Category Archives: Human Genetics

A medical team collects swabs from police personnel and their family members for COVID-19 tests in Borivali, Mumbai, April 7, 2020. Photo: PTI.

One patient fainted after seeing the nasopharyngeal swab before sample collection. Another was turned back because of staff shortage. Backlog,procuring quality collection kits, and prohibitive costs are some common problems associated with collection of nasopharyngeal (NP) and oropharyngeal (OP) samples to test for the novel coronavirus.

Currently, India has almost 4 lakh COVID-19 cases, and increasing by 10,000 per day or so these days even with limited testing (since you cant discover without tests). As of today, there are 960 testing labs around India. If the government intends to keep pace with the speed with which the virus is spreading, it should consider efficient diagnostic options in addition to increasing lab capacity and other control measures.

If its feasible, state health officials should test asymptomatic and mildcases as well to help plan effective isolation measures, including reverse quarantine. A diagnostic method should be scalable locally, nationally and globally. Monitoring progress diagnostically will also aid disease research.

However, the currently used NP and OP methods dont cater to these needs.

Swabbing the nasopharynx is an invasive and almost blind procedure.An NP swab is passed along the floor of the nasal cavity up to the back wall, swirled for a few seconds then drawn out. This procedure is not always pleasant, for the patient or the health worker. If not done correctly, it can injure the person and cause bleeding. It can also elicit sneezing or coughing, generating aerosols with infectious virus particles from a positive patient, exposing the worker to a potential infection.

Likewise, the OP sample, which is collected from the back of the throat, can also induce gagging and coughing. A deviated nasal septum, tumours or nasal polyps can hamper collection.

Then there are the inconsistencies in sample collection. Some centres perform only NP, some only OP (though its less sensitive compared to NP) and some both. Changes in the time of collection also affect test performance. The procedure requires a skilled and dedicated health worker, and a guarantee that their availability wont be affected by staff shortages typical during pandemics. Otherwise, collection centres may simply cut corners or defer testing.

Many healthcare personnel change their entire PPE gear, priced at nearly Rs 1,000 apiece, between swab collections. Irrational use of PPE adds to the tons of biomedical waste being generated. On the other hand, some centres dont have sufficient funds to afford good quality and adequate PPE for frontline staff.

If swabs are not of the right type, they can increase discomfort to patients and also affect test results. For example, a cotton or calcium alginate tip interferes with the polymerase chain reaction (PCR), and a flexible shaft is required to get to the nasopharynx. Although sterile saline is cheaper and accepted by WHO, viral transport medium (VTM) continues to be used widely to transport swabs. (VTM is a specific substance prepared to contain and transport samples containing viruses without damaging the viruses.) Saline and VTM have comparable efficacy in preserving viral RNA, in both refrigerated and frozen specimens, over seven days.

In India, NP and OP swabs are not sold separately without VTM. Moreover, VTM must have adequate and defined quantities of anti-fungal and antibacterial agents to prevent growth of fungi and bacteria that can interfere with a specimens integrity.

There is a global shortage of the right type of good-quality swabs and of VTM. Earlier, swabs used to be imported from the US and China. Last month, India launched Made in India brands by manufacturers in Delhi company and Mumbai. Their swabs reportedly cost less than Rs 5 apiece compared to Rs 20-30 for imported brands. In the private sector, the price of the collection kit with VTM continues to be Rs 180-200, and Rs 4,500-6,000 for one RT-PCR test (all inclusive).

Against this background, we recommend saliva or saline deep-throat lavage or gargled specimens. They have several advantages over swabbing and swab-testing.

The novel coronavirus uses ACE2 receptors, found on some cells in the body, to gain entry into the cells and hijack their resources to replicate. These receptors are found in the respiratory and cardiovascular systems, kidneys, the gastrointestinal tract, testes and in salivary glands.

When we sleep, the secretions in the upper respiratory tract flow backwards while specimens in the lower respiratory tract are drawn upwards. These two substances meet in the deep part of the throat. When you gargle, the gargling liquid can pick up viruses from this part of the throat.

A study from Guangzhou, China, published in April 2020 in the journal Clinical Infectious Diseases found that self-collected throat wash specimens could be more sensitive than NP specimens.

Viral loads from saliva specimens have also been shown to be consistent with clinical progression. A study by researchers at the Yale School of Medicine, of COVID-19 patients and health workers in COVID-19 wards, showed higher sensitivity and less result variation of saliva samples compared to NP swabs.

Obtaining saliva or gargled samples is quick, easy and safe. Some 1-2 ml of deep-throat saliva or a gargled sample with 10 ml of sterile isotonic saline needs to be spit into a sterile collection container. The collection container can be a sterile urine or sputum cup, which are already widely available, in common use and cost Rs 12-15 apiece, much lower than that of a swab kit.

Since it can be self-collected, saliva or gargled samples circumvent the need for skilled health workers at collection centres, minimising their exposure risk, and reduce PPE use.

Some patients need to undergo repeated tests, such as those whose immune systems are suppressed and those with false negative or indeterminate results. Saliva or lavage is a viable alternative in such cases, since repeated swabbing adds to the cost, workload and demand for PPE.

Tuberculosis centres already have good outreach and efficient specimen transport systems to and from Indias hinterlands. COVID-19 sample collection and transport can be modelled on the same lines.

Deep-throat saliva collection is the major sampling method used in outpatient settings and home collections in Hong Kong. Japan has also adopted saliva samples as alternatives to NP swabs. The US Food and Drug Authority has also issued an emergency use authorisation for a saliva-based test for COVID-19 developed at the Human Genetics Institute, Rutgers University, New Jersey.

Like India, many countries of the Global South are in the upward phase of this pandemic, and in desperate need of a cost-effective way to test more of their citizens. But not all of them have the capacity to manufacture swabs and/or other kit components, forcing them to depend on expensive imported kits. They also suffer from PPE and staff shortages. Overall cost reduction is one of the many advantages of saliva or wash testing. Swabs can be reserved for out-patients or for those who cant self collect or produce saliva.

Researchers should consider performing validation studies of self-collected deep throat gargle and saliva samples. These are sensitive, easy and cost-effective methods whose use can be scaled up manyfold in no time.

Dr Vasundhara Rangaswamy is a clinical microbiologist with international experience and a public health activist in Baroda.

Dr K.R. Antony is a consultant of public health, child survival and development in Kochi. He has served with UNICEF and as the director of Chhattisgarhs State Health Resource Centre, and is now an independent monitor for the National Health Mission.

The views expressed here are the authors own.

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COVID-19 Test Samples: Why Do We Swab Instead of Spit? - The Wire

In just over 75 years, DNA deoxyribonucleic acid has risen in public and scientific status from being an obscure molecule with presumed accessory or structural functions inside the nucleus, to the icon of modern bioscience.

So wrote Ralf Dahm, Director of Scientific Management at Germanys Institute of Molecular Biology, in the journal Developmental Biology in 2005.

The DNA story may appear to begin in 1944, Rahm adds, with crucial discoveries by researchers Oswald Avery, Colin MacLeod and Maclyn McCarty. But it really began back in 1869, with the young Swiss physician Johann Friedrich Miescher.

McCarty, an American, and Canadians Avery and MacLeod were working at Rockefeller University in New York when they discovered that DNA, not proteins, had the ability to transform the properties of cells.

An article published by the US National Human Genome Research Institute says biochemists had previously assumed that deoxyribonucleic acid was a relatively unimportant, structural chemical in chromosomes and that proteins, with their greater chemical complexity, transmitted genetic traits.

Avery, MacLeod and McCarty were studying Streptococcus pneumoniae bacteria that can cause pneumonia. They wanted to discover how a non-virulent strain could be transformed into a virulent form and to understand its chemical nature.

In 1944 they identified and isolated DNA as the transforming principle. This was the agent that could produce an enduring, heritable change in an organism.

Within 10 years of these experiments, Dahm says, James Watson and Francis Crick deciphered its structure and, yet another decade on, the genetic code was cracked.

But it would not have been possible without Miescher.

Born in Basel on 13 August 1844, he studied medicine, like his father and an uncle before him, receiving his qualification in 1868. But severe ear infections left him with impaired hearing and, believing this would hinder his ability to work as a doctor, he turned to a career in chemistry and medical research.

He went to work at the University of Tubingen in Germany, in a newly established faculty of natural science, tasked with researching the chemical composition of leukocytes, or white blood cells.

To obtain material, he would collect freshly used surgical bandages from a nearby hospital, wash off the pus and filter out the leukocytes.

Dahm, writing in the journal Human Genetics, says that in his experiments Miescher noticed a precipitate of an unknown substance, which he characterised further.

Analyses of its elementary composition revealed that, unlike proteins, it contained large amounts of phosphorous and lacked sulphur. Miescher recognised that he had discovered a novel molecule.

Because he had isolated it from the cells nuclei, he named it nuclein, a name preserved in todays designation deoxyribonucleic acid.

Dahm says that in subsequent work Miescher showed that nuclein was a characteristic component of all nuclei and hypothesised that it would prove to be inextricably linked to the function of this organelle. He suggested that its abundance in tissues might be related to their physiological status with increases in nuclear substances preceding cell division. Miescher even speculated that it might have a role in the transmission of hereditary traits, but subsequently rejected the idea.

Dahm believes Mieschers discovery was a matter of serendipity and the prepared mind.

He had set out to characterise proteins and discovered DNA, which he recognised as being very worthy of further investigation. However, the breakthrough in thought that his discovery deserved only occurred half a century after his death, when the data necessary to fully grasp the significance of DNAs function were emerging. In many ways, Mieschers discovery was well ahead of its time.

Miescher died of tuberculosis on 26 August 1895.

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Friedrich Miescher gets ahead of the double helix - Cosmos

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

Data revealed 32 new sites on the human genome where variations in DNA appear to alter the risks of getting breast cancer, according to a study published inNature Genetics.

This analysis of genetic studies covering 266,000 women is the first to link these specific risk variants to multiple, detailed subtypes of breast cancer.

The findings from this analysis enhance our understanding of the biology that differentiates subtypes and may improve our ability to predict womens breast cancer risks, even at the level of specific breast cancer subtype, said corresponding author Nilanjan Chatterjee, PhD, in a press release.

Of the 32 new risk variants identified by researchers, 15 were also independently linked to 1 or more specific breast cancer subtypes. Of that specific set of 15 variants, 7 were linked to estrogen receptor status, 7 to tumor grade, 4 to HER2 receptor status, and 2 to progesterone receptor status.

Five of these newly identified subtype-specific risk variants are linked to greater risk for some breast cancer subtypes, but a lower risk in others.

The study incorporated data from over 100 breast cancer studies from the last 15 years found in the Breast Cancer Association Consortium. This analysis used new methods to identify DNA variants that have heterogeneous effects across subtypes. These DNA variants, such as Luminal-A and triple negative, can be defined by various tumor characteristics.

This data is paramount to the scientific understanding of the genetic architecture of breast cancer. Even more, this data will allow oncologists to calculate accurate risk scores for women based on their variant combinations.

Each one of these variants has a small apparent effect on breast cancer risk, and there may be a substantial effect when a person has a combination of them, Chatterjee said in a press release.

More than 250,000 women are diagnosed with breast cancer annually in the United States, with over 40,000 deaths. Before the analysis, researchers had identified over 170 gene variants that either increase or lower risk of breast cancer.

The hope for the further identification of gene variants is to inform women as much as possible in regard to their likelihood of developing breast cancer. And if their risk is high, it allows women to be screened more frequently.

Moving forward, the researchers hope this data can open avenues to exploring the underlying biological pathways that drive cancer. How each risk-linked DNA variation impacts gene activity and signaling networks in cells is crucial information to identifying risk levels for women.

These variants are special and if followed up properly may lead to important insights into the biology of these breast cancer subtypes, Chatterjee said in a press release.

Reference:

Genome Study Links DNA Changes to the Risks of Specific Breast Cancer Subtypes [news release]. Published May 18, 2020. https://www.jhsph.edu/news/news-releases/2020/genome-study-links-dna-cha.... Accessed May 20, 2020.

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Data Reveals DNA Variations that Alter Breast Cancer Risk in Women - Cancer Network

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

The difference in COVID-19 death rates between white people and black, Asian and minority ethnic (BAME) people in the UK is shocking. One recent report found that, between the beginning of February and the end of April 2020, black people in England were 71% more likely than white people to die from COVID-19. And Asian people were 62% more likely.

This disparity has led to an inquiry by Public Health England and funding for urgent academic research into the issue. We expect many factors to be involved, including the disadvantages that BAME people face due to greater chances of poverty and health issues.

But its important that we examine whether there may also be a genetic component to the problem in order to fully understand whats going on. My colleagues and I are conducting research among frontline healthcare workers to try to see if there are any innate differences in the way different peoples immune systems respond to this specific virus, including genetic differences that may be associated with ethnicity.

Researchers have identified a greater chance of dying from COVID-19 among BAME people in several countries aside from the UK, including Norway and the US. There are many social reasons why ethnic minorities may generally be more vulnerable to disease, including a greater chance of malnutrition, more exposure to pollution due to where they live, or greater likelihood of working in less healthy environments.

Inequality and poverty also play a role in the fact that BAME people are more likely to suffer conditions that we know are linked to a greater chance of dying from COVID-19, such as diabetes and heart disease.

Initial data suggests that BAME healthcare workers are more likely to die from COVID-19 than their white colleagues. British Medical Association research has found that BAME doctors are twice as likely as white doctors to feel pressured into working with inadequate PPE when they are at risk of infection. And they are twice as likely not to feel confident enough to raise concerns about workplace safety.

However, all these established facts alone dont seem to explain why the risks of COVID-19 vary between different ethnic groups and are lowest among white people. This is particularly the case when we compare it with other forms of viral pneumonia that do not lead to such a difference.

The study that found BAME people in England were more likely to die from the disease accounted for differences in some underlying health conditions that are strongly linked to social issues, suggesting these werent the main factor. But the preliminary results from another study suggest ethnic minorities arent more likely to die once other factors linked to deprivation are taken into account.

To clarify this issue, its important to examine whether there may be some genetic component that predisposes ethnic minorities to a higher risk to COVID-19, while still recognising the critical role of other factors.

The way peoples immune systems work depends on genetic factors, not just environmental and social ones. There are effectively two parts to our immune systems. One is the part that produces antibodies, called the adaptive immune system. When our body has never seen a virus before, it can take several days for it to produce them, which is why some people get sick in the first place.

We also have an innate immune system that acts before our body has had time to make antibodies. This system is strong in children and young people, but not very good after the age of 65. This is likely to be one reason why older people are at higher risk of dying of COVID-19.

When a virus like the coronavirus SARS-CoV-2 enters a cell, molecules called toll-like receptors, or TLRs, alert the immune system that something potentially harmful is present. Interestingly, many of the bodys TLRs that can detect viruses come from genetic instructions found in the X chromosome, for which men have only one copy and women two.

We know that women can have a more effective innate immune response to other viruses such as HIV than men, and that oestrogen, the female hormone, enhances this type of immune response. We also know that women are less likely to die from COVID-19 than men.

Just as there are variations in DNA that are responsible for the differences in response of immune cells between the sexes, there can also be variations between people of different ethnic backgrounds. For example, the amount and type of genes that immune cells produce when the TLR-virus pathway is stimulated, are very different between people of African and of European origin.

This is not surprising, because we know that human populations from different parts of the planet have had to adapt to different types of infections. Ethnic differences in the risk to other respiratory viral diseases have been linked to genetic variation, and these variants are different in BAME groups and white people in these same pathways. However, the role of ethnicity in genetic susceptibility to viral diseases is still controversial.

We want to see if it could be a factor in the higher rate of BAME deaths from COVID-19. To do this, we are taking blood from frontline healthcare workers of a variety of ethnic backgrounds, assessing DNA differences and measuring the various substances the samples contain. The results could indicate if differences in the innate immune systems of BAME groups result in higher risk of developing severe COVID-19.

If there is some genetic element to the different death rates from COVID-19 between ethnic groups, its important that we understand it to give us the best chance of fighting the disease. For example, if we do find that the way the innate immune system works plays a role, we can advise people on ways to improve that system, such as through what we eat.

But that wont change the fact that the generally worse health among BAME groups in western societies is strongly linked to socioeconomic factors that are known to play a very significant role in this pandemic.

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Coronavirus: BAME deaths urgently need to be understood, including any potential genetic component - The Conversation UK

FROM 1960 till 2020, there has been a 28-fold increase in the number of centenarians. The path to longevity is strewn with false promises of expensive elixirs, exotic supplements, and stem cell rejuvenation. Human longevity is a complex interplay between the genes, the environment and lifestyle.

Genes and longevity

The study of human longevity genes is a developing science. Scientists estimate that between 15 and 30 per cent of the variation in human life span is determined by genes, but it is not clearly understood which genes are relevant, and how they contribute to longevity. In 2015, Ancestry, a genealogy and genetics company, partnered Calico, a Google spinoff, to study data from more than 54 million families and their family trees representing six billion ancestors, and were able to tease out a set of pedigrees that included over 400 million people. These individuals were connected to one another by either a parent-child or a spouse-spouse relationship.

In 2018, they published their results in Genetics, a journal of the Genetics Society of America. The study found that the lifespan of spouses were more similar and better correlated than in siblings of opposite gender. The study concluded that life span heritability is likely 7 per cent or less, and hence the contribution of genes to longevity is even lower.

Although genes seem to have only a small influence on lifespan, they appear to play a larger role in centenarians. Hence, there are a few genetic factors that do give you a headstart in the journey to longevity.

Being a first-degree relative of a centenarian makes it more likely for you to remain healthy longer and to live to an older age than your peers. First-degree relatives are less likely at age 70 years to have the age-related diseases that are common among older adults.

Women generally live longer than men , and the number of female centenarians is more than fourfold higher than that of male centenarians. It is thought that this is due to a combination of social and biological factors. Studies on mammals and Korean eunuchs has shown that the removal of testosterone at a young age was correlated with an increase in lifespan.

Genetic studies show that centenarians have a lower genetic risk of having heart disease, stroke , high blood pressure, high cholesterol, Alzheimer's disease and decreased bone mineral density. A study on Chinese centenarians published in 2013 showed that 55 per cent have normal systolic blood pressure, 82 per cent had normal diastolic blood pressure and less than 20 per cent were on long term medication. Hence, centenarians appear to have genes that reduce that risk of age-related chronic illnesses.

Biological clock

Epigenetics is the study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself. One of the major mechanisms in which epigenetics manifest itself is by the process of DNA methylation, which involves the chemical modification of the DNA, thereby modifying the gene function and expression.

Through this process, certain genes can be silenced or activated and potentially impact age-related diseases such as cancer, osteoarthritis, and neurodegeneration. The biological or epigenetic clock in centenarians show a decrease in DNA methylation age, indicating that they are biologically younger than their chronological age. There is also data to suggest that although circadian rhythms deteriorate during ageing, they seem to be well preserved in centenarians, including preserved sleep quality.

Environment and longevity

Environmental factors have a large impact on longevity. Better living environment, clean food, clean water, good sanitation, reduction of infectious diseases, and access to better healthcare have resulted in significant improvement in human longevity.

Using Italy as an example of the impact of a better living environment, the average life expectancy went up from 29 years in 1861 to 84 years in 2020. The number of centenarians in Italy increased from 165 in 1951 to more than 15,000 in 2011, and the incidence of deaths occurring in those less than 60 years of age, decreased from 74 per cent in 1872 to less than 10 per cent in 2011 .

The continuous increase in lifespan in recent decades is mainly due to the advances in medical science. It is estimated that medical advances have allowed an increase in lifespan of five years in the last two decades and additional two years in the last decade.

When comparing two countries at different stages of development in 1950, the average life expectancy increase of 11 years from 68 years in 1950 to 79 years in 2020 in the USA, which was more developed in 1950, was much less remarkable than the increase of 3114 years in average life expectancy from 43 years in 1950 to 77 years in 2020 in China, which was less developed in 1950. The significant improvement in the living environment in China has contributed to the narrowing in the average life expectancy between those living in the US and China.

Lifestyle and longevity

In addition to environmental factors, lifestyle factors have an important impact on longevity. A study of more than 300,000 individuals over 7.5 years showed that individuals with social relationships have more than 50 per cent greater probability of survival compared with those with few and poor social interactions.

A study on centenarians in Utah in the US between 2008 and 2015 suggested that sleep, life satisfaction and social attachment were significant predictors of days lived. There is an extricable linkage between lifestyle and socioeconomic status. The term socioeconomic status as used in longevity studies encompass all the factors that can impact longevity including wealth, geography, education, occupation, ethnicity, cultural environment, neighbourhood environment, quality of healthcare and quality of diet. It is well established that the socioeconomic status of an individual will have a major impact on health and longevity.

A study on more than 120, 000 individuals by researchers from Harvard, published in the Circulation journal in April 2018, identified five low-risk lifestyle factors for increased life expectancy. They were: no smoking, non obese ( body mass index of 18.5 to 24.9 kg/m2), exercise (at least 30 minutes per day of moderate to vigorous physical activity, including brisk walking), low-risk alcohol consumption (5 to 15 gm/day for women and 5 to 30 gm/day for men), and a high score for healthy diet.

In this study, the projected life expectancy at age 50 years was on average 14.0 years longer among female Americans with five low-risk factors compared with those with zero low-risk factors; for men, the difference was 12.2 years.

These findings are consistent with a study on Chinese centenarians in which less than 20 per cent were smokers and less than 40 per cent drank alcohol. Hence, in general, most centenarians do not smoke, do not drink alcohol or are low-risk alcohol drinkers, are sociable, friendly, cope well with stress, are satisfied with life, have healthy diets and sleep well.

In summary, the main drivers of longevity in the first eight decades of life are the socioeconomic environment and lifestyle choices. Beyond the eighties, the inheritance of genes that defer age-related chronic diseases and a younger biological clock will help to propel these individuals beyond a hundred years.

This series is produced on alternate Saturdays in collaboration with Singapore Medical Specialists Centre

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How to live to 100 - Business Times

When the human genome was first discovered, it revealed some amazing genetic secrets modern humans are way more complicated than we originally thought. During a long evolution, humankind picked up pieces of genetic material from other hominids. We may be the sole survivors of the Homo genus, but in our journey, weve carried genetic fragments from our long-extinct ancestors.

Just as interbreeding sometimes takes place between different animal species, the same thing happened in ancient times. Thanks to fossil DNA, geneticists now know that different lineages of our ancestors interbred with one another, creating new genetic lines and ensuring the modern human race is genetically diverse.

Research carried out on Neanderthal bones shows that people of non-African descent have 2% of Neanderthal DNA in their genome. Other research found that people from Australia and Papua New Guinea have Denisovan DNA in their genome.

New techniques have confirmed that the ancestors of modern humans mated with Neanderthals, thus allowing their genetic material to become a part of our modern genome. Indeed, researchers believe there is a lot of shared genetic material that has not yet been discovered.

Much of the genetic mixing and matching arose because of human migration patterns. As different humanoid groups migrated, they naturally intermingled and mated. Modern humans our ancestors are known to have evolved in Africa once the Neanderthals and Denisovans died out.

Fossil DNA of our prehistoric ancestors is revealing new secrets. Pictured: digital illustration DNA structure. ( k_e_n / Adobe stock)

Some scientists have posited that modern humans did not evolve from one population in Africa rather, they evolved from several interconnected populations migrating from the continent. As each group traveled farther afield, they mingled and interbred, allowing their genetic material to mix.

Smaller population groups were naturally absorbed into the larger Neanderthal population, who later interbred with our modern human ancestors.

All of this history is slowly coming to light as DNA analysis techniques improve and more ancient bone fragments and fossils are unearthed. Not surprisingly, this has led to an increased interest in our genetic origins.

Whereas our ancestors had no way of knowing their genetic origins, we can use DNA testing to discover more about our ancestors and genetic lineage. Every year, hundreds of thousands of people complete these tests and join a growing database of genetic information that has allowed people to develop their knowledge of their family history and even reconnect with long-lost family members.

Though there are many different genetic testing companies, they all work in very similar ways.

The best DNA kit will be delivered securely to your home, contain everything you need with detailed instructions, including return packaging, and should give you results in three to four weeks.

This is an area where some of the genetic testing companies differ. Some companies use a swab that will take a sample of DNA from inside your cheek. Other companies use a spit sample or a scrape of skin cells.

You should choose a method you are comfortable with, and this will help you refine your options. Ancestry DNA and 23andMe, for example, require you to fill a small tube with spit, which can be more difficult than it sounds, and then add a stabilization fluid and seal the sample. This can be awkward for some people, and more complicated than a simple cheek swab. Most companies recommend you dont drink, eat or smoke for up to an hour before taking a sample, to get a better sample.

The most important part of providing a sample is to register your sample with your chosen company online before you send it. This registration process will often include a special code, or even a printable barcode, to add to your sample that will help them track it while testing and ensure you get the correct results.

Representation of scientist inspecting fossil DNA samples. kkolosov / Adobe stock

After sending your sample, its a waiting game. Sometimes you can get your information sent to you quite quickly, depending on the number of samples the company is processing when it arrives.

The results of home genetic testing often give people one of two reactions. You may find nothing surprising in your DNA results, and it only confirms much that you already know about your genetics and your family history. For some people, however, the results you get can be life-changing, and shocking.

Home DNA testing has revealed many long-kept family secrets , as well as solving mysteries. There is a chance that your results will lead to more questions than answers.

If you are left with confusing or shocking results, by adding more DNA data you can help get a clearer picture. Ask close relatives like siblings and cousins to take tests too and add their genetic information to your family database. This can help you get a clearer picture of your family history if your results arent what you expected.

Top image: Thanks to fossil DNA, geneticists now know that different lineages of our ancestors interbred with one another, creating new genetic lines and ensuring the modern human race is genetically diverse. Pictured: Representation of our prehistoric ancestors. Source: Kovalenko I / Adobe stock

By Katya Smith

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How Ancient Fossil DNA Reveals the Secrets of Our Human Origins - Ancient Origins

Genome sequencing, big data and artificial intelligence are helping doctors to better understand, treat and hopefully beat Covid-19.

The global scientific response to the novel coronavirus pandemic, which so far has killed over 328,000 people worldwide, is unprecedented. On 10 January 2020, nine days after the first cases of suspected Covid-19 were identified, the first genome sequence of the virus was shared publicly. Since then, tens of thousands of samples have been sequenced.

Genomics, which is concerned with the genetic material of an organism, is one of the most promising areas of research for Covid-19. By unlocking the virus genetic code and that of the most severely affected hosts the patients experts hope to better inform public health decisions and find effective treatments.

Working to this end is the 20m UK government-funded Cog UK research consortium, which consolidates the resources of the highly regarded Sanger Institute, the NHS and leading universities. The alliance has already sequenced over 16,000 viral samples from patients with confirmed cases of Covid-19.

Detailed analysis of sequenced viral samples of Covid-19 can identify small changes in the virus as it passes through the population which can then be used to track its spread.

As a virus replicates itself in different hosts, it accumulates small typos in its code called mutations. While the vast majority of mutations are not functional, by identifying them in different viral samples we can track and trace the infections spread locally and from one to another, explains Emma Hodcroft, a post-doctoral researcher at the University of Basel in Switzerland.

If two samples have the same typos, it means they probably come from a parent virus that also has these typos, and so can be identified as more closely related or from the same infection chain, she adds.

Hodcroft is currently working on Nextstrain, a SARS-CoV-2 open-source project that provides a continually updated view of publicly available genome-sequencing data, alongside analytic and visualisation tools. From across the globe, nearly 20,000 sequences have been uploaded to the Global Initiative on Sharing All Influenza Data (GISAID), including some from Cog-UK. Researchers at Nextstrain are using this data to create a family tree of the virus spread.

From the first few sequences, we could identify similarities and confidently say these viruses had emerged very recently, within the past couple of months, in China. The genetics then led us to cases in other countries directly related to those Chinese samples, explains Hodcroft.

Because of the fast sharing of data, we are providing a real-time look at the pandemic, in a way previously not possible. I really hope this will transform how we can track other diseases in the future, she adds.

This underlying approach of using the genome of a pathogen to understand how it spreads, called genomic epidemiology, was pioneered during the AIDSepidemic in the 1990s and has expanded to other pathogens such as influenza. The falling cost of the sequencing technology has made it increasingly more accessible.

Dr Lauren Cowley, prize fellow of bioinformatics at the Department of Biology and Biochemistry at the University of Bath, used this tracing method in 2015 to track the spread of Ebola in Guinea. Using portable sequencing technology by Oxford Nanopore Technologies, called MinION, Cowley and her colleagues could determine the relatedness of samples from patients.

Roughly every two weeks the Ebola virus changes something in its genome, therefore if two samples had exactly the same sequence, then we would know they were likely part of the same transmission chain, explains Cowley.

This helped epidemiologists track whether a transmission chain was contained or whether more people were at risk and if there were contacts of the patients that needed to be monitored for symptom development.

Similarly, in its first public update at the end of March, Cog-UK said it had identified 12 viral lineages in the initial 260 viral genomes it sequenced, suggesting independent introductions ofCovid-19 to the UK coming from areas with large epidemics and high travel volumes, notably Italy and other parts of Europe.

Hodcroft says this technology will become particularly useful for informing public health decisions towards the end of the pandemic.

If we can determine new cases in a city are from local transmission, it tells us current measures are not working because the virus is spreading locally again. However, if it shows new cases are imported, then we know we need to be careful about people travelling from other areas. This is important when trying to understand how much to loosen restrictions on the public or to find weaknesses in your strategy, she explains.

Its hoped the research ongoing at the Cog UK consortium, which Hodcroft says is "above and beyond what any other country is doing", along with anti-body testing just approved by Public Health England, will help the government better understand infection among the UK population, down to individual transmission chains.

A characteristic of coronavirus that has healthcare professionals puzzled is why certain people are more adversely affected than others. While this could be explained by many factors, theres a hypothesis that mutations in a persons genetics could affect how they react to the disease and their chances of surviving it.

Everybody has a human genome in every single cell, and by and large, the code is the same, apart from some sporadic mutations. These change parts of the genome; some are incredibly rare and others very common.

We don't know how much of the variation in Covid-19 outcomes are driven by common genetic effects, some of which may be acting through frequently seen comorbidities (like diabetes or cardiovascular disease); or by rarer mutations, which predispose people to poor outcomes possibly related to different immune responses or uncontrolled inflammatory events, explains Professor Nicholas Timpson, a Professor of Genetic Epidemiology at Bristol University and a Wellcome Trust Investigator.

Timpson works on the University of Bristols Children of the '90s study, which has been collecting "everything from toenails and teeth" from a cohort ofchildren since birth. Timpson and his colleagues are now surveying participants about how they have been affected by Covid-19 and hope to use this information to assist ongoing medical research into the disease.

For example, weve been measuring respiratory health in participants for decades, so were in a very special position because we can bring retrospective data forward into the analysis; past healthcare trajectory could be extremely important in understanding who gets better from Covid-19 and who is badly affected, he says.

Similarly, consumer genetics testing and analysis company 23andMe has enrolled more than half a million of its customers onto a study to find potential genetic associations related to severity of coronavirus symptoms. The company will be studying de-identified, aggregate genetic information alongside answers to survey questions on experience with Covid-19 symptoms to get a fuller picture of potential correlations.

Identifying these genetic markers could help target the development of specific treatments and vaccines for coronavirus. Timpson, however, says this can be difficult because, unlike rare and specific changes in genomes, there may be a common variation that affects a significant chunk of the population, but its actual impact, though very real, is very small.

However, technology, such as artificial intelligence (AI) and machine learning can help speed-up this analysis, especially when working with sequenced genomes, which produce huge amounts of data.

Measuring the entire genome and working in a data-driven way, rather than generating hypotheses about which genes would be involved in which diseases, can be more efficient, says Timpson.

Swiss health-tech company SOPHiA GENETICS, which developed an AI-based platform that precisely analyses raw genome data to help clinicians better diagnose patients, is working in this way with its partner Paragon Genomics to help researchers make genetic discoveries related to Covid-19 outcomes.

The company wants to create a multi-modal approach to predict outcomes and tailor therapeutic approaches.

Using the genome of the virus and the host, combined with data about how the patient was treated and what happened to them, the SOPHiA platform could identify patterns by looking for a combination of data points to predict a patients clinical outcome and recommend treatments based on previous results of other patients with similar signatures, explains Dr Philippe Menu, chief medical officer atSOPHiAGENETICS.

The platform is already trained to do this for lung cancer patients using analysis of CT scans, known as radiomics, and other clinical data. For coronavirus, it could be used to triage patients better. The vision is to develop an optimised predictive score across genomics, radiomics and clinical data, that help doctors predict the most likely Covid-19 disease evolution at time of diagnosis and tailor therapeutic interventions accordingly, says Menu.

The platform is currently going through a validation phase for sequencing the whole viral genome. Once there is enough data, it will start looking for variations across viral samples. To pursue the multimodal analysis, Menu says the company is in discussions with different centres.

Similarly, in only a matter of weeks, AI-based drug-discovery company BenevolentAI used its machine-learning platform to identify a potential drug to treat some Covid-19 patients.

Using a biomedical Knowledge Graph it had curated over the past five years, researchers assessed potential treatments that could specifically inhibit the cellular processes the virus uses to infect human cells and reduce inflammatory damage. The predictive tools identified an existing rheumatoid arthritis pill, baricitinib, as a potential treatment. The drug is now being trialled by Eli Lilly.

In April, NHSX, the technology arm of the NHS, announced it was establishing a centralised UK repository of chest X-ray, CT and MRI images for use by AI applications to improve the understanding of Covid-19 and support treatment of the disease.

Zegami, an Oxford University spin-out, has developed a new machine-learning radiomics model on its AI platform that hopes to use these images to help radiologists more quickly identify coronavirus cases and provide better treatment outcomes by learning from past successes.

Doug Lawrence, a data scientist at Zegami who has been training the platform, says it has already shown 70-75 per cent proficiency in identifying coronavirus cases apart from images of viral and bacterial pneumonia, as well as images of healthy lungs, using a limited dataset of 226 Covid-19 infected lung images.

A tool that can filter people into a high or lower risk bracket, even at only 70 per cent accuracy, is still very useful in saving radiologists time, he says.

The longer-term ambition of the company, however, is to receive anonymous information about the treatment plan and outcome for each patient image.

If we had data about people in intensive care or who were treated with specific antibiotics, the platform could predict potential outcomes and recommend treatments based on this data, says Stephen Taylor, co-founder of Zegami and chief scientific officer. Its about binding the metadata with the image to give doctors more confidence in treatment and diagnosis.

But Taylor says the nature of the platform means it could be easily used to explore a range of hypothesis.

There's a whole bunch of characteristics you can measure, I think this provides a simple and easy-to-use interface from which its possible to investigate different parameters without doing lots of coding putting this tool in the hands of non-data scientists is very powerful because they can come up with interesting hypotheses and then test them, says Taylor.

Zegami has applied to NHSX for chest X-ray images, which it is hoping to receive soon.

While a vaccine for the novel coronavirus is still in development, there is hope that the throng of ongoing research can help with the management and treatment of the virus in the interim. In fact, there is a clear race to make discoveries and provide healthcare professionals with new tools. It will be interesting to see whois successful first.

One thing is certain though: the rapid rate of research, cross-border collaboration and fast deployment of technologies are among the few positives to emerge from the coronavirus crisis.

Health study

If you were born in or around Bristol in 1991 or 1992, then you could have been part ofChildren of the 90s health study.

It doesn't matter if you stopped taking part years ago, your data is important and you can re-join the study at any time.

To find out if you were involved in the study please text your full name and date of birth to 07772 909090 or visit childrenofthe90s.ac.uk

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Covid-19 versus genomics and other advanced technologies - E&T Magazine

BOTHELL, Wash.--(BUSINESS WIRE)-- Seattle Genetics, Inc., Inc. (Nasdaq:SGEN) today announced that the Swiss Agency for Therapeutic Products (Swissmedic) has granted approval for TUKYSA (tucatinib) tablets in combination with trastuzumab and capecitabine, for the treatment of patients with metastatic HER2-positive breast cancer, who have previously received two or more anti-HER2 regimens in any setting, including trastuzumab, pertuzumab and trastuzumab-emtansine (TDM1).

The application for TUKYSA approval was reviewed by Swissmedic as part of Project Orbis, an initiative of the U.S. Food and Drug Administration (FDA) Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology drugs among participating international regulatory agencies in Canada, Australia and Singapore. On April 17, the FDA approved TUKYSA in the U.S. under the FDAs Real-Time Oncology Review (RTOR) pilot program, four months prior to its action date, and represented the first new drug approved under Project Orbis.

Were grateful to Swissmedic for their collaboration through FDAs Project Orbis in approving this important new medicine in Switzerland, said Jennifer Stephens, Vice President of Regulatory Affairs at Seattle Genetics. We're committed to bringing new targeted therapies to patients, and we are excited about this important first step toward making TUKYSA available to patients in Switzerland.

TUKYSA is an oral, small molecule tyrosine kinase inhibitor (TKI) of HER2, a protein that contributes to cancer cell growth.i,ii

The approval is based on results from the pivotal trial HER2CLIMB, a randomized (2:1), double-blind, placebo-controlled trial that enrolled 612 patients with HER2-positive unresectable locally advanced or metastatic breast cancer who had previously received, either separately or in combination, trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1). The study results were published in The New England Journal of Medicine in December 2019.

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. In 2018, more than two million new cases of breast cancer were diagnosed worldwide, including 522,513 in Europe. iii Between 15 and 20 percent of breast cancer cases are HER2-positive.iv Historically, HER2-positive breast cancer tends to be more aggressive and more likely to recur than HER2-negative breast cancer.v,vi,vii Up to 50 percent of metastatic HER2-positive breast cancer patients develop brain metastases over time.viii,ix,x

About TUKYSA (tucatinib)

TUKYSA is an oral medicine that is a tyrosine kinase inhibitor of the HER2 protein. 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.xi In the U.S., TUKYSA is approved in combination with trastuzumab and capecitabine 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.

Important U.S. 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 cancer medicines to make a meaningful difference in peoples lives. ADCETRIS (brentuximab vedotin) and PADCEVTM (enfortumab vedotin-ejfv) use the companys industry-leading antibody-drug conjugate (ADC) technology. ADCETRIS is approved in certain CD30-expressing lymphomas, and PADCEV is approved in certain metastatic urothelial cancers. TUKYSATM (tucatinib), a small molecule tyrosine kinase inhibitor, is approved in certain HER2-positive metastatic breast cancers. The company is headquartered in Bothell, Washington, with locations 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 the potential use of TUKYSA in combination with trastuzumab and capecitabine for the treatment of patients with metastatic HER2-positive breast cancer, who have previously received two or more anti-HER2 regimens in any setting, including trastuzumab, pertuzumab and trastuzumab-emtansine (TDM1) and the potential to bring TUKYSA to patients in Switzerland. 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 reimbursement processes, the extent of reimbursement, the possibility that adverse events or safety signals may occur, the possibility that the ultimate utilization and adoption of TUKYSA by prescribing physicians may be limited, including due to impacts related to the COVID-19 pandemic, the possibility of difficulties in supplying and commercializing a new therapeutic agent, and the possibility of adverse regulatory actions. 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.

i TUKYSA [package insert]. Bothell, WA: Seattle Genetics, Inc.ii 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 ModelsMol Cancer Ther 2020;19:976-987.iii Breast. Globocan 2018. World Health Organization. 2019. https://gco.iarc.fr/today/data/factsheets/cancers/20-Breast-fact-sheet.pdf iv 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.v Loibli S, Gianni L. HER2-positive breast cancer. Lancet. 2017; 389(10087): 2415-29.vi 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.vii 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 March 9, 2020.viii 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.ix 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.x 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.xi TUKYSA [package insert]. Bothell, WA: Seattle Genetics, Inc.

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Seattle Genetics Announces the Approval of TUKYSA (tucatinib) in Switzerland for the Treatment of Patients with Metastatic HER2-Positive Breast Cancer...