CRISPR-cas9 is one of the most promising new developments in medicine, and in science in general.
For decades, editing genes was a laborious, difficult and expensive process. It could take many months to years to change just one gene, and it would cost hundreds of thousands of dollars, while requiring a state of the art lab. Presently, with CRISPR-cas9 you can change a gene in less than a day at a cost of around 50 dollars.
However, CRISPR-cas9, how revolutionary it may be, is being superseded by even better versions.
In other words, CRISPR 2.0 has arrived.
This is technology like CRISPR-cpf1, which is a smaller, less complex version of the original CRISPR-cas9 protein. Because of its smaller size, CRISPR-cpf1 is easier to insert into viruses, which can carry it into cells. Another advantage is that CRISPR-cpf1 cuts the DNA in a better way (it creates "sticky ends" instead of "blunt ends").
Another example is DNA base editors. The team of professor David Liu at Harvard University developed an adenine base editor (ABE), which is a hybrid of a cas9 protein and a protein that can edit specific pieces of DNA, called adenines.
Base editors are much more accurate than CRISPR-cas9, and this by a long margin. Contrary to CRISPR-cas9, they create much less double-strand breaks and other (off-target) mutations.
The adenine base editor can change an adenine base into a guanine base, which could fix about half of the 32 000 point mutations that cause disease (point mutations account for about two third of the mutations in the human genome associated with disease - about 32000 out of the 50000 disease-causing mutations).
Besides CRISPR-cas9, also CRISPR-cas13 has been developed, which can modify RNA instead of DNA, opening up a whole new world of possibilities to modify the transcriptome, enabling more fine-tuned control of cells compared to editing the genome (DNA).
The toolbox to manipulate the genome, transcriptome, and epigenome is being extended on a continuous basis, paving the way for the manipulation of cells, and life, in ways never seen before.
This is the top 12 of the most important future developments that will transform our society (in no particular order):
Of course, we have been talking for decades about many of these technologies, like artificial intelligence (AI) and robotics.
Why should this time be any different?
It seems that this time is indeed different. Take AI for example. The cards are now much better for AI than twenty years ago, because computers have finally become powerful enough, large datasets are now available for AI to learn from (like the huge amount of "labeled" information that can be found on the Internet) and important breakthroughs have occurred in the field of machine learning (like evolutionary algorithms and convoluted neural networks).
Idem for robotics, virtual reality and biotechnology.
Many of these technologies will also reinforce each other and have a synergistic effect. Stronger AI, for example, can enable breakthroughs in biotechnological research, improve self-driving cars, and make robots smarter and more versatile.
These technologies are evolving at a very fast pace. Take 3D printing. It’s a promising technology, but has some major drawbacks, like the long time it takes to print something layer by layer, and the fact that the layers make the surface of the printed object irregular (not smooth). But a new form of 3D printing, called "digital light synthesis", addresses these problems in one fell swoop because it prints without layers, using light that hardens plastics.
The same for biotechnology. Gene technology has been available for more than 30 years but has been very expensive, time-consuming and inaccurate. In 2012 the revolutionary gene editing technology CRISPR/Cas-9 came into the spotlight which addressed all of these problems. While this gene-modification technology is considered as a huge breakthrough, better successors are now available, which are even more accurate and efficient.
In short, the evolution of these (re)evolutions accelerates exponentially.
The world 50 years from now will be a totally different world.
Ok, so after the genome, epigenome, transcriptome, metabolome and proteome, why don’t we add a new member to the 'ome' family: the ribome?
The ribome is the collection of all the ribosomes in the cell. It’s clear that ribosomes deserve this term, they have always been underappreciated cellular parts, considered as immutable little factories that just churn out proteins according to specific sets of instructions, but in fact they are intricately complex, changing, mutable and interconnected structures that constantly interact with each other, the genome, epigenome, transcriptome and many other cellular processes.
Ribosomes enable the cells to carry out much more complex and refined functions, are at the nexus of the RNA and protein world having both DNA-like and enzymatic qualities, and are remnants of an evolutionary past that played out before life existed, at least bacterial life as we currently know it.
So ribosomes certainly deserve their own ‘ome’. Okay, we already have the translatome, being all the mRNA molecules getting translated, and the translational apparatus, encompassing the ribosomes, t-RNA, m-RNA and various other molecules involved in translation.
However, the ribome specifically refers to only the ribosomes. Recent discoveries show that ribosomes are not always the same immutable structures that can be found in every cell. To the contrary, research shows that different cells can contain different populations of ribosomes and that even in a specific cell different ribosomes can exist, in the sense that some populations of ribosomes prefer to translate specific genes compared to other groups or kinds of ribosomes for example. The fact that various different ribosomes with different functions exist, warrants their own 'ome' moniker.
So long live the ribome!
PS: Please note that when you google 'ribome', several results show up, but these 'ribomes' are writing errors of the word 'ribosome'.
Author: Kris Verburgh, MD
Producing stem cells from other persons would be a major step forward.
Usually, stem cells are made from cells from your own body. Taking a cell from your body, like a skin cell, and converting it into a stem cell is a time-consuming and very expensive process.
However, if you could use ready-made stem cells derived from other people, this would hasten the process considerably. You can pick prepared stem cells from the shelf and immediately implant them.
Also, these stem cells could be acquired from young people, so that these stem cells are also younger and less damaged. This is very interesting, because mostly elderly people would need stem cell treatments and creating stem cells from their already aged cells yields stem cells of lower quality compared to stem cells extracted from young people.
The Nobel prize winner Shinya Yamanaka is setting up a stem cell bank with stem cells of other people, tweaking specific receptors on the stem cells (HLA receptors), so that these stem cells won’t be rejected by a considerable part of the population.
Such stem cells could be produced in large quantities, can be of better quality when derived from a young person and would be immediately available, which would all entail huge advantages.
In the future, new technologies like CRISPR-cas 9 will allow scientist to tweak stem cells even more, giving them all kinds of new qualities, like evading rejection by the host, being more powerful, specific or versatile, among other things.
Source: Scientific American
A cancer cell (white) being attacked by immune cells (red).
Picture: National Institute of Health.
Immunotherapy is creating a revolution in the treatment of cancer. By inducing the immune system to attack cancer cells, cancer doctors have a powerful extra tool at their disposal to fight 'the king of all maladies' called cancer.
Immunotherapy consists of several methods that spur on white blood cells to attack cancer cells. This can be done by checkpoint inhibitors, dendritic cell therapy and chimeric antigen receptor T cell therapy.
Checkpoint inhibitors target the brakes that cancer cells put on the immune system. Tumor cells express proteins on their surface that make contact with white blood cells (T-cells) to dampen them down. The white blood cells can't destroy the tumor cells anymore. Checkpoint inhibitors are substances (antibodies) that latch onto specific proteins ('checkpoint detector proteins', like CTLA-4 or PD-L1) on the white blood cells that cancer cells normally target to deactivate the white blood cells. This enables the white blood cells to kill the cancer cells, with some impressive results. Certain checkpoint inhibitors can eliminate advanced skin tumors in one in five patients. That's encouraging because advanced skin cancer is very difficult to treat. Scientists are experimenting with combining different checkpoint inhibitors. Examples of some checkpoint inhibitors are:
Dendritic cell vaccines
Dendritic cells are immune cells that are spread across the body. They capture pieces of tumors (tumor antigens) and present them on their surface, enabling white blood cells to make contact with these tumor antigens, allowing the white blood cells to learn to recognize the tumor antigens. In this way, the white blood cells can attack the whole tumor. Dendritic cell vaccine therapy consists of imitating this process in the lab: dendritic cells are extracted from the body, put in a test tube together with tumor antigens. The dendritic cells then express these tumor antigens on their surface. The dendritic cells are re-injected into the human body, where white blood cells (T helper cells and cytotoxic T cells) learn to recognize these tumor antigens so that they can attack the tumor in the body.
Chimeric antigen receptor T cell (CAR-T cell) therapy
White blood cells (T cells) use antigen receptors (proteins that stick out of their surface as hooks to latch onto cancer cells) to attack and destroy cancer cells. CAR-T cell therapy consists of extracting white blood cells (T cells) from patients, infecting them with a virus that carries a chimeric antigen receptor (a powerful antigen receptor) resulting in the antigen receptor being expressed on the surface of the white blood cells. These cells are injected back into the body. With their powerful chimeric antigen receptor, they can seek out and destroy cancer cells. This therapy works especially well for liquid tumors, like leukemias and lymphomas. This therapy can destroy cancer in up to 90% of patients with aggressive leukemia. However, CAR therapy is very powerful and patients run the risk of succumbing to an overactivated immune system attacking the cancer, also called an 'immune storm'.
Even more promising therapies on the horizon?
These immunotherapy therapies have much potential. However, a new technology called CRISPR-cas 9 could be even more promising for treating cancer, since it can combine several of the immune methods described above.
Scientists can use CRISPR-cas 9 to rewrite the DNA of white blood cells so that these modified white blood cells don't express checkpoint detector proteins (making them unable to be deactivated by cancer cells) and are equipped with chimeric antigen receptors that recognize tumor pieces (tumor antigens).
This would make these white blood cells very powerful to destroy cancer cells. Perhaps too powerful. There is the risk that these modified cells could unrestrainedly attack non-tumor tissue, like the gut or adrenal glands, precipitating an auto-immune reaction. However, studies with animals and humans show that these side effects can be mitigated or avoided.
Author: Dr. Kris Verburgh
Many genes involved in the aging process have been discovered. These genes can in part predict our life span and our risk of aging-related diseases.
A well-known gene is the APOE gene. This gene is the most important predictor of the risk of contracting Alzheimer’s disease.
The APOE gene comes in 3 variants: APOEe2, APOEe3 and APOEe4. You always carry 2 variants. The e4 variant confers an increased risk of Alzheimer’s disease. People who carry one e4 variant (for example APOEe4/APOEe3), have twice the risk of developing Alzheimer’s disease. People who carry both e4 variants (APOEe4/APOEe4) have a nine times increased risk of Alzheimer’s disease.
Of course, nine times a small risk still equals a small risk, especially when you are still young (‘young’ referring to 50 to 70 years). However, research shows that e4 carriers have life expectancies that are 6 years shorter on average.
Interestingly, it seems that people who carry the e4 variant(s) have strong immune systems. They can ward off infections better. This would have been a big advantage in prehistoric times, when infectious diseases were rampant.
However, in this day and age, with improved hygiene and increased survival rates into older age, the tables are somewhat turned, and the e4 variant seems to be a disadvantage because the strong immune response can accelerate the aging process and increase your risk of Alzheimer’s disease.
The APOE gene is also involved in cholesterol and fat metabolism, and e4 carriers tend to accumulate more fat and cholesterol in their blood, raising the risk of cardiovascular disease, another aging-related disease.
About 65% of people of European ethnicity carry the e3 variant, and 25% the e4 variant.
Author: Kris Verburgh, MD
The older we get, the more our brains are susceptible to brain shrinkage. This shrinkage is accompanied by a steady cognitive decline, meaning difficulty to concentrate, forgetfulness or difficulty in retrieving words.
However, research has shown that this brain shrinkage can be substantially reduced by taking B vitamins.
Researchers from the University of Oxford gave old people vitamin B6, B9 (folic acid) and B12 during 2 years.
They found that the brains of people taking B vitamins shrunk seven times less compared to the placebo group.
The researchers concluded that B vitamins ‘may substantially slow down, or even potentially arrest the disease process in those with early stage cognitive decline' and that 'this is the first treatment that has been shown to potentially arrest Alzheimer's related brain shrinkage'.
B vitamins play an important role in metabolism. These vitamins are the oil that greases the wheels of our metabolism. The brain is metabolically very active and therefore needs a lot of B vitamins.
One can simply buy B vitamins in the supermarket or pharmacist and preferably a supplement that contains as much different B vitamins as possible (like vitamin B1, B2, B3, B5, B6, B9 and B12).
Author: Kris Verburgh, MD
- Preventing Alzheimer’s disease-related gray matter atrophy by B vitamin treatment. Proceedings of the National Academy of Sciences, 2013
- Vitamin B12 status and rate of brain volume loss in community-dwelling elderly. Neurology, 2008.
People with a peculiar form of dwarfism living in remote Ecuadorian mountain villages can provide some interesting insights into longevity and protection against aging-related diseases like cancer and diabetes.
Those people are called Laron dwarves. They have a short height because of a mutation in a growth hormone receptor protein. This mutation prevents the liver making IGF-1 (insulin-like growth factor-1).
IGF-1 is some sort of growth hormone that makes the body grow. If the body has a deficiency of it growth is stunted, like in people with Laron syndrome.
However, Laron dwarves hardly contract cancer or type 2 diabetes. They seem to be almost completely immune to these diseases, which points to a role of IGF-1 in cancer and diabetes.
Other research has indeed shown involvement of IGF-1 in cancer and diabetes. The more IGF-1 circulating in the body the higher the risk of cancer or diabetes. Other studies show a link between IGF-1 and longevity. Lab animals like worms without IGF-1-receptors even have a double life span.
Conversely, the more growth hormone, the more IGF-1 you make and the faster you seem to age.
Ironically, growth hormone is touted as a powerful remedy against aging on the internet and in many health books, despite studies showing a clear link between growth hormone, IGF-1, cancer, diabetes and accelerated aging.
Nonetheless, Laron dwarves provide scientists with yet some more tantalizing insights into the why of the aging process.
This is a movie about Laron dwarves and aging:
Author: Kris Verburgh, MD
Progeria is often called a disease of accelerated aging. Patients mostly die of a heart attack at age 13, looking frail and old with bald heads, a wrinkled skin, a beaked nose, tin lips and tired looking eyes. It’s a very rare disease, afflicting about 1 in 8 million people. The official medical name is Hutchinson-Gilford syndrome.
However, some scientists believe that progeria isn’t in fact a disease of accelerated aging. They consider progeria a disease that resembles aging, but that isn’t really like the aging process itself.
After all, progeria doesn’t exhibit all the symptoms of the classic aging process. Patients with progeria don’t seem to have an increased risk of other typical age-related diseases, like dementia, cancer, cataract, diabetes, a declining immune system, increased cholesterol and triglycerides (fats), deteriorating eyesight or hearing loss.
Why then does progeria looks so similar to the aging process itself? This is probably because the final result of progeria is in some way the same as the aging process: massive loss of cells. As well as in progeria as in aging, cells everywhere in the body die and the final result of this massive cell die off is that the body looks old and frail.
In progeria, cells massively die because of extensive DNA damage. A malfunctioning protein in the nucleus of the cell makes the nucleus (that stores the DNA) unstable. This contorted and twisted nucleus damages the DNA inside it and causes the cell to die.
In aging, cells everywhere in the body also die, but this because of other ways of damage than only DNA damage. As we age, cells get damaged by protein agglomeration, advanced glycation end products, continuous growth signals, clogged up lysosomes and malfunctioning mitochondria, inevitably resulting in cells succumbing everywhere in our body, making our tissues and organs frail and weak.
So it’s possible that progeria isn’t really an aging disease, but a syndrome that only bears resemblance with the aging process. The same goes for other seemingly ‘accelerated aging diseases’, like Werners syndrome or Cockayne syndrome, which also mainly involve DNA damage.
While many people look at progeria and other progeria-like diseases as evidence that aging mainly involves DNA damage, those diseases in fact show that the aging process involves much more than only DNA damage.
Author: Kris Verburgh, MD
Picture: The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises. PLoS Biology Vol. 3/11/2005. Creative Commons Attribution 2.5 Generic license.
We are often being told - especially by sellers of food supplements and skin cremes- that antioxidants slow down the aging process. Antioxidants would delay aging by mopping up reactive free radicals that otherwise damage our DNA. These dreadful free radicals are produced as a side effect by our metabolism.
But mounting evidence shows that antioxidants don’t slow down aging. And the free radicals aren’t always the bad guys. Free radicals can even function as a benign warning sign, revving up the cell’s defense mechanisms, like detoxification enzymes and repair proteins, protecting our cells against age-related damage.
Studies have shown that genetically modified worms that produce more free radicals, live 32% longer. Giving worms a weed-controlling herbicide that creates a surge in free radical production makes these worms even live 58% longer.
While free radicals aren’t always bad, antioxidants can be damaging. A large meta-analysis of 230 000 patients has shown that people who take antioxidants have an increased rate of death.
In conclusion, taking antioxidants isn’t always a good thing. Of course, when you are deficient of certain antioxidants, you do have to take them to replenish the ranks. But taking extra antioxidants to slow down the aging process doesn’t seem to work unfortunately. Meanwhile, aging seems much more complex than just free radicals damaging our cellular machinery.
Author: Kris Verburgh, MD
A Mitochondrial Superoxide Signal Triggers Increased Longevity in Caenorhabditis elegans. Wen Yang, Siegfried Hekimi. PLoS Biology, 2013.
Is the oxidative stress theory of ageing dead? Pérez VI et al. Biochim Biophys Acta, 2009. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. Bjelakovic, G. et al. JAMA, 2007. Picture: cc Wikicommons