Genetic testing is all the rage, but its promise is limited

New technologies often take decades to reach Indian shores. Not so in the case of genetic testing. Within 10 years of the launch of the world’s first direct-to-consumer service, genetic testing has found a booming market in India.

Your DNA, unless you have an identical twin, is unique. The idea behind any genetic test is to understand whether the sequence of bases in your DNA have something useful to tell you. Those on offer in India can cost anywhere from ₹1,000 to ₹50,000.

Who’s your daddy?

One of the most popular genetic tests in India is used to test paternity. Be it a doubting husband or a long-lost son, these “peace-of-mind tests” can set the record straight. Their effectiveness is so high that Indian courts have used paternity tests as definitive evidence. Take the example of Congress politician ND Tiwari. In 2008, 28-year-old Rohit Shekhar claimed that Tiwari was his biological father. After a long-drawn battle, the court ordered a paternity test in 2012 and closed the case in favour of Shekhar.

This is how paternity testing works. A child inherits half their DNA from each parent. For the test, DNA samples in the form of cheek swabs are taken from all three individuals. These samples are then treated with restriction enzymes, which cut each DNA at pre-determined places. These cut-up pieces are then suspended in a solution and run through a gel, which lets shorter pieces run faster than bigger pieces. The pieces show up as dark spots on a light background. If the parents are indeed those making the claim, the child’s DNA patterns will appear to be a combination of the patterns of the parents.

This technique, called DNA fingerprinting, was developed in 1984 and has also been used to produce forensic evidence in thousands of criminal cases. Instead of comparing a DNA sample of a child with two others, say, it could be used to compare DNA found in some hair at a crime scene with that of the accused perpetrator.

Not the oracle

Not all genetic tests are so effective at giving useful information though. Many companies market genetic test results as a fortune-telling scroll. They claim that, based on your genetic information, they can predict whether you will get a disease or not. This is far from the truth. At best, genetic testing for health outcomes can be seen as a weather map, where predictions can be true but quite often they aren’t.

Even if genetic testing companies make this clear in their fine print, they haven’t done enough to correct public perception. For instance, a 2010 European survey revealed that nearly half of those asked felt “all children will (soon) be tested at a young age to find out what disease they get at a later age”.

While certain diseases, such as Huntington’s disease, have specific genetic mutations to blame, most diseases are a combination of environment, lifestyle and genes. There is no “gene for breast cancer”. Genes are indeed powerful, and they influence our appearance, intelligence, behaviour and health. But unlike what the public believes, genes do not determine those outcomes.

These public beliefs matter because they can and will affect policy. After 13 years of debate, in 2008 the US passed the Genetic Information Non-discrimination Act to ensure that insurance providers do not discriminate customers based on their genes. Before the genetic testing market in India explodes to ₹800 crores by 2018, as some predict, we need a similar act to safeguard people’s privacy. And even after that, treat any genetic test results with skepticism and care.

First published in Lokmat Times.

Gene therapy

A technique intended to eliminate mitochondrial diseases would result in people with three genetic parents

Is it possible for a child to have three parents? That is the question raised by a paper just published in Nature by Shoukhrat Mitalipov and his colleagues at Oregon Health and Science University. And the answer seems to be “yes”, for this study paves the way for the birth of children who, genetically, have one father, but two mothers.

The reason this is possible is that a mother’s genetic contribution to her offspring comes in two separable pieces. By far the largest is packed into the 23 chromosomes in the nucleus of an unfertilised egg. In that, she is just like the child’s father, who provides another 23 through his sperm. But the mother also contributes what is known as mitochondrial DNA.

Mitochondria are a cell’s power-packs. They convert the energy in sugar into a form usable by the cell’s molecular machinery. And because mitochondria descend from a bacterium that, about 2 billion years ago, became symbiotic with the cell from which animals and plants are descended, they have their own, small chromosomes. In people, these chromosomes carry only 37 genes, compared with the 20,000 or so of the nucleus. But all of the mitochondria in a human body are descended from those in the egg from which it grew. The sperm contributes none. And it is that fact which has allowed doctors to conceive of the idea of people with two mothers: one providing the nuclear DNA and one the mitochondrial sort.

The reason for doing this is that mutations in mitochondrial DNA, like those in the nuclear genes, can cause disease. These diseases especially affect organs such as the brain and the muscles, which have high energy requirements. Each particular mitochondrial disease is rare. But there are lots of them. All told, there is about one chance in 5,000 that a child will develop such an inherited disease. That rate is similar, for example, to the rate of fragile-X syndrome, which is the second-most-common type of congenital learning difficulty after Down’s syndrome. Mitochondrial disease is thus not a huge problem, but it is not negligible, either.

New batteries, please

To find out whether mitochondrial transplantation could work in people (it has already been demonstrated in other species of mammal) Dr Mitalipov collected eggs from the ovaries of women with mutated mitochondria and others from donors with healthy mitochondria. He then removed the nuclei of both. Those from the healthy cells, he discarded. Those from the diseased cells, he transplanted into the healthy cells. He then fertilised the result with sperm and allowed the fertilised eggs to start dividing and thus begin taking the first steps on the journey that might ultimately lead to them becoming full-fledged human beings.

Nearly all of the experimental eggs survived the replacement of their nuclei, and three-quarters were successfully fertilised. However, just over half of the resulting zygotes—as the balls of cells that form from a fertilised egg’s early division are known—displayed abnormalities. That compared with an abnormality rate of just an eighth in control zygotes grown from untransplanted, healthy eggs.

This discrepancy surprised—and worried—Dr Mitalipov. The abnormality rate he observed was much higher than those seen when the procedure is carried out on other species. That, though, could be because this is the first time it has been attempted with human eggs. Each species has its quirks, and if mitochondrial transplants were to become routine, the quirks of humans would, no doubt, quickly become apparent. With tweaks, they could be fixed, Dr Mitalipov predicts.

However, turning this experiment into a medical procedure would be a long road, and not just scientifically. Dr Mitalipov has little doubt that his zygotes could be brought to term if they were transplanted into a woman’s womb. That experiment, though, is illegal—and, in the view of some, rightly so. But the fact that it now looks possible will surely stimulate debate about whether the law should be changed.

Two kinds of question arise. One kind is pragmatic: would the process usually work and, if it did, would it always lead to a healthy baby who would have a normal chance of growing into a healthy adult? The second kind of question is moral, for what is being proposed is, in essence, genetic engineering. Not, perhaps, as classically conceived because no DNA is artificially modified. But it is engineering nevertheless. And that might worry some people.

On the first kind of question, the auspices are good. When Dr Mitalipov tested his zygotes, he could find no trace of mutated mitochondrial DNA in them, so the purpose of the procedure seems to have been achieved. And an experiment on monkeys that he began three years ago has produced four healthy offspring that are not apparently different from any other young monkey of their age. These are preliminary results, but they are encouraging.

It is on the moral questions that things may stumble. There is no consensus. Some people oppose such genetic tinkering in principle. Some worry about the consequences of a third adult being involved in the traditionally two-person process of parenthood—though the mitochondrial contribution is restricted to genes for energy-processing proteins and is unlikely to have wider ramifications on, say, family resemblance. Some worry that three-parented individuals may themselves be worried by knowledge of their origin. But until recently such questions have been hypothetical. Now they are real. In September, for example, Britain’s Human Fertilisation and Embryology Authority, which deals with such matters, launched a public consultation to discuss the ethics of creating three-parent offspring of the sort Dr Mitalipov proposes. This consultation runs till December 7th and the results will be given to the government in the spring.

In the end, whether three-parent children are permitted will probably depend on the public “uggh!” factor. There was once opposition to in vitro fertilisation, with pejorative terms like “test-tube baby” being bandied about. Now, IVF is routine, and it is routine because it is successful. In the case of mitochondrial transplants what will probably happen is that one country breaks ranks, permits the procedure, and the world will then see the consequences. If they are good, you will never find anyone who will admit to having opposed the transplants in the first place. If they are bad, the phrase “I told you so” will ring from the rafters.

First published in The Economist. Also available in audio hereThis article also had an editorial that ran with it.

This story was mentioned on the cover page of the print issue and made it to the front page of  Reddit and Digg, receiving over 250,000 views in two days.

Image credit: The Economist

Genetic medicine

A new technique to help cure mitochondrial diseases should be permitted by the law

In September Britain’s Human Fertilisation and Embryology Authority launched a public consultation on what sounds like a crackpot idea: to create children with three genetic parents. Yet this could be a way to eliminate a set of rare but nasty diseases caused by problems with pieces of cellular machinery called mitochondria. According to research published this week (see article), the basic technique of substituting problem-free mitochondria has now been tested in a laboratory and the researchers seem confident that, given the green light, they could bring a healthy child into the world.

Most of a child’s genes would come from the couple it would learn to call mum and dad. A tiny fraction of the DNA, however, would come from a female donor who would provide part of the egg from which the child grew. At present the law in Britain, like that in most other places, prohibits any genetic modification of embryos. It should be changed.

An in-gene-ious idea

Mitochondria turn the energy in sugar into a form a cell can use, so if they go wrong the consequences are dire. The brain, the nerves and the muscles, all huge consumers of energy, are the organs that suffer most. Mitochondria are also special, because they contain their own genes, completely separate from those in the cell nucleus, which are thus transmitted from mother to child in the egg.

Some mitochondrial disease is caused by mutations in these genes and is thus also inherited solely from the mother. Such diseases affect one person in 5,000 during his or her lifetime. But the separateness of mitochondrial genes means that by moving the nucleus from an afflicted egg into a healthy one, the mutated, disease-causing genes can be left behind. In effect, the nucleus would receive a mitochondrial transplant.

This incorporation of the DNA of two women might be seen by the nervous as a step down the slippery slope towards the genetic engineering of people. But that is unlikely.

The principal worry about genetic engineering is that it will lead to “designer babies” with customised DNA. But mitochondrial transplants involve no tinkering with the DNA itself. Though on a microscopic scale, the process is quite like a heart, liver or kidney transplant, with the caveat that the transplant will be passed on to the recipient’s children, if she is female. Any organ transplant introduces new genes into the body. Mitochondrial genes are ubiquitous, it is true, but this difference is one of degree, not kind.

Another reason not to worry is that the mitochondria carry only 37 genes, compared with about 20,000 in the cell nucleus, and these genes are exclusively concerned with energy metabolism. Pushy parents will not be picking mitochondrial donors on the basis of looks, personality or intelligence.

Non-biological objections are sometimes raised as well. Some worry, for instance, that a person with three genetic parents might suffer an identity crisis. But that seems less likely than in the case of people conceived by in vitro fertilisation using sperm donated by strangers who have contributed half of their offspring’s genes, not a paltry three dozen. And for that reason mitochondrial donors are even less likely than sperm donors to want to be involved with bringing up children in whom they have but a fractional genetic interest.

But is the process safe? Doing the experiment is the only way of finding out. It should be preceded by a lot of tests in Petri dishes and laboratory animals. But in the end, you just have to try it and see.

First published as a Leader in The Economist. Also available in audio hereThis editorial also had an accompanying article with it.

Free image from here.

Beating nature at its own game

It was 150 years ago that Charles Darwin first showed to the world that nature makes subtle changes in species, and passes them onto future generations. The ones that help the species survive get passed on. The others die with the unfortunate. It wasn’t until 1944 that DNA was identified as the carrier of those traits. Following these critical discoveries, scientific research has enabled man to do what nature does, sometimes beating it at its own game.

Beating nature at its own game – Roundtable Review, 29 May 2012

How does epigenetics shape life?

Identical twins, despite being biologically identical at birth, grow up to become unique individuals. Sure they may have a lot more things in common than two randomly picked individuals, yet there are many characteristics which belong only to one or the other. If the twins have the exact same DNA, then what is that makes them different?

The common answer to this question is it’s the environment that they live in which shapes them differently. Researchers have found that such environmental factors cause chemical modifications to the genome without affecting the nucleotide sequence, leading to the unique characteristics that we observe. This field of research is called epigenetics, and beyond the DNA, it’s what shapes our lives.

Rat mothers nurture their pups by licking and grooming. Researchers in Canada studying epigenetic changes found that rats whose mothers licked them more than normal expressed hundreds of genes differently from those who were licked less than normal. These differences were consistent and predictable, and led to a number of behavioural changes among the rats, including one where highly licked rats’ response to stress was a lot better than the less‐licked rats’.

Epigenetic changes don’t just occur through environmental factors but are also a different form of inheritance, one that doesn’t have to suffer from the randomness of natural selection. The licking of the rat encodes specific information onto her pup’s DNA without modifying to the sequence of base pairs. Mom’s behaviour programs the pup’s DNA in a way that will make it more likely to succeed. Such information is stored in the DNA in many ways, one of which is through DNA methylation. Through this process methyl groups are attached on to the DNA, and their attachment at specific positions leads to genes being turned on or off. This makes epigenetic changes reversible. For example, you can take a low‐nutured rat, inject its brain with a drug that removes methyl groups, and make it act like a high‐nurtured rat.

DNA methylation also plays a key role in cell division and cancer cells are known to divide faster than normal cells. Researchers in the US have developed drugs to interfere with DNA methylation as a treatment for cancer. They use molecules that mimic cytosine, one of the four bases of DNA. In cell replication, the fake cytosine swaps places with real cytosine in the growing stand of DNA, which then in turn traps DNA methyltransferase. When used in low enough doses, the drug allows the formation of the cell but with less methylated DNA. These drugs are currently being used to treat myelodysplastic syndrome, a prelukemia condition.

As Brona McVittie says, like the conductor of an orchestra controls the performance of musicians, epigenetic factors govern how the cell plays the notes in DNA. A better understanding of these factors has the potential of revolutionising evolutionary and developmental biology, thus affecting practices from medicine to agriculture.

Further reading:

  1. Learn Genetics, The University of Utah
  2. Introduction to epigenetics from Science magazine
  3. More ways to fight cancer through epigenetics, The Economist
Image credit: SciShark

Elements of Life

As far as we know, there are very few planets in the universe which are just like our planet Earth. The elements it is made from have played a critical role in allowing life to exist here.  However, there may be planets out there whose composition is very different. There is a huge range of possibilities – perhaps there is no oxygen, only sulfur or very little phosphorus but a lot of arsenic. Could life exist on such planets? Scientists have thought about this question for decades. To answer it, we need to understand more about DNA, the molecule of life, the elements it is composed of and consider the results of some unusual experiments.

The elements of life – InfoChem, November 2011 Issue

Molecular decorators

US Researchers have harnessed enzymes hidden in the genomes of soil bacteria to modify a natural antibiotic molecule in ways that would be difficult or impossible by traditional synthesis. The technique could be applicable to other families of molecules, providing easy access to a huge variety of complex molecules.

Mining soil DNA for molecular decorators – Chemistry World, 21 October 2010