Is DNA splicing – the biggest breakthrough since antibiotics?

For those of us lucky enough to have been in our late teens or early twenties during the 1980’s nothing can have been more shocking or frankly frightening than the UK government’s AIDS awareness campaigns.  Hard hitting (for the time), the adverts featured funereal images including tombstones, lilies and coffins. All had the stark message, AIDS: Don’t die of ignorance

aids

1980’s Don’t die of ignorance campaign

The messaging within these adverts was equally shocking, making it very clear that this illness was incurable and would lead to death. Little was held back in terms of the danger HIV and AIDS posed to the nation’s health. In short, they were designed to scare the bejeezus out of you and did a very good job of doing just that.

 

For a period of time in the late 1980’s and early 1990’s, the HIV virus was a terrifying spectre hanging over everyone but focused particularly on gay men, sex workers and intravenous drug users. Many of these groups were seen as bringing the disease on themselves by their lifestyles. Funding for HIV research was challenging, having to overcome a ‘worthiness’ barrier among some donors.

It’s hard to describe to those who didn’t live through that period just how all-pervasive the fear of HIV and AIDS became. The ‘gay plague’ as some called it was in the long tradition of killer conditions dating back to consumption (tuberculosis) and the black death. Given this, it’s equally hard for those who experienced this to imagine a time where HIV was eradicated or made harmless to the body it infected. However, that prospect is no longer pure science fiction but is a strong possibility in the not too distant future.

The HIV Virus

The initial treatment regimes for HIV were little more than palliative, with many being highly toxic to the body. The modern era of treatment with the first protease inhibitors being introduced as recently as 1995. This development led to the introduction of increasingly effective combination therapies as the new millennium dawned. Yet despite these significant and life changing improvements, the virus remains present in the patient albeit at very low levels and in reservoir tissues such as bone marrow.  However, for the majority of HIV patients in 2017, a positive status signifies a condition which is usually entirely manageable with medication. In addition, the life expectancy of an HIV+ person on current treatments is virtually identical to that of an uninfected person (all other things being equal).

HIV Entry

HIV cell entry mechanism

In a simplified summary, the HIV virus infects cells by first binding itself to one of the host’s own immune cells (in the case of humans a CD4 cell). This then allows the virus to attach itself to healthy cells unchallenged by the immune system of the host. Ultimately the virus will enter those cells and reproduce releasing further copies of the virus into the body. They in turn bind to a CD4 cell and the cycle continues. The ‘hijacking’ of the host’s CD4 cell means the body sees the infected cell and the virus as being part of the host and the HIV virus is effectively made invisible to the host’s immune system. This mechanism of stripping and stealing host DNA to mask the virus was initially considered so devious, it was often used as evidence that the virus must be man made. It was asserted, nature wouldn’t design something so ‘evil’.

 

However, researchers in both the fields of medicine and nanotechnologies have long been interested in this type of mechanism. Some felt that as an immune cell could be ‘tricked’ into seeing a virus as part of the host, perhaps it could also be ‘tricked’ into seeing them as a virus again. Some even suggested the virus itself may be ‘tricked’ into receiving some form of targetted treatment – the much vaunted ‘silver bullet‘ medication aimed just at the HIV virus. Now, for the first time, this is more than a pipe dream.

DNA1

The dream of targetted gene therapy

Researchers have long hoped to achieve the dream of replacing portions of defective DNA in various types of gene therapy. This would allow treatments to target just target cells without damaging surrounding tissue/structures. It would also hold out the prospect of offering a more general delivery mechanism which could transfer into other areas of medicine. Some years ago, researchers in HIV treatment took the embryonic gene-editing tools of 2012 (byproducts of the Human Genome project) and linked this to the use of enzymes and proteins to ‘target’ specific cells types. This HIV research has now created some remarkable laboratory results.

 

In simple terms. they have developed a technique called CRISPR (pronounced crisper) which splices an enzyme into the DNA of a virus. In turn, this causes the virus to replicate its own RNA. This has the benefit of increasing the visibility of these cells to auto-immune processes without increasing the infective components of the virus. Although these early techniques don’t remove the virus they do take away one of its great strengths – invisibility.

Since 2015 when the possibilities of this approach began to interest the wider research communities there have been many parallel streams of research activity all producing similarly encouraging laboratory trials first in cell studies and more recently in live animal trials.

mice

Studies have been successful in mice

Researchers at the Louis Katz school of medicine and the University of Pittsburgh conducted experiments in which mice were given HIV-1 cells causing acute HIV infection responses. In humans, this equates to the period in which the HIV virus is most infectious. However, when the CRISPR therapy was used on the infected mice, the rate of cell replication fell dramatically, by between 60 and 95%. This was so successful it was classed as a successful genetic inactivation of the HIV-1 virus in living animals.

 

If this success transfers to other species well (early trials on primates suggest similar success rates), this could mean someone infected with HIV could be treated prior to systemic infection has taken place. Even more amazing is the possibility of a person living with HIV having the virus ‘removed’ from the body post infection.

Then, things became even more interesting when combined with advances from what might be considered an unrelated area of science, criminology.  In the late 1990’s a number of criminal cases were detected thanks to improvements in DNA identification techniques. Those techniques took small amounts of DNA and effectively ‘magnified’ them by a form of cellular replication. When researchers at MIT and Harvard employed this technique alongside CRISPR splicing they found they could ‘zoom in’ on traditionally hard to find viruses. The same RNA replication used in DNA magnification meant viruses and cells could be identified and targetted even when levels in the body are remarkably low.

zika2

Other viruses are now in scope of this therapy

We have now reached the point at which viruses which have previously eluded testing start coming within the scope of this technique. The first two to fall in this space are Dengue virus (responsible for Dengue fever) and the Zika virus which has been causing birth defects most recently in South America.

 

When Zika and similar viruses was seen as in the scope of treatment, researchers into some of the more elusive cancers also began to take a strong interest. At present, the research which originated in HIV is providing new treatment possibilities for a range of infectious diseases and increasingly ways to target historically difficult cancers.

Step2

Cancer cells are the next targets

In the same way that proteins and enzymes have allowed medications to enter cells in a targetted way for HIV and potentially Zika, the same method could apply for other conditions.

 

Research in this space is currently underway for the treatment of advanced breast and cervical cancer in women and advanced prostate cancer in men. This could, at last, be the practical delivery mechanism to target specific cells alone. The magic or silver bullet could indeed have been found.

I wonder how many of those who felt the money spent on HIV was somehow less worthy or deserved would still hold those views. I suspect very few if they had known just how many unrelated illnesses could benefit in the long run. It just goes to prove you never know where research will lead and how it will be applied.

Whilst their loss would still be as terrible, the thought that those who lost their lives to HIV/AIDS may have led to research that may defeat Dengue, Zika and potentially many cancers, would perhaps, be some consolation.

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