Tag: genetic engineering

Genetic Databases Are Leaving Marginalised People out of Their Data

Calculating the risk for schizophrenia when using UK Biobank data is only accurate for white European populations – leaving, for example, Indians at a disadvantage.

Imagine this: you are a cash-strapped early-career health scientist, looking for your next big project. One day, you get your big break — the chance to study half a million people, and the freedom to focus on virtually any topic you like, from DNA mutations to blue cheese intake. Best of all, this study will cost you virtually nothing.

It’s easy to imagine that organisations like the UK Biobank make anything possible. Biobanks are huge repositories containing health, genetic, and demographic information from volunteers. Researchers look through the vast amount of data to find new health patterns and trends. There are few limits: you can analyse scans of volunteers’ hearts, infer their sexual behaviours, or study their reasoning skills.

Over 850 UK Biobank papers have been published, with new studies appearing in journals constantly. Studies so far have found results which could improve global health, such as a study showing that anyone, regardless of their genetic background, can reduce their risk of dementia with a change in lifestyle.

However, as promising as biobanks might seem, the data may tell only partial or even misleading stories.

Criticisms of the project include that the research coming out of the UK Biobank will only benefit certain people, and even then, the usefulness of the health associations found are under question.

Compared to the 2011 UK census, Black, Indian, Pakistani and Chinese participants are all underrepresented in the Biobank by at least one third. David Curtis, at University College London, tested whether this under-representation of ethnic minority groups has any impact on schizophrenia genetics research.

Also read: How Do We Stop Genetic Medicine From Perpetuating Inequality?

He found that calculating the risk for schizophrenia when using Biobank data is only accurate for white European populations. This means that in the future, white people could be offered genetic tests for certain health conditions, while other people could be offered incorrect or no testing at all.

This is because of the complex evolutionary history of humans. While humans who migrated out of Africa and settled in Europe faced bottlenecks where their genetic diversity was reduced dramatically, Africans have maintained large and diverse populations, and so have a more unique genetic makeup.

Other researchers are investigating the Biobank’s data as well. Na Cai, a statistical geneticist at the Wellcome Trust Sanger Institute and European Bioinformatics Institute, began thinking about how what gets put into the Biobank affects what conclusions come out of it, similar to Curtis’ study on schizophrenia.

In her study, currently a pre-print posted on bioRxiv, Cai and colleagues decided to focus on major depressive disorder. Depression is one of the most common mental health disorders, and has been a major topic of investigation in genetic association studies.

Because of this, Cai was concerned that researchers might not be investigating depression specifically, but instead looking at the genetics of poor mental health in general.

Cai defined depression in five different ways, using both strict and loose criteria. For example, some people might tell their doctor that they feel depressed, but not meet the specific psychiatric definition of major depressive disorder. She looked to see if the same genetic variants were associated with each different definition of depression.

The results were surprising. She found less of a genetic contribution towards all the “looser” definitions of depression compared to the full assessment used by psychiatrists.

Also read: DNA Sequencing Is Inadvertently Exacerbating Social Biases and Inequalities

First, it shows that researchers do not have the power in their studies that they assume they do. Previously, it was assumed that it didn’t matter too much if researchers defined depression loosely. It could be that these broader definitions are just milder cases of depression, or show less of a genetic association because more people in these groups are misdiagnosed, which dilutes the signal.

However, when the researchers controlled for these factors, nothing changed. The strict psychiatric definition of depression was still genetically distinct from these other versions, meaning that it had more genes associated with it, and there wasn’t much overlap in the genes which all the definitions did share.

A technician works at a genetic testing laboratory in China. Photo: Reuters

This throws into question whether papers which have found links between depression and genes are coming to the right conclusions. Are they finding a genetic basis for major depressive disorder, or are they showing something else — like the less specific genetic basis for poor mental health in general?

Both Cai and Curtis conclude that we need to rethink how we collect biobank data. Both issues are the result of design flaws present since the UK Biobank’s inception. Cai does not necessarily think all participants need to be assessed by a psychiatrist. She suggests that we use new technologies, such as computer assessments and smartphone behavioral tracking, to diagnose people with clinical depression.

But tackling the lack of diversity in biobank data requires those in charge to recognise that the current design excludes marginalised and hard-to-reach groups.

John Savill, the Chief Executive of the UK Medical Research Council, the organisation which provided major funding for the Biobank, was reported by the Guardian to say in response to Curtis’ research that “I do not think it is helpful to cast concerns over experimental design as ‘equalities issues’”.

Also read: Widely-Available Genetic Risk Tests Aren’t Always Useful – and Could Even be Harmful

However, David Heel, who is the Chief Investigator of the East London Genes & Health Project, which aims to improve the health of South Asian people in the UK, thinks that the UK Biobank’s recruitment tactic of mailing a letter meant British-Bangladeshi and British-Pakistani people missed out. When reached via email, Heel said that, in regards to volunteers in the project, “A much better response rate comes from a face to face discussion,” or “a trusted setting” such as talking at a doctor’s office.

Curtis also thinks more can be done, but is not optimistic that we can save the UK Biobank from this bias. He said “It may be too late to try to make the UK Biobank more representative. We may need to look to other initiatives…and to look to samples recruited in other countries.”

The article was originally published on Massive Science. You can read it here.

Is There More to Gene Editing Than Creating ‘Designer’ Humans?

It may have greater consequences than climate change or unleashing the energy of the atom.

Today, the scientific community is aghast at the prospect of gene editing to create ‘‘designer” humans. Gene editing may be of greater consequence than climate change, or even the consequences of unleashing the energy of the atom.

CRISPR is an acronym for Clustered Regularly Interspaced Short Palindromic Repeats. This is the immune system that bacteria developed to protect themselves from infections by bacteriophages — the most abundant life form on the planet.

Smaller than any known life form

Bacteriophages were discovered in Paris by Felix d’Hérelle at the Pasteur Institute in 1917. He was studying a subset of patients spontaneously recovering from dysentery. D’Hérelle proposed that an antimicrobe smaller than any known life form had killed the bacteria in infected patients. He demonstrated conclusively the existence of this new life form, and named them bacteriophages: viruses that attack bacteria.

Also Read: Study Finds Antibiotic Resistance Gene in Fresh Food Samples

The bacteriophage has been studied intensely: its beauty was revealed with the electron microscope and its genome was the first life form sequenced.

Responding to a bacteriophage attack

In 2007, Rodolphe Barrangou and Philippe Horvath of the food production company Danisco collaborated with Sylvain Moineau of Laval University to solve a long-standing problem in yogurt production. They asked: Why were bacteria that were essential for the production of yogurt and cheese susceptible to bacteriophage attack, and how could this be prevented?

Barrangou, Horvath and Moineau made the astonishing discovery that bacteria actually had an immune system.

CRISPR: Acquired Bacterial Immune Systems.

After an initial bacteriophage attack, a small number of surviving bacteria would recognize the DNA of the newly attacking bacteriophages. The surviving bacteria would then mount an immune response leading to the death of the bacteriophages. The bacteria that survived a phage attack would embed a fragment of bacteriophage DNA within their bacterial genome to serve as a “memory” of the infection.

Also Read: Explained: US Court Settles Bitter Gene Editing Patent Case, Confusion Lingers

Target and sever

Barrangou, Horvath and Moineau then discovered how the invading bacteriophages were eliminated. Upon recognition of the newly invading bacteriophage, the bacteria would target and sever the DNA of the invading bacteriophage.

Fond de recherche de Québec: CRISPR-Cas9 : L’origine de la découverte | Sylvain Moineau.

Biologists Jennifer Doudna and Emmanuelle Charpentier discovered further that “guides” had evolved in the bacterial immune system. Any bacteriophage whose DNA corresponded to the acquired memory fragment from a prior infection would be recognized and severed by a “guided” elimination machinery. Together, the bacterial immune system encompassing memory fragments of the bacteriophage DNA and the bacterial response machinery are known as the CRISPR-Cas9 system.

Commercial exploitation of the discovery followed. Doudna, Charpentier and others recognized that this new biological system could be exploited to edit genes in any life form.

Bozeman Science: What is CRISPR?

The CRISPR-Cas9 system is not the first gene-editing system to be discovered. The late biochemist Michael Smith, while at the University of British Columbia, was awarded a Nobel Prize in 1993 for the discovery of a chemical means of gene editing with applications relevant to cancer and other diseases.

UBC Science: The Legacy of Dr. Michael Smith.

Bacteriophages as a potential solution

D’Hérelle observed that the same bacteriophage isolated from patients recovering from dysentery could be used to protect rabbits from an otherwise fatal infection. Coming before the discovery of antibiotics, d’Hérelle’s discovery inspired Sinclair Lewis to feature bacteriophage therapy of humans in his Pulitzer Prize-winning novel Arrowsmith.

One of the largest collections of bacteriophages globally is at Laval University. Sylvain Moineau is the curator, and the collection is named after Felix d’Hérelle.

Also Read: The DNA Detectives Hunting the Causes of Cancer

The hope now is that bacteriophage therapy may be considered a potential solution to antibiotic resistance. However, any expectations of phage therapy are dwarfed by the current exploitation of the commercial benefits of the CRISPR-Cas9 system.

Today, the consequences of opening a Pandora’s Box are upon us. The application of the CRISPR-Cas9 system to generate designer humans through “germ-line” gene editing of harvested human eggs would create permanent changes that continue through successive generations, and the fears over these actions may be comparable to the consequences of nuclear warfare and climate change.

But there are other potential applications of “non-germline” CRISPR-Cas9, like the gene editing of disease. This has recently been successfully accomplished for muscular dystrophy in dogs. Akin to the myth of Pandora’s Box, the pessimism about “germ-line” gene editing may be offset by the hope for future benefit to humankind.

John Bergeron gratefully acknowledges Kathleen Dickson as co-author.The Conversation

John Bergeron is an Emeritus Robert Reford Professor and Professor of Medicine at McGill, McGill University.

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Whether by Stealth or Aggression, Viruses Get to Make a Meal of it

The molecular processes leading to such devastating human diseases are an extension of a fundamental paradigm represented by obscure bacteria-eating viruses.

This article is the second of a two-part series on viruses and bacteriophages. The first part was published on November 26.

Bacteria-eaters, genetic engineers, disease causers. Credit: Zappys/Flickr, CC BY 2.0

Bacteria-eaters, genetic engineers, disease causers. Credit: Zappys/Flickr, CC BY 2.0

A paper published by a London-based scientist of limited financial means named Frederick Twort in The Lancet on December 4, 1915, described the discovery of an infectious agent with the power to kill bacteria. Twort was not sure what this agent might be, but proposed that it could be “an ultra-microscopic virus (that) belongs somewhere in (the) vast field of life more lowly organised than the bacterium or amoeba”.

He was right in this conjecture, but in the absence of assuring evidence, wondered if “it (might) be living protoplasm that forms no definite individuals, or an enzyme with power of growth.” Most scientific endeavours are not complete and always leave room for more interrogations. Twort “regret(ed) that financial considerations have prevented my carrying these researches to a definite conclusion, but I have indicated the lines along which others more fortunately situated can proceed.”

Though Twort was employed in a clinical setting, this first known description of a virus capable of infecting and killing bacteria didn’t arise from a vision to discover antibacterial therapies or natural genetic engineers immediately usable for human betterment – but from Twort’s esoteric interest in discovering viruses that could not cause disease and to develop methods to grow viruses in the laboratory in the absence of host cells (“an unfortunate avenue of research”). Today, viruses which infect bacteria are referred to as bacteriophages – phagein being Greek for ‘devour’. They’re the viral elements that are responsible for the disease causing traits of many bacteria, though this was certainly not suspected 100 years ago.

As an aside, it’s believed that a mysterious anti-bacterial agent whose presence in the Ganges was reported by Ernest Hankin in the 19th century might in fact have been a bacteriophage, but the author didn’t report any such suspicions. This study appears to have its origins in the author’s curiosity about the manner in which the Ganges, uniquely worshipped by the locals and treated as a medium of purification but ridiculed by Europeans, might differ from the “equally cloudy” European rivers.

Anyway, the story of the discovery of the bacteriophage is not without its controversies. Another scientist, Felix d’Herelle, of probably greater fame than Twort given his professorship at Yale and medical explorations in different parts of the world, reported his discovery of the bacteriophage two years after Twort’s publication. In fact, d’Herelle was the one who had coined the term “bacteriophage”.

Leading up to the ‘phage group’

D’Herelle was probably unaware of Twort’s discovery though some suspect that he was not being honest in making this claim. Nevertheless, d’Herelle was also more sure of his identification of his infectious antibacterial agent as a virus. He performed significant work suggesting that growth in the numbers of bacteriophages in the body of a patient was correlated with a decline in the severity of the bacterial infection that the patient was suffering from. This suggests the use of bacteriophage in therapies against bacterial infections, a concept which had mixed success.

The French-Canadian also made a big stride forward in showing that a bacteriophage of a certain type was highly choosy in which bacterium it could infect; it could evolve and attain properties that enabled it to infect related bacterial varieties; but could not – within the scope of his experiment – gain the ability to infect a widely different variety of bacteria. This finding in fact resonates with today’s fears that a virus that causes disease in an animal could evolve to become a pathogen of humans (read: swine flu or bird flu).

Just like living with bacterial and viral pathogens is not doom and gloom for the human race, living with numerous predatory bacteriophages is not the end of the world for bacteria as a class of organisms. As everyone ultimately ends up co-existing. Just as we have immune responses to pathogens, bacteria carry their own molecular immune systems to counter predation by bacteriophages.

We’ve come a long way from the early 20th century in many ways, including in our understanding of bacteriophages, but this is the result of the intellect and toil of many. The most famous among these was a group of scientists known as the ‘phage group’. It was nucleated in the 1930s and 1940s in the United States by the physicist Max Delbrück, who was interested in understanding the fundamental aspects of life. Members of the group and their colleagues believed that bacteriophages – given their simplicity as “lowly organised” creatures, their rapid multiplication and ease of handling – would serve as a perfect ‘model system’ for studying the foundational features of life. The term ‘model system’ and its applicability to science and biology in particular deserves special treatment.

We don’t have the space to discuss all the contributions of the phage group and their illustrious contemporaries, not even all their major findings, so we’ll limit ourselves to select discoveries pertaining to the lead-up to our present-day understanding of bacteriophages as nature’s genetic engineers.

First: a crash-course of what was known by the 1920s. A bacteriophage, after entering its target bacterium and before killing it, exists in a noninfectious form. In other words, if a bacterium newly infected by a bacteriophage is broken up and its internal contents applied on other healthy bacterial cells, the bacteriophage from the now-broken bacterial cell wouldn’t be able to infect the healthy cells. This existence of the bacteriophage in a noninfectious form inside the host bacterium was called lysogeny. It was also known that bacteriophages comprised DNA and protein (though the now-accepted wisdom that DNA is the genetic material of most life forms was not known then).

Hit, run and transfer genes

In the 1950s, two scientists from the phage group, Alfred Hershey and Martha Chase, demonstrated that during the infection of a bacterium by a bacteriophage, the viral DNA was injected into the bacterium while the protein coat that surrounded the DNA in an intact virus was left behind. The finding contributed to our understanding of bacteriophage biology as well as the establishment of DNA as the genetic material. Since the protein coat is the equipment that the virus uses to attach to a bacterium, its DNA on its own turns out to be noninfectious and thus defining lysogeny. This, to the best of our knowledge today, is a universal truth behind bacteriophage-bacteria antagonism.

We also know that the DNA injected into the bacterial cell contains information that enables the virus to go through a complete infection cycle: hijack the host bacterium’s resources to replicate the viral DNA, produce viral proteins, assemble many viral protein coats, break the host bacterial cell and its DNA into pieces, and assemble many live viruses by packaging the newly replicated viral DNA into the newly produced protein coats. The account book at the end of the process will tell us that a single virus infecting a single bacterium will end up producing the broken remains of a dead bacterium and about a hundred viruses looking for more bacterial victims.

This process is essentially a hit and run mode of predation with manifold reproduction built in, and incorporates features that enables a virus to engineer bacterial chromosomes. How? Using classical and simple bacterial growth experiments, Norton Zinder and Joshua Lederberg at the University of Wisconsin showed in 1952 that bacteria harbouring a certain special property could transfer this trait to otherwise similar bacteria, not necessarily by direct contact as demonstrated previously by Lederberg and Edward Tatum in the 1940s, but through a small intermediate particle – which was shown to be the bacteriophage.

In other words, bacteriophages can mediate transfer of genetic material from one organism to another. Such experiments in gene transfer using what are called nutritional auxotrophs had earlier led to the establishment of  the ‘one gene, one enzyme’ hypothesis by Tatum and George Beadle, a cornerstone in the development of molecular genetics.

How does the hit-and-run mode of viral predation result in gene transfer? When, during the infection of a bacterium by a bacteriophage, the bacterial cell breaks open and DNA gets packaged into the viral protein coat, the virus makes mistakes. Sometimes, it ends up packaging pieces of the bacterial chromosome instead of its own DNA into its protein coat. In these defective bacteriophages, the protein coat makes sure that it can attach to other bacteria but the DNA that it injects into these bacteria does not encode features that enable the virus to reproduce and kill the bacterium. Instead, this DNA of bacterial origin gets integrated into the host chromosome, and if many consequent events add together nicely, ends up introducing a new trait to this host bacterium.

Clearly, this trait transfer is not part of the normal reproduction of a parent to give progeny, and so represents an instance of horizontal gene transfer. In this mechanism, any piece of DNA can be moved around but only between very closely related bacteria. The constraint emerges from the limitation of the bacteriophage in being able to infect only a small set of closely-related bacterial varieties, a finding that can be traced back to d’Herelle. For example, it will have the ability to transfer a virulence trait from a bacterial pathogen to its benign relative.

Under controlled laboratory conditions, we can use manipulative techniques to observe such gene transfer events, as was done by Tatum and Lederberg. However, its true ecological impact might be tricky to estimate because in nature it rarely leaves a detectable signature on recipient chromosomes.  

Viruses in stealth mode

Yet another mode of bacteriophage-mediated genetic engineering of a bacterium is even more devious.

Experiments reported in 1956 by Lederberg, his wife Esther, and Melvin Morse showed that a type of bacteriophage dubbed lambda could also mediate gene-transfer. However, this lambda bacteriophage was able to transfer only a limited set of traits, and not all and sundry as resulting from the hit-and-run mode of gene transfer. This, further supported by later experiments by June Rothmann, Allan Campbell, Sankar Adhya and others, indicated that the lambda DNA was physically linked to the bacterial chromosome and also established that this linkage deterministically occurred at a specific site on the host chromosome.

In fact, the lambda DNA becomes part of the bacterial chromosome. It replicates along with the host chromosome and does not kill the host cell unless induced to do so. The presence of the DNA of such viruses can be easily identified in the genome sequence of a bacterium hosting it. Therefore, we can retrospectively identify traits conferred on a bacterium by a virus via this mechanism. The part of the source bacterium’s DNA that lambda is able to transfer to a second recipient bacterium is always the segment that is immediately adjacent to the site at which lambda DNA gets integrated.

The induction of lambda to kill its host is fascinating in itself, and its study has played a central role in establishing paradigms for how cells decide which proteins to produce when. Though killing off the host bacterium by a lambda is necessary for it to transfer genetic material from one bacterium to another, we will deal with this fantastic chapter of molecular biology in a separate instalment in this series.

Genetic engineering by bacteriophages such as lambda, which are capable of integrating with the host chromosome, isn’t limited to what they can transfer from one bacterium to another. The DNA of these viruses themselves carry many genes as a result of their long histories of mixing and matching their DNA with other viruses and bacteria. At times these genes might deliver beneficial and novel traits to the source bacterium. Thus, the integration of such viral DNA into the host chromosome can immediately give a novel characteristic to its host organism. The conferment of the ability to produce the disease-inducing toxin to Vibrio cholerae by a bacteriophage illustrates this. The bacteriophage DNA integrated into the host chromosome might never get induced to kill its host, and over time even lose the ability to do so, thus becoming an integral part of the host!

In the human context, the genetic material of HIV gets integrated in the human chromosome, stays there and secretly gets itself replicated alongside the human chromosome during the long latency period between infection and the expression of symptoms. Similarly, the integration of the DNA of human papilloma virus into the human genome plays a role in the series of consequent events that culminate in cervical cancer. The molecular processes leading to such devastating human diseases are an extension of a fundamental paradigm represented by obscure bacteria-eating viruses, first discovered and studied in the early to mid 20th century by a motley group of researchers searching for some basic truths of life.

Aswin Sai Narain Seshasayee runs a laboratory researching bacterial biology at the National Centre for Biological Sciences, Bengaluru. Beyond science, his interests are in classical art music and history.

Why Genetic Engineering is Stranger Than You Think it is

Genetic engineering and horizontal gene transfer are phrases that have been used with delight by scare-mongers with limited appreciation of subtleties essential to their understanding.

There are not too many words in the scientific vocabulary that have made it to the wordbook of the general public. This month’s column comprises two such phrases from the world of the life sciences which have captured the public imagination. Even if the phrases themselves may not always be familiar, their definitions have made a mark in popular depictions of genetics and the life sciences. These phrases are “genetic engineering” and “horizontal gene transfer”, which are being bandied about routinely in popular literature in medical and environmental contexts.

Often, these phrases have been used with delight by scare-mongers, with limited appreciation of subtleties essential to their understanding and application. They in fact merit a discussion on their meaning, and I’ll use examples where these terms imply processes and phenomena of public interest. It’s not a bad time to raise this issue: it’s been 100 years since a chap called Frederick Twort reported the discovery of a virus that infects and at times “engineers” (rather tinkers with) the genetic material of the infected bacterium.

Genetic engineering

First, the term “genetic engineering” typically refers to a precise, artificially introduced modification of the genetic content of an organism. Usually, the outcome of a genetic engineering experiment – in terms of which piece of genetic material is introduced and where – is predictable thanks to decades of fundamental research into cellular processes involved in genetic modification. At least more predictable than genetic modifications introduced by complex breeding crosses or random generation of mutants, followed by the selection of progeny with desired traits. Even more predictable than the variation in genetic material between the parents and progeny of sexually reproducing organisms such as humans.

In a genetic engineering experiment, an artificially constructed piece of DNA, the chemical entity that forms the genetic material of most known organisms with the exception of certain viruses, of a definite composition is introduced into a recipient cell. In many instances, this piece of DNA is not entirely artificial but is part of the natural genetic material of some organism or the other, but does not quite serve the engineer’s purpose in its natural home. In some applications, this piece of DNA exists as an autonomous unit, out of ‘contact’ with the rest of the host’s genetic material, which is composed of what’s called the chromosomal DNA or simply the chromosome. Here, the introduced DNA is referred to as a plasmid. In some situations, the host cell can lose the plasmid. This typically happens when the replication of the plasmid, which is independent of that of the essential host chromosome, is imprecise: certain progeny may not receive the plasmid, and if this subpopulation of cells are able to grow and divide faster than their siblings carrying the plasmid, it’s only a matter of time before the population of cells is dominated by the subset without the plasmid and we’re back to square one.

Such spontaneous loss of the introduced DNA is considerably less likely if it doesn’t exist as a plasmid but is in fact integrated into the host chromosome, something we can do routinely in many contexts today. It’s plausible that many concerns related to the subsequent transfer of an engineered piece of DNA into unanticipated hosts would also significantly diminish when it is introduced into the host chromosome. Genetic engineering does not refer exclusively to the addition of a new piece of DNA into a cell but also to deletions and other modifications of the endogenous DNA of the host cell. But this is beyond the scope of this article.

We’ve already said many things about chromosomes, plasmids and genetic engineering, but there’s an important question that needs answering here. How much of new DNA gets added to the host in a typical genetic engineering attempt? The chromosome – or the endogenous genetic material – of ‘famous’ bacteria such as Escherichia coli or Mycobacterium tuberculosis comprises about 4-5 million alphabets; that of the brewing yeast about thrice as much; and that of you and me about 1,000 times as much. The 4-5 million alphabets comprising the genetic material of the E. coli and M. tuberculosis bacteria can be divided into 4,000-5,000 functional units known as the genes. This relation of 1 gene per 1,000 alphabets does not quite hold for more complex organisms like us, but that’s for another day.

Anyway, a plasmid that is introduced into an E. coli cell, a famous tool for genetic engineering, is about 0.1% or 1 in a 1,000th of the size of its chromosome. Thus, most genetic engineering attempts involve a relatively modest modification of the host genome.

Horizontal gene transfer

Horizontal gene transfer is a form of genetic engineering that usually refers to a phenomenon that happens routinely in nature. Many organisms, chiefly bacteria, can ‘eat’ DNA from their environments. In most situations, they don’t like the DNA they eat and manage to get rid of them. In fact, many organisms have powerful defence mechanisms that prevent themselves from being invaded by foreign DNA while others are more inviting of these tourists. In other situations, a bacterial population that carries this DNA scores over its contemporaries, and so natural selection favours the maintenance of this DNA. As in the case of a genetic engineering experiment, these pieces of DNA can either stay as plasmids or get integrated into the host chromosome. The extent of genetic engineering that a horizontal gene transfer event can cause can vary from a few genes to several tens of genes that make up the complete genetic material of certain viruses.

What can get horizontally transferred, and who can transfer to whom, is also an important question. A naturally occurring plasmid that’s floating around in the environment can be transferred into a single-celled organism if the prospective host is capable of importing it. It’s a lot harder for segments of chromosomal DNA to be transferred this way, except by direct contact between the donor and the recipient cells or by intermediates such as certain viruses. All of these present powerful constraints to gene transfer. A single-celled organism can, by direct contact, transfer pieces of genetic material to another, if it has the right molecular machinery to do so.

Next month, we’ll see how viruses enable horizontal gene transfer and how this contributed to the development of molecular biology and biotechnology!

Relevance to genetically modified food

Both genetic engineering and horizontal gene transfer are subjects of public debate. Various microorganisms can be genetically engineered to produce molecules, including drugs, of our interest by introducing the necessary genes into them. This is done in industrial practice under carefully controlled and contained environments. Horizontal gene transfer is a major mode of spread of antibiotic resistance in bacterial populations. For the moment, it suffices to know this fact and we’ll discuss this phenomenon in greater detail in a later installment of this series. It’s also a mechanism by which certain bacteria acquire traits that make them virulent. In fact, horizontal gene transfer may be a major mechanism by which bacteria evolve. However, the extent to which this influences a multicellular organism like a human is debatable but certainly much less than in single-celled bacteria.

A contentious area of social relevance that involves both genetic engineering and horizontal gene transfer is GM crops. While it’s probably correct – especially in the face of incomplete knowledge – that the release of a genetically engineered organism including plants into the environment should be carefully regulated and subject to extensive testing, certain arguments against the use of such plants need to be critically evaluated. One argument is the unpredictability of a genetic modification. Another is the possibility of horizontal transfer of the introduced gene to humans.

As we’ve already seen, the outcome of a precise genetic modification is more predictable than exercises in crossing and breeding, a cornerstone of our agricultural practice over hundreds of years. Next, what are the chances of a novel gene present in our (cooked) food entering into our genetic material and causing disease, or be transmitted to our children? This can’t be a lot more than such events happening from the 1,000 trillion non-human, microbial inhabitants of each adult human body! To put things in perspective, living among a zoo of microbes, many of which are in persistent and intimate contact with our cells and with the potential of throwing out DNA, primates have incorporated probably a few tens of foreign genes over the million years of their evolution, and hardly any in recent millennia!

It’s also important to realise that the mere acquisition of a piece of foreign DNA – which is somehow depicted as being “unnatural” – does not necessarily result in an adverse effect on the recipient. And it is a fact that many (if not all) ‘non-GM’ crops have had their chromosomes genetically modified without human intervention by horizontal transfer of genes from infecting viruses! We do not stop eating in any case.

A brief history

Before we conclude this instalment of this series of articles, let’s trace the origins of the discovery of horizontal gene transfer as a mechanism of trait innovation. This can be safely credited to a quiet epidemiologist of the early 20th century called Frederick Griffith. He believed that effective control measures against infectious diseases could be taken only when armed with an understanding of the types of pathogenic bacteria that could be isolated from epidemics. Toward that goal, he was working on variants of the bacterial pathogen Streptococcus, which causes pneumonia (also referred to as Pneumococcus). Some variants of this bacterium cause disease and others do not.

Griffith reported in 1928 that when a heat-killed disease-causing variant of this bacterium was mixed with live but benign versions of the same bacterium, the benign acquired disease-causing traits. This resulted in the conclusion that certain material from the dead bacterium was transferred to the live variants, resulting in a new trait. In retrospect, we’ve come to appreciate the contribution of luck in major scientific discoveries. Not all bacterial types do a good job of taking in and utilising naked DNA from their environment, and today we know that Streptococcus happens to belong to the subset of bacteria which can. Had Griffith’s work been on bacteria of other types, he might have never made this discovery. Later experiments by Avery, Macleod and McCarty showed in 1943 that the material that was transferred was likely to be DNA.

Thus, the discovery by Griffiths was epoch-defining, not merely within the scope of describing a phenomenon or informing control measures against epidemics but also in its future impact in enabling us to learn that DNA is indeed our genetic material, and subsequently establishing the molecular basis of heredity and the continuity of life.

Aswin Sai Narain Seshasayee runs a laboratory researching bacterial biology at the National Centre for Biological Sciences, Bengaluru. Beyond science, his interests are in classical art music and history.