In genetics, genes are only half the story

In genetics, genes are only half the story

After the successful landing on D-Day, Allied Forces liberated the south of the Netherlands. But their efforts to liberate the rest of the country got stuck at Arnhem.

General Montgomery’s Operation Market Garden was intended to gain control of the bridge over the Rhine but it failed. Meanwhile the exiled Dutch Government, in an effort to help the Allies, had instigated a rail strike.

In retaliation for this defiance Germany placed an embargo on all food transport to the heavily populated western Netherlands. By the time this was partially lifted in November an unusually cold winter had frozen the canals which became impassable for barges.

The result was a severe food shortage. Desperate city dwellers ate grass and tulip bulbs, and went on hunger expeditions to the countryside to trade their valuables with the farmers for food.

‘My linens, all my silverware, my carpet, a Smyrna stair-carpet — I traded everything for food,’ recalled one.’ In the long run the farmers wouldn’t accept any more linen goods. Some of them even put up signs that said, “No more linen goods”.’

At the end of January the Red Cross brought in flour from Sweden and in April Allied planes dropped food parcels. But by then the Hunger Winter, as it became known, had claimed 20,000 lives.

But it is what happened next that is of interest to biotechnology. The Dutch survivors were a defined group and thanks to efficient maintenance of health records, epidemiologists have been able to follow the long term effects of this famine.

The children of women who were in late stage pregnancy during the famine tended to be small, which was no surprise.

However when these children grew up and had children of their own, they too tended to be small. The epidemiologists also found that the children of women who were pregnant during the famine were more likely to be obese, and to suffer from heart disease and other problems, and that these characteristics were also passed on to the next generation.

These consequences handed down from one generation to the next could not have been caused by changes in gene sequences which do not happen in such a short time.

Instead some factor must have interfered with the expression of the genes and this was passed on from one generation to the next. This was one of the first proofs of epigenetics. It showed that while our genes are the instructions for life, environmental factors can determine whether these instructions are acted upon.

Recent work has pinpointed a gene called IGF2. Children exposed to the famine during the first 10 weeks after conception had less DNA methylation (a sort of chemical muffler) of this gene than their unexposed same-sex siblings. By contrast, children exposed to the famine at the end of pregnancy showed no difference in methylation compared to their unexposed siblings.

A quick history of genetic science

The lesson of the Hunger Winter is just one of the milestones in the history of genetics described in ‘The Gene: An Intimate History’, by Siddhartha Mukherjee (who also wrote ‘The Emperor of All Maladies’, an excellent history of cancer and its treatment).

What is clear from his latest book is that our knowledge of gene function has accelerated rapidly since the 1970s. But curiosity about what makes us who we are goes a long way back. In the nineteenth century men such as Jean-Baptiste Lamarck, Charles Darwin and Gregor Mendel developed theories of evolution and inheritance.

But what was missing was the actual means by which the characteristics of one generation are passed down to the next. We know we resemble our parents, but exactly how do they transmit their characteristics to ourselves?

The Ancient Greeks had some ideas. In 530BC Pythagoras proposed that male semen carried all the hereditary information, while the mother only provided nourishment.

Two hundred years later Aristotle had a slightly different version, that the male semen contained the instructions for building a fetus while the mother carried the physical material. For over two thousand years we did not make much progress.

It was not until the early twentieth century that the Danish botanist Wilhelm Johannsen coined the word ‘genes’ to describe ‘units of inheritance’. He also came up with ‘genotype’ to describe an organism’s complete set of genes and ‘phenotype’ to describe its physical characteristics.

In 1944 the American physician Oswald Avery conducted experiments that proved that genes are contained within an organism’s DNA and then in 1953 Watson and Crick, with help from Rosalind Franklin and Maurice Wilkins, figured out the structure of DNA, the famous Double Helix. Complementary bases of Adenine, Thymine, Guanine and Cytosine on a sugar phosphate backbone are held together by hydrogen bonds in a conformation that makes possible the essential functions of regulation, replication and recombination.

Source: NHS National Genetics and Genomics Education Centre

From there it was soon discovered that three bases code for one amino acid, that the instructions of the DNA are transmitted via mRNA to make proteins, and while genes make proteins not all genes make proteins all of the time.

With the understanding that many diseases are the result of genetic defects there was huge interest in the Human Genome Project, which was launched in 1984 and made possible by the sort of DNA sequencing machines invented by Frederick Sanger.

The Human Genome Project did not in fact read the three billion pairs of DNA bases from one individual. Instead bits of the genome of several were pieced together to give a composite reference genome for researchers.

The project found that each gene consists of a long and not necessarily uninterrupted sequence of DNA, that we each have about 20,000 of these genes and that they are camouflaged within other stretches of DNA (known as introns) that were first considered to be junk, but are now thought to regulate the expression of the genes themselves.

What comes next?

We can now define physical outcomes, including diseases, by their underlying genetic basis and we can try to target genes and their ensuing RNA and proteins to create treatments.

There have been many notable successes. Women with mutations of the BRCA gene are much more likely to get breast cancer and can be treated accorcandingly.

Bubble boy syndrome has been successfully treated by gene therapy. Every day researchers uncover correlations between specific genes and outcomes.

The technology has advanced so rapidly that it is now reasonable to discuss editing the DNA of germ-line cells, thus determining the physical fate of future generations. And yet, as Mukherjee makes clear, we are still only at the start of our investigations into genes.

While we have uncovered many important connections, which you can find in the ‘Online Mendelian Inheritance in Man’ (www.omim.org), most diseases are the result of a network of genetic causes, while we also need to understand the epigenetic factors that govern the expression of genes.

There is a huge amount to do, but all over the world researchers are getting stuck in to the challenge. This is going to be a very major endeavor for a great many years to come, so if you are a shareholder in companies that are involved, such as Horizon Discovery, Oxford Biodynamics and Qiagen, I urge you to take the long term view.