There is a prevailing notion that our entire biological existence is predetermined by our DNA. This dates back to 1953, when two scientists in Cambridge, U.K., discovered the structure of DNA and the biology community believed it had found the scientific Book of Life.
Indeed, DNA contains billions of detailed chemical markers that are like letters that together form words that contain instructions on every aspect of life. The blueprint for just about everything, all the instructions for the 50 trillion cells in the human body (or any living animal and even plant, for that matter) are encoded in the DNA; the six billion letters tell the entire story of our lives. In 1989, when announcing the Human Genome Project to map out the entire human genome so we could understand which genes control which function, James Watson, one of the two scientists who discovered DNA, made a comparison to astrological signs. “Now we know, in large measure, that our fate is in our genes,” said Watson.
But if billions of letters sound like a long story, it turns out there’s even more to the story than that.
Genetics and Epigenetics
The human body has about 22,000 genes that provide instructions for the cells to function in every aspect of life. Nearly all of your genes are identical to those of any other human. The genes that are different are what make you different because they control traits like eye color, intelligence and voice. We inherit our genes from our parents and they remain the same for our entire lives.
One question has eluded scientists for many years: How can people who carry genetic mutations known to code for certain disorders never become affected by those disorders?
Part of the answer to this question is being uncovered as we learn about epigenetics. Epigenetics refer to changes in gene activity that are not the result of changes in the genome itself. “Epi-” means above. Epigenetics are caused by biological chemicals that mask gene expression and affect the function of certain genes. Epigenetic markers are like circuit breakers that can order the gene to simply be switched on or off.
For example, only 80% of women who carry the BRCA gene will develop the cancers that this gene is known to cause. The other 20% of women will never develop them, despite the fact that they have the mutation.
“Genetics is a probability; it is not your destiny. Just because you have a gene doesn’t mean you are destined to get the disease,” says Dr. John Loike, bioethicist and professor of Biology at Touro College. “That’s the first thing people need to understand about genetics.”
There are several reasons that a carrier may be unaffected by a gene. One reason is that there may be other genes that compensate for a defective mutation or prevent it from being expressed. Another key variable is epigenetics. The mutated gene that some people carry may simply be shut off and will not be expressed.
The Genome and the Epigenome
Every cell in the body has genes that are inactive. The DNA in each cell contains the entire genetic code for that species, including instructions for each organ and tissue, but each cell will use only the genes that it needs. The spleen cells, for example, only use the instructions that are relevant to it.
This happens because of epigenetic functions. Loike explains that in a zygote, the earliest stage of human development, there is only one genetic code. Yet that cell reproduces again and again. “Somehow,” says Loike, “it differentiates into a brain, into muscle, into nerves. But with the same gene code! How does it do that?
“It turns out that as this embryo develops from one cell to a whole child, different organs will turn on and turn off different genes. So, muscle cells may have several thousand genes that are turned on, and other thousands of genes that are turned off. And a nerve cell would have different genes that are turned on and off,” continues Loike.
Epigenetic changes continue throughout life, affecting us in ways we have yet to know or even imagine. The study of epigenetics is trying to understand the ways that genes are turned on and off.
Nature and Nurture: A Marriage
The concept of epigenetics changes the way most of us think about genetics. The immutability of genetics was once so established that it gave rise to the idiom “He has it in his genes.” This was a way of saying that one couldn’t help a certain trait. But epigenetics is challenging that notion.
To be clear, epigenetic functions don’t alter the genome in any way, nor do they diminish its importance. They can merely activate or deactivate existing genes.
Dr. Loike explains the relationship between genes and epigenetics with an analogy. Epigenetics are like software to the genes’ hardware. “There are two parts to genetic function: The genetic code is stable and serves as the hardware, and the epigenetics function like the software telling it when to produce and when to lie dormant. We’re not changing the letters. We’re just taking a magic marker and saying, ‘This gene I want to turn on. This gene I want to turn off.’ We can erase it. That’s what epigenetics is all about.”
The panoply of epigenetic markers and their functions as a whole are referred to as the epigenome. Your epigenome is just as important to your health as your genome. Moreover, while you are born with your genome and it will not change, your epigenome is very much in your hands. The evidence shows that environment, exercise, nutrition, stress and sleep are major factors in epigenetics.
Loike is forthright about the numbers. “Everybody alive has between 20 and [..] 40 genes that could be lethal. They could kill you. It doesn’t mean they’re going to, but you have those genes and the potential of death, because they’re embedded in your genome.”
The good news is that, thanks to epigenetics, there is often something you can do about it. So how do genetics and epigenetics interact? Loike prefaces his explanation with this disclaimer: “We don’t know a lot, but the key [word] here is lifestyle. We’re just learning now that what you eat, how you live, all can affect epigenetics, not the code — but it’s going to affect whether the genes are turned on or off.”
One example found in nature is the honeybee. The queen bee lays larvae that are all genetically identical. If you feed the larva honey from worker bees, it turns into a worker bee; feed it honey from the queen bee and it turns into a queen bee. Not only does the queen bee look very different from the worker bee, she also lives much longer than the worker bee. Nutrition alone can make a dramatic difference in the way genes are expressed.
There are several genes that control longevity. As we age, more and more of these genes become deactivated due to methylation, an epigenetic effect (see sidebar). We can now predict how long one will live based on those markers.
One of the most impactful points in epigenetics is during development — especially early development. Dr. Moshe Szyf, a geneticist at McGill University, at a TED conference in 2017, shared research showing that lab rats who were groomed more as pups were better able to manage stress. Analysis of epigenetic markers showed clear differences in relation to genes that control stress management. Empirical data showed that human babies who were cuddled a lot experienced less stress as adults.
Experiments in mice show the importance of lifestyle choices for expectant mothers and the profound impact that this can have on their children and even grandchildren. Experiments were conducted with gestational mice who were given unhealthy food and limited opportunities for exercise. The offspring of those mice tended to be more obese than average. Even after putting the offspring on restrictive diets with the best food and exercise, 30% of them remained obese. In many cases, the offspring of this litter, the next generation, still had higher rates of obesity.
This is perhaps the most revolutionary aspect of epigenetics: that epigenetic markers can be inherited. This is still controversial in the biological community and the evidence in human subjects is still a bit tenuous. Conventional understanding of the process of reproduction suggests that only the DNA is copied, not the other cellular material. But it appears that sometimes some epigenetic markers will be passed on in the offspring.
Professor Suzanne King of McGill University conducted a study during the devastating Ice Storm of 1998 in Quebec. She monitored mothers who were expecting during that disaster, controlling for specific details that relate to the level of stress they experienced. She has been monitoring those children from when they were born until now, when they are just reaching adulthood. These children tended to have a harder time in school and other measurements of success show difficulty as well. Thus, she demonstrated that levels of stress in the mother while expecting can significantly impact the child.
Obviously, this places tremendous responsibility on parents during the earliest formative months and years of a child’s development, considering that their actions and experiences could impact their children and possibly grandchildren for another 100 years. At the same time, there is cause for optimism as well. Parents can have a lasting, positive impact on children and future generations by providing them with a healthy childhood even in spite of negative genetic predispositions.
Not only are psychologists using epigenetics to understand stress and other results of trauma, there are many uses in the broader field of medicine.
In testing for cancer, as an example, epigenetics is already being used. Once a cancer has spread, it can be difficult to know what kind of cancer the patient has because the organ source isn’t always known. It may have started in the brain or the pancreas. But, as explained earlier, since cells differentiate using epigenetics, we can tell from what kind of cell the malignancy originated. If we see epigenetic markers for the lymphatic system, for example, we can determine that the patient has some form of lymphoma, R”l.
The promises for medical uses of epigenetics can hardly be overstated. Most cancers are the result of genetic mutations. If we could simply switch off the cancer-causing mutation, we could prevent and even cure cancer.
There are similar possibilities for many other diseases. Dr. Loike says that CRISPR technology, which has been used to edit genes and has been behind many breakthroughs in recent years, can be used to edit epigenetic markers to turn on and off genes for many beneficial uses.
We don’t have to be especially efficient to be effective. Experiments in mice with a predisposition to liver failure, who wouldn’t usually live longer than two months, show that we can genetically change a small number of liver cells to be effective. When scientists introduced a vector with a virus that alters the liver cells by editing out the disease-causing mutation, the mice lived to full term. Then, they checked how many liver cells were altered by the virus and it turns out that only 10-20% were affected. And that was sufficient to prevent the disease.
We may one day be able to turn stem cells into heart or brain tissue using epigenetics, as has been hoped for a long time. Time will tell if this becomes a reality or is the third millennium equivalent of alchemy.
The problem with developing treatments for humans is not so much the feasibility, says Dr. Loike, it’s ethical considerations. We can easily change your genome or epigenome to give you certain genetic advantages. The problem is that we don’t know what else that will do to you.
And informed consent is not sufficient with genetics because what happens to one’s genome can affect his offspring forever.
Scientists have already identified four million epigenetic markers but we still don’t know what their respective functions are. Similar to the Human Genome Project that was undertaken in the U.S. in the 1990s, the Human Epigenome Project (HEP) has set out to map out the entire human epigenome. This may be yet another way that Hashem preempts the malady with a cure.
HOW IT WORKS
If you are like me and will not be satisfied until you understand how it works, here you go.
Modern genetic science has always maintained that the way traits are inherited is through information stored in the cell that is transmitted from progenitor to progeny, called genes. With the discovery of DNA, we learned that the genes are written into strands of deoxyribonucleic acid (DNA) that are structured like a long, twisted ladder made of nucleotides. The nucleotides are like letters that combine to make coherent words of instructions for the cells; several rungs on the ladder might comprise one gene.
The strands of DNA in one cell, if laid end to end, would stretch for six feet. Yet it all fits into the nucleus of the cell, which is smaller than one millionth of a foot long, by being wrapped around clusters of proteins called histones.
How does the DNA get its message across? There are proteins made of amino acids that execute many functions in the body that are created by a cellular process. DNA molecules are polymers made of nucleotides. They are arranged in a sequence and every three nucleotides is a gene code for a certain amino acid. In a process call transcription, cellular proteins transcribe a copy of each gene using ribonucleic acid (RNA). This transcribed copy is called messenger RNA (mRNA)s. In the next step, called translation, the mRNA moves to the interior part of the cell where it works with ribosomes to assemble the protein specified in the gene. This is how genes are expressed.
This is where epigenetics come in. There are factors outside the genome that affect the function of expression. Chemical tags can attach to the nucleotides or the histones that will cause a gene to stop or start functioning. These tags can sometimes reduce its function of producing instructions. So, though the DNA is unchanged, the genes affected have been disabled.
Epigenetic mechanisms can also increase gene expression.
There are several mechanisms for epigenetics. One well understood mechanism that decreases gene activity is methylation. When methyl groups are attached to certain genes that inactivates them. Acetyl groups that attach themselves to histone proteins, will amplify gene function.
Interview with Dr. John Loike, Bioethicist and Professor of Biology at Touro College
There are many different definitions to “epigenetics” in the literature. How would you define it?
Hakadosh Baruch Hu created an amazing capacity of the body and cells to regulate which genes are turned on and which genes are turned off.
Genes are encoded by four specific chemicals or letters of the DNA. These letters form “words” and instructions of how a cell or organ functions. Epigenetics is part of gene regulation, where you do not change the letters (embedded instructions) of the gene, but you change whether a specific gene instruction is carried out.
Why is this important? Because if we understand how epigenetics works, we can use gene editing-technology like CRISPR to mark a gene so that it will turn on or off. If you have a gene that causes a certain cancer, in the future we will have the capacity to tell the body “Turn it off!” and you won’t develop the cancer.
CRISPR can do that?
Yes. It can not only change the code; it can change either the hardware (letters of the gene) or the software (whether a gene function is carried out).
How does this affect us as frum Jews?
Here’s what’s amazing about this for our frum community. As you know, the Ramban and others believe what you eat has not only a physical, bodily effect on who you are, but it has a spiritual effect as well. We don’t eat treif, according to the Ramban, because we don’t want those characteristics. And if you really think about it, what we would like to propose — I cannot prove it, it’s only a theory — is that changing your lifestyle by doing more mitzvos is [what I call] a “spiritual epigenetics.” And those genes are going to enable you to control your behavior. So if you have a gene for violence [or] a gene for risk taking, and you worry that you can’t control it, by engaging in a lifestyle of certain mitzvos, you can make a difference. And we have proof of this! Not on a biochemical level, but the Gemara says if you are born with an intense desire to kill, you can become a mohel or a shochet so you won’t be murdering people.
The Rambam says if you want to do teshuvah between Rosh Hashanah and Yom Kippur, engage in more mitzvos. And he gives only one example, tzedakah. Why? Because, I believe, certain lifestyle changes or activities don’t have an effect on one gene but have an effect on many genes. So maybe giving tzedakah is not going to affect one behavioral gene but many behavioral genes to enable you to be a more frum and a more Torah-observant Jew.
Now, theoretically I could prove this. I could take a hundred people, 50 of them I make into baalei teshuvah and 50 I won’t. I could measure the epigenetic markers before and after and I’m sure I will see a difference.
I call this spiritual epigenetics. And change can give you the power to control your middos and behavior.
Mendel is widely regarded as the father of modern genetics. Who would you say is the father of epigenetics?
People say that the father of modern genetics is Gregor Mendel. Not true — the father of modern genetics, as well as epigenetics, is Yaakov Avinu.
Yaakov comes to Lavan and asked to get paid. He asks for the spotted sheep. Lavan thought he was a chacham and he took away all the spotted sheep from Yaakov’s flock. But Yaakov understood what recessive traits meant. If both are recessive, there’s a 25% chance that the offspring will have the recessive trait.
That other thing Yaakov understood was epigenetics. What did he do? He put the sheep in front of a peeled bark. Why? Epigenetics. We know that certain environments and certain conditions affect the rate of epigenetic transmission during reproduction.