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Genetics

Seattle Genetics Announces Positive Results from Exploratory Analyses of HER2CLIMB for TUKYSA (tucatinib) in Brain Metastases Patients With…

BOTHELL, Wash.--(BUSINESS WIRE)--Seattle Genetics, Inc. today announced positive results from exploratory analyses of intracranial efficacy, including survival, in patients with HER2-positive metastatic breast cancer (MBC) who had stable or active brain metastases in the HER2CLIMB pivotal trial of TUKYSA (tucatinib). HER2CLIMB compared TUKYSA in combination with trastuzumab and capecitabine to trastuzumab and capecitabine alone in patients with unresectable, locally advanced or metastatic HER2-positive breast cancer with or without brain metastases. Of the patients enrolled in the trial, 48 percent had a presence or history of brain metastases. Results demonstrated that the addition of TUKYSA to trastuzumab and capecitabine in patients with brain metastases delayed progression in the brain, doubled the intracranial response rate (tumor shrinkage in the brain) and reduced the overall risk of death by nearly half. The data were consistent across patients who had either stable or active brain metastases. Results were presented in an oral presentation in the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in the Journal of Clinical Oncology.

TUKYSA in combination with trastuzumab and capecitabine was approved by the U.S. Food and Drug Administration (FDA) in April 2020 for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. Primary results from HER2CLIMB were first presented at the San Antonio Breast Cancer Symposium in December 2019 and published in the New England Journal of Medicine.

It is immensely gratifying to see for the first time, results for patients with stable or active brain metastases who are not typically included in clinical trials, especially when you consider that nearly half of patients with HER2-positive metastatic breast cancer experience disease progression to the brain, said Nancy U. Lin, M.D., director of the Metastatic Breast Cancer Program in the Susan F. Smith Center for Womens Cancers at Dana-Farber in Boston, MA. These additional analyses provide further evidence that TUKYSA improves survival and delays cancer progression in the brain for patients with HER2-positive metastatic breast cancer who have brain metastases.

These additional analyses, together with the primary analysis of HER2CLIMB, show TUKYSA is active for patients with and without disease that has spread to the brain, said Roger Dansey, M.D., Chief Medical Officer of Seattle Genetics. We continue to be encouraged by the remarkable clinical activity of TUKYSA in combination with trastuzumab and capecitabine and look forward to evaluating its potential in additional treatment settings and tumor types through our ongoing clinical program.

The new data that further examine TUKYSAs effect in the brain include exploratory analyses for central nervous system progression-free survival (CNS-PFS), overall survival (OS), intracranial objective response rate (ORR-IC) and duration of response in HER2-positive metastatic breast cancer patients whose disease had spread to the brain.

The exploratory analyses demonstrated that patients with brain metastases who received the TUKYSA combination versus trastuzumab and capecitabine alone had:

Endpoint

TUKYSA Arm (TUKYSA + trastuzumab + capecitabine)

Control Arm (Placebo + trastuzumab + capecitabine)

OS Benefit in All Patients with Brain Metastases

N=198

N=93

Risk Reduction

42% (Hazard Ratio [HR]=0.58 [95% Confidence Interval (CI): 0.40, 0.85]; p=0.005)

One-Year OS

70.1% (95% CI: 62.1, 76.7)

46.7% (95% CI: 33.9, 58.4)

Median OS

18.1 months (95% CI: 15.5, not estimable)

12 months (95% CI: 11.2, 15.2)

CNS-PFS Benefit in All Patients with Brain Metastases

N=198

N=93

Risk Reduction

68% (HR=0.32 [95% CI: 0.22, 0.48]; p<0.0001)

One-year CNS-PFS

40.2% (95% CI: 29.5, 50.6)

0%

Median CNS-PFS

9.9 months (95% CI: 8.0, 13.9)

4.2 months (95% CI: 3.6, 5.7)

Intracranial Objective Response Rate (ORR-IC) in Patients with Active Brain Metastases and Measurable Intracranial Lesions at Baseline

N=55

N=20

Complete Response (CR)

3 (5.5%)

1 (5.0%)

Partial Response (PR)

23 (41.8%)

3 (15.0%)

Stable Disease

24 (43.6%)

16 (80.0%)

Progressive Disease

2 (3.6%)

0

Not Available

3 (5.5%)

0

ORR-IC (CR+PR)

26 (47%) (95% CI: 34, 61)

4 (20%) (95% CI: 6, 44)

Duration of Response-IC

6.8 months (95% CI: 5.5, 16.4)

3 months (95% CI: 3.0, 10.3)

About HER2CLIMB

HER2CLIMB is a multinational randomized (2:1), double-blind, placebo-controlled, active comparator, pivotal clinical trial comparing TUKYSA in combination with trastuzumab and capecitabine compared with trastuzumab and capecitabine alone in patients with locally advanced unresectable or metastatic HER2-positive breast cancer who were previously treated with trastuzumab, pertuzumab and T-DM1. The primary endpoint of the trial was PFS per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as determined by blinded independent central review (BICR) in the first 480 patients enrolled in the trial. HER2CLIMB enrolled a total of 612 patients to support the analyses of key secondary endpoints, including OS, PFS per BICR in patients with brain metastases at baseline and confirmed ORR.1

Results of Primary Analysis of HER2CLIMB

Control Arm (Placebo + trastuzumab + capecitabine)

PFS by BICR in the first 480 patients

46% reduction in risk of progression or death (HR=0.54 [95% CI: 0.42, 0.71]; p<0.00001; N=480)

OS

34% reduction in risk of death (HR=0.66 [95% CI: 0.50, 0.87]; p=0.0048; N=612)

PFS* by BICR in patients with brain metastases

52% reduction in risk of progression or death (HR=0.48 [95% CI: 0.34, 0.69]; p<.0.00001; N=291)

One-Year PFS

25% (95% CI: 17, 34)

0%

Median PFS

7.6 months (95% CI: 6.2, 9.5)

5.4 months (95% CI: 4.1, 5.7)

*standard RECIST, includes brain and body

In HER2CLIMB, serious adverse reactions occurred in 26 percent of patients who received TUKYSA. Serious adverse reactions occurring in 2 percent or more of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea, abdominal pain, and seizure (2% each). The most common adverse reactions occurring in 20 percent or more of patients who received TUKYSA were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash. Adverse reactions leading to treatment discontinuation occurred in 6 percent of patients who received TUKYSA; adverse reactions leading to treatment discontinuation of TUKYSA (in 1 percent or more of patients) were hepatotoxicity (1.5%) and diarrhea (1%).1

About HER2-Positive Breast Cancer

Patients with HER2-positive breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. An estimated 279,100 new cases of breast cancer will be diagnosed in the U.S. in 2020.2 Between 15 and 20 percent of breast cancer cases are HER2-positive.3 Historically, HER2-positive breast cancer tends to be more aggressive and more likely to recur than HER2-negative breast cancer.3,4,5 Up to 50 percent of metastatic HER2-positive breast cancer patients develop brain metastases over time. 6,7,8

About TUKYSA (tucatinib)

TUKYSA is an oral, small molecule tyrosine kinase inhibitor (TKI) of HER2, a protein that contributes to cancer cell growth.1,9 In vitro (in lab studies), TUKYSA inhibited phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell growth (proliferation), and showed anti-tumor activity in HER2-expressing tumor cells. In vivo (in living organisms), TUKYSA inhibited the growth of HER2-expressing tumors. The combination of TUKYSA and the anti-HER2 antibody trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either medicine alone.1

Important Safety Information

Warnings and Precautions

If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA.

Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.

Adverse Reactions

Serious adverse reactions occurred in 26% of patients who received TUKYSA. Serious adverse reactions in 2% of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock.

Adverse reactions led to treatment discontinuation in 6% of patients who received TUKYSA; those occurring in 1% of patients were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions led to dose reduction in 21% of patients who received TUKYSA; those occurring in 2% of patients were hepatotoxicity (8%) and diarrhea (6%).

The most common adverse reactions in patients who received TUKYSA (20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.

Lab Abnormalities

In HER2CLIMB, Grade 3 laboratory abnormalities reported in 5% of patients who received TUKYSA were: decreased phosphate, increased ALT, decreased potassium, and increased AST. The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

Drug Interactions

Use in Specific Populations

For more information, please see the full Prescribing Information for TUKYSA here.

About Seattle Genetics

Seattle Genetics, Inc. is a global biotechnology company that discovers, develops and commercializes transformative medicines targeting cancer to make a meaningful difference in peoples lives. The company is headquartered in the Seattle, Washington area, and has offices in California, Switzerland and the European Union. For more information on our robust pipeline, visit http://www.seattlegenetics.com and follow @SeattleGenetics on Twitter.

Forward Looking Statements

Certain statements made in this press release are forward looking, such as those, among others, relating to the therapeutic potential of TUKYSA including its efficacy, safety and therapeutic uses, including its use in combination with trastuzumab and capecitabine to treat patients with HER2-positive metastatic breast cancer with brain metastases who have received one or more previous anti-HER2 therapies, and its potential use in additional treatment settings and tumor types. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the difficulty and uncertainty of pharmaceutical product development; the possibility that adverse events or safety signals may occur; that utilization and adoption of TUKYSA by prescribing physicians may be limited due to impacts related to the COVID-19 pandemic, availability and extent of reimbursement or other factors; and that adverse regulatory actions may occur. More information about the risks and uncertainties faced by Seattle Genetics is contained under the caption Risk Factors included in the companys Quarterly Report on Form 10-Q for the quarter ended March 31, 2020 filed with the Securities and Exchange Commission. Seattle Genetics disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

1 TUKYSA [package insert]. Bothell, WA: Seattle Genetics, Inc.2 Cancer Facts & Figures 2020. American Cancer Society website. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf. Accessed May 28, 2020.3 Loibli S, Gianni L. HER2-positive breast cancer. Lancet. 2017; 389(10087): 2415-29.4 Slamon D, Clark G, Wong S, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987; 235(4785): 177-82.5 Breast Cancer HER2 Status. American Cancer Society website. http://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-her2-status.html. Accessed May 28, 2020.6 Freedman RA, Gelman RS, Anders CK, et al. TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J Clin Oncol. 2019;37:1081-1089.7 Olson EM, Najita JS, Sohl J, et al. Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the post-trastuzumab era. Breast. 2013;22:525-531.8 Bendell JC, Domchek SM, Burstein HJ, et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer. 2003;97:2972-2977.9 Anita Kulukian, Patrice Lee, Janelle Taylor, et al. Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models. Mol Cancer Ther 2020;19:976-987.

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Seattle Genetics Announces Positive Results from Exploratory Analyses of HER2CLIMB for TUKYSA (tucatinib) in Brain Metastases Patients With...

Genetics

How to know your risk factors for hypertension and whether high blood pressure is genetic – Insider – INSIDER

Hypertension is the medical term for high blood pressure. It can cause serious health problems, like heart disease or stroke, if left untreated.

There are many risk factors that make it more likely for someone to develop hypertension. These include genetic factors, age, race, medical conditions, and unhealthy lifestyle choices.

Here's what you need to know about what increases the risk of high blood pressure.

Overall, one or more of these factors are most likely to cause high blood pressure:

One of the biggest culprits is smoking, which can double or triple the risk of developing hypertension. That's because smoking damages blood vessels and can reduce blood flow to the heart.

But these factors won't always cause hypertension alone genetics and medical conditions can also increase your risk.

"I would say the simplest answer to this is, yes, there is a genetic component," says Joshua Shatzkes, MD, a cardiologist at Mt. Sinai Hospital.

If your parents have hypertension, you are at an increased risk for high blood pressure.

A 2018 study involving over a million people identified 500 genes that influence blood pressure. Some of these genes influence the cells lining blood vessels, causing them to be abnormally constricted and raise blood pressure.

Other genes can cause high cholesterol, especially in a condition known as hypercholesterolemia, which can also increase blood pressure.

In addition, genetic factors often combine with other adverse lifestyle choices, which can further increase the risk of hypertension.

For example, when you're growing up, if your family eats an unhealthy diet high in sodium, creates a high stress environment, smokes too many cigarettes, and doesn't exercise often, then you're more likely to inherit those behaviors and more likely to develop hypertension.

While there's no universal way to describe obesity, it's often considered a condition where someone has a high body mass index (BMI). A BMI over 40 can double or triple your likelihood of developing obesity-related illnesses.

"When someone is obese, it simply takes more work for the heart to pump blood throughout the whole body," says Christopher Granger, MD, a cardiologist at Duke Health. "And when it has to pump blood throughout the whole body, it has to generate a higher kind of pressure to do so."

In fact, a study from 2015 suggests that excess body fat accounts for 65% to 75% of hypertension cases. Moreover, a 2017 study found that childhood obesity increased the rate of developing adult hypertension by 65%.

Diabetes is a condition where your body doesn't react to high blood sugar properly, which may cause it to be too high or too low longer than normal. Insulin is the hormone designed to take glucose (sugar) from the blood to the cells, but if there's not enough insulin, glucose stays in the blood, elevating blood sugar levels.

Over time, high blood sugar can cause plaque to build up in your blood vessels, which narrows the vessel and increases blood pressure.

Granger explains that high blood sugar can cause the arteries to stiffen because it can increase the production of free radicals tiny particles that damage cells and reduce nitrous oxide, a chemical that dilates blood vessels.

As a result, 30% of people with type 1 diabetes develop hypertension. Those with type 2 diabetes are 2.5 times more likely to develop hypertension and 50% to 80% will develop hypertension. However, diabetics who carefully control their blood sugar levels can effectively decrease the risk of developing hypertension.

The American Heart Association has found that over 40% of non-Hispanic African-Americans have high blood pressure, and that it can develop earlier in their lives and become more severe.

Overall, black Americans are twice as likely to develop hypertension by the age of 55 compared to white Americans. Systemic issues could explain this increase in blood pressure.

There's an association between racism and higher blood pressure in African-American men, according to the CDC. Black Americans are also exposed to more factors that can increase chronic stress such as discrimination and lower socioeconomic status which may contribute to high blood pressure.

Older people are more likely to develop hypertension because the arteries stiffen as we age. This process is called atherosclerosis, and it describes plaque build-up in blood vessels.

According to Granger, young people's arteries are able to expand and more effectively accommodate the pulse of blood flow.

Overall, your lifetime risk for developing hypertension is 90%, according to Johns Hopkins Medicine. Even if you have heart-healthy habits, you'll still most likely develop hypertension, according to the National Institute on Aging.

However, certain lifestyle changes, such as exercising every day, sleeping adequately, and avoiding smoking, can lower the risk of developing high blood pressure.

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How to know your risk factors for hypertension and whether high blood pressure is genetic - Insider - INSIDER

Genetics

Did you have COVID-19? 23andMe wants you for a study – KENS5.com

The biotech company 23andMe is launching a massive study to see if there is a connection.

SAN ANTONIO Scientists around the world are racing to understand coronavirus and why most people who are infected show mild to moderate symptoms or sometimes no symptoms at all and others develop a severe form of the disease, in some cases resulting in death.

23andMe has provided personalized genetic reports for years. But now he biotechnology company is switching gears to help battle coronavirus with a new study, and they're looking for those with a positive diagnosis to take part.

"Given that COVID-19 has taken a turn of turning our lives upside down so very, very quickly, at this stage we just don't know to what extent genetics plays a role in determining the severity of outcomes," said Adam Auton, the principal scientist of statistical genetics at 23andMe.

To participate in the study, you must be over 18 years of age and live in the U.S., be willing to provide a saliva sample for DNA testing, complete an online survey, have a positive coronavirus diagnosis, and you must have been hospitalized due to coronavirus-related symptoms. The stronger your symptoms, the likelier you could play a big part in the research.

"In order to maximize our abilities to make a discovery, we would really like to provide people with severe outcomes (the opportunity) to come into the study and participate in the study," Auton said.

This study could even shed some light on a phenomenon known as the COVID cliff when patients who seem to be improving suddenly get worse and whether or not genetics play a role. Dr. Diego Maselli, the Medical Director of respiratory therapy at University Hospital told us,

"Unfortunately, some of these patients, when this happens or this phenomenon starts to happen, then they get sicker and they end up in the ICU and sometimes on a ventilator," said Diego Maselli, the medical director of respiratory therapy at University Hospital.

"The hope (is) that our study can help provide information that will provide some answers to those sorts of questions," Auton said.

So far, 600,000 Americans have agreed to participate, but only 9,000 say they had COVID-19. 23andMe is looking for thousands more.

"It's the nature of genetic studies that we really need very large numbers of people to participate," Auton said.

If you would like more information about the study or to participate, click here.

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Genetics

COVID-19 study looks at genetics of healthy people who develop severe illness – Washington University School of Medicine in St. Louis

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Researchers seek answers to viruss mysteries, clues to possible treatments

Washington University School of Medicine in St. Louis is one of more than 30 genome sequencing hubs worldwide participating in a study to sequence the DNA of young, healthy adults and children who develop severe COVID-19 despite having no underlying medical problems. The researchers also will study people who never become infected despite repeated exposures to coronavirus. Knowledge gained from understanding COVID-19s extremes could lead to new therapeutic strategies for the illness.

To help unravel the mysteries of COVID-19, scientists are sequencing the DNA of young, healthy adults and children who develop severe illness despite having no underlying medical problems. The researchers are looking for genetic defects that could put certain individuals at high risk of becoming severely ill from the novel coronavirus.

The McDonnell Genome Institute at Washington University School of Medicine in St. Louis is one of more than 30 genome sequencing hubs worldwide participating in the study. Rheumatologist Megan A. Cooper, MD, PhD, an associate professor of pediatrics, is leading the research at Washington University. Called the COVID Human Genetic Effort, the international project is co-led by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH), and Rockefeller University.

The researchers also plan to study people who never become infected with SARS-CoV-2, the virus that causes COVID-19, despite repeated exposures. Such individuals may have genetic variations that protect against infection. For example, certain rare genetic variants are known to thwart some types of viral infections, including HIV and norovirus. Knowledge gained from understanding COVID-19s extremes unusual susceptibility and resistance could lead to new therapeutic strategies for the illness.

The first focus of our study will be patients with severe responses to SARS-CoV-2 infection severe enough to require intensive care who appear otherwise healthy and are younger than 50, said Cooper, who also leads the clinical immunology program and the Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies at St. Louis Childrens Hospital.

These patients dont have uncontrolled diabetes, heart disease, chronic lung disease or any other condition that we know increases the risk of severe complications from COVID-19, she said. For example, we sometimes see stories about, say, a marathon runner or a generally fit, healthy person who nevertheless got very sick from this virus, or the few healthy children who are getting very sick with COVID-19. These are the kinds of patients were interested in for this study. A small proportion of hospitalized patients will fit this category, likely less than 10%.

Cooper studies primary immunodeficiencies in children. Primary immunodeficiencies are a group of more than 450 genetic disorders of the immune system. They often are caused by mutations in single genes that affect different aspects of immunity.

With this pandemic, we can use our skills in gene hunting to search for genes that might be associated with severe COVID-19 in children and younger adults, she said. We can foresee a future ability to do a genetic sequencing test for individual patients hospitalized with SARS-CoV-2 and get an idea of whether they are likely to need more intensive care. In the meantime, we will be able to learn a great deal about how the immune system responds to this virus and what it needs to be able to respond effectively and in an appropriate manner.

These patients genetics could reveal the important immune pathways that the body needs to fight the virus. That knowledge could lead to therapies that also could help other patients who dont have a genetic susceptibility to the virus but perhaps have high-risk conditions, such as diabetes or heart disease.

Our immune systems have never seen this virus before, Cooper said. Were seeing severe COVID-19 complications play out across the world right now. It is going to take a global effort to investigate the genetic factors and the immune system factors that really control this infection.

Research related to COVID-19, including collecting and distributing of patient samples, is managed through Washington Universitys Institute of Clinical and Translational Sciences (ICTS), led by William G. Powderly, MD, who is also the Larry J. Shapiro Director of the Institute for Public Health, the J. William Campbell Professor of Medicine and co-director of the Division of Infectious Diseases.

This research is supported by funding from the St. Louis Childrens Hospital Foundation and the Jeffrey Modell Foundation.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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COVID-19 study looks at genetics of healthy people who develop severe illness - Washington University School of Medicine in St. Louis

Genetics

What the genetics of COVID-19 mean for the survival of wild great apes – Landscape News

In 1994, researchers found two chimpanzees dead in Cte dIvoires Ta National Park, which holds West Africas largest rainforest. Autopsies of the chimpanzees revealed signs of hemorrhage resembling those found in humans during outbreaks of ebolavirus that occurred decades earlier in Zaire and Sudan. Indeed, further studies led to the designation of Ta Forest ebolavirus, one of five known strains of the virus that can lead to the ebolavirus disease. One researcher in the park contracted the disease during this time.

This is one of many stories of a zoonotic disease, also referred to as a zoonosis, which is a disease transmitted to humans by animals. Zoonoses are transmitted via direct or indirect contact with an infected individual, consuming contaminated food or water, or through vectors for example, being bitten by a mosquito carrying the disease.

The focus on transmission to humans dominates the global narrative of zoonoses, which include West Nile, rabies, Lyme and others. But certain pockets of the zoological research community focus on the reverse: humans transmitting zoonoses to wildlife, known as zooanthroponosis or anthroponosis.

In the current case of COVID-19, researchers of non-human primates have sounded alarm bells for the risks humans pose for transmitting SARS-CoV-2, the viral pathogen that causes the COVID-19 or coronavirus disease, to species of primates, including monkeys and apes. Being among some of the worlds most endangered species, of particular concern are wild great apes, including bonobos, eastern and western gorillas, orangutans and chimpanzees.

These types of outbreaks can have really devastating effects on primate populations, says says Amanda Melin, a biological anthropologist who runs the Primate Genomics and Ecology lab at the University of Calgary. This is a great example of the risks that we pose to other animals in the earth.

So far, there have been no positive tests of COVID-19 in wild great apes but the deadliness of the disease, should transmission occur, is likely high.

Its the quickest study Ive ever been involved in, says Melin of a study she co-led with Mareike Janiak, a postdoctoral scholar in molecular anthropology, and James Higham, a primate evolutionary biologist at New York University, that helps dispel the guesswork of which non-human primate species are at greatest risk. The study was conducted within about seven days in early April and posted to a preprint server shortly thereafter because of the urgency of its findings, which examine the genetics behind how the SARS-CoV-2 pathogen triggers the COVID-19 disease itself.

In order for a viral pathogen to take hold in a host, the proteins on its surface must bind with certain proteins on the surfaces of a hosts cells. Once the pathogens protein has found its cellular protein match, known as a receptor, the pathogen can enter the cell and trigger the disease. Coronavirus pathogens not just of COVID-19, but of other coronaviruses as well express spike proteins on their surfaces.

If the viruss protein cant find anywhere to bind, then its not going to become infectious, Melin puts simply.

Genes determine which proteins are formed on which cells. Melins study examines the coding sequence of the ACE2gene, which codes the cellular protein (the ACE2 receptor) for the SARS-CoV-2 pathogen. These receptors are found in endothelial tissues throughout the body, including in the lungs, hence the diseases respiratory effects.

As is the case concerning most forms of life, less diversity means less resilience to threat, and so too does it go for genetic predisposition to COVID-19.

Proteins are made of amino acids. Genes can vary in the sequences of their comprising DNA, and the variants of a gene will code protein receptors with different structures of their amino acids. Receptors with a range of structures make it more difficult for a pathogen to find its match.

With that context, consider this statement from Melins study: Here, we show that all apes, including chimpanzees, bonobos, gorillas, and orangutans, and all African and Asian monkeys, exhibit the same set of twelve key amino acid residues as human ACE2.

In other words, we and many of our primate cousins are in the same boat of being highly susceptible because we have highly similar ACE2 genes and receptors, making it easier for the SARS-CoV-2 pathogen to find its binding match on our cells.

Interestingly, the study found that monkeys in the Americas, and some tarsiers, lemurs and lorisoids, had more ACE2 genetic variation, indicating that many species are likely less susceptible. However, Melin warns, some lemur species are also likely to be highly susceptible, which is worrying as they are also among the most endangered primates.

(Bats, notorious for being hosts and spreaders of coronaviruses, have exceptionally high ACE2 genetic variation. Within just the handful of bat species that we looked at, we saw genetic variation equivalent to the variation we saw across the entire range of other mammals we included, says Melin.)

Its easy to imagine that were closely related to other non-human primates, and so we should be careful with diseases. But knowing that they have the exact same sites and should be equally susceptible to us, and seeing what its doing to humans around the world its really concerning.

At the end of 2016 and into early 2017, chimpanzees in the Ta forest were seen with cold-like symptoms. While it did not prove deadly, the illness was found by researchers to have been a coronavirus passed to the chimpanzees from humans, likely poachers.

Similar to Gombe, disease is the leading challenge for conservation of chimpanzees at Ta, says Thomas Gillespie, whose work with wild great apes in Africa includes directing theGombe Ecosystem Health Project, in addition to running the Gillespie Lab at Emory University. Because of that, were always alert to the risk of disease exposure from people. The Ta team, 10 years ago or so, had a major respiratory outbreak that killed all the young chimpanzees

The tell-tale signs of COVID-19 are likely also the same for human and non-human primates, namely dry cough and fever.

We expect to see human-like symptoms, or more extreme versions of those. Laboratory-based infection of macaques resulted in similar disease progression to what were seeing in humans, says Gillespie.

Because best practices of wildlife conservation, and especially with wild great apes, demand limited human interaction, researchers rely on technology to check animals for symptoms from a safe and hidden distance. Laser thermometers are used to check fecal masses immediately after defecation to determine body temperatures. Blood meals from mosquitos are tested to keep track of pathogens circulating between them and animals. Carrion flies, which feast on dead animals, can give insights on mortality.

The Cross River gorillas, for example we never see them because theyre very cryptic, says Gillespie of the critically endangered species. Only an estimated 200 or 300 remain, residing at the border of Nigeria and Cameroon. But the flies are still going to find them. Flies are going to let us know if theres a spike in mortality. And then that can alert us to potential issues.

Should COVID-19 begin to be found in wild great apes, there is good and bad news. The bad is that quarantining isnt an option. Because of group dynamics, individual animals within most groups cannot be removed They dont respond well it tends to go quite badly, says Gillespie making the likelihood of virus spreading to the entire group of a single infected animal quite high.

And, once a wild animal has left the wild, he adds, there are tremendous threats involved with putting them back in the wild because we might have exposed them to additional pathogens in the sanctuary setting.

So we cant think about things like darting individuals, removing them from the group, quarantining them. We have to really focus on them not becoming infected. And thats the most important thing.

Gillespie nonetheless expects the virus to make its way into at least some populations of wild apes populations. The key now is to understand how it is likely to spread among species, based on exposure as well as the apes behavior and ecology. For example, in some places, habituated apes those accustomed to proximity to humans might be exposed to SARS-CoV-2, but will likely never come into contact with non-habituated apes. In other areas, this might not be the case.

And in yet other areas, monkeys that share habitats with apes baboons and vervet monkeys in Africa; macaques in Asia might spread the virus among great ape groups, or act as intermediaries, carrying the virus from humans to great apes.

This is something were actively working on, says Gillespie, who is leading a team focused on creating a model of sites across Africa and Asia to guide location-based best practices for ape conservation during the pandemic. Were modeling the different ape species, including variables like demographics, behavioral ecology, and proximity to humans and other susceptible species. This can all influence the dynamics of transmission to wild great apes.

Many protected areas inhabited by wild great apes have quickly developed lockdown measures of their own, such as shutting down tourism, logging and mining operations and extensively testing staff and researchers.

One of the major efforts currently addressing this is led by the Primate Specialist Group and the Wildlife Health Specialist Group, both of the International Union for Conservation of Nature. The two groups released a joint statement in early March, listing ways that humans can minimize risks to wild great apes, including disinfecting their footwear, wearing surgical masks, quarantining when coming from abroad, and immediately leaving an area when feeling the need to cough or sneeze and not returning.

But for local communities who depend on the use of certain forests, current measures might mean theyre left without a livelihood. To this end, the IUCN has created a task force, which includes Gillespie, focused on COVID-19s impacts on areas where wildlife and communities share and depend on the same ecosystems. One component of this effort has been distributing funds to communities that might otherwise be forced to resort to actions that could threaten wildlife.

Melins and Gillespies studies and others like them are proving crucial tools for these conservationists to know where and how to allocate resources to protect species highly vulnerable to the disease, as well as provide scientific backing to policy- and decision-makers about the vulnerability of these species.

Even after the heightened phase of the pandemic has lessened, changes must continue to be made, she says: For primate observational research, we need to continue to be really careful about quarantining ourselves and about our proximities, always using best practices when were interacting with non-human primates. More generally, I hope we can slow and then stop the illegal trade of wildlife, which might help prevent future, different outbreaks.

And then she broadens her thoughts: How will it feel collectively, as humans, if were responsible for the rapid extermination of these species from the Earth?

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What the genetics of COVID-19 mean for the survival of wild great apes - Landscape News

Genetics

Are genetics a factor in COVID-19 severity? – KOIN.com

PORTLAND, Ore. (KOIN) President Donald Trump announced Friday that his administration was declaring houses of worship as essential services. He said that the declaration would allow them to reopen in spite of local stay-home orders.

KOIN 6 News spoke to local religious leaders to see if this order changes things for them. So far, two have said no, they are going to opt to remain closed in the name of safety for their members and for the community. The senior minister at First Unitarian Church in Portland and a spokesperson for the Ahmadiyya Muslim Community both said they are keeping their doors closed for the time being.

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Are genetics a factor in COVID-19 severity? - KOIN.com

Genetics

mRNA vaccines could provide a breakthrough for coronavirus and other illness – Boston Herald

A new vaccine platform that harnesses the power of genetics has been thrust into the public eye as the success of Modernas coronavirus vaccine continues to grow, which if proven safe and effective, would be the first of its kind.

Theres never been a successful vaccine developed this way before, so it would be very, very novel, which is exciting, but potentially risky, said Dr. Helen Boucher, chief of the division of geographic medicine and infectious diseases at Tufts Medical Center.

Messenger ribonucleic acid, or mRNA, is a chemical readout of DNA that can be transferred into cells to make proteins.

Dr. Mark Poznansky, director of the Vaccine and Immunotherapy Center at Massachusetts General Hospital, compared DNA to delivery of information to the immune system from a book about coronavirus, and RNA to a chapter or two about it.

You are fundamentally engineering the cells in your body to make a foreign protein from the virus that your immune system can then react to, said Poznansky.

The mRNA vaccine encodes proteins of a virus, which are inserted into a cell to trigger an immune response.

Cambridge-based company Modernas mRNA coronavirus vaccine is highly regarded by health experts and was created at lightning speed after the virus sequence was released.

The companys stock has soared and the vaccine attracted the attention of the public and top health officials alike.

The vaccine has shown positive results in early participants of its Phase 1 study and after two doses, all participants showed binding antibody levels and neutralizing antibody levels that were at or above those who have recovered from coronavirus, according to Moderna.

There are several other mRNA coronavirus vaccines in development, such as one from Pfizer and German company BioNTech and another developed by PharmaJet and Tawainese company Abnova that uses needle-free technology.

If any make it past Phase 3 studies and onto consumers, it would be a major breakthrough, not just for the coronavirus pandemic, but for accelerated vaccine development in general, said Poznansky.

We always need more platforms that generate effective vaccines and having an additional one based on mRNA would be a great advantage, said Poznansky.

He added, If it turned out to be safe and effective in Phase 3 studies, that would be enormous success.

But making it to Phase 3 is pretty rare, said Poznansky, and safety is key in vaccine development.

In many ways we are very, very early on in this very accelerated process of multiple platforms going after a target and I think thats our biggest advantage at this point, there are lots of horses in the race, said Poznansky.

A report published in Nature Research Journal said the mRNA vaccine field is developing quickly and the technology offers a lot of positives.

mRNA is non-infectious, can be administered repeatedly and modifications can make it stable and highly translatable, the report states.

The vaccines have potential for rapid, cheap scalability, as well, the paper said.

Many drugs, therapies and interventions are being developed to combat the coronavirus crisis, but a vaccine will make the ultimate impact.

To really impact disease on a global level we are going to need a vaccine, said Boucher.

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mRNA vaccines could provide a breakthrough for coronavirus and other illness - Boston Herald

Genetics

Enhancing food diversity in the midst of a climate crisis: How plant genetic material ensures future food security – Kenya – ReliefWeb

Throughout history 6 000 -- 7 000 plant species have been cultivated for food. Yet today 40 percent of our daily calories come from just three crops: rice, wheat and maize. Humans depend on little more than 30 plant species, many of which are struggling in the face of today's environmental changes. With biodiversity and entire ecosystems in serious decline, the International Treaty on Plant Genetic Resources for Food and Agriculture plays an increasingly important role in promoting farmers and their essential contribution to diversifying the crops that feed the world. The Treaty was negotiated by FAO and the Commission on Genetic Resources for Food and Agriculture (CGRFA) and adopted in 2001 to create a global system that provides farmers, plant breeders and scientists with access to plant genetic materials.

The genetic material in each variety of species is unique and precious. Derived from human and natural selection for many decades, these genetics are fundamental to our future of food. Genetic material ensures agricultural biodiversity and gives different species the ability to cope with changes, whether it be climate change, new pests and diseases, drought and even flooding. The Treaty's Benefit-sharing Fund invests in projects that conserve and develop crop genetic resources to improve food security in cooperation with farmers.

Here are three examples of how this Treaty has helped farming communities in developing countries cope with climate change and other environmental threats.

1. Exchanging and developing biodiverse potato varieties in Peru, Nepal and Bhutan

There are over 4 000 native varieties of potato growing in the Andean highlands. These varieties are well-adapted to harsh conditions and a changing climate. In contrast, Nepal and Bhutan have only two locally adapted potato varieties but face similar conditions and environmental threats as the Andes. With this in mind, the project sought to reduce the vulnerability of these mountain communities by introducing potatoes that are more resilient to extreme temperatures and offer better nutritional quality. Working closely with the International Potato Centre in Peru, farmers in Nepal and Bhutan became directly involved in selecting new, high-yielding, resilient and biodiverse varieties of potato. The genetic material from these potatoes has since been conserved, multiplied and used by national agricultural research systems in all three countries.

** 2. Conserving plant genetic resources to improve food and nutrition in Zimbabwe, Malawi and Zambia

Being heavily reliant on the success of the maize crop, communities in Zimbabwe, Malawi and Zambia have in recent years faced a severe food shortage because maize crops have been unable to withstand the effects of climate change, such as higher temperatures and torrential rains. "Because of the changing climate, our farm was producing less food, and most crops have not been doing so well apart from millet and sorghum," explained Lovemore Tachokere, a smallholder farmer from Malawi. Through the Benefit-sharing fund and the introduction of 159 Farmer Field Schools across the three countries, farmers were given support and a voice. They started introducinglost varieties of different crops, creating diversity in their fields that also ensured more varied and nutritious diets. As part of the project a total of 300 lost or forgotten small grain crop varieties were retrieved from national, regional and international gene banks as part of the Treaty's Multilateral System. These seeds are now available to farmers and scientists for further study and the development of new climate-smart varieties.

3. Ensuring a resilient cassava crop in Tanzania and Kenya

Cassava is the third largest source of carbohydrates in the world, playing a particularly important role in agriculture in sub-Saharan Africa because it does well in poor soils and with low rainfall. Additionally, because it is a perennial, cassava acts as a famine reserve. In recent years, however, extreme temperatures, drought, flooding and a new virus, provoking 'brown streak disease', have affected cassava cultivation in the region. In Tanzaniaand Kenya, a project implemented through the Benefit-sharing Fund has led to new, more resistant and tolerant cassava breeding lines, including 30 that are heat and disease tolerant. While the farmers are now experimenting with planting new cassava varieties and using improved agricultural practices, breeders and scientists have access to improved plant material from which to select essential genetic material for future use. Community seed banks have been established through the Benefit-sharing Fund in conjunction with Farmer Field Schools and are an important initiative to collect and conserve local crop varieties. They function as a platform for farmers to control and make informed decisions on the conservation of agrobiodiversity and the cultivation of a variety of crops with nutritional value.

In the 15 years since it came into force, the International Treaty hosted by FAO has created the largest global gene pool for sharing plant material for food and agriculture, the Multilateral System of Access and Benefit-sharing (MLS). The Benefit-sharing Fund has supported over one million people through 80 agricultural development projects in 67 developing countries. These projects are clear examples of how effective the sharing of skills and knowledge across continents can be and they are crucial in the race to meet the Sustainable Development Goals (SDGs), in particular SDG 15 (Life on Land) and SDG2 (Zero Hunger). Projects under the Benefit-sharing Fund are an indication that FAO's Strategy on mainstreaming biodiversity across agricultural sectors is already taking shape and showing positive results, demonstrating that the greater the diversification of crops, the more food secure a community can become and the more resilient they find themselves in the face of current threats like climate change, pests and disease.

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Enhancing food diversity in the midst of a climate crisis: How plant genetic material ensures future food security - Kenya - ReliefWeb

Genetics

U of T researchers help lead national effort to explore role of genes in COVID-19 – News@UofT

The global spread of COVID-19 has forced us to become familiar with terminology from contact tracing to social distancing most of us didnt know a few months ago. Now, if the hunch of many scientists is correct, we are about to hear a lot about genome sequencing, too.

In search of a genetic explanation for why the novel coronavirus affects some people much more severely than others, the federal government has invested $20 million into a national project to sequence and analyze the genomes of 10,000 Canadians who have had COVID-19.

The project, part of a larger $40 million investment in the Canadian COVID Genomics Network, will be managed by CGEn, a federally funded national platform for genome sequencing, a complex process that, among other things, can help spot DNA mutations in individuals or groups that predispose them to certain illnesses.

There seems to be a genetic component to this virus. You can see that in the individuals who have had the same level of exposure to the virus but respond very differently, says Lisa Strug, associate director of The Centre for Applied Genomics (TCAG) at The Hospital for Sick Children (SickKids) and an associate professor in the department of statistical sciences in the University of Torontos Faculty of Arts & Science.

That points to this idea that our genetics could impact our response to the virus and how some people can fight it off and some cant. So, we need to know what are the genetic variations that are determining this variable response?

Strug, who is scientific lead of the CGEn sequencing project, says published studies have already examined so-called heritability.

Researchers have looked at whether some of the symptoms being seen with COVID-19 run in families, she says. Some families are experiencing the virus in the same way they all have mild symptoms, or all have very severe experiences. So it appears that there is some hereditary component. And thats another piece of evidence pointing to genetics.

Strug will work with scientists at CGEn nodes at U of T and SickKids, McGill University and at the University of British Columbia. CGEn will collect blood samples from 10,000 patients from across the country, of all ages and genders, who have COVID-19. The researchers will then extract the DNA from the samples, sequence and analyze it with sophisticated computing and statistical techniques and put all the clinical and genetic information in a protected database so researchers around the world can use it in their COVID-19 projects. A similar project is being conducted in the United Kingdom, which will involve about 20,000 patients.

The large sample size is essential because there are likely different factors that contribute to the response to COVID-19 infection in different individuals and at different ages, and the more data we have, the greater the ability researchers will have to identify these, says Strug. There is a huge benefit in not just looking at one patient at a time, but across the population and across all genes.

How will this information benefit research into the novel coronavirus? Strug says the results will be useful in identifying who is the most susceptible to COVID-19 and in understanding which genes scientists should be targeting when developing drugs to treat the virus and, ideally, a vaccine that will help control it.

There is also another major benefit of starting this massive, two year-long project immediately: data that can be used to protect ourselves from future illnesses.

U of Ts StephenScherer,the lead principal investigator of CGEn,says the genetic information gleaned from the project can be used to help guard against future outbreaks (photo courtesy of SickKids)

This is Canadas first time doing a large-scale project like this, says Stephen Scherer, TCAGs director and a University Professor of molecular genetics at U of T. When global society moves past the COVID-19 pandemic, there will be another one. All this genetic information will be extremely useful for that point in the future.

Were about to get an excellent genetic cross-section of the Canadian population. This virus has been destructive, but it is also forcing us to create new knowledge that we will be able to leverage for years to come.

For example, knowledge gained from the SARS epidemic of the early 2000s has been useful during the current outbreak, according to Strug and Scherer. Thats because of the similarities between the two coronaviruses.

That has helped the global research community be able to respond quickly to this new virus, says Strug.

That said, genetic sequencing must deal with a huge amount of data. The numbers are staggering the human genome contains three billion base chemical units that code for about 25,000 to 35,000 genes, and this project will sequence 10,000 genomes.

This is very big data analysis, Strug says.

Both scientists note that computing technology used for sequencing is far more advanced than even a decade ago. The technology has become so sophisticated and affordable that we can propose to look at entire DNA sequences, says Scherer. In 2003, for SARS 1, we couldnt do this.

Scherer, who is the lead principal investigator of CGEn, a senior scientist at SickKids and director of U of Ts McLaughlin Centre, says hes impressed with how the global research community has pivoted to focus on solving the COVID-19 puzzle.

Its amazing how scientists around the world have come together on this, he says. Just at U of T, there are researchers working on COVID-19 who I would have never predicted would be. I would say that 75 per cent of the people Im talking with every day, now, are not the same people I was talking with eight weeks ago. But they have a specific technology or some useful knowledge that links in.

Thats how scientific research needs to work to be effective: By bringing in a wide breadth of perspectives and specialists, cracking COVID-19 could become this generations moonshot.

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U of T researchers help lead national effort to explore role of genes in COVID-19 - News@UofT