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Here are five things you must know for Wednesday, January 19:

U.S. equity futures edged higher Wednesday, while Treasury yields extended their recent surge amid bets that the Federal Reserve will quicken the pace of near-term rate hikes as inflationary pressures continue to build in the world's largest economy.

Stocks were hit hard by the prospects of faster rate hikes yesterday, while weaker-than-expected quarterly earnings from Goldman Sachs GS kept the Dow Jones Industrial Average deeply in the red, closing out its worst day since November, and pushed the S&P 500 into a year-to-date decline of around 4%.

A 0.25% March rate hike is all but assured from the Fed, but bets on a 50 basis point move are starting to creep in, lifting 2-year Treasury note yields to a February 2020 high of 1.075%.

Further upside pressures on oil prices, which have lifted WTI crude to the highest levels in seven years, were evident overnight amid disruption in a pipeline between Iraq and Turkey, while benchmark 10-year German bund yields traded in positive territory for the first time since 2019.

Bond market moves are likely to loom large over the markets again Wednesday, although a series of blue-chip earnings reports -- including updates from Dow components UnitedHealth (UNH) - Get UnitedHealth Group Incorporated Report and Procter & Gamble (PG) - Get Procter & Gamble Company Report-- will also provide direction prior to the start of trading.

Futures tied to the Dow are indicating a modest 35 point opening bell gain while those linked to the S&P 500 are priced for an 8 point bump to the upside.

Nasdaq Composite futures are indicating a 40 point opening bell gain as benchmark 10-year Treasury note yields climb to a post-pandemic high of 1.895% in overnight trading.

Ford F shares edged lower in pre-market trading after the carmaker said late Tuesday that its early investment in Rivian Automotive (RIVN) - Get Rivian Automotive, Inc. Class A Reportwould add around $8.2 billion to its fourth quarter bottom line.

In an investor update ahead of its formal earnings release on February 3, Ford said gains from Rivian's November IPO would be booked as a special item over the three months ending in December. Ford invested $500 million in Rivian in 2019 and has a total stake of around 12% in the Irvine, California-based EV group.

Rivian shares, once valued at more than $100 billion, closed at $73.16 last night, pegging their market cap at just under $66 billion.

Ford shares were marked 0.12% lower in pre-market trading Wednesday to indicate an opening bell price of $24.35 each.

U.S. air travelers could face another day of delay and disruption Wednesday as carriers around the world cancel flights in and out of the country following the initial rollout of 5G networks by AT&T (T) - Get AT&T Inc. Reportand Verizon (VZ) - Get Verizon Communications Inc. Report.

Although the wireless groups said they would pause rollouts near major U.S. airports, following warnings from both airline bosses and the Federal Aviation Administration linked to concerns that the 5G frequencies could affect some flight navigation instruments -- particularly in planes made by Boeing (BA) - Get Boeing Company Report-- several international carriers have cancelled flights or substituted aircraft to U.S. destinations.

President Joe Biden said the agreement to pause 5G rollouts at key airport towers would "avoid potentially devastating disruptions to passenger travel, cargo operations, and our economic recovery, while allowing more than 90% of wireless tower deployment to occur as scheduled."

United Airlines (UAL) - Get United Airlines Holdings, Inc. Reportwas marked 0.1% lower in pre-market trading at $45.60 each, while American Airlines (AAL) - Get American Airlines Group, Inc. Reportedged 0.2% higher to $17.94. Delta Air Lines (DAL) - Get Delta Air Lines, Inc. Reportwas marked 0.15% higher at $39.60 each while Boeing was little-changed at $225.05 each.

U.S. chip stocks jumped higher in pre-market trading aftersemiconductor equipment makerASML NV (AMSL) posted stronger-than-expected fourth quarter earnings and issued a robust near-term outlook for the sector.

ASML said demand for its extreme ultraviolet lithography systems, or EUV, machines, which design complex chips used by, sector titans such as Samsung Electronics, Intel and Taiwan Semiconductor and cost as much as $120 million, would help overall sales grow more than 20% this year, easing concerns that a fire in one of its German-based factories would impact supplies.

ASML's bullish outlook follows a similar assessment from TaiwanSemi (TSM) - Get Taiwan Semiconductor Manufacturing Co. Ltd. Reportthe world's biggest contract chipmaker and a lead supplier for Apple Inc. (AAPL) - Get Apple Inc. ReportiPhones, which posted record fourth quarter profits last week and boosted itscompound annual growth rate targets and capital spending plans.

Nvidia (NVDA) - Get NVIDIA Corporation Reportshares were marked 0.5% higher in pre-market trading Wednesday while Advanced Micro Devices (AMD) - Get Advanced Micro Devices, Inc. Reportgained 0.1% to $132.00 each. Intel (INTC) - Get Intel Corporation Reportwas marked 0.2% higher at $54.86 while Micron (MU) - Get Micron Technology, Inc. Report gained 0.85% to $93.65 each.

Former President Donald Trump was accused by the state of New York of using"fraudulent or misleading" asset valuations to obtain loans and tax deductions for his family organization.

New York Attorney General Letitia James said Trump, as well as his son Donald Jr. and daughter Ivanka, must provide sworn testimony as part of her investigation into the Trump Organization's financial affairs.

"Thus far in our investigation, we have uncovered significant evidence that suggests Donald J. Trump and the Trump Organization falsely and fraudulently valued multiple assets and misrepresented those values to financial institutions for economic benefit," James said in a statement.

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Stocks Edge Higher, Ford Cashes In, 5G Rollout Pause, Bullish ASML And Donald Trump - 5 Things You Must Know - TheStreet

Learning Objectives

By the end of this section, you will be able to:

Biotechnology is the use of artificial methods to modify the genetic material of living organisms or cells to produce novel compounds or to perform new functions. Biotechnology has been used for improving livestock and crops since the beginning of agriculture through selective breeding. Since the discovery of the structure of DNA in 1953, and particularly since the development of tools and methods to manipulate DNA in the 1970s, biotechnology has become synonymous with the manipulation of organisms DNA at the molecular level. The primary applications of this technology are in medicine (for the production of vaccines and antibiotics) and in agriculture (for the genetic modification of crops). Biotechnology also has many industrial applications, such as fermentation, the treatment of oil spills, and the production of biofuels, as well as many household applications such as the use of enzymes in laundry detergent.

To accomplish the applications described above, biotechnologists must be able to extract, manipulate, and analyze nucleic acids.

To understand the basic techniques used to work with nucleic acids, remember that nucleic acids are macromolecules made of nucleotides (a sugar, a phosphate, and a nitrogenous base). The phosphate groups on these molecules each have a net negative charge. An entire set of DNA molecules in the nucleus of eukaryotic organisms is called the genome. DNA has two complementary strands linked by hydrogen bonds between the paired bases.

Unlike DNA in eukaryotic cells, RNA molecules leave the nucleus. Messenger RNA (mRNA) is analyzed most frequently because it represents the protein-coding genes that are being expressed in the cell.

To study or manipulate nucleic acids, the DNA must first be extracted from cells. Various techniques are used to extract different types of DNA (Figure 10.2). Most nucleic acid extraction techniques involve steps to break open the cell, and then the use of enzymatic reactions to destroy all undesired macromolecules. Cells are broken open using a detergent solution containing buffering compounds. To prevent degradation and contamination, macromolecules such as proteins and RNA are inactivated using enzymes. The DNA is then brought out of solution using alcohol. The resulting DNA, because it is made up of long polymers, forms a gelatinous mass.

RNA is studied to understand gene expression patterns in cells. RNA is naturally very unstable because enzymes that break down RNA are commonly present in nature. Some are even secreted by our own skin and are very difficult to inactivate. Similar to DNA extraction, RNA extraction involves the use of various buffers and enzymes to inactivate other macromolecules and preserve only the RNA.

Because nucleic acids are negatively charged ions at neutral or alkaline pH in an aqueous environment, they can be moved by an electric field. Gel electrophoresis is a technique used to separate charged molecules on the basis of size and charge. The nucleic acids can be separated as whole chromosomes or as fragments. The nucleic acids are loaded into a slot at one end of a gel matrix, an electric current is applied, and negatively charged molecules are pulled toward the opposite end of the gel (the end with the positive electrode). Smaller molecules move through the pores in the gel faster than larger molecules; this difference in the rate of migration separates the fragments on the basis of size. The nucleic acids in a gel matrix are invisible until they are stained with a compound that allows them to be seen, such as a dye. Distinct fragments of nucleic acids appear as bands at specific distances from the top of the gel (the negative electrode end) that are based on their size (Figure 10.3). A mixture of many fragments of varying sizes appear as a long smear, whereas uncut genomic DNA is usually too large to run through the gel and forms a single large band at the top of the gel.

DNA analysis often requires focusing on one or more specific regions of the genome. It also frequently involves situations in which only one or a few copies of a DNA molecule are available for further analysis. These amounts are insufficient for most procedures, such as gel electrophoresis. Polymerase chain reaction (PCR) is a technique used to rapidly increase the number of copies of specific regions of DNA for further analyses (Figure 10.4). PCR uses a special form of DNA polymerase, the enzyme that replicates DNA, and other short nucleotide sequences called primers that base pair to a specific portion of the DNA being replicated. PCR is used for many purposes in laboratories. These include: 1) the identification of the owner of a DNA sample left at a crime scene; 2) paternity analysis; 3) the comparison of small amounts of ancient DNA with modern organisms; and 4) determining the sequence of nucleotides in a specific region.

In general, cloning means the creation of a perfect replica. Typically, the word is used to describe the creation of a genetically identical copy. In biology, the re-creation of a whole organism is referred to as reproductive cloning. Long before attempts were made to clone an entire organism, researchers learned how to copy short stretches of DNAa process that is referred to as molecular cloning.

Cloning allows for the creation of multiple copies of genes, expression of genes, and study of specific genes. To get the DNA fragment into a bacterial cell in a form that will be copied or expressed, the fragment is first inserted into a plasmid. A plasmid (also called a vector in this context) is a small circular DNA molecule that replicates independently of the chromosomal DNA in bacteria. In cloning, the plasmid molecules can be used to provide a vehicle in which to insert a desired DNA fragment. Modified plasmids are usually reintroduced into a bacterial host for replication. As the bacteria divide, they copy their own DNA (including the plasmids). The inserted DNA fragment is copied along with the rest of the bacterial DNA. In a bacterial cell, the fragment of DNA from the human genome (or another organism that is being studied) is referred to as foreign DNA to differentiate it from the DNA of the bacterium (the host DNA).

Plasmids occur naturally in bacterial populations (such as Escherichia coli) and have genes that can contribute favorable traits to the organism, such as antibiotic resistance (the ability to be unaffected by antibiotics). Plasmids have been highly engineered as vectors for molecular cloning and for the subsequent large-scale production of important molecules, such as insulin. A valuable characteristic of plasmid vectors is the ease with which a foreign DNA fragment can be introduced. These plasmid vectors contain many short DNA sequences that can be cut with different commonly available restriction enzymes. Restriction enzymes (also called restriction endonucleases) recognize specific DNA sequences and cut them in a predictable manner; they are naturally produced by bacteria as a defense mechanism against foreign DNA. Many restriction enzymes make staggered cuts in the two strands of DNA, such that the cut ends have a 2- to 4-nucleotide single-stranded overhang. The sequence that is recognized by the restriction enzyme is a four- to eight-nucleotide sequence that is a palindrome. Like with a word palindrome, this means the sequence reads the same forward and backward. In most cases, the sequence reads the same forward on one strand and backward on the complementary strand. When a staggered cut is made in a sequence like this, the overhangs are complementary (Figure 10.5).

Because these overhangs are capable of coming back together by hydrogen bonding with complementary overhangs on a piece of DNA cut with the same restriction enzyme, these are called sticky ends. The process of forming hydrogen bonds between complementary sequences on single strands to form double-stranded DNA is called annealing. Addition of an enzyme called DNA ligase, which takes part in DNA replication in cells, permanently joins the DNA fragments when the sticky ends come together. In this way, any DNA fragment can be spliced between the two ends of a plasmid DNA that has been cut with the same restriction enzyme (Figure 10.6).

Plasmids with foreign DNA inserted into them are called recombinant DNA molecules because they contain new combinations of genetic material. Proteins that are produced from recombinant DNA molecules are called recombinant proteins. Not all recombinant plasmids are capable of expressing genes. Plasmids may also be engineered to express proteins only when stimulated by certain environmental factors, so that scientists can control the expression of the recombinant proteins.

Reproductive cloning is a method used to make a clone or an identical copy of an entire multicellular organism. Most multicellular organisms undergo reproduction by sexual means, which involves the contribution of DNA from two individuals (parents), making it impossible to generate an identical copy or a clone of either parent. Recent advances in biotechnology have made it possible to reproductively clone mammals in the laboratory.

Natural sexual reproduction involves the union, during fertilization, of a sperm and an egg. Each of these gametes is haploid, meaning they contain one set of chromosomes in their nuclei. The resulting cell, or zygote, is then diploid and contains two sets of chromosomes. This cell divides mitotically to produce a multicellular organism. However, the union of just any two cells cannot produce a viable zygote; there are components in the cytoplasm of the egg cell that are essential for the early development of the embryo during its first few cell divisions. Without these provisions, there would be no subsequent development. Therefore, to produce a new individual, both a diploid genetic complement and an egg cytoplasm are required. The approach to producing an artificially cloned individual is to take the egg cell of one individual and to remove the haploid nucleus. Then a diploid nucleus from a body cell of a second individual, the donor, is put into the egg cell. The egg is then stimulated to divide so that development proceeds. This sounds simple, but in fact it takes many attempts before each of the steps is completed successfully.

The first cloned agricultural animal was Dolly, a sheep who was born in 1996. The success rate of reproductive cloning at the time was very low. Dolly lived for six years and died of a lung tumor (Figure 10.7). There was speculation that because the cell DNA that gave rise to Dolly came from an older individual, the age of the DNA may have affected her life expectancy. Since Dolly, several species of animals (such as horses, bulls, and goats) have been successfully cloned.

There have been attempts at producing cloned human embryos as sources of embryonic stem cells. In the procedure, the DNA from an adult human is introduced into a human egg cell, which is then stimulated to divide. The technology is similar to the technology that was used to produce Dolly, but the embryo is never implanted into a surrogate mother. The cells produced are called embryonic stem cells because they have the capacity to develop into many different kinds of cells, such as muscle or nerve cells. The stem cells could be used to research and ultimately provide therapeutic applications, such as replacing damaged tissues. The benefit of cloning in this instance is that the cells used to regenerate new tissues would be a perfect match to the donor of the original DNA. For example, a leukemia patient would not require a sibling with a tissue match for a bone-marrow transplant.

Why was Dolly a Finn-Dorset and not a Scottish Blackface sheep?

Because even though the original cell came from a Scottish Blackface sheep and the surrogate mother was a Scottish Blackface, the DNA came from a Finn-Dorset.

Using recombinant DNA technology to modify an organisms DNA to achieve desirable traits is called genetic engineering. Addition of foreign DNA in the form of recombinant DNA vectors that are generated by molecular cloning is the most common method of genetic engineering. An organism that receives the recombinant DNA is called a genetically modified organism (GMO). If the foreign DNA that is introduced comes from a different species, the host organism is called transgenic. Bacteria, plants, and animals have been genetically modified since the early 1970s for academic, medical, agricultural, and industrial purposes. These applications will be examined in more detail in the next module.

Watch this short video explaining how scientists create a transgenic animal.

Although the classic methods of studying the function of genes began with a given phenotype and determined the genetic basis of that phenotype, modern techniques allow researchers to start at the DNA sequence level and ask: What does this gene or DNA element do? This technique, called reverse genetics, has resulted in reversing the classical genetic methodology. One example of this method is analogous to damaging a body part to determine its function. An insect that loses a wing cannot fly, which means that the wings function is flight. The classic genetic method compares insects that cannot fly with insects that can fly, and observes that the non-flying insects have lost wings. Similarly in a reverse genetics approach, mutating or deleting genes provides researchers with clues about gene function. Alternately, reverse genetics can be used to cause a gene to overexpress itself to determine what phenotypic effects may occur.

Nucleic acids can be isolated from cells for the purposes of further analysis by breaking open the cells and enzymatically destroying all other major macromolecules. Fragmented or whole chromosomes can be separated on the basis of size by gel electrophoresis. Short stretches of DNA can be amplified by PCR. DNA can be cut (and subsequently re-spliced together) using restriction enzymes. The molecular and cellular techniques of biotechnology allow researchers to genetically engineer organisms, modifying them to achieve desirable traits.

Cloning may involve cloning small DNA fragments (molecular cloning), or cloning entire organisms (reproductive cloning). In molecular cloning with bacteria, a desired DNA fragment is inserted into a bacterial plasmid using restriction enzymes and the plasmid is taken up by a bacterium, which will then express the foreign DNA. Using other techniques, foreign genes can be inserted into eukaryotic organisms. In each case, the organisms are called transgenic organisms. In reproductive cloning, a donor nucleus is put into an enucleated egg cell, which is then stimulated to divide and develop into an organism.

In reverse genetics methods, a gene is mutated or removed in some way to identify its effect on the phenotype of the whole organism as a way to determine its function.

anneal: in molecular biology, the process by which two single strands of DNA hydrogen bond at complementary nucleotides to form a double-stranded molecule

biotechnology: the use of artificial methods to modify the genetic material of living organisms or cells to produce novel compounds or to perform new functions

cloning: the production of an exact copyspecifically, an exact genetic copyof a gene, cell, or organism

gel electrophoresis: a technique used to separate molecules on the basis of their ability to migrate through a semisolid gel in response to an electric current

genetic engineering: alteration of the genetic makeup of an organism using the molecular methods of biotechnologygenetically modified organism (GMO): an organism whose genome has been artificially changed

plasmid: a small circular molecule of DNA found in bacteria that replicates independently of the main bacterial chromosome; plasmids code for some important traits for bacteria and can be used as vectors to transport DNA into bacteria in genetic engineering applications

polymerase chain reaction (PCR): a technique used to make multiple copies of DNA

recombinant DNA: a combination of DNA fragments generated by molecular cloning that does not exist in naturestrong>recombinant protein: a protein that is expressed from recombinant DNA molecules

restriction enzyme: an enzyme that recognizes a specific nucleotide sequence in DNA and cuts the DNA double strand at that recognition site, often with a staggered cut leaving short single strands or sticky ends

reverse genetics: a form of genetic analysis that manipulates DNA to disrupt or affect the product of a gene to analyze the genes function

reproductive cloning: cloning of entire organisms

transgenic: describing an organism that receives DNA from a different species

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10.1 Cloning and Genetic Engineering Concepts of Biology ...

Despite all that controversy surrounding it, genetic engineering is here to stay and progress, as biomedical engineering technologies become smarter. Read about the different types of genetic engineering in the following article.

The advance of genetic engineering makes it quite conceivable that we will begin to design our own evolutionary progress.~ Isaac Asimov

Well, whether or not we begin to actually design our evolutionary progress is a different matter altogether but the fact that genetic engineering widens the scope of treating and curing various hereditary and terminal illnesses surely deserves some amount of attention and respect. You see, contrary to what most of us have been made to believe, thanks to those extravagant Hollywood sci-fi flicks, genetic engineering is not just about creating weird new species or making mutants out of men.

Genetic engineering, as it exists today, is more about improving the quality of the existing species of various organisms by way of enhancing their health, yield (in agriculture and livestock) and overall quality. This is usually done by tampering with the subjects genetic matter in such a way that their anatomies get conditioned to work in the survival mode, rather than the victim mode, in the face of disabling defects and life-threatening illnesses. For achieving these and similarly related ends, there exist three different types of genetic engineering, based upon their functions and fields of application. Lets proceed to the next segment and check out what they are.

The scope of genetic engineering is not restricted to curious human tampering of genetic paraphernalia in a bid to come up with various medical and scientific solutions. The greatest genetic engineer of all, Mother Nature, has been carrying out genetic manipulations all this time, since way long before the primate ancestors of humans were even introduced on Earth as a distinct species! Dont get me? Well, how else would you explain the phenomena of evolution, natural selection and selective breeding? Designing the blueprints of different versions of Software Life and creating appropriate hardware for each software version is no mean task! As far as human interest and efforts in genetic engineering are concerned, we are still way behind Nature and are way below the nascent stage. However, following are the three main categories of genetic engineering. Take a look.

This is the research branch of genetic engineering in which virtual genetic models are created using computer software. Various computer programs are used to theoretically study the implications of various genetic engineering activities if they are to be carried out in practice. For instance, before going ahead and splicing two different genes in actual practice, preparing an analytical model based upon an appropriate program, developed for the purpose, will give the researchers an idea whether such splicing would be successful at all and if successful, if the desired end would be achieved. This is a better way of carrying out the trial-and-error stage and reduces risks of disaster during experiments using real organisms, especially animals.

Applied genetic engineering, as the name suggests, is that field of genetic engineering which pertains to practical application of genetic engineering tools to manipulate the genes of living organisms for making genetic copies of them or to introduce certain different characteristics in them that are not usual for the subjects. The first instance is what we typically refer to as cloning and the second instance refers to the premises of transgenesis. While cloning is a highly regulated and controversial field, it has been carried out in various subjects of animal and plant species with mixed results and uncertain success rates. Transgenesis, on the other hand, is a comparatively common area and most of us have partaken of the results of transgenesis sometime or the other. Dont believe me? Well, what about hybrid fruits and vegetables? They are the most common and abundant examples of transgenesis.

Chemical genetic engineering can be called the grass root level of applied genetic engineering as it deals with separating, classifying and graphing genes to prepare them for applied genetic engineering activities and experiments. Chemical genetic engineering includes genetic mapping, studying genetic interaction and genetic coding. In genetic mapping, DNA fragments are assigned to individual chromosomes and thus, a genetic map is created after the complete DNA sequencing of a subject is done. Genetic mapping is very crucial to understanding the disease-gene link and this understanding lays the foundation of various gene therapies. Studying genetic interactions helps researchers understand exactly what set and combination of genes would produce a particular phenotype or set of morphological, physiological and behavioral characteristics. Genetic coding deals with studying and experimenting with amino acid sequences of DNA and RNA so as to understand the heredity trends and characteristics of a subject. This helps in understanding the bases, possibilities and conditions of undesirable hereditary characteristics, defects and disease in a bid to come out with medical solutions for the same.

So, those were the three major categories of genetic engineering that have been developed till date. Other than the aforementioned genetic engineering types, two emerging fields in genetic engineering are somatic cell engineering and germ-line engineering. Both of these are, at present, the most significant types of genetic engineering in humans and both are used in gene therapy for correcting defective genes and for preventing the transmission of hereditary defects or diseases from one generation to subsequent generations. Both of these classes of genetic engineering hold the potential of coming up with effective cures for degenerative conditions such as Parkinsons, Alzheimers and Huntingtons disease.

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Types of Genetic Engineering - Biology Wise

Abstract

Genetic engineering opens new possibilities for biomedical enhancement requiring ethical, societal and practical considerations to evaluate its implications for human biology, human evolution and our natural environment. In this Commentary, we consider human enhancement, and in particular, we explore genetic enhancement in an evolutionary context. In summarizing key open questions, we highlight the importance of acknowledging multiple effects (pleiotropy) and complex epigenetic interactions among genotype, phenotype and ecology, and the need to consider the unit of impact not only to the human body but also to human populations and their natural environment (systems biology). We also propose that a practicable distinction between therapy and enhancement may need to be drawn and effectively implemented in future regulations. Overall, we suggest that it is essential for ethical, philosophical and policy discussions on human enhancement to consider the empirical evidence provided by evolutionary biology, developmental biology and other disciplines.

Lay Summary: This Commentary explores genetic enhancement in an evolutionary context. We highlight the multiple effects associated with germline heritable genetic intervention, the need to consider the unit of impact to human populations and their natural environment, and propose that a practicable distinction between therapy and enhancement is needed.

There are countless examples where technology has contributed to ameliorate the lives of people by improving their inherent or acquired capabilities. For example, over time, there have been biomedical interventions attempting to restore functions that are deficient, such as vision, hearing or mobility. If we consider human vision, substantial advances started from the time spectacles were developed (possibly in the 13th century), continuing in the last few years, with researchers implanting artificial retinas to give blind patients partial sight [13]. Recently, scientists have also successfully linked the brain of a paralysed man to a computer chip, which helped restore partial movement of limbs previously non-responsive [4, 5]. In addition, synthetic blood substitutes have been created, which could be used in human patients in the future [68].

The progress being made by technology in a restorative and therapeutic context could in theory be applied in other contexts to treat non-pathological conditions. Many of the technologies and pharmaceutical products developed in a medical context to treat patients are already being used by humans to enhance some aspect of their bodies, for example drugs to boost brain power, nutritional supplements, brain stimulating technologies to control mood or growth hormones for children of short stature. Assistive technology for disabled people, reproductive medicine and pharmacology, beside their therapeutic and restorative use, have a greater potential for human enhancement than currently thought. There are also dual outcomes as some therapies can have effects that amount to an enhancement as for example, the artificial legs used by the South African sprinter Oscar Pistorius providing him with a competitive advantage.

This commentary will provide general ethical considerations on human enhancement, and within the several forms of so-called human biomedical enhancement, it will focus on genetic engineering, particularly on germline (heritable) genetic interventions and on the insights evolutionary biology can provide in rationalizing its likely impact. These insights are a subject often limited in discussions on genetic engineering and human enhancement in general, and its links to ethical, philosophical and policy discussions, in particular [9]. The rapid advances in genetic technology make this debate very topical. Moreover, genes are thought to play a very substantial role in biological evolution and development of the human species, thus making this a topic requiring due consideration. With this commentary, we explore how concepts based in evolutionary biology could contribute to better assess the implications of human germline modifications, assuming they were widely employed. We conclude our brief analysis by summarizing key issues requiring resolution and potential approaches to progress them. Overall, the aim is to contribute to the debate on human genetic enhancement by looking not only at the future, as it is so often done, but also at our evolutionary past.

The noun enhancement comes from the verb enhance, meaning to increase or improve. The verb enhance can be traced back to the vulgar Latin inaltiare and late Latin inaltare (raise, exalt), from altare (make high) and altus (high), literally grown tall. For centuries human enhancement has populated our imagination outlined by stories ranging from the myths of supernormal strengths and eternal life to the superpowers illustrated by the 20th century comic books superheroes. The desire of overcoming normal human capacities and the transformation to an almost perfect form has been part of the history of civilization, extending from arts and religion to philosophy. The goal of improving the human condition and health has always been a driver for innovation and biomedical developments.

In the broadest sense, the process of human enhancement can be considered as an improvement of the limitations of a natural version of the human species with respect to a specific reference in time, and to different environments, which can vary depending on factors such as, for example, climate change. The limitations of the human condition can be physical and/or mental/cognitive (e.g. vision, strength or memory). This poses relevant questions of what a real or perceived human limitation is in the environment and times in which we are living and how it can be shifted over time considering social norms and cultural values of modern societies. Besides, the impact that overcoming these limitations will have on us humans, and the environment, should also be considered. For example, if we boost the immune system of specific people, this may contribute to the development/evolution of more resistant viruses and bacteria or/and lead to new viruses and bacteria to emerge. In environmental terms, enhancing the longevity of humans could contribute to a massive increase in global population, creating additional pressures on ecosystems already under human pressure.

Two decades ago, the practices of human enhancement have been described as biomedical interventions that are used to improve human form or functioning beyond what is necessary to restore or sustain health [10]. The range of these practices has now increased with technological development, and they are any kind of genetic, biomedical, or pharmaceutical intervention aimed at improving human dispositions, capacities, or well-being, even if there is no pathology to be treated [11]. Practices of human enhancement could be visualized as upgrading a system, where interventions take place for a better performance of the original system. This is far from being a hypothetical situation. The rapid progress within the fields of nanotechnology, biotechnology, information technology and cognitive science has brought back discussions about the evolutionary trajectory of the human species by the promise of new applications which could provide abilities beyond current ones [12, 13]. If such a possibility was consciously embraced and actively pursued, technology could be expected to have a revolutionary interference with human life, not just helping humans in achieving general health and capabilities commensurate with our current ones but helping to overcome human limitations far beyond of what is currently possible for human beings. The emergence of new technologies has provided a broader range of potential human interventions and the possibility of transitioning from external changes to our bodies (e.g. external prosthesis) to internal ones, especially when considering genetic manipulation, whose changes can be permanent and transmissible.

The advocates of a far-reaching human enhancement have been referred to as transhumanists. In their vision, so far, humans have largely worked to control and shape their exterior environments (niche construction) but with new technologies (e.g. biotechnology, information technology and nanotechnology) they will soon be able to control and fundamentally change their own bodies. Supporters of these technologies agree with the possibility of a more radical interference in human life by using technology to overcome human limitations [1416], that could allow us to live longer, healthier and even happier lives [17]. On the other side, and against this position, are the so-called bioconservatives, arguing for the conservation and protection of some kind of human essence, with the argument that it exists something intrinsically valuable in human life that should be preserved [18, 19].

There is an ongoing debate between transhumanists [2022] and bioconservatives [18, 19, 23] on the ethical issues regarding the use of technologies in humans. The focus of this commentary is not centred on this debate, particularly because the discussion of these extreme, divergent positions is already very prominent in the public debate. In fact, it is interesting to notice that the moderate discourses around this topic are much less known. In a more moderate view, perhaps one of the crucial questions to consider, independently of the moral views on human enhancement, is whether human enhancement (especially if considering germline heritable genetic interventions) is a necessary development, and represents an appropriate use of time, funding and resources compared to other pressing societal issues. It is crucial to build space for these more moderate, and perhaps less polarized voices, allowing the consideration of other positions and visions beyond those being more strongly projected so far.

Ethical and societal discussions on what constitutes human enhancement will be fundamental to support the development of policy frameworks and regulations on new technological developments. When considering the ethical implications of human enhancement that technology will be available to offer now and in the future, it could be useful to group the different kinds of human enhancements in the phenotypic and genetic categories: (i) strictly phenotypic intervention (e.g. ranging from infrared vision spectacles to exoskeletons and bionic limbs); (ii) somatic, non-heritable genetic intervention (e.g. editing of muscle cells for stronger muscles) and (iii) germline, heritable genetic intervention (e.g. editing of the CC chemokine receptor type 5 (CCR5) gene in the Chinese baby twins, discussed later on). These categories of enhancement raise different considerations and concerns and currently present different levels of acceptance by our society. The degree of ethical, societal and environmental impacts is likely to be more limited for phenotypic interventions (i) but higher for genetic interventions (ii and iii), especially for the ones which are transmissible to future generations (iii).

The rapid advances in technology seen in the last decades, have raised the possibility of radical enhancement, defined by Nicholas Agar, as the improvement of human attributes and abilities to levels that greatly exceed what is currently possible for human beings [24]. Genetic engineering offers the possibility of such an enhancement by providing humans a profound control over their own biology. Among other technologies, genetic engineering comprises genome editing (also called gene editing), a group of technologies with the ability to directly modify an organisms DNA through a targeted intervention in the genome (e.g. insertion, deletion or replacement of specific genetic material) [25]. Genome editing is considered to achieve much greater precision than pre-existing forms of genetic engineering. It has been argued to be a revolutionary tool due to its efficiency, reducing cost and time. This technology is considered to have many applications for human health, in both preventing and tackling disease. Much of the ethical debate associated with this technology concerns the possible application of genome editing in the human germline, i.e. the genome that can be transmitted to following generations, be it from gametes, a fertilized egg or from first embryo divisions [2628]. There has been concern as well as enthusiasm on the potential of the technology to modify human germline genome to provide us with traits considered positive or useful (e.g. muscle strength, memory and intelligence) in the current and future environments.

To explore some of the possible implications of heritable interventions we will take as an example the editing (more specifically deletion using CRISPR genome editing technology) of several base pairs of the CCR5 gene. Such intervention was practised in 2018 in two non-identical twin girls born in China. Loss of function mutations of the CCR5 had been previously shown to provide resistance to HIV. Therefore, the gene deletion would be expected to protect the twin baby girls from risk of transmission of HIV which could have occurred from their father (HIV-positive). However, the father had the infection kept under control and the titre of HIV virus was undetectable, which means that risk of transmission of HIV infection to the babies was negligible [29].

From an ethical ground, based on current acceptable practices, this case has been widely criticized by the scientific community beside being considered by many a case of human enhancement intervention rather than therapy [29, 30]. One of the questions this example helps illustrate is that the ethical boundary between a therapy that corrects a disorder by restoring performance to a normal scope, and an intervention that enhances human ability outside the accepted normal scope, is not always easy to draw. For the sake of argument, it could be assumed that therapy involves attempts to restore a certain condition of health, normality or sanity of the natural condition of a specific individual. If we take this approach, the question is how health, normality and sanity, as well as natural per se, are defined, as the meaning of these concepts shift over time to accommodate social norms and cultural values of modern societies. It could be said that the difficulty of developing a conceptual distinction between therapy and enhancement has always been present. However, the potential significance of such distinction is only now, with the acceleration and impact of technological developments, becoming more evident.

Beyond ethical questions, a major problem of this intervention is that we do not (yet?) know exactly the totality of the effects that the artificial mutation of the CCR5 may have, at both the genetic and phenotypic levels. This is because we now know that, contrary to the idea of one gene-one trait accepted some decades ago, a geneor its absencecan affect numerous traits, many of them being apparently unrelated (a phenomenon also known as pleiotropy). That is, due to constrained developmental interactions, mechanisms and genetic networks, a change in a single gene can result in a cascade of multiple effects [31]. In the case of CCR5, we currently know that the mutation offers protection against HIV infection, and also seems to increase the risk of severe or fatal reactions to some infectious diseases, such as the influenza virus [32]. It has also been observed that among people with multiple sclerosis, the ones with CCR5 mutation are twice as likely to die early than are people without the mutation [33]. Some studies have also shown that defective CCR5 can have a positive effect in cognition to enhance learning and memory in mice [34]. However, its not clear if this effect would be translated into humans. The example serves to illustrate that, even if human enhancement with gene editing methods was considered ethically sound, assessing the totality of its implications on solid grounds may be difficult to achieve.

Beyond providing the opportunity of enhancing human capabilities in specific individuals, intervening in the germline is likely to have an impact on the evolutionary processes of the human species raising questions on the scale and type of impacts. In fact, the use of large-scale genetic engineering might exponentially increase the force of niche construction in human evolution, and therefore raise ethical and practical questions never faced by our species before. It has been argued that natural selection is a mechanism of lesser importance in the case of current human evolution, as compared to other organisms, because of advances in medicine and healthcare [35]. According to such a view, among many others advances, natural selection has been conditioned by our niche-construction ability to improve healthcare and access to clean water and food, thus changing the landscape of pressures that humans have been facing for survival. An underlying assumption or position of the current debate is that, within our human species, the force of natural selection became minimized and that we are somehow at the end-point of our evolution [36]. If this premise holds true, one could argue that evolution is no longer a force in human history and hence that any human enhancement would not be substituting itself to human evolution as a key driver for future changes.

However, it is useful to remember that, as defined by Darwin in his book On the Origin of the Species, natural selection is a process in which organisms that happen to be better adapted to a certain environment tend to have higher survival and/or reproductive rates than other organisms [37]. When comparing human evolution to human genetic enhancement, an acceptable position could be to consider ethically sound those interventions that could be replicated naturally by evolution, as in the case of the CCR5 gene. Even if this approach was taken, however, it is important to bear in mind that human evolution acts on human traits sometimes increasing and sometimes decreasing our biological fitness, in a constant evolutionary trade-off and in a contingent and/or neutralin the sense of not progressiveprocess. In other worlds, differently from genetic human enhancement, natural selection does not aim at improving human traits [38]. Human evolution and the so-called genetic human enhancement would seem therefore to involve different underlying processes, raising several questions regarding the implications and risks of the latter.

But using genetic engineering to treat humans has been proposed far beyond the therapeutic case or to introduce genetic modifications known to already occur in nature. In particular, when looking into the views expressed on the balance between human evolution and genetic engineering, some argue that it may be appropriate to use genetic interventions to go beyond what natural selection has contributed to our species when it comes to eradicate vulnerabilities [17]. Furthermore, when considering the environmental, ecological and social issues of contemporary times, some suggest that genetic technologies could be crucial tools to contribute to human survival and well-being [2022]. The possible need to engineer human traits to ensure our survival could include the ability to allow our species to adapt rapidly to the rate of environmental change caused by human activity, for which Darwinian evolution may be too slow [39]. Or, for instance, to support long-distance space travel by engineering resistance to radiation and osteoporosis, along with other conditions which would be highly advantageous in space [40].

When considering the ethical and societal merits of these propositions, it is useful to consider how proto-forms of enhancement has been approached by past human societies. In particular, it can be argued that humans have already employedas part of our domestication/selective breeding of other animalstechniques of indirect manipulation of genomes on a relatively large scale over many millennia, albeit not on humans. The large-scale selective breeding of plants and animals over prehistoric and historic periods could be claimed to have already shaped some of our natural environment. Selective breeding has been used to obtain specific characteristics considered useful at a given time in plants and animals. Therefore, their evolutionary processes have been altered with the aim to produce lineages with advantageous traits, which contributed to the evolution of different domesticated species. However, differently from genetic engineering, domestication possesses inherent limitations in its ability to produce major transformations in the created lineages, in contrast with the many open possibilities provided by genetic engineering.

When considering the impact of genetic engineering on human evolution, one of questions to be considered concerns the effects, if any, that genetic technology could have on the genetic pool of the human population and any implication on its resilience to unforeseen circumstances. This underlines a relevant question associated with the difference between health and biological fitness. For example, a certain group of animals can be more healthyas domesticated dogsbut be less biologically fit according to Darwins definition. Specifically, if such group of animals are less genetically diverse than their ancestors, they could be less adaptable to environmental changes. Assuming that, the human germline modification is undertaken at a global scale, this could be expected to have an effect, on the distribution of genetically heritable traits on the human population over time. Considering that gene and trait distributions have been changing under the processes of evolution for billions of years, the impact on evolution will need to be assessed by analysing which genetic alterations have been eventually associated with specific changes within the recent evolutionary history of humans. On this front, a key study has analysed the implications of genetic engineering on the evolutionary biology of human populations, including the possibility of reducing human genetic diversity, for instance creating a biological monoculture [41]. The study argued that genetic engineering will have an insignificant impact on human diversity, while it would likely safeguard the capacity of human populations to deal with disease and new environmental challenges and therefore, ensure the health and longevity of our species [41]. If the findings of this study were considered consistent with other knowledge and encompassing, the impact of human genetic enhancements on the human genetic pool and associated impacts could be considered secondary aspects. However, data available from studies on domestication strongly suggests that domestication of both animals and plans might lead to not only decreased genetic diversity per se, but even affect patterns of variation in gene expression throughout the genome and generally decreased gene expression diversity across species [4244]. Given that, according to recent studies within the field of biological anthropology recent human evolution has been in fact a process of self-domestication [45], one could argue that studies on domestication could contribute to understanding the impacts of genetic engineering.

Beyond such considerations, it is useful to reflect on the fact that human genetic enhancement could occur on different geographical scales, regardless of the specific environment and geological periods in which humans are living and much more rapidly than in the case of evolution, in which changes are very slow. If this was to occur routinely and on a large scale, the implications of the resulting radical and abrupt changes may be difficult to predict and its impacts difficult to manage. This is currently highlighted by results of epigenetics studies, and also of the microbiome and of the effects of pollutants in the environment and their cumulative effect on the development of human and non-human organisms alike. Increasingly new evidence indicates a greater interdependence between humans and their environments (including other microorganisms), indicating that modifying the environment can have direct and unpredictable consequences on humans as well. This highlight the need of a systems level approach. An approach in which the bounded body of the individual human as a basic unit of biological or social action would need to be questioned in favour of a more encompassing and holistic unit. In fact, within biology, there is a new field, Systems Biology, which stresses the need to understand the role that pleiotropy, and thus networks at multiple levelse.g. genetic, cellular, among individuals and among different taxaplay within biological systems and their evolution [46]. Currently, much still needs to be understood about gene function, its role in human biological systems and the interaction between genes and external factors such as environment, diet and so on. In the future if we do choose to genetically enhance human traits to levels unlikely to be achieved by human evolution, it would be crucial to consider if and how our understanding of human evolution enable us to better understand the implications of genetic interventions.

New forms of human enhancement are increasingly coming to play due to technological development. If phenotypic and somatic interventions for human enhancement pose already significant ethical and societal challenges, germline heritable genetic intervention, require much broader and complex considerations at the level of the individual, society and human species as a whole. Germline interventions associated with modern technologies are capable of much more rapid, large-scale impacts and seem capable of radically altering the balance of humans with the environment. We know now that beside the role genes play on biological evolution and development, genetic interventions can induce multiple effects (pleiotropy) and complex epigenetics interactions among genotype, phenotype and ecology of a certain environment. As a result of the rapidity and scale with which such impact could be realized, it is essential for ethical and societal debates, as well as underlying scientific studies, to consider the unit of impact not only to the human body but also to human populations and their natural environment (systems biology). An important practicable distinction between therapy and enhancement may need to be drawn and effectively implemented in future regulations, although a distinct line between the two may be difficult to draw.

In the future if we do choose to genetically enhance human traits to levels unlikely to be achieved by human evolution, it would be crucial to consider if and how our understanding of humans and other organisms, including domesticated ones, enable us to better understand the implications of genetic interventions. In particular, effective regulation of genetic engineering may need to be based on a deep knowledge of the exact links between phenotype and genotype, as well the interaction of the human species with the environment and vice versa.

For a broader and consistent debate, it will be essential for technological, philosophical, ethical and policy discussions on human enhancement to consider the empirical evidence provided by evolutionary biology, developmental biology and other disciplines.

This work was supported by Fundao para a Cincia e a Tecnologia (FCT) of Portugal [CFCUL/FIL/00678/2019 to M.A.].

Conflict of interest: None declared.

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7 Future Genetic-Engineering Technologies | Genetically ...

New technologies, desires and threats from biological research

Rapid developments in biotechnology, genetics and genomics are undoubtedly creating a variety of environmental, ethical, political and social challenges for advanced societies. But they also have severe implications for international peace and security because they open up tremendous avenues for the creation of new biological weapons. The genetically engineered 'superbug'highly lethal and resistant to environmental influence or any medical treatmentis only a small part of this story. Much more alarming, from an arms-control perspective, are the possibilities of developing completely novel weapons on the basis of knowledge provided by biomedical researchdevelopments that are already taking place. Such weapons, designed for new types of conflicts and warfare scenarios, secret operations or sabotage activities, are not mere science fiction, but are increasingly becoming a reality that we have to face. Here, we provide a systematic overview of the possible impact of biotechnology on the development of biological weapons.

The history of biological warfare is nearly as old as the history of warfare itself. In ancient times, warring parties poisoned wells or used arrowheads with natural toxins. Mongol invaders catapulted plague victims into besieged cities, probably causing the first great plague epidemic in Europe, and British settlers distributed smallpox-infected blankets to native Americans. Indeed, the insights into the nature of infectious diseases gained by Louis Pasteur and Robert Koch in the nineteenth century did not actually represent a great breakthrough in the use of infectious organisms as biological weapons. Similarly, the development of a bioweapon does not necessarily require genetic engineeringsmallpox, plague and anthrax are deadly enough in their natural states. But the revolution in biotechnology, namely the new tools for analysing and specifically changing an organism's genetic material, has led to an increased risk of biowarfare due to several factors. First, the expansion of modern biotechnology in medical and pharmaceutical research and production has led to a worldwide availability of knowledge and facilities. Many countries and regions, where 30 years ago biotechnology merely meant brewing beer and baking bread, have established high-tech facilities for vaccine or single-cell-protein production that could be subverted for the production of biological weapons. Today, nearly all countries have the technological potential to produce large amounts of pathogenic microorganisms safely (). Second, classical biowarfare agents can be made much more efficiently than their natural counterparts, with even the simplest genetic techniques. Third, with modern biotechnology it becomes possible to create completely new biological weapons. And for technical and/or moral reasons, they might be more likely to be used than classical biowarfare agents. These possibilities have generated new military desires around the world, including within those countries that have publicly renounced biological weapons in the past. This paper deals predominantly with the last two factors, and with the use of real-life examples, we shall discuss the possibilities for such military abuse of biotechnology.

The US Army Medical Research Institute of Infectious Diseases in Fort Detrick, Maryland, is the centre of the USA's defensive research on biological weapons. ( (2001) Jan van Aken/Sunshine Project.)

By using genetic engineering, biological researchers have already developed new weapons that are much more effective than their natural counterparts. Countless examples from the daily work of molecular biologists could be presented here, not least the introduction of antibiotic resistance into bacterial pathogens, which today is routine work in almost any microbiology laboratory. Indeed, many research projects in basic science showsometimes unwillingly and unwittinglyhow to overcome current scientific and technological limits in the military use of pathogenic agents. Furthermore, genetic engineering is not merely a theoretical possibility for future biowarfare: it has already been applied in past weapons programmes, particularly in the former Soviet Union. One example is the USSR's 'invisible anthrax', resulting from the introduction of an alien gene into Bacillus anthracis that altered its immunological properties (Pomerantsev et al., 1997). Existing vaccines proved to be ineffective against this new genetically engineered strain.

...genetic engineering will not necessarily have a major role in the early stages of a biowarfare programme

In debates about genetic engineering and biological weapons it is often stated that natural pathogens are sufficiently dangerous and deadly, and that genetic engineering is not necessary to turn them into more effective biological weapons. This is indeed true in that biological weapons can be used without genetic engineeringor, for that matter, without any scientific knowledgeas has been shown by their effective use in past centuries. In fact, genetic engineering does not necessarily have a central role in the early stages of a biowarfare programme. The development of reliable, effective biological weapons requires an intense and resource-demanding research programme that must, step by step, solve increasingly complex problems: the procurement of virulent strains of suitable agents, the mass production of the agents without loss of pathogenicity, and the development of an effective means of delivery. In particular, the third step is very demanding, and has rarely been accomplished, with the exception of the huge former biowarfare programmes in the USA () and the USSR. Even Iraq, after several years of an active biowarfare programme, had developed only rudimentary methods of delivery. From this perspective, genetic engineering is a step taken relatively late in the development of biowarfare potential, which most probably will not be taken before the first, essential steps are solved. Indeed, we know only from the massive biowarfare programme in the former Soviet Union that pathogens have been genetically modified to increase their effectiveness as bioweapons, but there may have been other, so far undetected, attempts elsewhere.

The so-called '8-ball', a 1 million litre steel ball built in 1949 in which the US Army tested the effectiveness of biological weapons. The ball is in Fort Detrick, Maryland, and is a 'historical monument' today. ( (2001) Jan van Aken/Sunshine Project.)

By contrast, it must not be underestimated that hardly any natural pathogens are really well suited to being biowarfare agents from a military point of view. Such a bioweapon must fulfil a variety of demands: it needs to be produced in large amounts, it must act fast, it must be environmentally robust, and the disease must be treatable, or a vaccine must be available, to allow the protection of one's own soldiers. This explains why only a minority of natural pathogens are suitable for military purposes. Anthrax is of course the first choice because the causative agent, B. anthracis, fulfils nearly all of these specifications (). However, potential victims of an anthrax attack can be treated with antibiotics even several days after an infection. Therefore, only a minority of the infected persons will die from an anthrax attack in most instances, as has been shown by the anthrax attacks in 2001 in the USA. However, a very simple genetic intervention could produce much more drastic and deadly results.

Until 1969, the US Army produced anthrax spores for offensive warfare in this building at Fort Detrick, Maryland. ( (2001) Jan van Aken/Sunshine Project.)

In addition, another important restriction of bioweapons might be overcome by genetic engineering techniques in the future. Today, access to highly virulent agents and strains is increasingly regulated and restricted. In particular, smallpox, which was eradicated more than 20 years ago, is officially only stored at two high-security laboratories in the USA and Russia, and it is at present virtually impossible to gain access to these virus stocks. But considering the rapid development of molecular biology, it is only a question of time before the artificial synthesis of agents or new combinations of agents becomes possible. This danger was highlighted last year by a worrying article in Science: a research team at the State University of New York in Stony Brook chemically synthesized an artificial polio virus from scratch (Cello et al., 2002). They started with the genetic sequence of the agent, which is available online, ordered small, tailor-made DNA sequences and combined them to reconstruct the complete viral genome. In a final step, the synthesized DNA was brought to life by adding a chemical cocktail that initiated the production of a living, pathogenic virus.

In principle, this method could be used to synthesize other viruses with similarly short DNA sequences. This includes at least five viruses that are considered to be potential biowarfare agents, among them Ebola virus, Marburg virus and Venezuelan equine encephalitis virus. The first two in particular are very rare viruses that might be difficult to acquire by potential bioweaponeersaccording to rumours, members of the Japanese cult Aum Shinrikyo, famous for the nerve gas attack on the Tokyo subway, tried unsuccessfully to get their hands on Ebola virus during an outbreak in former Zaire in the 1990s. Using the method that has been published for polio, such a group or an interested state could theoretically construct Ebola virus in the laboratory. However, it should be noted that this method is complex, and probably only a few highly trained experts would be able to master this technique, at least for the time being.

The polio virus itself is not an effective biological weapon, but the experiment shows the tremendous potential of genetic engineering and also highlights its problems, particularly when applied to smallpox. The current risk assessments with regard to this virus rate the likelihood of an attack as being rather low, because it is highly unlikelyalthough not completely impossiblethat countries other than Russia and the USA have access to it. If it should become possible to rebuild variola major, the smallpox virus, in the laboratory from scratchand the virus's genome sequence is available from biological databasesthis risk could change greatly. Smallpox is an ideal biological weapon, particularly for terrorist groups, because it is highly infectious and lethal and there is no effective treatment available. The relative safety that can be assumed today will then be gone.

However, the method for creating polio virus artificially cannot be directly transferred to the smallpox virus. The variola genome, with more than 200,000 base pairs, is far bigger than that of polio, and even if it were possible to recreate the full smallpox sequence in vitro, it could not easily be transformed into a live infectious virus particle. But there might be other ways. It would, for example, be possible to start with a closely related virus, such as monkeypox or mousepox, and to alter specifically those bases and sequences that differ from human smallpox. Some months ago, researchers documented for the first time that the sequence of a pathogenicity-related gene from the vaccinia virus could be transformed through the targeted mutation of 13 base pairs into the sequence of the corresponding smallpox gene (Rosengard et al., 2002). It is probably only a matter of time before this technique is applicable to full genomes, and then we shall have to reconsider our current assessment of the smallpox threat. Considering the extreme danger that smallpox poses to a now largely unvaccinated human population, it seems at least questionable to make the smallpox sequence available on the World Wide Web.

However, the genetic enhancement of classical pathogens is only a small part of the broad array of possibilities that new biomedical techniques have created. From the point of view of disarmament, another trend is much more alarming: new types of biological weapons are becoming possible that were entirely fictitious until a few years ago. This is especially true of so-called 'non-lethal' weapons that are designed for use outside classical warfare. The danger is that these new possibilities generate desires even in countries that previously renounced the use and development of classical biological weapons.

The global norm against biological weapons, laid down in the 1925 Geneva Convention and the 1972 Biological and Toxin Weapons Convention, clearly contributed to the fact that few countries have been engaged in research into offensive biowarfare during recent decades. This moral barrier seems to be lower for 'non-lethal' weapons that are targeted against materials or drug-producing plants. Indeed, today's technical possibilities are creating a new interest in this area that might be leading to a new biological arms race. In the following paragraphs, we document three real examples of biological and chemical weapons development that are now being pursued by democracies in the Western world. All three examples have been researched and extensively published by the Sunshine Project (further reading is available at http://www.sunshine-project.org).

The US military has repeatedly discussed possible uses of biotechnology for warfare scenarios, including the development of material-degrading microorganisms to destroy fuel, constructional material or stealth paints (Strategic Assessment Center of Science Applications International Corporation, 1995; US Army War College, 1996). This idea is based on the fact that natural microorganisms are able to degrade nearly every material and are already being used to detoxify environmental pollution. The natural organisms are rather slow-acting and unreliable, but, with the help of genetic engineering, the development of much more effective organisms might become possibleprobably effective enough to be used as biological weapons (Sayler, 2000). The specific interest of military researchers in material-degrading microbes is due to the synergistic effects of two concurrent developments: first, the military, particularly in the USA, has a renewed interest in these non-lethal weapons for use in mediasensitive mili-tary operations so that visible civilian victims can be avoided; second, rapid developments in biotechnology provide the

Considering the extreme danger that smallpox poses to a now largely unvaccinated human population, it seems at least questionable to make the smallpox sequence available on the World Wide Web

technological basis to change natural microorganisms into anti-material microbes. New technological possibilities met new military concepts in the USA and led to a renewed interest in weapons that, until recently, had been banned and rejected.

In 1998, it became public that the US Naval Research Laboratory in Washington DC was developing genetically engineered fungi with offensive biowarfare potential. They isolated natural microorganisms that degrade a variety of materials, such as plastics, rubber and metals, and used genetic engineering to make them more powerful and focusedone of these genetically engineered microbes can destroy military paints in 72 hours. The principal investigator at the Naval Research Laboratory, James Campbell, described possible applications of this technology in his presentation at the 3rd Non-Lethal Defense Symposium in 1998. Among them were microbial derived or based esterases [that] might be used to strip signature-control coatings from aircraft, thus facilitating detection and destruction of the aircraft (www.dtic.mil/ndia/NLD3/camp.pdf). This work is purportedly defensive in nature, although no threat has been articulated, and continuing research by the US Navy and Army continues to strive towards taking these weapons from the laboratory to the field. Just a few years later, in 2002, several research proposals by the US military that were clearly offensive in nature became public.

New technological possibilities met new military concepts in the USA and led to a renewed interest in weapons that, until recently, had been banned and rejected

About a decade ago, the USA also increased their efforts to identify microorganisms that kill drug-producing crops; by the late 1990s, this research focused largely on two fungi. The testing of one, Pleospora papaveracea, against opium poppy, was conducted in Tashkent, Uzbekistan, with financial and scientific support from the USA, and was completed in 2001. Pathogenic Fusarium oxysporum strains developed in the USA to kill coca plants were scheduled for field tests in Colombia in 2000, but international protests halted this project. These fungi provide a quintessential example of the hostile use of biological agents. In Colombia, the biggest areas of coca and opium poppy cultivation are in combat zones, and the 'War on Drugs' is part of the country's continuing armed conflict. These biological agents are lowering the political threshold for the use of biological weapons and are likely to have tremendous environmental and health impacts. The pursuit of crop-killing fungi as weapons would be a further slide down a slippery slope that, by following the same logic, could easily lead to the use of other plant pathogens, animal pathogens or even non-lethal biological weapons against humans (van Aken & Hammond, 2002).

The third example is not about biological weapons but new types of chemical, or rather biochemical, weapons. As in the other examples, the revolution in biomedicine created new desires in the East and the West, and there are already new weapons under development that violate international treaties. This area came under the spotlight of the international media after the use of psychoactive substances in the Moscow hostage crisis last year, causing the death of more than 170 people. These supposedly 'non-lethal' chemical weapons had been developed as early as the 1950s, particularly a substance called 'BZ', known in the US army as 'sleeping gas'. But BZ caused very different effects in different individuals and was considered to be unreliable, leading to its banishment from the US chemical arsenal in the late 1960s. Today, however, modern neurobiology provides comprehensive knowledge about a broad range of neuroreceptors and manifold psychoactive substances that make 'non-lethal' chemical weapons attractive for the military once more. For instance, the US Marine Corps recently investigated the potential military usefulness of calmatives such as benzodiazepines and 2-adrenoreceptor agonists. However, the identification of suitable substances is only one part of the renewed chemical weapons research in the USA. Recently published documents show that the US military forces are also developing new delivery devices for chemicals with a range of more than 2.5 kma distance that makes sense only for warfare scenarios as opposed to police operations, in which ranges from 10 to 50 m for tear gas grenades are common. The Chemical Weapons Convention prohibits any use of chemicals, including 'non-lethal' chemicals, in warfare situations. Even the use of tear gas is prohibited because of the enormous danger of escalation. In a specific combat situation, the attacked side will be unable to identify the nature of the chemical used and might feel tempted to retaliate in kind with potentially lethal chemicals.

Molecular biology and genetic engineering are still in their infancy, and more technical possibilities will arise in the years to comefor military abuse too (Fraser & Dando, 2001). More efficient classical biowarfare agents will probably have only a marginal role, even if the genetically engineered 'superbug' is still routinely featured in newspaper reports. More likely and more alarming are weapons for new types of conflicts and warfare scenarios, namely low-intensity warfare or secret operations, for economic warfare or for sabotage activities. To prevent the hostile exploitation of biology now and forever, a bundle of measures must be taken, from strengthening the Biological and Toxin Weapons Convention to building an awareness in the scientific community about the possibilities and dangers of abuse. Any kind of biotechnological or biomedical research, development or production must be performed in an internationally transparent and controlled manner. In cases in which military abuse seems to be imminent and likely, alternative ways to pursue the same research goal have to be developed. Furthermore, as we mentioned above with regard to the smallpox genome sequence, it might also be necessary to apply restrictions to certain research and/or publications.

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Genetic engineering and biological weapons

After exhausting all available options, doctors approached David Bennett Sr with a last-ditch effort to save his life receive a heart transplant from a gene-edited pig. Three days after the transplant, David remains in stable condition, a positive sign that some experts suggest may foreshadow a new era of organ transplantation.

The transplantation of organs from one species to another, known as xenotransplantation, has been the target of medical curiosity for centuries. In 1905, a French scientist attempted to transplant slices of rabbit kidney into a child suffering from chronic kidney disease. Although unsuccessful, this procedure was followed by decades of attempts to transfer organs from lambs, pigs, and primates into human patients.

Scientists would discover that xenotransplantation frequently triggers deadly immune responses in organ recipients. The presence of foreign animal cells sets off a cascade of molecular signals that can kill patients in a matter of days or even minutes.

Advancements in genetics and immunology have uncovered the genes, proteins, and molecular pathways linked to organ rejection. In parallel, rapid improvements in gene-editing technologies like CRISPR have given scientists the ability to precisely edit dozens of sequences across an animals genome. In theory, targeted genetic changes could camouflage foreign organs and prevent a deadly immune response, a proposition that multiple companies are pursuing.

In October 2021, surgeons at New York University's Langone Health completed a proof-of-concept experiment by attaching a pig kidney to a brain-dead human body. The organ continued to function normally for two days post-treatment. The kidney came from the Virginia-based regenerative medicine company Revivicor. A year prior, Revivicor had received regulatory approval to genetically-engineer pigs for both food and medical uses.

The issue, however, is that pigs produce a sugar in their cells, which causes an immune response in humans during an organ transplant. By eliminating that sugar through genetic engineering, Revivicor created organs capable of evading an immune response.

On January 7 2022, xenotransplantation took another monumental leap forward with the successful transferring of a gene-edited pig heart into a living human. This time Revivicor provided a heart from a donor pig, engineered to have 10 genetic alterations. They eliminated three genes responsible for organ rejection within the pig's genome while introducing six human genes to help the patients body accept the new heart. They knocked out one additional gene to prevent the pig heart from growing too large.

Scientists are hesitant to draw conclusions from this procedure since the surgery was not part of a formal clinical trial and the patient was on novel immunosuppressive drugs. Further monitoring and evaluation of the patients health and recovery will reveal whether this one-off experiment is a glimpse of whats to come. Companies like eGenesis and Qihan Biotech see this as a step in the right direction and are moving their xenotransplantation research closer to the clinic.

Thousands of people die every year waiting for an organ transplant. Demand for organs outpace supply. Where precious organs are available, the distance between donor and recipient can create huge hurdles. Xenotransplantation is, therefore, an applauded technological innovation, but the benefits are not without concern.

David Bennett Srs heart transplant has renewed debates on the ethics of using animals for organs. Pigs are historically the donors of choice thanks to their human-sized organs, short gestation periods, and the opinion that pigs are less ethically fraught than primates. Some animal activists contest these arguments, arguing that pigs shouldnt be engineered or used as organ donors.

Instead of xenotransplantation, experts suggest alternatives for society and governments to address organ donation shortages. One long-fought policy change involves switching organ donation systems from opt-in to opt-out. Some countries, like the USA, give citizens a choice to become organ donors. Others, like the UK, automatically enrol people with the option to opt-out of the programme. This simple change can dramatically increase the number of available donors and shorten the long waiting list.

Next-generation artificial organs may one day act as an alternative to human organ donation. Compared to earlier generations, which use mechanical pumps, advances in 3D printing and tissue engineering are propelling the creation of new artificial hearts made of flesh and blood. Even with an emerging class of organs that blur the line between artificial and natural, there will still be patients who may not meet eligibility requirements, leaving a demand for xenotransplantation.

Written by

Kevin Doxzen, Hoffmann Fellow, Precision Medicine and Emerging Biotechnologies, World Economic Forum

The views expressed in this article are those of the author alone and not the World Economic Forum.

Excerpt from:

Gene-edited pig heart transplanted into a human patient - World Economic Forum

Gene therapy is a lot like landing a Mars rover.

Hear me out. The cargoa rover or gene editing toolsis stuffed inside a highly technical protective ship and shot into a vast, complex space targeting its destination, be it Mars or human organs. The cargo is then released, and upon landing, begins its work. For Perseverance, its to help seek signs of ancient life; for gene editors, its to redesign life.

One critical difference? Unlike a Mars missions seven minutes of terror, during which the entry, descent, and landing occur too fast for human operators to interfere, gene therapy delivery is completely blind. Once inside the body, the entire flight sequence rests solely on the design of the carrier spaceship.

In other words, for gene therapy to work efficiently, smarter carriers are imperative.

This month, a team at Harvard led by Dr. David Liu launched a new generation of molecular carriers inspired by viruses. Dubbed engineered virus-like particles (eVLPs), these bubble-like carriers can deliver CRISPR and base editing components to a myriad of organs with minimal side effects.

Compared to previous generations, the new and improved eVLPs are more efficient at landing on target, releasing their cargo, and editing cells. As a proof of concept, the system restored vision in a mouse model of genetic blindness, disabled a gene associated with high cholesterol levels, and fixed a malfunctioning gene inside the brain. Even more impressive, its a plug-and-play system: by altering the targeting component, its in theory possible for the bubbles to land anywhere in the body. Its like easily rejiggering a Mars-targeting spaceship for Jupiter or beyond.

Theres so much need for a better way to deliver proteins into various tissues in animals and patients, said Liu. Were hopeful that these eVLPs might be useful not just for the delivery of base editors, but also other therapeutically relevant proteins.

Overall, Liu and colleagues have developed an exciting new advance for the therapeutic delivery of gene editors, said Dr. Sekar Kathiresan, co-founder and CEO of Verve Therapeutics, who was not involved in the study.

We already have families of efficient gene editors. But carriers have been lacking.

Take base editing. A CRISPR variant, the technology took gene editing by storm due to its precision. Similar to the original CRISPR, the tool has two components: a guide RNA to hunt down the target gene and a reworked Cas protein that swaps out individual genetic letters. Unlike Cas9, the CRISPR scissors, base editing doesnt break the DNA backbone, causing fewer errors. Its the ultimate genetic search and replace, with the potential to treat hundreds of genetic disorders.

The problem is getting the tools inside cells. So far, viruses have been the go-to carrier, due to their inherent ability to infect cells. Here, scientists kneecap a viruss ability to cause disease, instead hijacking its biology to carry DNA that encodes for the editing components. Once inside the cell, the added genetic code is transcribed into proteins, allowing cells to make their own gene editing tools.

Its not optimal. Viruses, though efficient, can cause the cells to go into overdrive, producing far more gene editing tools than needed. This stresses the cells resources and leads to side effects. Theres also the chance of viruses tunneling and integrating into the genome itself, damaging genetic integrity and potentially leading to cancer.

So why not tap into a viruss best attributes and nix the worst?

eVLPs are like their namesakes: they mimic viral particles that are efficient at infecting cells, but cut out the dangerous parts: DNA. Picture a multi-layered pin cushion, but with an empty cavity to hold cargo.

Unlike viruses, these bubbles dont carry any viral DNA and cant cause infections, potentially making them far safer than viral carriers. The downside? Theyre traditionally terrible at carrying cargo to its targets. Its akin to a spaceship with awful homing machinery that crashes into other planets and causes an unexpected wave of disaster. Theyre also not great at releasing the cargo even on the target site, trapping CRISPR machinery inside and making the whole gene-editing fix moot.

In the new study, Lius team started by analyzing those pain points. By limiting proteins inside the eVLPs that act as the carriers safety belts, they found, its easier for the cargothe base editor proteinsto release. How they packed the cargo inside the particle bubbles also made a difference. The balance between the twoseat belt to protein passengersseems to be key to protecting the cargo but allowing them to quickly bail when needed. And finally, dotting the outer shell of the spaceship with specific proteins helps the spaceship navigate towards its designated organ.

In other words, the team figured out the rules of the game. Now that we know some of the key eVLP bottlenecks and how we can address them, even if we had to develop a new eVLP for an unusual type of protein cargo, we could probably do so much more efficiently, said Liu.

The result is that a carrier can pack 16 times more cargo and up to a 26-fold increase in gene editing efficacy. Its a fourth-generation carrier, said the authors.

After first testing their new molecular spaceship in cultured cells in the lab, the team moved on to treating genetic disorders. They targeted three different biological planetsthe eye, liver, and brainshowcasing the flexibility of the new carrier.

In mice with an inherited form of blindness, for example, the carrier was loaded with the appropriate gene editing tools and injected into a layer of tissue inside the eye. In just five weeks, the single injection rebooted retinal function to a point thatbased on previous studies from the same labcan restore the mices ability to see.

In another study, the team focused on a gene that often leads to brain disorders. Because of a tough barrier between the brain, blood, and other tissues, the brain is a notoriously difficult organ to access. With the new eVLP spaceship, the gene editors smoothly sailed through the barrier. Once inside brain cells, the tools had a roughly 50 percent chance of transforming damaged genes.

As an additional proof of concept, the new carriers honed in on the livers of mice with cholesterol problems. One injection amped up the mices ability to produce a protective molecule that thwarts heart disease.

Gene editing has always been haunted by the ghost of off-target effects. Using viruses to deliver the tools, for example, runs those risks as they last a long time, potentially overwhelming cells.

Not so for the new eVLPs. Because theyre completely engineered, they carry zero viral DNA and are safer. Theyre also highly programmablejust a few changes to the targeting proteins can shift them towards another docking location in the body.

For the next step, the team is engineering better seat belt proteins inside the carriers for different moleculeseither gene editors or therapeutic proteins such as insulin or cancer immunotherapies. Theyre also further unpacking what makes eVLPs tick, aiming for next-generation carriers that can explore every nook and cranny of our bodies complex universe.

Image Credit: nobeastsofierce/Shutterstock.com

Excerpt from:

New Virus-Like Particles Can Deliver CRISPR to Any Cell in the Body - Singularity Hub

A key breakthrough came in the early 2000s, when Japanese researchers hit on a simple formula to turn any type of tissue into powerful stem cells, similar to ones in an embryo. Imaginations ran wild. Scientists realized they could potentially manufacture limitless supplies of nearly any type of cellsay, nerves or heart muscle.

In practice, though, the formula for producing specific cell types can prove elusive, and then theres the problem of getting lab-grown cells back into the body. So far, there have been only a few demonstrations of reprogramming as a way to treat patients. Researchers in Japan tried transplanting retina cells into blind people. Then, last November, a US company, Vertex Pharmaceuticals, said it might have cured a mans type 1 diabetes after an infusion of programmed beta cells, the kind that respond to insulin.

The concept startups are pursuing is to collect ordinary cells such as skin cells from patients and then convert these into hair-forming cells. In addition to dNovo, a company called Stemson (its name is a portmanteau of stem cell and Samson) has raised $22.5 million from funders including from the drug company AbbVie. Cofounder and CEO Geoff Hamilton says his company is transplanting reprogrammed cells onto the skin of mice and pigs to test the technology.

Both Hamilton and Lujan think there is a substantial market. About half of men undergo male-pattern baldness, some starting in their 20s. When women lose hair, its often a more general thinning, but its no less a blow to self-image.

These companies are bringing high-tech biology to an industry known for illusions. There are plenty of bogus claims about both hair-loss remedies and the potential of stem cells. Youve got to be aware of scam offerings, Paul Knoepfler, a stem-cell biologist at UC Davis, wrote in November.

JIYOON LEE AND KARL KOEHLER, HARVARD MEDICAL SCHOOL

So is stem-cell technology going to cure baldness or become the next false hope? Hamilton, who was invited to give the keynote at this years Global Hair Loss Summit, says he tried to emphasize that the company still has plenty of research ahead of it. We have seen so many [people] come in and say they have a solution. That has happened a lot in hair, and so I have to address that, he says. Were trying to project to the world that we are real scientists and that it's risky to the point I cant guarantee its going to work.

Right now, there are some approved drugs for hair loss, like Propecia and Rogaine, but theyre of limited use. Another procedure involves cutting strips of skin from someplace where a person still has hair and surgically transplanting those follicles onto a bald spot. Lujan says in the future, hair-forming cells grown in the lab could be added to a persons head with a similar surgery.

I think people will go pretty far to get their hair back. But at first it will be a bespoke process and very costly, says Karl Koehler, a professor at Harvard University.

Hair follicles are surprisingly complicated organs that arise through the molecular crosstalk between several cell types. And Koehler says pictures of mice growing human hair aren't new. Anytime you see these images, says Koehler, there is always a trick, and some drawback to translating it to humans.

Koehlers lab makes hair shafts in an entirely different wayby growing organoids. Organoids are small blobs of cells that self-organize in a petri dish. Koehler says he originally was studying deafness cures and wanted to grow the hair-like cells of the inner ear. But his organoids ended up becoming skin instead, complete with hair follicles.

Koehler embraced the accident and now creates spherical skin organoids that grow for about 150 days, until they are around two millimeters across. The tube-like hair follicles are clearly visible; he says they are the equivalent of the downy hair that covers a fetus.

One surprise is that the organoids grow backwards, with the hairs pointing in. You can see a beautiful architecture, although why they grow inside out is a big question, says Koehler.

The Harvard lab uses a supply of reprogrammed cells established from a 30-year-old Japanese man. But its looking at cells from other donors to see if organoids could lead to hair with distinctive colors and textures. There is absolutely demand for it, says Koehler. Cosmetics companies are interested. Their eyes light up when they see the organoids.

More here:

Going bald? Lab-grown hair cells could be on the way - MIT Technology Review

An estimated 37,470 animal, plant, and fungi species are now listed as threatened (vulnerable, endangered, critically endangered) by the International Union for the Conservation of Nature (IUCN) Red List (downloaded August 2021) with most known species (72%) still to be assessed (1). Species listing on the IUCN Red List is rigorous, with multiple assessments, reviews, and consistency checks to ensure robustness of the global list (1). However, global biodiversity is not evenly spread across the globe, with just 17 megadiverse countries home to 60 to 80% of all life on earth (2). As a result, the responsibility of conserving much of the worlds biodiversity tends to fall upon these few nations, 15 of which are classified as developing economies by the United Nations (3). The range of threats contributing to the global biodiversity crisis (4) are broad, including habitat loss and fragmentation, invasive pest species, disease, and climate change (5). As the human population continues to increase and encroach on the natural world, a 10-year program has commenced (6)The United Nations Decade of Ecosystem Restoration 20212030to help slow biodiversity loss. Fragmentation and modification of habitat reduces population size and connectivity for many species and threatened species are typically found in small, isolated populations susceptible to genetic risks and other stochastic processes (7). Conservation practitioners are more frequently using conservation translocations as a restoration tool for maintaining populations of threatened fauna and flora (8, 9). Yet, translocations can further entrench small population risks because when managing a species in a fragmented landscape, behind a fence, or on an island, natural gene flow is reduced (7). As a result, genetic management is becoming integral to the conservation of an ever-greater number of species.

Genomes, and their associated downstream applications, are powerful tools for discovery of new knowledge around species behavior and biology. They can improve our understanding of species taxonomy, provide information regarding past and future evolutionary processes, and complement current ecological survey and study methods (10). In 2018, of the 13,500 animal species on the IUCN Red List, less than 0.8% of species had published genomes on the National Center for Biotechnology Information (11); in the past 3 y this has increased slightly to 2.4% of the 15,521 listed threatened species. Although there is an increase in global genome consortia, such as the Earth Biogenome Project (10, 12), the Vertebrate Genome Project (13), and the Global Invertebrate Genomics Alliance (14), that are creating genomes for nonmodel species, genomic resources for some of our most critically endangered species are still lacking. Furthermore, developing reference genomes for species does not impact their conservation on their own, but rather it is the downstream applications and tools that use reference genomes that can significantly improve species conservation.

A recent review by Supple and Shapiro (15) highlighted that the transition to genomic technologies is only just beginning and that there needs to be an expansion in the available datasets so researchers can ask different questions applicable to conservation. Here, we reviewed the conservation-focused peer-reviewed literature to explore the trends in increasing use of genomic data in studies regarding the management of threatened or endangered species (see SI Appendix for methodological details). We identified a total of 498 papers containing a variety of sequencing methods and types of studies: 263 (52.8%) used either microsatellites, SNPs, or whole genome data, to address population genetics/genomics; and 89 (17.9%) were some form of review (SI Appendix, Table S1). Of the 212 papers that used nuclear DNA to address population genetics/genomics, there has been a marked decrease in the use of microsatellites and an increase in the use of SNPs since 2010 (Fig. 1). As expected, with genome technologies becoming more prominent in nonmodel species after 2010, there was an increase in using next-generation sequencing to improve the development of microsatellite markers (20152020) and an increased use of thousands of SNPs to improve genome-wide diversity studies (Fig. 1). More recently (since 2017) there has been a steady increase in the number of studies using resequenced whole genomes (Fig. 1). Although this is not a fully comprehensive search of all the conservation genomics/genetics works currently published, we find that even in the absence of available reference genomes for threatened species, there has been a sustained uptake of other genomic approaches in conservation genetic studies of threatened species, with many leading to explicit conservation recommendations (see refs. 1517 for more comprehensive reviews).

As Supple and Shapiro (15) (and others) point out, the suite of genomic tools available to researchers to understand both genome-wide and functional diversity within and between species and populations, can be greatly expanded when reference genome information is available, enabling more precise targeting of conservation measures (11, 15, 16). Indeed, we know that conservation practitioners use genetic information in their decision-making (SI Appendix, Table S2), particularly when it comes to managing threatened species in small populations within fragmented landscapes (18). However, the use of big data genomic approaches presents challenges for practitioners to access and interpret the available information.

Australia is one of the 17 megadiverse nations. Separating from other continents over 42 to 53 million y ago (19, 20) means many of the species in Australia are unique, with 87% of mammals, 45% birds, 93% reptiles, 94% amphibians, and 92% of plants endemic to the island continent (21). However, many Australian species have seen marked declines since European settlement in 1788, with 1,774 species (480 animals; 1,294 plants, as of 2016) listed as threatened under the Australian Environment Protection and Biodiversity Conservation Act (22). Various recovery and other conservation plans have been put in place by the Australian, State, and Territory Governments with actions to address threats and support the long-term recovery of these species. Globally, Australia has the worst record of mammal extinctions in the world. Multiple species have faced population declines of over 90% in the past two decades (23). The loss of Australian mammal species is largely due to predation by introduced species and changes to fire regimes (23, 24), with our first mammal extinction attributed to anthropogenic climate change declared in 2016 (25). Apart from managing species in often increasingly fragmented landscapes, to address the challenges of rapidly declining populations, many threatened species are increasingly being managed in large, fenced areas, in zoological/botanic garden insurance populations, and on offshore islands. Consequently, genetic diversity and gene flow are reduced for many species and this needs to be accounted for in ongoing management actions.

Conservation biologists and practitioners have a range of technological tools at their disposal to address the various challenges of conserving biodiversity (26). However, for many conservation practitioners there is often an implementation gap between research and development of new tools and their application in conservation practice (27). One such research implementation gap that has been widely discussed is the use of genomics and associated tools for conservation of threatened species (2830). Although recent reviews (see refs. 15 and 3133) discuss the value of genomes for conservation and protection of biodiversity, as sequencing technology improves, there are increasing requirements around genome quality, bioinformatic knowledge, and handling of big data. This creates an ever-widening researchimplementation gap between the creation of genomic resources by genome biologists and bioinformaticians and the application of these resources in conservation management by conservation practitioners.

Bioplatforms Australia (Bioplatforms), a nonprofit organization that supports Australian Life Science research by investing in state-of-the-art infrastructure and expertise in genomics, proteomics, metabolomics, and bioinformatics, has invested in a number of genome initiatives over the past 10 y, producing genomic resources for Australian species (Table 1). The focus of many of these initiatives has been on reference genome production, comparative genomics, and phylogenomics to resolve species taxonomy for conservation application. Building on the success of these programs, the mission of the Threatened Species Initiative (TSI), launched in May 2020, is to bridge the implementation gap between the production of genomic resources and their application in conservation management (https://threatenedspeciesinitiative.com/). From the outset, TSI has been developed in direct consultation with governmental threatened species managers and other conservation practitioners, around their needs and knowledge gaps (SI Appendix, Table S2). It brings together genome biologists, population biologists, bioinformaticians, population geneticists, and ecologists with conservation agencies across Australia, including government, zoos, botanic gardens, and nongovernment organizations (NGOs). Our objective is to create a foundation of genomic data to advance our understanding of representative Australian threatened species, in addition to fast-tracking genomic information to conservation end-users through online resources and open-access data. We aim to empower conservation practitioners to leverage genomic information to tackle critical biological and conservation issues, including genetic data to inform translocations, captive breeding, seed banking, and ongoing population management.

Environmental genome initiatives that have been supported by Bioplatforms Australia that have produced genomic resources for Australian wildlife and plant species

Studies from New Zealand/Aotearoa (28) and Australia (34) show that conservation practitioners know the value of using genetic data in conservation decision-making, but access to easily interpretable information is lacking. In Australia, projects such as Devil Tools & Tech (34) and Restore & Renew (35) have shown that by creating partnerships between academic researchers and conservation practitioners, the latest genome technologies and techniques can be applied in real-time to conservation decision-making. It was the success of these programs with specific species and their philosophy of open access to the latest research data that led to the development of the TSI. TSIs goal is to undertake applied research that has direct management applications, while ensuring the research is innovative and novel for peer-review publication and to attract competitive research funding.

Our approach to engineering and building a bridge for the current genomic researchimplementation gap is threefold: 1) use genome sequencing technologies that meet the needs of the conservation end-users while maximizing the limited conservation resources available (both funding and sample access), so genomic data can be developed for as many threatened species as possible; 2) develop an on-line interface where TSI project teams can obtain protocols and use a set of established bioinformatic tools and workflows to provide genetic outputs in a standardized reporting format for conservation practitioners; and 3) open-data access, where genomic data will be open access but other related metadata may be restricted due to threatened species and indigenous sensitivities (36). To ensure seamless delivery of the larger project, a pilot phase was commenced in August 2020, to test and bed down workflows and pipelines to ensure outputs were fit-for-purpose for conservation management and decision-making. Eight species (two birds: eastern bristlebird, Dasyornis brachypterus and orange-bellied parrot, Neophema chrysogaster; two marsupials: eastern barred bandicoot, Perameles gunnii, and western barred bandicoot, Perameles bougainville; two mammals: ghost bat, Macroderma gigas and Hastings River mouse, Pseudomys oralis; one fish: swan galaxias, Galaxias fontanus; and one plant: native guava, Rhodomyrtus psidioides) were selected for the pilot phase through consultation with the Australian, State, and Territory threatened species managers. Note, the Australian Amphibian and Reptile Genomics (AusARG) project commenced at the same time as the TSI and is undertaking similar activities for reptiles and amphibians, so these taxa were not included in the initial TSI pilot phase. The species were grouped into five scenarios to enable comprehensive testing of the different stages of the TSI conservation genomics pipeline: 1) the species has no reference genome, no population genetic data; 2) the species has closely related species with a reference genome, but no population genetic data; 3) the species has no reference genome, and population genetic data exists; 4) the species has a reference genome, or conspecific genome, some population genetic data, and is subject to conservation action which mixes genetically distinct populations; and 5) the species has no reference genome, but short-read data exists, and some population genetic data exists.

This pilot phase was followed by a Request for Partnership round in early 2021, and with a second scheduled for early 2022. In the Request for Partnership academic researchers are encouraged to select species from a preselected list of threatened species, which has been prioritized by the Australian Federal, State, and Territory government agencies. Initially it was anticipated that the current TSI funding (AUD$1.4M) would be able to provide genomic resources for between 40 and 50 threatened plant, animal, and invertebrate species over its 3-y lifespan. In 2021, this goal was superseded, with 61 species currently supported by the program from across Australia (Fig. 2 and SI Appendix, Table S3), representing extinct in the wild (n = 3), critically endangered (n = 16), endangered (n = 17), vulnerable (n = 15), and data-deficient species (n = 9). Note, one least concern species is supported to investigate its value as a genetic rescue surrogate for a critically endangered species. Participating project teams are encouraged to leverage other funding opportunities using TSI resources as seed funding; this will see a multiplier effect from the base investment and provide genomic resources for more species. Of the 61 species projects, there are over 130 project team members representing government (46%), academia (35%), and nongovernment/conservation organizations (19%). All participating project teams are encouraged to work with local Aboriginal nations where possible and provide tangible on-ground conservation outcomes as part of their projects.

Species involved in the TSI by: (A) geographical location, noting some species are found in more than one State or Territory; (B) IUCN threat status: extinct in the wild (EW), critically endangered (CR), endangered (EN), vulnerable (VU), least concern (LC), data deficient (DD); and (C) taxa. Base Australia map by Free Vector Maps (https://freevectormaps.com/).

There are more than 30 genomes of Australian species, with 40 draft genomes in development through the Bioplatforms Australia initiatives. These genomes have used a variety of sequencing technology over the years, including whole-genome shotgun approach with Sanger sequencing [e.g., Tammar wallaby, Macropus eugenii (37)]; Illumina platform [e.g., Tasmanian devil, Sarcophilus harrisii (38)]; PacBio RS II platform with Illumina HiSeq [e.g., koala, Phascolarctos cinereus (39)], and 10X Genomics linked-read sequencing on NovaSeq. 6000 [e.g., brown antechinus, Antechinus stuartii (40)]. Some of these genomes may be now classified as low-quality by todays genome standards, but their conservation application has been significant. For example, the original 2012 Tasmanian devil genome (38) (Table 2) has been used with much success for the management of both wild and captive populations of this endangered species (see full review, ref. 11)]. The Tasmanian devil genome allowed for the development of conservation-based tools, such as species-specific microsatellite markers, characterization of immune gene families, blocking primers for use in metagenomics studies, as a few examples (11). The 2018 koala genome (39) (Table 2), is permitting a large-scale genomic survey of the species to understand both genome-wide and functional diversity in light of the recent Australian megafires, which saw more than 126,000 km2 of habitat burned (41). This genomic survey will inform potential future management actions around habitat restoration and translocations for a globally recognized species. Other draft genomes for the woylie [Bettongia penicillate ogilbyi (42)] have been used in real-time (as the genome was assembled) to inform management actions and translocation success for both the woylie (43), and other cogeneric species (16), such as the boodie (Bettongia lesueur). It should be noted that most of these genomes are not chromosome length assemblies, although the recently released koala chromosome assembly (https://www.dnazoo.org/assemblies/Phascolarctos_cinereus, January 2021) has improved the 2018 assembly (Table 2). During the 17 y between the human genome being published (44, 45) and the chromosome-scale, haplotype-resolved assembly being released (46), the original genome exponentially changed human medicine and our understanding of Homo sapiens. As a result, the TSI Steering Committee has opted to fund long-read genome data [HiFi reads of PacBio Sequel II system (47)] with associated species-specific transcriptome data for more species to meet conservation needs, rather than focusing on producing chromosome-length assemblies for a few species. Project teams are encouraged to seek funding to facilitate chromosome-length assemblies in the future using HiC (48) technology. Appropriately collected and stored tissue samples are being archived where possible within Australian museum collections to ensure future assemblies use the same specimen (49).

Assembly features of Tasmanian devil (38), koala (39) and Hi-C scaffolded koala genomes (dnazoo.org)

Sampling requirements for high-quality genomes can be extremely difficult to meet for threatened species, particularly those that are listed as critically endangered (49, 50). Many long-read technologies require nonfragmented DNA, which is most easily obtained from tissue samples that are flash-frozen or freshly collected. While relatively large amounts of fresh, preferably young, leaves are required for the high molecular weight DNA extraction needed for assembling a plant genome, collecting leaf tissue for genotype by sequencing is less stringent and requires significantly smaller amounts of silica-dried tissue (and can even work from herbarium specimen). Given the static nature of plants, and the small population size of many of the most threatened species, sometimes most living individuals can be sampled (51). For animal species, however, collecting fresh tissue samples that need to be flash-frozen from cryptic species is more problematic. It is also impractical in a large geographic country like Australia 7.69 million km2, with a relatively small human population (25.4 million), where access to liquid nitrogen in remote locations is logistically challenging and transport networks from remote locations are limited, resulting in difficulties transporting samples to laboratory facilities in a timely manner. Furthermore, many Australian animal species are small, and so blood volumes greater than 100 to 500 L may not be achievable.

Although sequencing costs in the United States, Europe, and China are relatively low, the nature of distance and small turnover in other parts of the world means that discounted sequencing costs tend not to be available for many. Of the 17 megadiverse nations (2), the United States has the cheapest sequencing. To ensure the full value of genomic resources for the conservation of global biodiversity, it is important to invest in local conservation communities and empower them to develop resources within country. For many threatened and endemic species, sending samples to the United States, Europe, and China may be also be constrained by international (e.g., CITES) and national (e.g., United States Endangered Species Act; Australian Environment Protection and Biodiversity Conservation Act) biosecurity, trade regulations, and permit requirements. Furthermore, for many Indigenous and First Nations peoples the natural world, and their affiliation with it, holds cultural significance, meaning that movement of samples, or even extracted DNA, across international borders is often restricted. This brings to the fore potential issues with sampling and the Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from their Utilization (52, 53). Globally we need to embed indigenous principles into genomic research (36, 54), and be able to facilitate genome projects within nations, often where sequencing is not cheap. This requires us to rethink what kinds of genomes we are seeking to produce to effect change in conservation practice and ensure the genomic resources, and associated downstream tools that are created, are utilized to their full potential (50).

TSI is also producing supporting population genetic data (for up to 190 individuals) for species that require it to inform conservation management action (Fig. 3). This will not cover all the population genetic data that will be required for some species, but rather is a launchpad for coinvestment into using genetic data for conservation management. Reduced representation sequencing (RRS) has been selected for population genetic data, although it does have limitations for some population analyses, such as runs of homozygosity (RoH), identification of alleles within species genes, or effective population sizes. For these analyses, whole-genome resequencing (WGS) is needed but is also currently costly for many taxa with larger genomes (e.g., mammals, amphibians). Either double-digest RADseq (55) (ddRAD) or Diversity Arrays Technology (56) (DArTseq), have been selected as the sequencing methods of choice for TSI population genetics, as both are readily available within Australia from commercial providers and will ensure that the bioinformatic workflows are useful across the range of taxa to be undertaken in this project. Our current workflow can either align RRS data to a reference genome or be used de novo (57). Using species-specific transcriptome data to annotate the genomes allows for conservation managers to have access to functional data, particularly around gene families that are not conserved between species, such as the immune genes.

Components and the interoperable framework of the TSI. Currently, smaller working groups are supporting the development of workflows and protocols for sample collection and storage, bioinformatics, and standardized reporting.

To facilitate the long-term uptake of genetic data into population monitoring and management, TSI is also trialing the use of low-density SNP arrays, where reduced subsets of informative SNP loci identified through the above WGS and population genomic approaches are selected and optimized for high-throughput automated genotyping. SNP arrays can be flexibly designed to contain loci targeted to specific conservation applications: for example, to ascertain population structure and monitor neutral and adaptive genetic diversity (5860), assess parentage and kinship (61, 62), and monitor introgression/hybridization (63). Besides the initial investment in SNP discovery and multiplex primer design, downstream genotyping costs are highly affordable (e.g., MassARRAY iPlex system AUD$11 per sample per 50-plex) with minimal requirements for data analysis, making the routine genetic analysis of populations accessible to a wider array of end-users. Furthermore, SNP genotyping systems, such as MassARRAY, are suitable for application with noninvasive samples (scats, hair) (64), expanding the utility of the method in wildlife monitoring scenarios. We advocate for developing arrays and calling SNPs against reference genomes to ensure future use of the data as SNP locations will be known. As more high-quality reference genomes become available and sequencing costs reduce, WGS will become the norm. In the interim however, using RRS data aligned to a draft reference genome can permit a wide-range of conservation actions for a species [see Brandies etal. (11)].

A key aim of the TSI is to develop an online platform, an applied conservation genomics hub, to empower nongeneticists to be able to use these genomic resources in their conservation decision-making. The TSI is committed to developing such a platform (Fig. 3). The Hub will host protocols for sample collection and storage, in addition to a suite of existing analytical pipelines and workflows [e.g., STACKS (57), dartR (65), Sequoia (66)] with a user-friendly interface that has point-and-click options, rather than a command-line interface. The outputs from these workflows can be used to answer some of the most common conservation management questions (SI Appendix, Table S2). Users will be able to manipulate their data for their specific species, but the output report will be standardized, with different modules for different management questions. The report will be in a simple, consistent format to ensure that conservation practitioners are receiving the same information for their species in a standardized way so they can become familiar with summary methods for genetic data. Reports will include standard genetic metrics (such as heterozygosity, inbreeding, relatedness) in addition to an appendix with sequencing methods used, number of filtered SNPs, filtering used, and compute requirements for the datasets. Standardizing the reporting will assist with reproducibility over time. Users who are creating the reports will also have the option to add more outputs/variables if they so desire. By standardizing the output report, we aim to further promote the education of the conservation practitioners in the use of genetic data in the management practice and encourage the uptake of longer-term genetic monitoring in-line with the Convention of Biological Diversity targets (67, 68). This is perhaps TSIs biggest innovation, because while techniques can change and initial interpretations might be complex, once baseline genomic information is developed and there is standardized management reporting, cheap, effective, long-term monitoring tools can become a reality.

We fully recognize that this online platform and associated standardized reporting will not be a simple task to achieve, as there are many nuances in the interpretation of genetic data for management purposes. However, with the ever-widening gap between genome biologists and conservation practitioners, we need to develop solutions to bridge this divide. Not knowing how to interpret and use the information, nor how it is generated or who to contact, are a few of the reasons that have been flagged by conservation practitioners for why they are not routinely using genetic data in their management practice (28). The platform will be a living, iterative system, which we anticipate will start small and grow with time, use, need, and technological development. TSI has recognized that we need to start to fill this niche, as the gap between the genome biologists and the conservation practitioners is widening each year as the costs of sequencing reduce, bioinformatics becomes more challenging, and the need for genomic resources for conservation management increases.

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Threatened Species Initiative: Empowering conservation action using genomic resources - pnas.org