors first described pleural and peritoneal tumors in the 1700s and 1800s, respectively. A pathologist first used the word mesothelioma in 1920.

The earliest connection experts made to asbestos was in the 1930s. Doctors found that people with asbestosis, scarring in the lungs caused by asbestos fibers, also often had tumors.

In 1960, researchers in South Africa published a paper that linked cancer with mined asbestos. They noted that mesothelioma occurred much more often in the part of the country with asbestos mines.

In 1964, a doctor in the U.S. reported that asbestos insulation workers had high mortality rates from asbestosis and cancer. After these studies, evidence that asbestos causes mesothelioma continued to grow.

Occupational exposure is the main source of asbestos exposure. Secondary exposure from workers who bring fibers home on their clothing and exposure through nearby industries or naturally-occurring asbestos is much less common.

Historically, some of the industries that carried the highest risks of asbestos exposure for workers included:

Today, these jobs are safe, thanks to asbestos regulations. However, asbestos is still used in some materials and lingers in many materials these workers encounter.

All construction workers still face asbestos risks, but especially those in demolition and who repair or renovate older buildings. The same is true of older ships and auto mechanics working with asbestos parts in older cars.

A military career can also cause asbestos exposure, although that risk is much lower today. Nearly one-third of all mesothelioma diagnoses are in veterans. Navy veterans have the highest rates because of the extensive use of asbestos on ships.

The U.S. Veterans Administration offers compensation and healthcare to veterans whose asbestos exposure occurred during service. In addition to world-class care at leading VA hospitals, veterans may also be eligible for disability compensation.

Diagnosing mesothelioma is difficult. The symptoms of pleural and peritoneal mesothelioma are typically mild until the cancer is advanced:

Many victims of asbestos exposure are misdiagnosed because these symptoms are similar to more common illnesses. Often the true diagnosis comes later, when the cancer is advanced and more difficult to treat.

Diagnosis for mesothelioma typically includes a physical exam; an X-ray to rule out other illnesses; more advanced imaging scans to look for tumors; a biopsy to determine if cells are malignant and part of the mesothelium; and blood tests to look for mesothelioma-specific markers.

Treatment for mesothelioma depends on the type, the cell structure, the stage, and the patients health and preferences. Most patients receive some combination of:

Mesothelioma is challenging to treat for several reasons: It is often diagnosed in later stages; the tumors are multiple and small, making surgery a challenge; and the cancer is aggressive and spreads rapidly. Too often, the standard treatments are inadequate to extend life by more than months or a year.

Researchers keep working on newer, better treatments to help patients live longer. Some important advances include:

Asbestos abatement, the safe removal of asbestos materials, is often needed in older buildings constructed during heavy asbestos use. Abatement professionals must be trained to do this skilled work and licensed by the state in which they work.

Homeowners may use home test kits to determine if they have asbestos or call in professionals to do it. Once the presence of asbestos is known, abatement usually follows these steps:

Most asbestos is disposed of, but technological advances may make it possible to recycle materials contaminated with the mineral.

Because asbestos lingers in so many older buildings, abatement professionals will continue to find work. Becoming an abatement professional does not require a degree. Most workers receive on-the-job training and then earn licensing through the appropriate state department. Workers may also become abatement managers with experience and additional training.

According to the U.S. Bureau of Labor Statistics, careers for skilled hazardous materials removal workers are growing. Abatement is not limited to asbestos. These workers also handle and remove lead, mold, radioactive materials, and harmful chemicals. Job responsibilities include:

Construction companies, asbestos, and other hazardous materials abatement contractors, government agencies, environmental companies and organizations, and disaster response organizations employ hazmat removal workers.

Abatement professionals play an important role in preventing asbestos exposure. Other professionals work with the victims of exposure who have become ill:

Victims of asbestos exposure and mesothelioma, and their loved ones, can benefit from charities, support groups, awareness events, and other resources:

The Meso Foundation began Mesothelioma Awareness Day, which takes place every September 26. The organization hosts nationwide events, and local groups create smaller events to raise awareness for this rare cancer.

The coronavirus pandemic has made life difficult for everyone, but patients with compromising illnesses like mesothelioma are most affected. Patients have felt the impact in a few ways:

Mesothelioma is a terrible diagnosis, and so many cases could have been prevented. Today, professionals who work in abatement, medicine, and non-profit organizations are helping victims and ensuring no one has to suffer from asbestos exposure anymore.

Dave has been a mesothelioma Patient Advocate for over 10 years. He consistently attends all major national and international mesothelioma meetings. In doing so, he is able to stay on top of the latest treatments, clinical trials, and research results. He also personally meets with mesothelioma patients and their families and connects them with the best medical specialists and legal representatives available.

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Combine Cardio and Strength With This 20-Minute Jump Rope and Dumbbell Workout – LIVESTRONG.COM

September 26th, 2020 5:59 am

Jump rope is an easy, minimal-equipment way to get your heart rate up.

Image Credit: Innocenti/Cultura/GettyImages

Combining strength training and cardio in the same workout is a fantastic way to multitask. From increasing endurance to blasting calories to building lean muscle to gaining strength, consider the two a perfect pair.

Strength training builds muscle, which can help boost your metabolism and burn more calories at rest, according to the Mayo Clinic. Cardio, on the other hand, is amazing for supporting heart health, burning calories and increasing the "feel good hormones," such as serotonin, according to a April 2019 study published in Preventative Medicine.

So grab your jump rope and a set of dumbbells and get ready for a heart-pumping, strength building, fat-blasting workout!

Do: each of the exercises below, alternating between jumping rope for 30 to 60 seconds and performing 15 reps of the dumbbell exercise listed. Rest for 30 to 60 seconds before repeating the circuit once more.

The curling motion can be performed three ways: alternating arms, both arms at the same time or one arm at a time.

Don't let your knees go forwards past your toes.

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Dr. Birx praised Texas A&Ms low COVID rates. Its higher than both Rice and Baylor. – Houston Chronicle

September 26th, 2020 5:59 am

White House Coronavirus Response Coordinator Dr. Deborah Birx visited Texas A&M Universitys campus Tuesday and praised its COVID-19 positivity rate, saying its one of the lowest shes seen, but is it really low?

The College Station flagship, which has more than 65,000 students and 10,160 faculty, reported that its weekly positivity rate for its random testing program, which includes student test results collected at special testing sites in the area, was 1.6 percent for the week ending on Sept. 12, according to A&Ms online dashboard. Tests in this program are performed specifically by its Student Health Services in efforts to identify students who are asymptomatic or where there are hotspots for transmission.

Texas A&Ms overall positivity rate, however which includes results of students, faculty and staff was around 10 percent. The college reports that tests factored into this postivity rate are conducted by both its health services and contracted company Curative Inc. within the Bryan-College Station area. The university also reported that more than 600 students and 23 faculty have tested positive this month, and 255 of these cases are still considered active as of Sept. 22.

A White House media representative did not immediately respond to requests for comment.

Ten percent seems pretty high to me, said Peter Hotez, co-director of Texas Childrens Hospitals Center for Vaccine Development. Maybe she was looking at the wrong number.

Compared to other Texas colleges, like Rice and Baylor universities, both of which provide their positivity rates and cases online and test both asymptomatic and symptomatic individuals like Texas A&M, Texas A&M results are higher.

Birx also visited Auburn University, Louisiana State University, and Virginia Tech University. University of Kentucky, USC, Columbia

Rice, with about 8,000 students, reported a 0.09 percent positivity rate on its dashboard as of Thursday morning. The private Houston college has had 21 people test positive for the virus since Aug. 1 13 of them students and eight of them faculty or staff.

On HoustonChronicle.com: White House official Birx praises A&Ms low COVID-19 rates, vaccine manufacturing

Kevin Kirby, Rice vice president for administration, said positivity rates between different schools can vary depending on the testing strategy. For example, some schools test only those who are symptomatic, which can result in higher positivity rates. At Rice, officials test both those with and without symptoms, which can result in a lower positivity rate.

But Kirby adds that Rice has some structural advantages compared to many larger universities.

For one, Rice is situated next to the Texas Medical Center, which has been a crucial resource when it comes to testing and advice, Kirby said. Additionally, the opportunity and temptation of being around more people or to attend events, which can spread a virus, can be stronger at larger institutions. Rice also doesnt have fraternities and sororities, which Kirby believes has helped.

Rice has also aimed to implement best practices used at colleges around the country, including wearing masks, limiting class sizes, testing and prompt delivery of results. In addition, the college gives students and faculty the option of how they would like to engage in instruction and education, whether it be in-person, remote or hybrid.

Birx also visited Baylor University Monday. The Waco college boasts a 2.6 positivity rate as of Thursday, with 75 active COVID-19 cases reported within its community on Sept. 24 a drastic decline from the 477 cases reported on Sept. 3. Nearly all of its current active cases are students.

Baylor spokesman Jason Cook credits the private Baptist colleges decline to following the Centers for Disease Control and Preventions guidelines on contract tracing, maintain social distancing, and adamant enforcement of masks and face coverings.

Cook said many colleges went into the semester expecting that there would be a spike in cases at some point.

Our students have indicated they want to be on campus for the fall semester and that has been a great motivating factor, Cook said. That desire from students prompted Baylor officials to prepare the college on how it would manage a spike with preventative education, quarantine efforts, and mask wearing.

As a result, Cook said Baylor, which enrolled 19,297 students this fall, has not had any COVID-19 cases linked to classrooms.

A lot of it is the infrastructure of the institution leading into the semester coupled with the ability to institute behavior change, Cook said.

As for Birxs assessment of low COVID-10 positivity rates, Hotez questions whether it is a reliable statement.

The White House Coronavirus Taskforce is such an unreliable source of information, Hotez said. Theres often a heavy political spin on it. Its really hard to sort out whats right, and its getting worse now.

Hotez, who also serves as dean of the National School of Tropical Medicine at Baylor College of Medicine, has predicted that there will be a third peak or surge of the virus later this fall, following the first in April-May and the second peak in Southern states in July-August. The third peak, he said, could be the worst, contributed to colleges and schools reopening for on-campus learning.

Hotez said in some cases U.S. colleges and universities have opened in areas of high transmission and are a bit oblivious to the greater impact on the communities and states that theyre in.

In-person voting in November, considering the restrictions to mail-in voting, could also contribute to an uptick, Hotez said.

Without more awareness and strong leadership, especially in the Southern states, its not going to go well, he said.

brittany.britto@chron.com

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From the Ophthalmologist’s Eye: Managing Ocular Toxicities With Belantamab Mafodotin in Myeloma – OncLive

September 26th, 2020 5:59 am

Ophthalmologists are filling a critical role in the collaborative management of patients with relapsed/refractory multiple myeloma who are receiving belantamab mafodotin-blmf (Blenrep), said Shaily Shah, MD, who added that the potential ocular toxicities that can occur with the antibody-drug conjugate (ADC) require consistent screening and management.

As a junior attending, what opened my eyes has been how incredible the field of medicine is in general, and how eager people are to work together to do what is best for the patient, Shah said. It is very exciting, in general, [that] oncology is a multidisciplinary specialty.

On August 5, 2020, the FDA approved belantamab mafodotin for use in patients with relapsed/refractory multiple myeloma who have received 4 prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 agent.1

Findings from the DREAMM-2 trial, which served as the basis for the approval, demonstrated a 31% overall response rate (ORR) with the recommended 2.5 mg/kg dose of belantamab mafodotin (n = 97).2 The ORR was 34% among patients who received the 3.4-mg/kg dose (n = 99).

Grade 3/4 keratopathy was observed in 27% of patients who received the 2.5 mg/kg dose versus 21% of patients who received the 3.4 mg/kg dose.

At 13 months of follow-up, deep responses were seen; more than half of responders in the 2.5 mg/kg (58%) and 3.4 mg/kg groups (66%) achieved a very good partial response or better.3

No new safety signals were identified with longer-term follow-up. Although keratopathy was common, only 6 patients discontinued treatment due to corneal events, suggesting that they were well managed with dose modifications.

According to Shah, with this ocular safety signal, patients treated with belantamab mafodotin should receive prophylactic treatment for dry eye, as well as have routine eye examinations to ensure ocular changes are identified early.

There is still a lot to be learned here, said Shah. Of course, the studies have been done, but now that belantamab mafodotin is going to be prescribed on a larger scale, there is going to be so much that we learn specifically regarding that agent, as well as how we can improve collaborative management for these patients.

In an interview with OncLive, Shah, an assistant attending ophthalmologist at NewYork-Presbyterian Hospital and an assistant professor of ophthalmology at Weill Cornell Medicine, discussed disease and treatment-related ocular toxicities that can arise in patients with cancer, specific management strategies for patients receiving belantamab mafodotin who develop ocular toxicities, and the importance of collaborative management of these patients.

OncLive: What is the frequency of disease-related ocular toxicities among patients with cancer?

Shah: I dont have an exact percentage offhand, but [ocular toxicities] are more common than one may think. Oftentimes, it is not related to the cancer itself but, there are certain types of cancers that manifest with ocular findings, such as some lymphomas and leukemias. Multiple myeloma in itself can produce crystalline keratopathy, but it is uncommon that we see that.

How frequently are treatment-related ocular toxicities observed in oncology?

Treatment-related adverse effects (TRAEs) are fairly common to see. At Cornell, we are right next to Memorial Sloan Kettering Cancer Center, so we see quite a few patients with graft-versus-host disease (GVHD), as well as patients who have received bone marrow transplants for leukemia. Those patients will often develop significant ocular toxicity from their systemic GVHD. Patients will sometimes come in with severe dry eye, lack of tear production, corneal haze, or corneal opacities. Patients could eventually develop limbal stem cell deficiency and go down a path of significantly decreased quality of life and visual acuity.

We have gotten good at having a protocol in place for our patients with GVHD. We know that patients may not respond to typical dry eye management, so we have steps to help them.

There are also certain medications such as chemotherapeutic agents that can cause cancer treatment-related ocular toxicities. We know that treating breast cancer with tamoxifen can cause retinopathychanges in the retina of the eye where crystal-type deposits [form] in the macula.

We may also see radiation-related toxicities in patients who had radiation near the face or around the chest and neck. Oftentimes, these patients will have problems with their tear ducts, tear drainage system, and sometimes, their tear production glands. They may develop significant dry eye either from scarring of the eyelids where they cant blink easily and the eyes dry out from exposure, or from a problem with tear production or drainage.

What ocular toxicities have been observed with belantamab mafodotin specifically? What sort of issues could arise if these AEs are not managed correctly?

Certainly, now with [the approval of] belantamab mafodotin, we have been seeing corneal toxicities [in patients with myeloma]. Throughout the clinical [trial] process for belantamab mafodotin with the DREAMM-1 and DREAMM-2 studies, the ocular toxicities [observed were] specific to the ocular surface. When [investigators] studied that further, they found that it [has] a corneal epithelial pathology. The cornea is the most superficial layer of the eye, and the epithelium is the most superficial layer of the cornea. Therefore, it is really [on] the most superficial layer of the ocular surface that we are seeing the majority of these toxicities.

Even just being confined to 1 portion of the tissue, the range of symptoms that the patient can feel is broad. Patients could be completely asymptomatic [although] the [ocular] changes are seen on the exam from the physicians standpoint, or the exam may not show changes, but the patient could have significant ocular surface-related complaints.

In general, these complaints will be similar to dry eyerelated complaints, including burning, grittiness, a foreign body or sandy sensation, an achy sensation, redness, and significant tearing. Oftentimes, patients may experience decreased visual acuity, so they may come in with complaints of blurred vision.

Our exam findings can range from no findings at all, to mild or moderate dry eye. We would see signs of dryness on the surface exam where a dye used to stain the surface of the cornea can pick up changes that correlate with dry eye and highlight dry spots in the corneal epithelium.

In terms of parameters, we look at whether there are any staining patterns. Are there any punctate epithelial erosions? An interesting finding that we have seen, and that was reported after the DREAMM-1 and DREAMM-2 studies, is microcystic keratopathy. These are small microcysts that we can see just underneath the surface layer of the epithelium.

[Microcysts] usually start in the periphery of the cornea and work their way in toward the center. That is consistent with what the studies had shown. Initially, the 2 patients I had seen who developed microcysts were completely asymptomatic. They came in for a routine follow-up with no visual complaints and their vision hadnt changed on their exams. It was an incidental finding.

Corneal exams [can also show] corneal haze. Again, this very fine opacity starts around the edges of the cornea and can eventually progress to the center. Sometimes the exam findings are correlated with patient symptoms such as blurred vision or discomfort, but again, patients may be completely asymptomatic.

It is important to screen these patients. If they do not have symptoms, they wont necessarily come in of their own accord. We have a great system in place where right before every infusion, we see patients for screening exams.

If a patient on belantamab mafodotin does develop ocular toxicities, what are some of the management strategies that can be used to treat these AEs?

With this expanded access [program] that I have been part of at Cornell through GlaxoSmithKline, the protocol that we have in place is to treat our patients prophylactically with artificial tears. We will start patients on preservative-free artificial tears anywhere from 4 to 6 times a day, or more if patients get [relief] from them. The idea is to lubricate the eyes and keep them as healthy and wet as possible to try to minimize discomfort and surface level toxicity.

One of the proposed pathophysiologic mechanisms for why corneal toxicity occurs is that some of the drug may be carried in through the tear film of the patient. Then every time that patient blinks and produces tears, the drug sits on the surface of their eye. In addition to keeping patients comfortable and preventing dry eye symptoms, artificial treats help to dilute their natural tear film and potentially prevent toxicity from building up.

Even if patients dont have dry eye, but they have any other eye conditions that can contribute to dry eye such as meibomian gland dysfunction (MGD), I will oftentimes have them start treatment for that ahead of time. The treatment [for MGD] is simple. At home, patients are asked to use warm compresses to try to open up the glands to increase oil production and improve the quality of their natural tears.

At this point, most treatment is preventative, and we try to maximize patients ocular health before they even start treatment. As soon as I see them for screening, I will go over the details of what the [potential] toxicities are and why it is so important to start these preventative treatments.

Additionally, some studies have shown that putting a cold compress on the eye during the time of infusion can increase patients comfort levels and potentially improve the ocular toxicity profile. That is also something that is built into our protocol.

How do these ocular toxicities affect the use of belantamab mafodotin?

It depends on the level of toxicity the patient is experiencing. If patients have mild toxicity with a little bit of dry eye on the exam, no significant haze, no microcysts, and they are asymptomatic, we would call that grade 1 toxicity. Patients can usually continue with their treatment as planned.

If they start to develop peripheral microcystic changes or corneal haze, with or without changes in their visual acuity, oftentimes we will dose reduce or halt the next dose of belantamab mafodotin until they resolve back to grade 1 or baseline.

If a patient has cysts in the central portion of their cornea, their vision has [declined] significantly, or they have haze in the center of their cornea, those are definite indications to hold the next treatment. If patients get back to a certain healthy baseline, we can start belantamab mafodotin at either a decreased dose or full dose depending on the patients corneal health.

In the DREAMM-2 study, [investigators] evaluated whether the use of corticosteroids would help in [preventing the] development of these changes. The toxicities associated with a drug are often thought to be related to the inflammation that they induce in a certain tissue.

However, it was found that prophylactic corticosteroid use did not make a difference in the ocular toxicity profile, so that is no longer recommended for patients starting on belantamab mafodotin.

Could you speak to the collaborative efforts required between oncologists and ophthalmologists to manage patients receiving belantamab mafodotin?

One of the really beautiful things about the expanded access protocol, as well as the DREAMM-1 and DREAMM-2 studies and the FDA approval, is that it encourages and requires collaborative management of patients. It is about collaborating with the patient, their oncology team, including the infusion specialist, nurses, pharmacists, and the ophthalmology team.

With the FDA approval, [we have seen] a lot of outreach into the community [regarding this agent and this collaboration]. Community oncologists are going to be prescribing this medication now, so community oncologists and community ophthalmologists [need to be educated on] what these toxicities are, how frequently patients should be screened, and how frequent follow-ups should be. The lines of communication between the ophthalmology team and the oncology team need to be kept open.

What are some of the challenges that remain in this space?

In an academic center, it is much easier to collaborate with other departments. For example, the ophthalmology department is in full collaboration with the oncology department [at Cornell] so that we can get these patients seen quickly and get the [treatment] decision over to the oncology department. Once community doctors are prescribing belantamab mafodotin more, the challenge will be getting patients quickly to an ophthalmologist or having ophthalmologists ready to see these patients. Additionally, making sure that the ophthalmologists are communicating efficiently, quickly, and clearly to the oncology team could become a challenge as well.

What would you like to emphasize regarding the management of ocular toxicities among patients receiving belantamab mafodotin?

The most important thing is to make sure that all parties are equally aware of the importance of communication with one another, as well as communication with the patient. Oftentimes, patients [receiving belantamab mafodotin] may feel like this drug is their last resort. Patients may ignore certain AEs that they are having or may not be aware of what AEs are important [to report]. Keeping those lines of communication open, not just among providers, but with the patient, as well as educating patients on the potential toxicities that could manifest is important. Additionally, making sure that patients follow up with the ophthalmologist, even if they are asymptomatic, is important.

It is a really exciting time because it affords us, as ophthalmologists, the opportunity to collaborate on a truly systemic disease. It is also exciting to be able to be part of a larger treatment team and to work within other specialties.

References:

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Scientists discover genetic and immunologic underpinnings of some cases of severe COVID-19 – National Institutes of Health

September 26th, 2020 5:59 am

Media Advisory

Thursday, September 24, 2020

New findings by scientists at the National Institutes of Health and their collaborators help explain why some people with COVID-19 develop severe disease. The findings also may provide the first molecular explanation for why more men than women die from COVID-19.

The researchers found that more than 10% of people who develop severe COVID-19 have misguided antibodiesautoantibodiesthat attack the immune system rather than the virus that causes the disease. Another 3.5% or more of people who develop severe COVID-19 carry a specific kind of genetic mutation that impacts immunity. Consequently, both groups lack effective immune responses that depend on type I interferon, a set of 17 proteins crucial for protecting cells and the body from viruses. Whether these proteins have been neutralized by autoantibodies orbecause of a faulty genewere produced in insufficient amounts or induced an inadequate antiviral response, their absence appears to be a commonality among a subgroup of people who suffer from life-threatening COVID-19 pneumonia.

These findings are the first published results from the COVID Human Genetic Effort, an international project spanning more than 50 genetic sequencing hubs and hundreds of hospitals. The effort is co-led by Helen Su, M.D., Ph.D., a senior investigator at the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH; and Jean-Laurent Casanova, M.D., Ph.D., head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University in New York. Major contributions were made by Luigi Notarangelo, M.D., chief of the NIAID Laboratory of Clinical Immunology and Microbiology (LCIM); Steven Holland, M.D., director of the NIAID Division of Intramural Research and senior investigator in the NIAID LCIM; clinicians and investigators in hospitals in the Italian cities of Brescia, Monza and Pavia, which were heavily hit by COVID-19; and researchers at the Uniformed Services University of the Health Sciences in Bethesda, Maryland.

The wide variation in the severity of disease caused by SARS-CoV-2, the virus behind COVID-19, has puzzled scientists and clinicians. SARS-CoV-2 can cause anything from a symptom-free infection to death, with many different outcomes in between. Since February 2020, Drs. Su and Casanova and their collaborators have enrolled thousands of COVID-19 patients to find out whether a genetic factor drives these disparate clinical outcomes.

The researchers discovered that among nearly 660 people with severe COVID-19, a significant number carried rare genetic variants in 13 genes known to be critical in the bodys defense against influenza virus, and more than 3.5% were completely missing a functioning gene. Further experiments showed that immune cells from those 3.5% did not produce any detectable type I interferons in response to SARS-CoV-2.

Examining nearly 1,000 patients with life-threatening COVID-19 pneumonia, the researchers also found that more than 10% had autoantibodies against interferons at the onset of their infection, and 95% of those patients were men. Biochemical experiments confirmed that the autoantibodies block the activity of interferon type I.

Q Zhang et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science DOI: 10.1126/science.abd4570 (2020).

P Bastard et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science DOI: 10.1126/science.abd4585 (2020).

NIAID Director Anthony S. Fauci, M.D., NIAID Senior Investigator Helen C. Su, M.D., Ph.D., and Luigi Notarangelo, M.D., chief of the NIAID Laboratory of Clinical Immunology and Microbiology, are available for interviews.

To schedule interviews, please contact NIAID Office of Communications, (301) 402-1663, NIAIDNews@niaid.nih.gov.

NIAID conducts and supports research at NIH, throughout the United States, and worldwide to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

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U of T researchers identify genes that enable cancer to evade the immune system – News@UofT

September 26th, 2020 5:59 am

Researchers at the University of Toronto have mapped the genes that allow cancer cells to avoid being killed by the immune system a finding that paves the way for the development of immunotherapies that could be effective for large patient populations and across different tumour types.

Over the last decade, different forms of immunotherapy have emerged as really potent cancer treatments, but the reality is that they only generate durable responses in a fraction of patients and not for all tumour types, saysJason Moffat, a professor of molecular genetics at the Donnelly Centre for Cellular and Biomolecular Research who led the work.

The study, published inNature, also revealed the need for new therapy to take into account the genetic composition of tumours because of mutations in the cancer cells that can potentially make the disease worse in response to treatment, often referred to as cancer resistance mutations.

Its very important to understand at the molecular level how cancer develops resistance to immunotherapies in order to make them more broadly available, saysMoffat, who holds a Canada Research Chair in Functional Genomics of Cancer.Advances in systematic genetic approaches have let us key in on genes and molecular pathways that are commonly involved in resistance to therapy.

In immunotherapy, a patients own immune cells, known as T killer cells, are engineered to find and destroy cancer. But treatment resistance has precluded its use in most patients, especially those with solid tumours.

Its an ongoing battle between the immune system and cancer, where the immune system is trying to find and kill the cancer whereas the cancers job is to evade that killing, saysKeith Lawson, a co-lead author who iscompleting a PhD in Moffats lab as part of his medical training in the surgeon-scientist program at U of Ts Faculty of Medicine.

Tumour heterogeneity genetic variation in tumour cells within and across individuals that can impact therapy response further complicates treatment.

Its important to not just find genes that can regulate immune evasion in one model of cancer, but what you really want are to find those genes that you can manipulate in cancer cells across many models because those are going to make the best therapeutic targets, Lawson says.

The team, including collaborators from Agios Pharmaceuticals in Cambridge, Mass., looked for genes that regulate immune evasion across six genetically diverse tumor models derived from breast, colon, kidney and skin cancer. The cancer cells were placed in a dish alongside the T cells engineered to kill them, where the ensuing onslaught served as a baseline. The researchers next deployed the gene editing tool CRISPR to switch off one-by-one every gene in the cancer cells and measured the resulting deviations from the killing baseline.

They identified 182 core cancer intrinsic immune evasion genes whose deletion makes the cancer cells either more sensitive or more resistant to T cell attack. Among the resisters were all the genes known to develop mutations in patients who stopped responding to immunotherapy, giving the researchers confidence that their approach worked.

Many of the discovered genes had no previous links to immune evasion.

That was really exciting to see, because it means that our dataset was very rich in new biological information,Lawson says.

Genes involved in autophagy, a process when cells ramp up recycling their components to mitigate damage following stress, came up as key for immune evasion. This raises the possibility that cancers susceptibility to immunotherapy could be boosted by targeting its autophagy genes.

But as the researchers delved deeper, they found that deleting certain autophagy genes in pairs rendered the cells resistant to T cell killing. That means that if a tumour already harbours a mutation in one autophagy gene, a treatment that combines immunotherapy with a drug targeting another autophagy gene could make the disease worse in that patient.

We found this complete inversion of gene dependency,says Moffat. We did not anticipate this at all. What it shows us is that genetic context what mutations are present very much dictates whether the introduction of the second mutationwill cause no effect, resistance or sensitivity to therapy.

As more research explores combinatorial effects of mutations across different types of cancer cells, it should become possible to predict from a tumours DNA what type of therapy will be most effective.

The research was funded by the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research and Agios Pharmaceuticals.

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U of T researchers identify genes that enable cancer to evade the immune system - News@UofT

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Bacterial viperins prove effective against human viruses: Researchers – Express Pharma

September 26th, 2020 5:59 am

Virus-fighting viperins, part of the human immune system, turn out to have bacterial counterparts that might boost the fight against human disease.

By tracking the evolution of what may be our oldest means of fighting off viral infection, a group at the Weizmann Institute of Science has uncovered antiviral substances that may lead to the development of highly effective antiviral drugs. These substances are made by virus-fighting enzymes known as viperins, which were previously known to exist only in mammals, and have now been found in bacteria. The molecules produced by the bacterial viperins are currently undergoing testing against human viruses such as the influenza virus and COVID-19. The study was published in Nature.

Studies conducted over the past decade by Prof Rotem Sorek and his group in the Institutes Molecular Genetics Department, as well as those by other scientists, have revealed that bacteria have highly sophisticated immune systems, despite their microscopic size. In particular, they are equipped to fight off phages viruses that infect bacteria. These differ from the kind that infect humans in their choice of targets, but they all consist of genetic material DNA or RNA that hijacks parts of the hosts replication machinery to make copies of themselves and spread.

Prof Sorek has found that some of these bacterial immune responses suggest evolutionary links to our own immune systems, and the present study in his lab shows the strongest evidence yet: They discovered that viperin antiviral enzymes whose function in the human immune system was understood only two years ago play a role in the immune system of bacteria.

In humans, viperin belongs to the innate immune system, the oldest part of the immune system in terms of evolution. It is produced when a signalling substance called interferon alerts the immune system to the presence of pathogenic viruses. The viperin then releases a special molecule that is able to act against a broad range of viruses with one simple rule: The molecule mimics nucleotides, bits of the genetic material needed to replicate their genomes. But the viperin molecule is fake: It is missing a vital piece that enables the next nucleotide in the growing strand to attach. Once the faux-nucleotide is inserted into the replicating viral genome, replication comes to a halt and the virus dies.

This simplicity and broad action against many different viruses suggested viperins had been around for some time, but could they go back as far as our common ancestors with bacteria? Led by former postdoctoral fellow Dr Aude Bernheim in Soreks lab, the group used techniques that had been developed in his lab to detect bacterial sequences encoding possible viperins. They then showed that these viperins did, indeed, protect bacteria against phage infection.

Whereas the human viperin produces a single kind of antiviral molecule, we found that the bacterial ones generate a surprising variety of molecules, each of which can potentially serve as a new antiviral drug, says Sorek.

Based on the genetic sequences, Sorek and his team were able to trace the evolutionary history of viperins: We found that this important component of our own antiviral immune system originated in the bacterial defence against viruses that infect them, says Sorek.

If the bacterial viperins prove effective against human viruses, Sorek thinks it may pave the way for the discovery of further molecules generated by bacterial immune systems that could be adopted as antiviral drugs for human diseases. As we did decades ago with antibiotics antibacterial substances that were first discovered in fungi and bacteria we might learn how to identify and adopt the antiviral strategies of organisms that have been fighting infection for hundreds of millions of years.

The current study was conducted in collaboration with researchers from Pantheon Biosciences, which has licensed the rights through Yeda Research and Development, the technology transfer arm of the Weizmann Institute of Science, to develop anti-viral drugs based on the findings. Further studies are underway to determine which of the bacterial viperins could be best adapted to fighting human viruses, including, COVID-19. Also participating in this research were Adi Millman, Gal Ofir, Gilad Meitav, Carmel Avraham, Sarah Melamed and Dr Gil Amitai, all of Soreks group in the Weizmann Institute of Sciences Molecular Genetics Department.

Prof Rotem Sorek is Head of the Knell Family Center for Microbiology; his research is also supported by the Willner Family Leadership Institute for the Weizmann Institute of Science; the Sagol Weizmann-MIT Bridge Program; the Schwartz/Reisman Collaborative Science Program; the Ben B and Joyce E Eisenberg Foundation; the Yotam Project; and the European Research Council.

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Bacterial viperins prove effective against human viruses: Researchers - Express Pharma

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Virus-Fighting Enzymes in Bacteria Could Lead to Development of Highly Effective Antiviral Drugs Against COVID-19 – HospiMedica

September 26th, 2020 5:59 am

Image: The viperins in bacteria have evolved to fight a variety of viruses (Photo courtesy of Weizmann Institute of Science)

A group of scientists at the Molecular Genetics Department at the Weizmann Institute of Science (Rehovot, Israel) has uncovered a gold mine of antiviral substances made by virus-fighting enzymes known as viperins. The molecules produced by the bacterial viperins are currently undergoing testing against human viruses such as the influenza virus and COVID-19.

Earlier studies conducted by the group as well as other scientists have revealed that bacteria have highly sophisticated immune systems, despite their microscopic size. In particular, they are equipped to fight off phages - viruses that infect bacteria. These differ from the kind that infect humans in their choice of targets, but they all consist of genetic material - DNA or RNA - that hijacks parts of the hosts replication machinery to make copies of themselves and spread.

The group of scientists have now found that some of these bacterial immune responses suggest evolutionary links to our own immune systems, and the present study in their lab shows the strongest evidence yet: They discovered that viperin antiviral enzymes - whose function in the human immune system was understood only two years ago - play a role in the immune system of bacteria.

In humans, viperin belongs to the innate immune system, the oldest part of the immune system in terms of evolution. It is produced when a signaling substance called interferon alerts the immune system to the presence of pathogenic viruses. The viperin then releases a special molecule that is able to act against a broad range of viruses with one simple rule: The molecule mimics nucleotides, bits of genetic material needed to replicate their genomes. But the viperin molecule is fake: It is missing a vital piece that enables the next nucleotide in the growing strand to attach. Once the faux-nucleotide is inserted into the replicating viral genome, replication comes to a halt and the virus dies.

This simplicity and broad action against many different viruses suggested viperins had been around for some time, but could they go back as far as our common ancestors with bacteria? The group used techniques that had been developed in their lab to detect bacterial sequences encoding possible viperins. They then showed that these viperins did, indeed, protect bacteria against phage infection. Based on the genetic sequences, the team was able to trace the evolutionary history of viperins. If the bacterial viperins prove effective against human viruses, then it may pave the way for the discovery of further molecules generated by bacterial immune systems that could be adopted as antiviral drugs for human diseases. Further studies are underway to determine which of the bacterial viperins could be best adapted to fighting human viruses, including, of course, COVID-19.

As we did decades ago with antibiotics - antibacterial substances that were first discovered in fungi and bacteria - we might learn how to identify and adopt the antiviral strategies of organisms that have been fighting infection for hundreds of millions of years, said Prof. Rotem Sorek from the Institutes Molecular Genetics Department.

Related Links:Weizmann Institute of Science

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Virus-Fighting Enzymes in Bacteria Could Lead to Development of Highly Effective Antiviral Drugs Against COVID-19 - HospiMedica

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Molecular Diagnostics Market Incredible Possibilities, Growth Analysis and Forecast To 2025 – The Daily Chronicle

September 26th, 2020 5:59 am

Molecular diagnostics is a way of performing a diagnostic test to discover ailment, circumstance or infection in an artificial surroundings. Molecular diagnostic is one of the principal segments of in-vitro diagnostics marketplace. Molecular diagnostics is used to measure and stumble on the presence of genetic fabric related to specific disorder. It is used to identify DNA and RNA at molecular stage. Molecular diagnostics is a device to improve clinical effects and clinical decisions. Molecular diagnostic consists of all exams used to become aware of a disorder, by analyzing molecules such as DNA, protein or RNA in a fluid or tissue. In recent times molecular diagnostics is utilized in early detection of infectious sicknesses, most cancers and genetic ailment, by way of the usage of molecular and genetic technologies. Molecular diagnostics is likewise utilized in detection of abnormalities in pre-natal stage. Further, molecular diagnostic kits are utilized in pharmacogenetics trying out and blood donor screening.

The Global Molecular Diagnostics Market is expected to exceed more than US$ 12.50 billion by 2024 and will grow at a CAGR of more than 8.5% in the given forecast period.

You Can Browse Full Report @: https://www.marketresearchengine.com/reportdetails/molecular-diagnostics-market

The report covers detailed competitive outlook including the market share and company profiles of the key participants operating in the global market. Key players profiled in the report include Roche Diagnostics (U.S.), QIAGEN N.V. (Netherlands), Hologic Inc. (U.S.), Grifols (Spain), Abbott Laboratories (U.S.), Siemens Healthcare (Germany), Becton, Dickinson and Company (U.S.), Beckman Coulter Inc. (U.S.), bioMrieux SA (France), and Cepheid Inc. (U.S.). Company profile includes assign such as company summary, financial summary, business strategy and planning, SWOT analysis and current developments.

The molecular diagnostics market is segmented by product, by technology, by application and by end user analysis. Under the product and service segmentation it contains instruments, reagents and services & software. It uses different technologies such as polymerase chain reaction (PCR), isothermal nucleic acid amplification technology (INAAT), hybridization, DNA sequencing and next-generation sequencing, microarrays, mass pectrometry, flow cytometry, and electrophoresis. Molecular diagnostics techniques are used in different application such as infectious diseases, oncology, genetics, blood screening, microbiology, cardiovascular diseases, neurological diseases, and DNA fingerprinting. The end user of molecular diagnostics are reference laboratories, hospital laboratories, blood banks, local public health laboratories, home health agencies, nursing homes, point-of-care settings, and self-testing. The molecular diagnostics market is geographic segmentation covers various regions such as North America, Europe, Asia Pacific, Latin America, Middle East and Africa. Each geography market is further segmented to provide market revenue for select countries such as the U.S., Canada, U.K. Germany, China, Japan, India, Brazil, and GCC countries.

The scope of the report includes a detailed study of global and regional markets for various types of molecular diagnostics market with the reasons given for variations in the growth of the industry in certain regions.

The Molecular diagnostics Market has been segmented as below:

The Molecular diagnostics Market is Segmented on the lines of Application Analysis, Product and service Segment Analysis, Technology Analysis, End-user Analysis and Regional Analysis. By Application Analysis this market is segmented on the basis of Infectious Diseases, Oncology, Genetics, Blood Screening, Microbiology and Others (Cardiovascular Diseases, Neurological Diseases, and DNA Fingerprinting). By Product and service Segment Analysis this market is segmented on the basis of Instruments, Reagents and Services & Software.

By Technology Analysis this market is segmented on the basis of Polymerase Chain Reaction (PCR), Isothermal Nucleic Acid Amplification Technology (INAAT), Hybridization, DNA Sequencing and Next-generation Sequencing, Microarrays and Others (Mass Spectrometry, Flow Cytometry, and Electrophoresis). By End-user Analysis this market is segmented on the basis of Reference Laboratories sector, Hospital Laboratories sector and Others (Blood Banks, Local Public Health Laboratories, Home Health Agencies, Nursing Homes, Point-of-care Settings, and Self-testing) sector. By Regional Analysis this market is segmented on the basis of North America, Europe, Asia-Pacific and Rest of the World.

The major driving factors of Global Molecular Diagnostics Market are as follows: Increasing application in blood screening Increasing prevalence of chronic and infectious diseases such as HIV and hepatitis Rising awareness and acceptance of personalized medicine

The restraining factors of Global Molecular Diagnostics Market are as follows:

Require more time for approval of many new molecular diagnostic tests Changing reimbursement regulations

This report provides:1) An overview of the Global Molecular Diagnostics Market and related technologies.2) Analyses of global market trends, with data from 2015, estimates for 2016 and 2017, and projections of compound annual growth rates (CAGRs) through 2024.3) Identifications of new market opportunities and targeted promotional plans for Global Molecular Diagnostics Market.4) Discussion of research and development, and the demand for new products and new applications.5) Comprehensive company profiles of major players in the industry.

Reasons to Buy this Report:1) Obtain the most up to date information available on all Global Molecular Diagnostics Market.2) Identify growth segments and opportunities in the industry.3) Facilitate decision making on the basis of strong historic and forecast of Global Molecular Diagnostics Market data.4) Assess your competitors refining portfolio and its evolution.

Request Sample Report from here: https://www.marketresearchengine.com/reportdetails/molecular-diagnostics-market

Table of Contents

1 INTRODUCTION

2 Research Methodology

3 Executive Summary

4 Premium Insights

5 Molecular Diagnostics Market Overview

6 Molecular Diagnostics Market, By Application

7 Molecular Diagnostics Market, By Technology

8 Molecular Diagnostics Market, By Products and Services

8.1 Introduction8.2 Reagents & Kits8.3 Instruments8.4 Software & Services

9 Molecular Diagnostics Market, By End User

10 Molecular Diagnostics Market, By Region

11 Competitive Landscape

12 Company Profiles

12.1 Introduction

12.2 Abbott Laboratories

12.3 Qiagen N.V.

12.4 Roche Diagnostics

12.5 Hologic, Inc.

12.6 Grifols

12.7 Siemens Healthcare

12.8 Becton, Dickinson and Company

12.9 Beckman Coulter Inc. (A Wholly Owned Subsidiary of Danaher Corporation)

12.10 Biomrieux Sa

12.11 Cepheid Inc.

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Molecular Diagnostics Market Incredible Possibilities, Growth Analysis and Forecast To 2025 - The Daily Chronicle

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Kill fish to save fish: Behind Colorado’s effort to revive the Rio Grande cutthroat trout – The Colorado Sun

September 26th, 2020 5:59 am

On a beautiful early September day, Ken Gierhart hiked a trail familiar since boyhood to Music Pass in the Sangre de Cristo mountains above Westcliffe. As he dropped off the saddle toward the Sand Creek lakes, he noticed people heading the opposite direction with fishing poles.

Hows the fishing? he asked one woman.

Theyre all dead, she replied, saying nothing more as she passed.

Puzzled, Gierhart came upon another woman heading away from the lakes and tried his question again.

There is no fishing, she said. Theyre all dead.

This time, the angler paused to explain that Colorado Parks and Wildlife, according to signs posted in the area, had used a chemical called rotenone to kill all the fish in the lakes and Sand Creek, which meanders south down the mountain before veering west to eventually disappear, after 13 miles, into the depths of the Great Sand Dunes.

The project is part of a long-planned strategy to restore the native Rio Grande cutthroat trout to waters where its numbers have dwindled toward the edge of extinction.

Increasingly scarce in a dwindling native range and hybridized with other species like non-native cutthroats, which had been stocked alongside it many years ago, the Rio Grande cutthroat eventually will be reintroduced to the mountain lakes and streams where it once thrived. But the process can be disconcerting especially to an unsuspecting hiker like Gierhart.

It wasnt until he got closer to Lower Sand Creek Lake that he saw the informational signs for himself. Then he headed toward the upper lake, following the trail that crosses the creek several times along the way. He said piles of dead earthworms filled seemingly every crevice in the rocks. And then it got worse.

It was horrifying at that level to see what had been done to the lake, Gierhart said. When I got to the lake I saw fish belly-up, carcasses on the bank where animals or birds had pulled them out.

Gierhart, a 54-year-old wholesale tree grower, hadnt heard anything about the fish management plan, and he stewed all the way back to his home in Westcliffe. There, he fired up his Facebook account and vented in a post that estimated thousands of dead fish and that attracted nearly 100 comments, most expressing concern over an undertaking they, too, seemed unaware of.

Ive always been preservation conscious, Gierhart said, still steamed a couple weeks later, but to see aquatic life dead like that, I started thinking about the watershed, the lasting effects, side effects.

The rant and its response caught the attention of CPW officials, who expressed frustration over response to a broad regional project that has been years in the making and which framed its intent in a compact signed in 2003 and renewed in 2013 by six federal entities, state agencies in Colorado and New Mexico and three American Indian tribal agencies. The agreement also received non-signatory support from two Trout Unlimited groups.

The Sand Creek drainage was officially listed in a 2013 strategy document.

In 2019, meetings on both the Westcliffe and Alamosa sides of the mountain yielded no opposition other than concern over the temporary loss of fishing and little public comment. The project moved ahead, though a year later than originally scheduled due to a late fish spawn.

Its something we need to do, said John Alves, the Durango-based senior aquatic biologist for CPWs Southwest Region. With only 11% of its historic range left, the Rio Grande cutthroat trout is always susceptible to petitions to list it as endangered, and also to extrication if there are events like fire. Its a constant process for us.

Joe Lewandowski, spokesman for CPWs Southwest Region, which includes the Sand Creek drainage, notes that the state agency has done similar projects before and will do more of them throughout Colorado.

We dont get a great deal of pleasure having to poison a stream, but it is necessary to restore native species, he said in an email to The Colorado Sun. This has been done in waters to restore the Rio Grande, greenback and the Colorado River cutthroat; and these projects will continue.

We know people are not happy to see dead fish, and it is confusing. Its very difficult often impossible to explain to the general public why we have to do these projects.

The intersection of history, science and politics of wildlife management can be complex. And while in this case the ultimate goal to restore the Rio Grande cutthroat to its native range is mostly a shared interest, the path to achieving it can be challenging.

After the 2003 conservation agreement, federal and state authorities started doing reconnaissance in 2004 to determine if the drainage could be restored. Geography that essentially isolated water flow, and therefore fish migration, proved fortuitous.

Its an ideal situation in a lot of regards, because its a closed system, said Fred Bunch, chief of resources management for the Great Sand Dunes National Park and Preserve, which takes in the Sand Creek drainage. The creeks have their headwaters high in the Sangres, they flow into those lakes and the lakes flow out to the dunes. Thirty-four square miles of sand is a pretty substantial fish barrier.

Bunch points to several reasons why reintroduction of the Rio Grande cutthroat looms important. First, theres federal policy that favors native species in national parks and preserves. Another has to do with the essential characteristics of a wilderness area. A third is for preservation of the species.

This is an ideal opportunity to restore 13 miles of habitat for the Rio Grande cutthroat trout, he said.

The stakeholders who signed the conservation agreement meet annually to discuss the status of its efforts. The key thing, Bunch said, is to prevent the listing of the Rio Grande cutthroat as an endangered species and ensure it has robust habitat.

And thats where politics can come in.

The Center for Biological Diversity, a nonprofit organization that claims roots in the fear that government authority alone will not always protect flora and fauna when powerful business interests can exert political leverage. (The timber industry was its founders nemesis.) Now, it contests threats to biodiversity on a range of levels, from climate change to encroachment of off-road vehicles.

The group has petitioned multiple times to place the Rio Grande cutthroat trout on the endangered species list, including one case thats still pending an appeal.

From the standpoint of state wildlife managers like Alves, who shares the groups desire to see the native species rebound, the fishs presence on the list represents another potential layer of bureaucracy that state workers on the ground would have to contend with.

Once a species is listed by the U.S. Fish and Wildlife Service, local agencies dont make decisions, he said. Theyre made by the federal government. For years, since the late 90s, there have been petitions to list the Rio Grande cutthroat trout. (The Center for Biological Diversity) sees listing as a way to get timber and mining off public lands.

That is true, said Noah Greenwald, the centers Portland, Oregon-based endangered species director.

Those things present a real threat to their habitat and to the species, so we want to make sure those things are done in a careful way or theres avoidance of trout habitat or, to the extent that theres damage, theres mitigation which is what the Endangered Species Act requires.

Aside from territorial concerns stemming from listing the species, both the center and the state agree on some key issues. The center supports and applauds the effort to repopulate the Sand Creek drainage with the native fish. But Greenwald also claims that his organizations petitions to list the Rio Grande trout spurred the state to take action to conserve them more than they were before.

We havent succeeded in putting them on the protected list, but weve pressured the state to do more for them, which is a benefit for the species, he said. Theyve done a tremendous amount of surveys and used staffing resources in an effort to avoid listing them. We dont think thats the right tradeoff. It makes more sense to list them and work for recovery.

The center doesnt even have problems with the kill-to-restock method, or the rotenone compound used to achieve it.

Greenwald calls the CPW a credible messenger with regard to the safety of rotenone.

We dont love having to use poisons, he said. But theres been a lot of work done on this issue, and there are not other effective means. As chemicals go, rotenone is pretty specific to fish. We definitely think it needs to be done carefully and we dont relish the thought of poison being used. But its the only way.

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Although the battle over listing the fish persists, all sides celebrate the ideas that in the case of the Sand Creek drainage, the area could become a refugium for the species, where the fish could naturally multiply and be used as a source for future stocking or restoration if some other habitat experiences problems say, from wildfire.

So were doing it for many things, Bunch said. One is the philosophy of land managers, but theres also the species itself. Also theres a recreational piece. Its a great situation where a hiker can backpack in and catch native fish. Thats a pretty great situation to have, and thats what were shooting for.

From the start, the effort to restore the species has been a multipartner project, including federal, state and county agencies and even private groups like Trout Unlimited. Some of the early upfront money came from the National Park Service but functionally, the reintroduction process is a CPW project done in a national preserve. Cost of a helicopter, boats and other equipment is covered mostly by the state.

This year, phase one of the process got underway. But before fish and wildlife authorities took any action, they needed to know exactly how many different species they were dealing with in those waters that stretch from the Sand Creek lakes to the sand dunes.

And thats where science played a big role.

John Wood founded Pisces Molecular more than 20 years ago, just a few years before efforts began in earnest to restore the Rio Grande cutthroat trout.

Though it has just four people on staff, the Boulder-based biotech lab has clients all over the world, not to mention right in its backyard. Woods lab has worked with Colorado Parks and Wildlife on multiple different fish projects, including when in 2007, in conjunction with University of Colorado post-doc Jessica Metcalf, it discovered that CPWs stock of supposed greenback cutthroat trout which happens to be Colorados state fish were actually Colorado River cutthroat trout.

How do scientists figure out what species are in a waterway? One method is simply catching a sample of fish, clipping off the tiniest bits of their fins, and sending the material to a lab for DNA sequencing. Wood notes that can be laborious and difficult to get an accurate representation of the species makeup of a waterway.

The other option is environmental DNA testing. Just as humans regularly shed skin, hair, saliva and other sources of DNA, so do fish. Field researchers can collect a sample of water, filter out all the bits from the water, and send the gunked-up, DNA-laden filter to the lab for testing. These results will indicate the presence of species upstream of where the sample was taken.

Regardless of the type of sample, once it gets to the lab, Woods team uses polymerase chain reactions, also known as PCR, to check for species-specific genetic markers. For reference, this is the same kind of procedure used in the SARS-CoV-2 coronavirus test; Wood says its become a very sexy technique since the patent on PCR expired in the 2000s. And its remarkably precise; if one-tenth of a drop of a fishs DNA solution were mixed into an Olympic-sized swimming pool, Wood said, we would pick it up.

The only technical field that is changing as fast as computers is molecular genetics, so the sort of techniques that we use now are incredibly more sophisticated than when I was in graduate school, and I find that really fun, Wood said.

Theoretically, this could happen all in the field, but Wood says that it requires a lot of coordination, because you dont keep wild fish outside of their water body for very long. More often, its an iterative process between the lab and the wildlife managers testing the waterway, analyzing the results for the percent purity for individual fish or the population at large, then removing or restocking fish as needed, and doing it all over again.

Though Pisces was not directly involved with last months rotenone treatment, it has generally worked on identifying species in the Upper Sand Creek Lake drainage. In 2015, Woods team found evidence that the drainage had native Rio Grande cutthroat trout that were hybridizing with other subspecies, including Yellowstone cutthroat, greenback cutthroat and Colorado River cutthroat.

Wood called CPWs attitude on restoring native species enlightened, especially when compared to previous practices. Much of the 20th century was spent stocking the states waterways with outside fish such as rainbow trout, which are especially susceptible to whirling disease; when that struck the state in the 1990s, the rainbow trout population quickly spread it to other fish species, including native cutthroats. And this wasnt just in one or two rivers; in the process of moving fish around from waterway to waterway, stocking and other efforts inadvertently introduced the disease to 15 of the 17 hydrographic drainages in the state.

Along Sand Creek, the CPW found ponds on private property that harbored the parasites that transmit whirling disease. But the ponds were removed with stimulus funds during the Great Recession. Since they qualified as gravel pits, they could be remediated as abandoned mines. The whirling disease went away and the reintroduction plans moved forward.

Humans, when we mess with ecology, we generally make a mess, Wood said. So its probably philosophically better to do less interventions and strive to maintain whats there than presume that were smarter than Mother Nature.

That said, its not like leaving the river to rebound on its own would work. Part of it has to do with the different life cycles of fish species: brook trout, for example, spawn in the fall, giving them a full six months head start to grow before cutthroats spawn in the spring. And while rainbow trout spawn in the spring, like cutthroats, Wood notes that the jurys still out as to the impact of the two species interbreeding freely.

In other words: humans made this mess, and only humans can clean it up.

We now know more about genetics, we can discern finer level details, we have a longer history of how our attempts to alter ecologies tend not to work very well, so lets see if we can remediate some of the damage that weve done, Wood said.

In June, weeks before implementation of the first phase of the Rio Grande cutthroat project began, the CPW declared a fish emergency public salvage in the Sand Creek drainage. That tactic, which allows anglers to catch an unlimited number of fish from the waterways, has been used more times this summer, for a variety of reasons, than in the past 10 years.

On this occasion, the CPW wanted to let anglers help make best use of the fish before the chemical rotenone was administered to kill any that remained.

Alves, of the CPWs Southwest Region, noted that removing the bag limit seemed to be a particularly effective strategy in the lakes.

Get enough anglers out there, he said, they do a pretty good job.

The rest is left to rotenone, a plant-based compound effective only on gill-breathing organisms primarily fish and insects. The CPW workers secured the necessary permissions and trained to use it. During the first week of September, they began the process in the two high mountain lakes and the creeks below up to a point where waterfalls along Sand Creek provide a natural barrier to fish migration. Phase 2 of the operation will involve clearing Sand Creek from below the waterfalls to the Great Sand Dunes.

A helicopter from the Colorado Division of Fire Protection and Control had been busy fighting wildfires, but eventually was freed up to transport boats, motors, pumps and the 5-gallon buckets of rotenone itself to the lakes. Workers mixed the chemical with water. It was administered from a boat throughout the lake, in volumes dictated by the waters depth. The mixture shaded the water slightly white, a change that diminishes within several hours.

To apply rotenone to streams, workers spread out drips that added the rotenone/water solution to the flow every 15 seconds. A four-hour drip produced the desired solution throughout the streams.

The chemical works quickly. At one of the drip stations, Alves noticed that as soon as the organic green dye marker reached him from a drip point upstream, fish started dying. Workers also sprayed backwaters where fish might be lurking.

Rotenone, though extremely toxic to fish and some insects, is harmless to man and all warmblooded vertebrates, according to the journal Nature. Alves notes that it breaks down quickly in streams, but in lakes, at a water temperature of 50 degrees, takes about 28 days to decompose.

Then, the waiting begins. The dead fish decompose and, if all goes perfectly, the waterways will be clear for stocking. First, the water is tested environmental DNA sampling comes in handy here to make sure no fish survived that could taint the reintroduction of the native Rio Grande.

Youve got to wait and see,Alves said. Well do a lot of sampling, electrofishing in the streams, gill netting in the lakes, probably use environmental DNA, and test to see if there are genetic markers. We use that as a confirming tool.

If any fish remain, CPW will come back and repeat the process.

If theres zero live fish, Alves said, well start to restock in the fall.

Typically, CPW uses airplanes to stock the high mountain lakes. Workers on foot or on horseback, and sometimes by helicopter, stock the streams. By stocking fish in a variety of age groups, managers can hasten the turnaround.

The Sand Creek drainage, with its hiking trails and beautiful vistas, is a highly used area, Alves said. Though remote, its only about an hour-and-a-half hike in from the trail head. What he wants people to understand is that what the CPW is doing is definitely the right thing. Yes, the fish are all gone but thats only temporary.

As soon as we can, well put in Rio Grande cutthroat trout, really a pretty fish, growing to the same size theyre used to catching, a 15- or 16-inch fish, he said. So theyre temporarily losing their opportunity, but itll come back. I predict within five years, theyll see really good cutthroat trout in the lakes.

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Kill fish to save fish: Behind Colorado's effort to revive the Rio Grande cutthroat trout - The Colorado Sun

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Elo Life Systems Appoints Food and Beverage Industry Technology Leader Alec Hayes as Vice President of Technology and Products – GlobeNewswire

September 26th, 2020 5:59 am

Alec Hayes, Vice President Technology & Products

Alec Hayes, Vice President Technology & Products

DURHAM, N.C., Sept. 21, 2020 (GLOBE NEWSWIRE) -- Elo Life Systems, a food and agriculture company with a mission to improve human health and wellness, today announcedthat Alec Hayes, Ph.D., has joined Elo Life Systems as Vice President of Technology and Products. In his role, Alec will be responsible for Elos research and development pipeline and strategic expansion of Elos integrated suite of capabilities to enable accelerated product development.

Through thoughtful analysis of opportunities and challenges in the industry, Elo has embarked on impactful programs of immediate relevance to human nutrition and the health of our planet, commented Fayaz Khazi, Ph.D., Chief Executive Officer of Elo Life Systems. Alecs experience at the nexus of food and human health will be instrumental as we fast-track Elos pipeline and long-term vision.

With a product-ready genome editing platform, world-class expertise in target discovery, and an end-to-end infrastructure that enables expedited trait validation, Elo is uniquely positioned to improve human health through rapid product development, said Alec Hayes. I look forward to joining the incredibly talented group at Elo, working to create sustainable production of a more nutritious, and climate-resilient food supply.

Prior to joining Elo,Alec served as the Technical Director of Agricultural Technologies at The Coca-Cola Company in Atlanta. There, he helped drive long-term strategic opportunities in beverage innovation and address agricultural supply chain challenges. Prior to that, Alec held technical leadership roles at PepsiCo and Altria and brings over 20 years of industry experience in translational agriculture, developing plant-based strategies to advance consumer-focused product solutions.Alec holds a Ph.D. in plant molecular genetics from Virginia Tech.

About Elo Life Systems, Inc.Elos mission is to create novel products that enhance the nutrition and diversity of the global food supply. To address agricultural needs, Elo partners with stakeholders in the food systems value chain to bridge gaps and meet needs across agricultural productivity, nutritional demand, food security, climate-resilience, and human wellness. Elo Life Systems, Inc. is a wholly owned subsidiary of Precision BioSciences, Inc. (NASDAQ: DTIL). To learn more about Elo Life Systems please visit http://www.elolife.ag.

Investor and Media Contact:Maurissa MessierSenior Director, Corporate Communicationsmmessier@elolife.ag

A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/620459d9-8c82-48a2-ae64-e9ea9d183566

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Elo Life Systems Appoints Food and Beverage Industry Technology Leader Alec Hayes as Vice President of Technology and Products - GlobeNewswire

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Zelis and Concert Genetics Launch Genetic Testing Claim Editing Solution – Business Wire

September 26th, 2020 5:59 am

BEDMINSTER, N.J. & NASHVILLE, Tenn.--(BUSINESS WIRE)--Zelis, the healthcare industrys leading claims cost and payments optimization platform with superior technology and solutions to price, pay and explain claims, and Concert Genetics, a technology company dedicated to advancing precision medicine, have launched a claim editing solution for the complex and rapidly-growing area of genetic testing.

The solution embeds Concerts claim editing capabilities, which are powered by robust genetic testing market data and machine learning, into Zelis existing claim editing platform. This leading-edge platform already contains more than 18 million edits sourced to national coding standards. The partnership adds specialized content in genetic testing that other platforms lack, enabling Zelis and Concert to improve coding and billing accuracy of these complex and ambiguous genetic test claims before they are paid.

Our clients are experiencing higher costs due to the complexity of managing the variability of genetic testing codes and volume of new tests entering the market, said R. Andrew Eckert, Zelis CEO. Combining our payment integrity expertise with Concerts precision technology will enable us to proactively identify inaccurate claims and continue to support our clients with innovative solutions to reduce costs.

This solution comes at a critical time, as the availability and demand for genetic tests grow with the global genetic testing market expected to reach $17.6 billion by 2025, from $7.5 billion in 2017.1 Additionally, the total number of available genetic testing products has surpassed 150,000, up from around 10,000 in 2012. Meanwhile, much of the growth in volume is represented by multi-gene panel tests, which are particularly difficult for health plans to process in an efficient and accurate way because they are billed using multiple billing codes in widely varying combinations. Some categories of genetic tests are billed in thousands of different code combinations.

The pace of advancement in the science and clinical application of genetics is remarkable, and the healthcare system has had difficulty keeping up, said Rob Metcalf, CEO of Concert Genetics. Concert has assembled the data and digital infrastructure to enable transparency, connectivity, and value in this space, and we are pleased to partner with Zelis to make our technology available to its clients.

A key enabler of this claim editing solution is its ability to match complex claims with multiple billing codes back to its catalog of tests on the market. The combined solution is available to Zelis clients effective immediately.

About Zelis

Zelis is the healthcare industrys leading claims cost and payments optimization platform with superior technology and solutions to price claims, pay claims and explain claims, all at enterprise scale on a claim-by-claim basis. Zelis leverages proprietary technology, robust analytics, extensive payment and provider networks, and innovative claim savings channels to deliver to the industry superior administrative and medical cost savings. Zelis was founded on a belief that there is a better way to determine the cost of a healthcare claim, manage payment related data, and make the claim payment. Zelis provides the industrys only comprehensive, integrated platform to take a claim through the entire pre-payment to payments lifecycle. Zelis ~1000 associates serve more than 700 payor clients, including the top-5 national health plans, Blues plans, regional health plans, TPAs and self-insured employers, and more than 1.5 million providers. Zelis delivers more than $5B of claims savings, $50B of provider payments and 500 million payment data communications annually.

About Concert Genetics

Concert Genetics is a software and managed services company that advances precision medicine by providing the digital infrastructure for reliable and efficient management of genetic testing. Concerts market-leading genetic test order management platform leverages a proprietary database of the U.S. clinical genetic testing market today more than 150,000 testing products and genetic testing claims from more than 100 million lives. Learn more at http://www.ConcertGenetics.com.

1 Allied Market Research report, Genetic Testing Market by Type (Predictive Testing, Carrier Testing, Prenatal & Newborn Testing, Diagnostic Testing, Pharmacogenomic Testing, and Others), Technology (Cytogenetic Testing, Biochemical Testing, and Molecular Testing), and Application (Chromosome Analysis, Genetic Disease Diagnosis, Cardiovascular Disease Diagnosis, and Others): Global Opportunity Analysis and Industry Forecast, 20182025

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Insights on the Predictive and Presymptomatic Testing Global Market to 2027 – Featuring Mapmygenome, Myriad Genetics & Pathway Genomics Among…

September 26th, 2020 5:59 am

DUBLIN--(BUSINESS WIRE)--The "Predictive and Presymptomatic Testing - Global Market Trajectory & Analytics" report has been added to ResearchAndMarkets.com's offering.

The publisher brings years of research experience to the 6th edition of this report. The 142-page report presents concise insights into how the pandemic has impacted production and the buy side for 2020 and 2021. A short-term phased recovery by key geography is also addressed.

Global Predictive and Presymptomatic Testing Market to Reach $7.7 Billion by 2027

Amid the COVID-19 crisis, the global market for Predictive and Presymptomatic Testing estimated at US$4.1 Billion in the year 2020, is projected to reach a revised size of US$7.7 Billion by 2027, growing at a CAGR of 9.6% over the period 2020-2027.

The U.S. Market is Estimated at $1.1 Billion, While China is Forecast to Grow at 12.7% CAGR

The Predictive and Presymptomatic Testing market in the U.S. is estimated at US$1.1 Billion in the year 2020. China, the world's second largest economy, is forecast to reach a projected market size of US$1.6 Billion by the year 2027 trailing a CAGR of 12.7% over the analysis period 2020 to 2027. Among the other noteworthy geographic markets are Japan and Canada, each forecast to grow at 6.6% and 8.2% respectively over the 2020-2027 period. Within Europe, Germany is forecast to grow at approximately 7.5% CAGR.

Competitors identified in this market include, among others:

Key Topics Covered:

I. INTRODUCTION, METHODOLOGY & REPORT SCOPE

II. EXECUTIVE SUMMARY

1. MARKET OVERVIEW

2. FOCUS ON SELECT PLAYERS

3. MARKET TRENDS & DRIVERS

4. GLOBAL MARKET PERSPECTIVE

III. MARKET ANALYSIS

IV. COMPETITION

For more information about this report visit https://www.researchandmarkets.com/r/f4gfph

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Insights on the Predictive and Presymptomatic Testing Global Market to 2027 - Featuring Mapmygenome, Myriad Genetics & Pathway Genomics Among...

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Houston sampling wastewater to track spread of COVID-19 – Associated Press

September 26th, 2020 5:59 am

HOUSTON (AP) Results from a program thats testing Houstons wastewater to monitor the local spread of the coronavirus have shown that it could be a faster way of detecting outbreaks in the nations fourth-largest city, officials said Thursday.

Since May, the city and scientists from Rice University and Baylor College of Medicine have tested wastewater from the citys 39 treatment plants. Studies indicate genetic material from the virus can be recovered from the stools of about half of patients with the COVID-19 virus. Wastewater analysis looks for that genetic material.

The goal is to help develop an early warning system, allowing the health department to identify the citys COVID-19 hot spots sooner and put measures in place to slow the spread of this disease, said Mayor Sylvester Turner.

During the summer, Houston had a surge in coronavirus cases as the areas intensive care units were filled with patients. Since then, hospitalizations have decreased and the citys positivity rate for the virus has gone from a high of nearly 26% in July to 6.1% as of last week.

Turner has said that while the numbers are better, the city is still reporting positive cases and deaths at levels higher than the spring. Houston has reported 72,196 cases and 1,069 deaths as of Thursday.

Houston is among communities around the world that have implemented wastewater testing programs to help deal with the virus spread. Colleges across the U.S. are also testing wastewater to detect outbreaks.

The wastewater data can show which parts of Houston have a higher virus load, prompting the health department to send teams to those areas that can go door to door and inform residents and encourage people to get tested, said Dr. David Persse, Houstons health authority.

This will give us that early warning that we may have otherwise missed so we empower people to take care of themselves, Persse said.

The wastewater testing can also provide a more current view of whats going on with the virus in the city. The testing is done weekly and the results come back that same week. By comparison, 40% or more of testing data from nasal swabs are more than 2 weeks old, Persse said.

The wastewater data can be used to look at specific locations.

After COVID-19 cases were found at a homeless shelter earlier this year, the city monitored the facilitys wastewater and was able to detect when the virus came back a second time, Persse said.

This isnt the first time wastewater surveillance has been used in Houston to detect a viral outbreak. In 1962, Joseph Melnick, who worked at Baylor College of Medicine and was a pioneer in polio research, realized polio could be detected in wastewater and started sampling it.

That research prompted Melnick to push for a quicker use of the then-new oral polio vaccine, which helped stop outbreaks of the disease, said Anthony Maresso, an associate professor of molecular virology and microbiology at Baylor College of Medicine.

So, we can learn from this lesson of history of the importance of doing such measures for public health interventions, Maresso said.

State officials reported 3,840 new confirmed cases of the virus Thursday, bringing the Texas total since it began tracking the pandemic in early March to nearly 724,000. Of those, the Department of State Health Services estimated that 66,483 cases were now active and 3,204 people are hospitalized. Also, 138 new COVID-19 deaths were reported Thursday, bringing the states pandemic death toll to 15,267.

___

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Sex is real – aeon.co

September 26th, 2020 5:59 am

Its uncontroversial among biologists that many species have two, distinct biological sexes. Theyre distinguished by the way that they package their DNA into gametes, the sex cells that merge to make a new organism. Males produce small gametes, and females produce large gametes. Male and female gametes are very different in structure, as well as in size. This is familiar from human sperm and eggs, and the same is true in worms, flies, fish, molluscs, trees, grasses and so forth.

Different species, though, manifest the two sexes in different ways. The nematode worm Caenorhabditis elegans, a common laboratory organism, has two forms not male and female, but male and hermaphrodite. Hermaphroditic individuals are male as larvae, when they make and store sperm. Later they become female, losing the ability to make sperm but acquiring the ability to make eggs, which they can fertilise with the stored sperm.

This biological definition of sex has been swept up into debates over the status of transgender people in society. Some philosophers and gender theorists define a woman as a biologically female human being. Others strongly disagree. Im addressing those who reject the very idea that there are two biological sexes. Instead, they argue, there are many biological sexes, or a continuum of biological sexes.

Theres no need to reject how biologists define the sexes to defend the view that trans women are women. When we look across the diversity of life, sex takes stranger forms than anyone has dreamt of for humans. The biological definition of sex takes all this in its stride. It does so despite the fact that there are no more than two biological sexes in any species youre likely to have heard of. To many people, that might seem to have conservative implications, or to fly in the face of the diversity we see in actual human beings. I will make clear why it does not.

I call this the biological definition of sex because its the one biologists use when studying sex that is, the process by which organisms use their DNA to make offspring. Many philosophers and gender theorists will protest at making the creation of offspring foundational to how we define sex or distinguish different sexes. Theyre surely right that sex as a social phenomenon is much richer than that. But the use of DNA to make offspring is a central topic in biology, and understanding and explaining the diversity of reproductive systems is an important scientific task. Gender theorists are understandably worried about how the biology of sex will be applied or misapplied to humans. What they might not appreciate is why biologists use this definition when classifying the mind-stretching forms of reproduction observed in limpets, worms, fish, lizards, voles and other organisms and they might not understand the difficulties that arise if you try to use another definition.

Many people assume that if there are only two sexes, that means everyone must fall into one of them. But the biological definition of sex doesnt imply that at all. As well as simultaneous hermaphrodites, which are both male and female, sequential hermaphrodites are first one sex and then the other. There are also individual organisms that are neither male nor female. The biological definition of sex is not based on an essential quality that every organism is born with, but on two distinct strategies that organisms use to propagate their genes. They are not born with the ability to use these strategies they acquire that ability as they grow up, a process which produces endless variation between individuals. The biology of sex tries to classify and explain these many systems for combining DNA to make new organisms. That can be done without assigning every individual to a sex, and we will see that trying to do so quickly leads to asking questions that have no biological meaning.

While the biological definition of sex is needed to understand the diversity of life, that doesnt mean its the best definition for ensuring fair competition in sport or adequate access to healthcare. We cant expect sporting codes, medical systems and family law to adopt a definition simply because biologists find it useful. Conversely, most institutional definitions of sex break down immediately in biology, because other species contradict human assumptions about sex. The United States National Institutes of Health (NIH) uses a chromosomal definition of sex XY for males and XX for females. Many reptiles, such as the terrifying saltwater crocodiles of northern Australia, dont have any sex chromosomes, but a male saltie has no trouble telling if the crocodile that has entered his territory is a male. Even among mammals, at least five species are known that dont have male sex chromosomes, but they develop into males just fine. Gender theorists have extensively criticised the chromosomal definition of human sexes. But however well or badly that definition works for humans, its an abject failure when you look at sex across the diversity of life.

The same is true of phenotypic sex, the familiar idea that sex is defined by the typical physical characteristics (phenotypes) of males and females. Obviously, this approach will produce completely different definitions of male and female for humans, for worms, for trees and so forth. Incubating eggs inside your body, for example, is a female characteristic in humans but a male one in seahorses. That doesnt mean that human institutions cant use the phenotypic definition. But it isnt useful when studying the common patterns in the genetics, evolution and so forth of female humans, female seahorses and female worms.

Understanding the complex ways in which chromosomes and phenotypes relate to biological sex will make clear why the biological definition of sex shouldnt be the battleground for philosophers and gender theorists who disagree about the definition of woman. There might be very good reasons not to define woman in this way, but not because the definition itself is poor biology.

Why did sexes evolve in the first place? Biologists define sex as a step towards answering this question. Not all species have biological sexes, and biology seeks to explain why some do and others dont. The fact that no species has evolved more than two biological sexes is also a puzzle. It would be quite straightforward to engineer a species that has three, but none has evolved naturally.

Many species reproduce asexually, with each individual using its own DNA to create offspring. But other species, including our own, combine DNA from more than one organism. Thats sexual reproduction, where two sex cells gametes merge to make a new individual. In some species, these two gametes are identical; many species of yeast, for example, make new individuals from two, identical gametes. They reproduce sexually, but they have no sexes, or, if you prefer, they have only one sex. But in species that make two different kinds of gamete and where one gamete of each kind is needed to make a new organism there are two sexes. Each sex makes one of the two kinds of gamete.

In complex multicellular organisms, such as plants and animals, these two kinds of gamete are very different. One is a large, complex cell, what wed typically call an egg. Its similar to the eggs produced by asexual species, which can develop into a new organism all on their own. Many species of insect and some lizards, snakes and sharks can reproduce using just an egg cell. The other kind of gamete is a much smaller cell that contains very little beyond some DNA and some machinery to get that DNA to the larger gamete. We are familiar with these two kinds of gametes from human eggs and sperm.

Theres no obvious reason why complex multicellular organisms need to have two kinds of gamete, or why these two kinds are so different in size and structure. Its perfectly possible to make three or more different kinds of gamete, or gametes that vary continuously, just as people vary continuously in height. One question that biologists seek to answer, then, is why those forms of sexual reproduction arent observed in complex organisms such as animals and plants.

Earthworms are hermaphrodites: one part of the worm produces sperm and another part produces eggs

When a species produces two different kinds of gamete, biologists call this anisogamy, meaning not-equal-gametes. Some anisogamic species have separate sexes, like humans do, where each individual can produce only one kind of gamete. Other anisogamic species are hermaphrodites, where each individual produces both kinds of gamete. Because they produce two kinds of gametes, hermaphroditic species still have two biological sexes they simply combine them in one organism. When a biologist tells you that earthworms are hermaphrodites, they mean that one part of the worm produces sperm and another part produces eggs.

Some single-celled and very simple multicellular organisms have evolved something called mating types. These are gametes that are identical in size and structure, but in which the genome of each gamete contains genetic markers that affect which other gametes it can combine with. Typically, gametes with the same genetic marker cant recombine with one another. Some species have many hundreds of these mating types, and newspapers often report research into this phenomenon under headlines such as: Scientists discover species with hundreds of sexes! But, formally, biologists refer to these as mating types, and reserve the term sexes for gametes that are different in size and structure.

Why distinguish between these two phenomena? One reason is that the evolution of anisogamy gametes that differ in size and structure explains the later evolution of sex chromosomes, sex-associated physical characteristics and much more. But the existence of mating types doesnt have these dramatic knock-on evolutionary effects. Another reason to keep the distinction is that anisogamy and mating types are thought to have evolved via different evolutionary processes. One theory is that anisogamy appeared when mating-type genome markers somehow became linked to genes that controlled the size of the gamete, or mutated in some way that affected gamete size. These differences in gamete size would then kickstart the evolution of sexes.

The evolution of sex seems to be strongly associated with multicellularity, so the obvious place to look for a shift from mating types to sexes is in organisms that sit at the multicellular boundary such as algae, which sometimes exist as single-celled organisms, and sometimes as colonies of cells. And indeed, there are species of algae where gametes are just a little bit anisogamous, blurring the distinction between mating types and sexes. Theres much we dont know about how sex evolved, and how it might have evolved differently across species. But the point is that sexes and mating types are very different phenomena, with different causes and consequences.

The fact that sex evolved in some species but not others tells us something important about how biologists think about sex. Many cultures take the difference between male and female to be something fundamental, and label other natural phenomena such as the Sun and the Moon as male or female. But for biologists, the separation between male and female is no more fundamental or universal than photosynthesis or being warm-blooded. Some species have evolved these things, and some havent. They exist when they do only because of the local advantages they afforded in evolutionary competition.

So why did some species evolve two, distinct sexes? To answer this question, we need to forget about creatures with complex sex organs and mating behaviours. These evolved later. Instead, think of an organism that releases its gametes into the sea, such as coral, or into the air, such as fungal spores. Next, consider that there are two goals that any gamete must achieve if its to reproduce sexually. The first is finding and recombining with another gamete. The second is producing a new individual with enough resources to survive. One widely accepted idea, then, is that the evolution of sexes reflects a trade-off between these goals. Because no organism has infinite resources, organisms can either produce many small gametes, making it more likely that some of them will find a partner, or produce fewer but larger gametes, making it more likely that the resulting individual will have what it needs to survive and thrive.

Since the 1970s, this idea has been used to model how anisogamic species might have evolved from species with only one kind of gamete. As mutations introduce differences in gamete size, two winning strategies emerge. One is to produce a large number of small gametes too small to create viable offspring unless they recombine with a larger, well-provisioned gamete. The other winning strategy is to produce a few, large, well-resourced gametes that can create viable offspring, no matter how small the recombinant they end up merging with. Intermediate approaches, such as producing a moderate number of moderately well-provisioned gametes, dont do well. Organisms that try to follow the middle way end up with gametes less likely to find a partner than smaller gametes, and more likely to have insufficient resources than larger gametes. When the two successful complementary strategies have evolved, fresh evolutionary pressures make the gametes even more distinct from one another. For example, it can be advantageous for the small gametes to become more mobile, or for the large, immobile gametes to send signals to the mobile ones.

Once anisogamy has evolved, it shapes many other aspects of reproductive biology. Most species of limpet shellfish that you see on rocks at the beach are sequential hermaphrodites. When young and small they are male, and when mature and large they become female. This is believed to be because small limpets dont have sufficient resources to produce large female gametes, but theyre capable of producing the smaller male ones. In some other species, successful males can arrest their growth and remain small (and male) for their entire life.

Chromosomes arent male or female because these bits of DNA define biological sex. Its the other way around

Sequential hermaphroditism occurs in the opposite direction too. Australian snorkellers love to spot the large blue males of the eastern blue groper, but its rare to see more than one. Most groper are smaller, brown females. They are all born female and become sexually mature after a few years, when 20 or 30 cm in length. At around 50 cm, they change sex and acquire other male characteristics, such as being blue. Unlike the limpet, the main problem facing a male groper is controlling a territory on the reef, so becoming male when youre small is a losing strategy.

Biology aims to understand the extraordinary diversity of ways in which organisms reproduce themselves, as well as to identify common patterns, and to explain why they occur. In general, organisms become sexually mature when they reach an optimal size for reproduction. This optimal size is often different for the two sexes, because the two sexes represent divergent strategies for reproduction. The limpet and the groper are two of many examples. In constructing these explanations, biological sex is defined as the production of one type of viable anisogamous gamete. If we defined sex in some other way, it would be hard to see the common patterns across the diversity of life, and hard to explain them.

So-called sex chromosomes, such as the XX and XY chromosome pairs seen in humans, are often brandished as something thats fundamental to sex. Its partly the inadequacy of this definition that drives scepticism about the existence of two, discrete biological sexes. Molecular genetics is likely to require a shift from binary sex to quantum sex, with a dozen or more genes each conferring a small percentage likelihood of male or female sex that is still further dependent on micro- and macroenvironmental interactions, writes the gender scholar Vernon Rosario.

But any biologist already knows that theres more to sex determination than chromosomes and genes, and that male and female sex chromosomes are neither necessary nor sufficient to make organisms male and female. Several species of mammal, all rodents of one kind or another, have completely lost the male Y chromosome, but these rats and voles all produce perfectly normal, fertile males. Other groups of species, such as crocodiles and many fish, have neither sex chromosomes nor any other genes that determine sex. Yet they still have two, discrete biological sexes. The Australian saltwater crocodile, whom we met before, lays eggs that are very likely to develop into gigantic, highly territorial males if incubated between 30 and 33 degrees Celsius. At other temperatures, genetically identical eggs develop into much smaller females.

The reality is that chromosomes arent called male or female because these bits of DNA define biological sex. Its the other way around in some species that reproduce using two discrete sexes, those sexes are associated with different bits of DNA. But in other species this association is either absent or unreliable. Medical institutions use a chromosomal definition of sex because they judge, rightly or wrongly, that this is a reliable way of categorising humans. But humans really arent the best place to start when trying to understand sex across the diversity of life.

So much for genes. But perhaps sex could be defined by the physical characteristics that organisms develop, which then add up to constitute an organisms sex? An organism with more female than male characteristics would be more female than male and vice-versa. Thats a reasonable way to think about sex, and this idea of phenotypic sex is widely used. But if we apply the biological definition of sex, some of the individuals who are in the middle as far as sex-associated characteristics go are bona fide members of one biological sex. Others are not clearly members of either biological sex.

Nothing in the biological definition of sex requires that every organism be a member of one sex or the other. That might seem surprising, but it follows naturally from defining each sex by the ability to do one thing: to make eggs or to make sperm. Some organisms can do both, while some cant do either. Consider the sex-switching species described above: what sex are they when theyre halfway through switching? What sex are they if something goes wrong, perhaps due to hormone-mimicking chemicals from decaying plastic waste? Once we see the development of sex as a process and one that can be disrupted it is inevitable that there will be many individual organisms that arent clearly of either sex. But that doesnt mean that there are many biological sexes, or that biological sex is a continuum. There remain just two, distinct ways in which organisms contribute genetic material to their offspring.

Whats more, the physical characteristics of an organism can be labelled as male or female only if there is already a definition of sex. Whats so male about a groper being blue as opposed to brown? Many male organisms are brown. Whats so female about incubating eggs in a womb? After all, in many pipefish and seahorse species the male incubates the eggs in his brood pouch. What makes this part of the hermaphroditic earthworm male and that part female? Gender studies scholars have noticed this logical discrepancy, and some have gone on to argue that the sexes must therefore be defined in terms of gender. But from a biological perspective, what makes an observable physical characteristic male or female is not its association with gender, but its association with something more tangible: the production of one or other of the two kinds of gamete.

This explains why the existence of individuals with combinations of male and female characteristics doesnt show that biological sex is a continuum. These organisms have a combination of characteristics associated with one biological sex and characteristics associated with the other biological sex. They do not have some part of the ability to make small gametes combined with some part of the ability to make large gametes. Their phenotypic sex might be intermediate, but their biological sex is not. Being fully biologically male and fully biologically female hermaphroditic can be an effective evolutionary strategy, and we have encountered several hermaphroditic species already. But making both kinds of gametes incompletely would be an evolutionary dead-end.

Like phenotypic characteristics, sex chromosomes can be more or less reliably associated with biological sex. The eastern three-lined skink, an Australian lizard, has sex chromosomes, and under some circumstances XY skinks become male and XX skinks become female, just as in humans. But in cold nests, every skink becomes male, whatever their chromosomes. By becomes male, biologists mean that they grow up to produce small gametes sperm.

No animal is conceived with the ability to make sperm or eggs (or both). This ability has to grow

This effect of temperature on sex is not surprising, as many reptile species produce genetically identical offspring whose sex is determined by incubation temperature. Whats more surprising is that varying the size of the egg yolk in this species of skink can produce both sexes with the wrong sex chromosomes: XX males and XY females. The skink seems to have three mechanisms for determining sex chromosomes, temperature and hormones in the yolk. This is not a mere quirk of nature. The skink is one of many species that actively control the sex of their offspring, responding to environmental cues that predict whether male or female offspring have better chances of surviving and reproducing.

If all species were like the skink, we probably wouldnt label sex chromosomes as male or female. After all, we dont think of extreme nest temperatures as female and intermediate temperatures as male, merely because they produce male and female crocodiles or male and female geckos. We think of sex chromosomes as male or female because we focus on species where they are reliably associated with the production of male or female gametes.

Sex chromosomes play much the same role in sex determination as nest temperatures and hormones. Theyre simply mechanisms that organisms use to turn genes on and off in offspring so that they develop a biological sex. No animal is conceived with the ability to make sperm or eggs (or both). This ability has to grow, through a cascade of interactions between genes and environments. In some species, once an individual acquires a sex, it remains that sex for the rest of its life. In others, individuals can switch sex one or more times. But in every case, the underlying mechanisms are designed to grow organisms that make either male or female gametes (or both). The other changes the body undergoes as it becomes male, female or hermaphroditic are designed to fit the reproductive strategies that this species has evolved.

These mechanisms by which organisms develop or switch biological sex are complex, and many factors can interfere with them. So they produce a lot of phenotypic diversity. Sometimes, organisms grow up able to make fertile gametes, but otherwise atypical for their biological sex. Sometimes, they grow up unable to make fertile gametes of either kind. This is usually an accident, but sometimes by design. In bees, eggs that arent fertilised develop into males, so male bees have half as many chromosomes as female bees. Meanwhile, all fertilised eggs start to develop into females, but most of them never complete their sexual development. The queen sends chemical signals that block the development of the worker bees ovaries at an early stage. So worker bees are female in the extended sense that they would develop into fertile females if they werent actively prevented from doing so. Occasionally, worker bees manage to evade these controls and lay their own eggs. They are not popular with beekeepers, who select against these mutant strains.

The diversity of outcomes in individual sexual development doesnt mean that there are many biological sexes or that biological sex is a continuum. Whatever the merits of those views for chromosomal sex or phenotypic sex, they are not true of biological sex. A good way to grasp this is to imagine a species that really does have three biological sexes. Biotechnologists have proposed curing mitochondrial diseases by removing the nucleus from an egg with healthy mitochondrial DNA, and inserting a new nucleus containing the nuclear DNA from an unhealthy egg and the nuclear DNA from a sperm. The resulting child would have three genetic parents.

Now imagine if there was a whole species like this, where three different kinds of gametes combined to make a new individual a sperm, an egg and a third, mitochondrial gamete. This species would have three biological sexes. Something like this has actually been observed in slime moulds, an amoeba that can, but need not, get its mitochondria from a third parent. The novelist Kurt Vonnegut imagined an even more complex system in Slaughterhouse-Five (1969): There were five sexes on Tralfamadore, each of them performing a step necessary in the creation of a new individual. But the first question a biologist would ask is: why havent these organisms been replaced by mutants that dispense with some of the sexes? Having even two sexes imposes many extra costs the simplest is just finding a mate and these costs increase as the number of sexes required for mating rises. Mutants with fewer sexes would leave more offspring and would rapidly replace the existing Tralfamadorians. Something like this likely explains why two-sex systems predominate on Earth.

We can also imagine a species where biological sex really does form a continuum. Recall that some algae have slightly anisogamous gametes, much closer together than sperm and eggs. We can imagine a more complex organism using this system, with some slightly smaller gametes and some slightly larger ones. Successful reproduction might require two gametes that, when added together, are big enough but not too big. But the sexually reproducing plants and animals that actually exist all have just two, very different kinds of gamete male and female. Theyre not merely different in size, theyre fundamentally different in structure. This is the result of competition between organisms to leave the greatest number of genetic descendants. In complex multicellular organisms such as plants and animals, we know of only three successful reproductive strategies: two biological sexes in different individuals, two biological sexes combined in hermaphroditic individuals, and asexual reproduction. Some species use one of these strategies, some use more than one.

Human beings have come up with many ways to classify the diversity of individual outcomes from human sexual development. People who want to apply the biological definition of sex to humans should recognise that its ill-suited to do what many human institutions want, which is to sort every individual into one category or another. What sex are worker bees? They are sterile workers whose genome was designed by natural selection to terminate ovary development on receipt of a signal from the queen bee. They share much of the biology of fertile female bees but if someone wants to know Are worker bees really female?, theyre asking a question that biology simply cant answer.

Nor is being a sterile worker a third biological sex alongside male and female. This is easier to see in ants, where there is more than one sterile caste. Workers, soldiers, queens and male flying ants each have specialised bodies and behaviour, but there are not four biological sexes of ant. Workers and soldiers are both female in an extended sense, but not in the full-blown sense that queen ants are female. There is a human imperative to give everything a sex, as mentioned above, but biology doesnt share it.

The biological definition of sex wasnt designed to ensure fair sporting competition, or settle healthcare disputes

Juvenile organisms and postmenopausal human females also cant produce either kind of gamete. Juveniles are assigned to the sex they have started to grow into. But once again, this is more complicated than it seems when we focus only on humans. In almost all mammals, sexual differentiation is initiated by a region of the Y chromosome, so a mammalian egg can become either male or female. In birds, its the other way around the egg carries the sex-determining W chromosome, so sperm can become either male or female. After fertilisation, therefore, we can say that an individual mammal or bird has a sex in the sense that it has started to grow the ability to produce either male or female gametes. With a crocodile or a turtle, though, wed have to wait until nest temperature had its sex-determining effect. But that doesnt mean that we need to create a third biological sex for crocodile eggs!

More importantly, nothing guarantees that any of these organisms, including those with sex chromosomes, will continue to grow to the point where they can actually produce male or female gametes. Any number of things can interfere. From a biological point of view, there is nothing mysterious about the fact that organisms have to grow into a biological sex, that it takes them a while to get there, and that some individuals develop in unusual or idiosyncratic ways. This is a problem only if a definition of sex must sort every individual organism into one sex or another. Biology doesnt need to do that.

In human populations, there are plenty of individuals whose sex is hard to determine. Biologists arent blind to this. The definition of biological sex is designed to classify the human reproductive system and all the others in a way that helps us to understand and explain the diversity of life. Its not designed to exhaustively classify every human being, or every living thing. Trying to do so quickly leads to questions that have no biological meaning.

Human societies cant delegate to biology the job of defining sex as a social institution. The biological definition of sex wasnt designed to ensure fair sporting competition, or to settle disputes about access to healthcare. Theorists who want to use the biological definition of sex in those ways need to show that it will do a good job at the Olympics or in Medicare. The fact that its needed in biology isnt good enough. On the other hand, whatever its shortcomings as an institutional definition, the concept of biological sex remains essential to understand the diversity of life. It shouldnt be discarded or distorted because of arguments about its use in law, sport or medicine. That would be a tragic mistake.

The authors research is supported by the Australian Research Council and the John Templeton Foundation. He would also like to thank Nicole Vincent, Jussi Lehtonen, Stefan Gawronski and Joshua Christie for their feedback on earlier drafts.

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Thwarting AAV-Neutralizing Antibodies Could Improve Gene Therapy – The Scientist

September 26th, 2020 5:58 am

A little more than a decade ago, seven patients with hemophilia Ba disease caused by a mutation on the F9 gene that prevents patients from forming crucial clotting proteinsvolunteered to be the first humans to receive a gene therapy delivered using an adeno-associated virus as a vector. This particular treatment didnt move past the Phase 1/2 trial because, while it was deemed safe, the patients did not sustain expression of the gene. But two other gene therapies based on an adeno-associated virus (AAV), Luxturna for rare forms of blindness and Zolgensma for spinal muscular atrophy, have since been approved by the US Food and Drug Administration (FDA), and several pharmaceutical companies are now pursuing regulatory approval of AAV-carried gene therapies for hemophilia B.

Recently, scientists followed up with four of those original patients. In a study published in Molecular Therapy in September, they report that the men are still free of any worrisome toxicities related to the treatment. The study wasnt all good news, though. The team also found that after all these years, the men still had elevated levels of AAV-neutralizing antibodies. That means that if an AAV gene therapy is approved to treat their illness, they likely wont be able to benefit from itthe antibodies would chew up the vector before it could insert the corrective gene.

Administration of an AAV gene therapy is essentially a vaccine against AAV, says Lindsey George, a hematologist at the Childrens Hospital of Philadelphia who led the research. Hers was not the first study to identify antibodies as a problem for those receiving AAV gene therapies, but it is the first to show that elevated titers can last this long. This role of AAV neutralizing antibodies is huge, says George, as it stands to undermine the effectiveness of gene therapies.

Because AAVs are viruses, the human immune system creates antibodies upon exposure that recognize and neutralize them in subsequent encounters. Sometimes patients have neutralizing antibodies in their blood before ever having received a gene therapy because theyre exposed to AAVs in the environment.

The ability to effectively modulate the antibody-mediated immune response could make AAV gene therapies far more effective for far more patients than they are now.

Along with high levels of antibodies to the specific AAV vector that theyd receivedAAV2the patients Georges team evaluated also had neutralizing antibodies to several other commonly used AAV vectors, namely, AAV5 and AAV8, she tells The Scientist.

Andrew Davidoff, a pediatric surgeon at St. Jude Childrens Research Hospital who studies AAV gene therapies but was not involved in the study, says, This paper suggests that not only will they not be able to receive a second dose of vector of the same [type of AAV], but potentially even other [types].

If scientists can prevent antibodies from neutralizing the AAV, they would not only give patients like these another opportunity to receive a more effective dose of gene therapy, but it will expand the patients that we can treat with the therapy to include the 3050 percent of patients who have already been exposed to AAVs in the environment, says Giuseppe Ronzitti, who heads a lab focused on gene therapy research at Genethon.

But, Davidoff says, nobody has found a suitable solution yet that is likely to be accepted by patients. The body has evolved over millions of years, this immune system that helps fight off infections. So to overcome that, even temporarily, is not an easy task.

Some immunosuppressant drugs wont work if the body has already developed specific antibodies to a particular pathogen, such as AAV. Scientists are therefore testing combinations of different types of immunosuppressants they hope will prevent the body from attacking AAVs, but these are likely to come with major risks, chiefly, susceptibility to infection.

Another option is plasmapheresisa process in which a persons blood is removed from the body and the cells separated from the plasma so that they can be reinfused without the antibodies found in the plasmabut, like immunosuppressant drugs, the technique is nonspecific and comes with similar risks. Its a matter of risk-benefit with the continued immunosuppression, says Ronzitti.

So scientists have been looking for other ways to control the bodys response to these gene therapy vectors.

Ronzitti and his team recently proposed a solution in Nature Medicine. The scientists used the imlifidase (IdeS) protein, conditionally approved by the European Commission, to degrade immunoglobulin G (IgG) antibodies that are developed after the body encounters a specific antigen so that it can remember and target that antigen in the future, and thus might cause a patient to reject a transplanted kidney. IgG antibodies are responsible for the immune systems response to AAVs. Its a newer, less invasive alternative to plasmapheresis, Ronzitti tells The Scientist in an email.

The team injected monkeys with the IdeS protein before administering a dose of gene therapy targeting the liver. The treatment appeared safe, the monkeys levels of preexisting AAV antibodies went down, and the AAV vector successfully made its way to the liver. To model a scenario in which a patient would need more than one dose of gene therapy, the scientists administered an AAV gene therapy to another group of monkeys before giving them the IdeS protein to degrade the antibodies theyd developed in response, then readministered the gene therapy. Again, AAV antibodies diminished after the IdeS treatment and the second gene therapy dose was successfully delivered.

One drawback to the approach is that IgGs are the most prevalent type of antibody found in the blood, and destroying all of them may have undesirable side effects. In an attempt to develop a more targeted therapy, one group published a study in January demonstrating that a specialized version of plasmapheresis could reduce the levels of antibodies against human AAVs in mice to the point where a new gene therapy should be effective, without depleting all other immunoglobulins that formed in response to infections.

More recently, a team of researchers at the University of Pittsburgh Medical Center made use of CRISPR-Cas9 to increase the efficacy of AAV gene therapy in mice. Pathologist Samira Kiani and her team werent looking for ways to improve gene therapy, but instead were seeking to temporarily modulate immunity in hopes of changing the course of diseases such as septicemia, a precursor to sepsis that occurs when an infection makes its way to the blood. The researchers aimed to temporarily downregulate the Myeloid differentiation primary response 88(Myd88) gene, which would briefly dampen the immune response, and then remove the brakes.

The gene that we chose to target is known to a be a central gene for innate and adaptive immunity, says Kiani. It controls the production of IgG antibodies in response to AAV exposure, which provided a simple way to measure whether the strategy was effective. If the team administered an AAV to an animal shortly after it had received the CRISPR-Cas9 treatment, it should have a substantially lower antibody response to the virus.

First, they administered the CRISPR to tamp down Myd88 activity and measured a reduction in the expression of the Myd88 gene, as theyd expected. Then, the team used the technique to treat mice just before giving them a dose of AAV-based gene therapy that was designed to lower their cholesterol.

Weeks later, the researchers administered a second dose of the same AAV vector to determine if the temporary immunosuppression during the first dose had prevented the mice from making enough antibodies to thwart a second dose. The mice that were pretreated with the immune-modulating CRISPR showed lower levels of AAV-neutralizing antibodies and more dramatic responses to the cholesterol-lowering AAV treatment. The study was published in NatureCell Biologyin September.

If given prior to the administration of an AAV gene therapy, this approach would prevent the formation of new antibodies, so the patient could receive a second dose later, if needed, says Kiani. Given that the CRISPR treatment only prevents the development of antibodies temporarily, it shouldnt cause any long-term suppression of the rest of the immune system. On the flip side, because it doesnt clear existing antibodies, if the patients have already pre-existing antibodies [from natural exposure] this approach might not be the best approach.

All of the potential solutions have a long way to go, including still needing to be tested in human patients, but the ability to effectively modulate the antibody-mediated immune response could make AAV gene therapies far more effective for far more patients than they are now, says Ronzitti. The immune response to these vectors is quite a complex story, he says. But we are solving the issues one by one.

L. George et al., Long-term follow-up of the first in human intravascular delivery of AAV for gene transfer: AAV2-hFIX16 for severe hemophilia B,Molecular Therapy,doi:10.1016/j.ymthe.2020.06.001, 2020.

F. Moghadam et al., Synthetic immunomodulation with a CRISPR super-repressor in vivo,Nature Cell Biology,doi:10.1038/s41556-020-0563-3, 2020.

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Gene therapy company Taysha completes sprint from first funding to IPO – BioPharma Dive

September 26th, 2020 5:58 am

Dive Brief:

Gene therapies have graduated from the laboratory bench to doctor's offices. The first wave of agents, Roche's Luxturna and Novartis' Zolgensma, are already altering the course of disease in two conditions, respectively an inherited form of blindness and the degenerative, often fatal disease spinal muscular atrophy.

In both cases those treatments were developed by companies that had relatively smaller pipelines, Spark Therapeutics for Luxturna and AveXis for Zolgensma.

Enter Taysha, which is headed by a former AveXis business development vice president, R.A. Session II. The company has highly ambitious hopes to launch a new product every two to three years, with the goal of building a durable business around adapting its technology across many diseases driven by defects in single genes.

The company also plans to build a commercial-scale manufacturing plant from the start, aiming to avoid some of the setbacks that can occur when production moves from facilities built to supply clinical trials.

The linchpin of the company's business is an agreement with UT-Southwestern, under which Taysha funds research and can obtain exclusive rights to experimental therapies for central nervous system disorders, through the end of 2021. Neurodegenerative disorders have proven challenging for some gene therapies because of the difficulties in delivering the viral vectors that carry gene replacements to brain tissue.

In spinning out Taysha, UT-Southwestern took an ownership stake in Taysha, amounting to 2.2 million shares, which is now worth more than $40 million. These ownership stakes have become more common with gene therapies in particular, as big pharma companies have been reluctant to license intellectual property straight out of university laboratories.

Taysha's lead project is called TSHA-101, which seeks to treat a condition called GM2 gangliosidosis, a disorder in which lipid accumulation destroys nerves in the brain and spinal cord. The first clinical trial is scheduled to begin in Canada by the end of 2020.

The company's shares rose following their first trades on the NASDAQ exchange, gaining 20% to close the day at $24.06.

Editor's note: This story was updated to reflect the share price at the close of trading.

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Gene therapy company Taysha completes sprint from first funding to IPO - BioPharma Dive

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BioMarin, Pioneer in Phenylketonuria (PKU) and Gene Therapy, Doses First Participant in Global PHEARLESS Phase 1/2 Study of BMN 307 Gene Therapy | DNA…

September 26th, 2020 5:58 am

DetailsCategory: DNA RNA and CellsPublished on Friday, 25 September 2020 11:15Hits: 398

BioMarin Builds Upon 15+ Year Commitment to PKU Community with Potential 3rd Therapy in PKU Franchise

Company Leverages Gene Therapy Manufacturing Expertise Using Commercial-Ready Process

SAN RAFAEL, CA, USA I September 24, 2020 I BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) announced today that it has dosed the first participant in the global PHEARLESS Phase 1/2 study with BMN 307, an investigational gene therapy for the treatment of individuals with PKU. BMN 307 is an AAV5-phenylalanine hydroxylase (PAH) gene therapy designed to normalize blood phenylalanine (Phe) concentration levels in patients with PKU by inserting a correct copy of the PAH gene into liver cells. BMN 307 will be evaluated to determine safety and whether a single dose of treatment can restore natural Phe metabolism, normalize plasma Phe levels, and enable a normal diet in patients with PKU.

BioMarin will conduct this study with material manufactured with a commercial-ready process to facilitate rapid clinical development and potentially support approval. BMN 307 represents a potential third PKU treatment option in BioMarin's PKU franchise and a second gene therapy development program.

"More than 70 years ago, the first child was treated for PKU in the United Kingdom at Birmingham Women's and Children's Hospital. Today, we continue to make strides in PKU treatment through the clinical study of a gene therapy for PKU," said Tarekegn G. Hiwot at University Hospitals Birmingham NHS Foundation Trust and principal investigator for the PHEARLESS study. "There is a tremendous unmet need for PKU patients. As a treating physician, it is important to me to be involved in clinical research to evaluate innovative therapies that have the potential to change the treatment paradigm in PKU for good."

"BioMarin has been committed to the PKU community for more than 15 years and remains dedicated to the research and development of innovative therapies to advance the standard of care for people with PKU," said Hank Fuchs, M.D., President, Worldwide Research and Development at BioMarin. "Building upon our experience of delivering two approved PKU therapies to the PKU community, BMN 307 gene therapy combines BioMarin's leadership in the development of PKU therapies with our expertise in gene therapy development and manufacturing."

"PKU is a serious condition and many individuals struggle to manage their disorder on a daily basis. BioMarin is a pioneer in PKU treatments delivering the first two drug therapies to individuals with PKU. We applaud their unwavering commitment to drive research to bring a third treatment to the PKU community and for their substantial contributions to the overall body of scientific knowledge in PKU that they continue to make," said Christine S. Brown, MS, Executive Director, National PKU Alliance. "We are encouraged by BioMarin's efforts to develop a gene therapy that brings together their experience in PKU drug development, gene therapy development and gene therapy manufacturing. "

PKU is a rare genetic disease that manifests at birth and is marked by an inability to break down Phe, an amino acid that is commonly found in many foods. Left untreated, high levels of Phe become toxic to the brain and may lead to serious neurological and neuropsychological issues, affecting the way a person thinks, feels, and acts. Due to the seriousness of these symptoms, in many countries, infants are screened at birth to ensure early diagnosis and treatment to avoid intellectual disability and other complications. According to treatment guidelines, PKU patients should maintain lifelong control of their Phe levels.

Both the FDA and European Medicines Agency have granted BMN 307 Orphan Drug Designation. The Company is actively preparing regulatory submissions to open additional clinical sites in other countries.

BMN 307 Clinical Program

BioMarin's clinical program is composed of two key studies. PHEARLESS, a Phase 1/2 study, will evaluate the safety, efficacy, and tolerability of a single intravenous administration of BMN 307 in patients with PKU. The study consists of a dose-escalation phase, followed by a cohort expansion phase once an initially efficacious dose has been demonstrated. In addition, BioMarin is sponsoring an observational study, PHENOM, which includes patients with PKU to measure both established and new markers of disease and clinical outcomes over time.

BioMarin's 15-Plus Year Commitment to PKU Research

For more than 15 years, BioMarin has been a pioneer in ongoing research to help improve the lives of PKU patients. BioMarin has treated approximately 7,000 PKU patients around the world. The company has two approved PKU therapies, and the investigational gene therapy BMN 307 is currently in development. BioMarin has conducted 41 clinical studies in PKU and has sponsored 44 external clinical studies. BioMarin researchers have authored 65 publications in medical and scientific journals on PKU and supported another 57 publications by external researchers.

About Gene Therapy

Gene therapy is a form of treatment designed to address a genetic problem by adding a normal copy of the defective gene. The functional gene is inserted into a vector containing a small DNA sequence that acts as a delivery mechanism, providing the ability to deliver the functional gene to targeted cells. The cells can then use the information from the normal gene to build the functional proteins that the body needs, potentially reducing or eliminating the cause of the disease.

Gene Therapy Manufacturing

BioMarin has leveraged its knowledge and experience in manufacturing complex biological products to design, construct and validate a state-of-the-art vector production facility in Novato, California that was cGMP certified by the EMA in Q2 2020. This facility is the site of production for both valoctocogene roxaparvovec and BMN 307, investigational gene therapies. Manufacturing capabilities are an essential driver for BioMarin's gene therapy programs and allows the Company to control quality, capacity, costs and scheduling enabling rapid development. Production of BMN 307 with a commercial ready process at scale reduces risk associated with making process changes later in development and may speed overall development timelines significantly.

Ongoing process development efforts and experience gained at commercial scale have led to improvements in productivity and operational efficiency. The ability to scale out the facility with additional equipment combined with the improvements in productivity result in a doubling of overall potential capacity to 10,000 doses per year, combined for both products, depending on final dose and product mix. This improvement in productivity is anticipated to meet both commercial and clinical demand for both valoctocogene roxaparvovec and BMN 307 well into the future.

About Phenylketonuria

PKU, or phenylalanine hydroxylase (PAH) deficiency, is a genetic disorder affecting approximately 70,000 diagnosed patients in the regions of the world where BioMarin operates and is caused by a deficiency of the enzyme PAH. This enzyme is required for the metabolism of Phe, an essential amino acid found in most protein-containing foods. If the active enzyme is not present in sufficient quantities, Phe accumulates to abnormally high levels in the blood and becomes toxic to the brain, resulting in a variety of complications including severe intellectual disability, seizures, tremors, behavioral problems and psychiatric symptoms. As a result of newborn screening efforts implemented in the 1960s and early 1970s, virtually all individuals with PKU under the age of 40 in countries with newborn screening programs are diagnosed at birth and treatment is implemented soon after. PKU can be managed with a severe Phe-restricted diet, which is supplemented by low-protein modified foods and Phe-free medical foods; however, it is difficult for most patients to adhere to the life-long strict diet to the extent needed to achieve adequate control of blood Phe levels. Dietary control of Phe in childhood can prevent major developmental neurological toxicities, but poor control of Phe in adolescence and adulthood is associated with a range of neurocognitive disabilities with significant functional impact.

To learn more about PKU and PAH deficiency, please visit http://www.PKU.com. Information on this website is not incorporated by reference into this press release.

About BioMarin

BioMarin is a global biotechnology company that develops and commercializes innovative therapies for patients with serious and life-threatening rare and ultra-rare genetic diseases.The company's portfolio consists of six commercialized products and multiple clinical and pre-clinical product candidates.For additional information, please visitwww.biomarin.com. Information on such website is not incorporated by reference into this press release.

SOURCE: BioMarin Pharmaceutical

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BioMarin, Pioneer in Phenylketonuria (PKU) and Gene Therapy, Doses First Participant in Global PHEARLESS Phase 1/2 Study of BMN 307 Gene Therapy | DNA...

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FDA sets back Novartis plans to expand use of SMA gene therapy – BioPharma Dive

September 26th, 2020 5:58 am

Dive Brief:

Zolgensma's approval was a notable milestone, making it both the second gene therapy approved in the U.S., and the second treatment for SMA, a potentially deadly disease for which no medicines existed until four years ago.

But it's been a bumpy ride for Novartis since that 2019 approval. The FDA charged the company of manipulating preclinical data supporting its original application, a controversy that led Novartis to fire some top scientists and shake up its quality control operations. (The agency opted against sanctioning Novartis, however.)

And the drugmaker has now faced multiple delays in its effort to broaden the reach of Zolgensma beyond newborns and young infants.

That effort is crucial to the commercial prospects of Zolgensma. While SMA diagnosed in infancy, known as Type 1, is the most deadly, more people are living with the less severe forms of the disease. The nonprofit SMA foundation, for instance, estimates 88% of patients living with the disease have either Type 2 or Type 3, which can either stop people from walking or rob them of that ability later on.

Younger SMA patients need the muscle-boosting protein Zolgensma helps create to be expressed throughout the body, while older patients require a more targeted approach, which is why Novartis is developing the intrathecal version for them.

Currently, intravenous Zolgensma is approved in the U.S. and Japan for patients under two, and in Europe for children who weigh up to 21 kilograms. By comparison, Biogen's Spinraza and recently, Roche's Evrysdi are approved for much wider groups of SMA patients.

The intrathecal dose of Zolgensma is meant to even that playing field, though it may now be a few years until Novartis can bring that version to market.

The FDA initially halted testing of the intrathecal formulation in October, citing safety concerns from an animal study. That test is still on hold, but even when it restarts, Novartis will need more time to complete the new trial requested by the FDA. The company said the two developments are unrelated.

Novartis is discussing the details of the trial with the agency and said it will give a "comprehensive update" on its SMA program in the future. The pharma had been planning an approval submission next year, but Jefferies analyst Peter Welford now predicts that won't occur until at least 2023.

The delay boosts Roche's and Biogen's drugs, delaying would-be competition in older SMA patients. Novartis noted it's developing a similar type of drug to Roche's Evrysdi that's taken once a week orally.

Some 600 patients have been treated with Zolgensma through clinical trials, expanded access programs and commercially.

News of the FDA's request sent shares of gene therapy developer Regenxbio, which holds royalty rights to Zolgensma, down by as much as 9% Wednesday morning.

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FDA sets back Novartis plans to expand use of SMA gene therapy - BioPharma Dive

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AVROBIO to Present at Two Upcoming Investor Conferences – Business Wire

September 26th, 2020 5:58 am

CAMBRIDGE, Mass.--(BUSINESS WIRE)--AVROBIO, Inc. (Nasdaq: AVRO), a leading clinical-stage gene therapy company with a mission to free people from a lifetime of genetic disease, today announced that members of its senior management team are scheduled to participate in two upcoming virtual investor conferences.

Jefferies Virtual Gene Therapy/Editing SummitDate: Thursday, Oct. 1, 2020Time: 12:30 p.m. ET

Chardan Virtual 4th Annual Genetic Medicines ConferenceDate: Tuesday, Oct. 6, 2020Time: 2:00 p.m. ET

Live webcasts of the presentations will be available on the investors section of the AVROBIO website at avrobio.com. After the live webcasts, the events will remain archived on the AVROBIO website for 90 days.

About AVROBIO

Our vision is to bring personalized gene therapy to the world. We aim to halt or reverse disease throughout the body by driving durable expression of functional protein, even in hard-to-reach tissues and organs including the brain, muscle and bone. Our clinical-stage programs include Fabry disease, Gaucher disease and cystinosis and we also are advancing a program in Pompe disease. AVROBIO is powered by the plato gene therapy platform, our foundation designed to scale gene therapy worldwide. We are headquartered in Cambridge, Mass., with an office in Toronto, Ontario. For additional information, visit avrobio.com, and follow us on Twitter and LinkedIn.

Forward Looking Statement

This press release contains forward-looking statements, including statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words and phrases such as aims, anticipates, believes, could, designed to, estimates, expects, forecasts, goal, intends, may, plans, possible, potential, seeks, will, and variations of these words and phrases or similar expressions that are intended to identify forward-looking statements. These forward-looking statements include, without limitation, statements regarding our business strategy for and the potential therapeutic benefits of our prospective product candidates, the design, commencement, enrollment and timing of ongoing or planned clinical trials, clinical trial results, product approvals and regulatory pathways, anticipated benefits of our gene therapy platform including potential impact on our commercialization activities, timing and likelihood of success, the expected benefits and results of our implementation of the plato platform in our clinical trials and gene therapy programs and the expected safety profile of our investigational gene therapies. Any such statements in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Results in preclinical or early-stage clinical trials may not be indicative of results from later stage or larger scale clinical trials and do not ensure regulatory approval. You should not place undue reliance on these statements, or the scientific data presented.

Any forward-looking statements in this press release are based on AVROBIOs current expectations, estimates and projections about our industry as well as managements current beliefs and expectations of future events only as of today and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risk that any one or more of AVROBIOs product candidates will not be successfully developed or commercialized, the risk of cessation or delay of any ongoing or planned clinical trials of AVROBIO or our collaborators, the risk that AVROBIO may not successfully recruit or enroll a sufficient number of patients for our clinical trials, the risk that AVROBIO may not realize the intended benefits of our gene therapy platform, including the features of our plato platform, the risk that our product candidates or procedures in connection with the administration thereof will not have the safety or efficacy profile that we anticipate, the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical or clinical trials, will not be replicated or will not continue in ongoing or future studies or trials involving AVROBIOs product candidates, the risk that we will be unable to obtain and maintain regulatory approval for our product candidates, the risk that the size and growth potential of the market for our product candidates will not materialize as expected, risks associated with our dependence on third-party suppliers and manufacturers, risks regarding the accuracy of our estimates of expenses and future revenue, risks relating to our capital requirements and needs for additional financing, risks relating to clinical trial and business interruptions resulting from the COVID-19 outbreak or similar public health crises, including that such interruptions may materially delay our development timeline and/or increase our development costs or that data collection efforts may be impaired or otherwise impacted by such crises, and risks relating to our ability to obtain and maintain intellectual property protection for our product candidates. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause AVROBIOs actual results to differ materially and adversely from those contained in the forward-looking statements, see the section entitled Risk Factors in AVROBIOs most recent Annual or Quarterly Report, as well as discussions of potential risks, uncertainties and other important factors in AVROBIOs subsequent filings with the Securities and Exchange Commission. AVROBIO explicitly disclaims any obligation to update any forward-looking statements except to the extent required by law.

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