CRISP(e)R babies and human genome

A Chinese researcher has claimed that he has created the first genetically-engineered babies using a gene-editing technique called CRISPR. CRISPR or CRISPR-cas9 edits or makes changes in Deoxyribonucleic Acid (DNA), also called the ‘thread of life’.

Why should editing the DNA cause such a furore in the scientific community? In size, DNA is insignificantly small. It is present in the cells of the body and its function is to code for all the proteins of the body. The skin, brain, eyes, stomach — every component of the body is made up of different proteins in different permutations and combinations.

Proteins form the very basis of life. Growing up, walking, breathing, digestion of food — all these activities and many more are controlled by proteins. The muscle, for example, would have about 10,000 different proteins. These proteins interact with each other with unsurpassed precision; their activity manifests in Priya Varrier’s wink as well as in Donald Trump’s frown.

Now, if one considers that the DNA in the cell ‘codes’ or guides the body in the manufacture of proteins, the functional importance of DNA automatically assumes mammoth proportions. If the DNA does not function properly, the result would be a wrong protein. This is exactly what happens in genetic diseases like Downs syndrome and Thalassemia. The DNA is ‘turned on’ to manufacture a protein and ‘turned off’ when the protein is no longer required.

In short, DNA produces proteins. But how does the body know when to manufacture a specific protein? For example, if the blood has an adequate amount of haemoglobin (the oxygen-carrying protein in the red blood cell), why should it manufacture more haemoglobin? The answer lies in the capacity of the cell to turn on and turn off genes with exquisite control so that only required proteins are synthesised.

For example, during the process of growing up, the coding DNA synthesises proteins until the body has five fingers. The genes coding for the proteins which would synthesise fingers is then turned off so that a sixth finger is not created.

So, do we know all about the human genome and its functioning? The Human Genome Project was a research project which was to determine the DNA sequences in the human genome from both a physical and a functional standpoint.

Although the Human Genome Project has accurately mapped the genes and extrapolated that data to the proteins which are coded by those genes, there are still several gaps in our knowledge. Genes constantly interact with each other and with the non-coding sites in the DNA molecule. It is difficult to translate the genetic code of the DNA to the final protein product since there are so many variables between the cup and the lip.

This concept is best explained by mathematics. Imagine a 2 x 2 table where you have the numbers 1 and 2 on the horizontal axis and the alphabets a and b on the vertical axis. The possible combinations are 1a, 1b, 2a and 2b. You can also have 1a + 1b, 1a + 2b and so on, giving a total of 15 possibilities.

Now, imagine a situation where there are 20,000 genes on a horizontal axis which interact with another 20,000 genes on a vertical axis. The number of possible combinations is mindboggling. Going one step further, imagine that it is not just one gene on the horizontal axis which would interact with a second gene on the vertical axis. Multiple genes could interact with each other in varying combinations. The number of options defies imagination.

Let’s come back to the gene-splicing experiment which was performed by Dr He Jiankui. He claims to have edited a gene in an embryo which he believes would provide the baby protection against HIV infection in the future. He removed or spliced out a portion of the genome of the embryo and replaced it with a sequence which would prevent HIV infection in the individual. The implication of his achievement is no doubt staggering. However, by changing one portion of the genome, would some other portion be affected? We really do not know.

A recent paper published in ‘Nature Biotechnology’ by Kosicki, et al, has outlined the problems in CRISPR technology. They state that “…there are significant on-target changes such as large deletions and more complex genomic rearrangements at the targeted sites…”.

This translates to the fact that editing a small portion of the genome could translate to other unexpected changes. These changes maybe localised to the same portion of the genome which has been edited or could occur in an area of the genome which is far removed from the targeted site. Considering that the human genome has more than three billion base pairs, the difficulties associated with identifying such undesirable changes are enormous.

If you reverse a telescope, you get a microscope. The secrets of the human genome are no less difficult to interpret than the secrets of outer space. DNA first appeared on this earth about four billion years ago. DNA has been constantly evolving ever since.

The earliest reference to CRISPR technology is about 30 years old. The comparison is obvious. Perhaps, humanity would do well to wait until the technology is established; playing with technology which has not been completely established may boomerang on the human race.

(The writer is a Senior Consultant, Surgical Pathology and Molecular Diagnostics, Neuberg Anand Reference Laboratory, Bengaluru)