Genomic medicine is an emerging medical discipline that involves using genomic information about an individual as part of their clinical care (e.g. for diagnostic or therapeutic decision-making) and the health outcomes and policy implications of that clinical use. Already, genomic medicine is making an impact in the fields of oncology, pharmacology, rare and undiagnosed diseases, and infectious disease.

Did you know that there are truly rare people born all the time? Around 350 million people on earth are living with rare disorders - this is a disorder or condition with fewer than 200,000 people diagnosed. About 80 percent of these rare disorders are genetic in origin, and 95 percent of them do not have even one treatment approved by the FDA.

The ability to read the human genome quickly and cheaply has led to substantial advances in discovering the causes of rare disorders. Many families have gone through years of "diagnostic odysseys," going from one specialist to another trying to find the root cause for their family member's rare disorder. It is difficult to overstate the relief that genomic testing has brought to many of these patients and families, not just for themselves but eventually for other affected families who are finally able to connect and share their challenges. In the last 10 years, a large number of patient groups have formed after the genomic cause has been identified for a specific rare disorder. These groups allow family members and patients to communicate with each other through social media or conferences. Perhaps more importantly, many of these patient groups are accelerating research on rare diseases by recruiting patients with the same condition to participate in scientific studies. When families band together, their efforts sometimes shrink the path for establishing the genetic basis for a rare condition from decades (and unfortunately many patient lifetimes) to a year or two.

Bertrand's Story: Families Banding Together

Matt Might and his family provide one such genome sequencing story. Matt and his wife Cristina knew almost right away that their son Bertrand had some difficulties, which became worse over time. They obtained testing for a number of known genetic conditions, but Bertrand did not have any of them. In 2010, they enrolled in a study at Duke University that used DNA sequencing to help children with undiagnosed disorders. It took over a year, but they finally learned that Bertrand had a mutation in each copy of a gene called NGLY1.

Bertrand's mutations meant that he had no functioning copy of this gene, and therefore no N-glycanase 1 protein (which the gene encodes). His disorder was so rare that mutations in this gene had never been documented, and he was the first known human to lack this protein. So, he helped define the list of symptoms observed when someone does not have the NGLY1 protein, including an inability to produce tears or properly move some muscles. Knowing Bertrand's symptoms and mutations quickly allowed for the identification of at least 15 other children with the same disease, and the establishment of the NGLY1 Foundation to support research about the disease and pursue possible treatments. In 2015, Matt was one of those invited to the White House by President Obama to celebrate the announcement of the Precision Medicine Initiative.

Sonia's Story: Looking for a Treatment

Another inspiring story of how genome sequencing can transform the life of someone with a rare disease comes from Sonia Vallabh and Eric Minikel. After a rare disease took her mother's life, they learned through genetic testing that Sonia had inherited the same mutation that causes familial fatal insomnia, or FFI. This fatal disease, caused by abnormal proteins in the brain called prions, makes the brain start functioning abnormally, with symptoms that eventually include a total inability to fall asleep. Sonia and Eric quit their jobs and careers to go back to graduate school in biomedicine, and are earning their doctoral degrees from Harvard Medical School by studying the mutations in the PRNP gene that cause prion diseases like FFI.

Along with their colleagues, the couple have already conducted a groundbreaking study on the impact of PRNP mutations. We already knew that different PRNP mutations lead to different conditions based on where in the gene the mutation is located. However, Eric and Sonia's team made the surprising discovery that PRNP mutations are more common than we previously thought, and these mutations don't seem to cause disease at the same rate in everyone who has them. In other words, there are still factors we don't understand that determine whether or not a PRNP mutation will lead to certain symptoms. This information opens up more questions, but it also points to important directions for any future studies of this and other rare diseases.

Science For Everyone

If you have a family member who has seen a number of medical professionals but not yet received a diagnosis, they could apply to the NIH's Undiagnosed Disease Network. This national network of medical and research centers aims to help both individual patients and to contribute to the understanding of how the human body works. That's what Zarko Stanacev did - after 12 years of mysterious symptoms but no diagnosis, his genome was sequenced and interpreted by a team including Dr. William Gahl at the U.S. National Institutes of Health. They found a mutation in the gene NLRP3, which causes abnormal inflammation throughout the body. After only one treatment with a medicine to dampen this inflammation, Zarko's symptoms improved.

Just like Sonia and Bertrand, he has contributed to medical research by allowing his genome to be sequenced and studied.

Did you know that just knowing the genome sequence of an organism only reveals part of the story - and that it is also important to determine how that organism interprets its genome and uses that information to build and operate itself accordingly? Less than 2 percent of the human genome corresponds to "genes," but we know other parts are important for regulating and translating the genome as well as responding to environmental influences. Even still, the job of large parts of the genome remains a bit of a mystery!

When scientists started the Human Genome Project, they didn't even know how many genes were in the human genome. It then came as a big surprise to learn that human beings only require roughly 20,000 genes! Those 20,000 or so genes are encoded by less than 2 percent of our genome. What is the rest of it doing? And how does each cell read and interpret its genome?

How Your Cells Use the Genome

Although it's appealing to think of the genome sequence as the "book of life" for an organism - one that contains all of the biological instructions to develop and operate that organism - we now know that the DNA bases are only the starting point.

It can be useful to think of a genome and how it works by a set of maps. Some maps are very simple; they may represent basic information such as the locations and intersections of roads. Such a simple map would be like the sequence of a genome: it would reflect the structure of the road, but would not give information about how it's used. As genomic technology improved, more complicated maps could be developed, adding many features and layers of information to a simple genome map. For instance, we learned that the basic sequence of a genome has stop signs and start signs added to it, just like roads do, and that these additions direct the "traffic" of proteins that bind to DNA and allow the cell use the genome. Other technologies also became available to map traffic patterns, revealing the presence of high- versus low-traffic area. In a genome, a high-traffic area might be a place where many genes are turned on by proteins binding to the DNA. These areas call for multiple layers of regulation, just like in a city where you might have high-rise buildings on top of a busy street with a subway underneath. In low-traffic areas, a genome can have deserts of hundreds of thousands of bases with no genes, with little sign of proteins binding the DNA. In the 15 years since the completion of the Human Genome Project, scientists have developed better and better methods for constructing three-dimensional "satellite" maps of genomes, where we can see what proteins bind to what DNA sequences in a single cell and at a specific time. It is the different patterns of "on" and "off" genes that helps produce the different types of cells that makes you, you.

Some of the stop and start signals that direct our cells to translate the map of our genomes are called "epigenomic modifications." Epigenomic modifications are often chemical groups that are added or subtracted from DNA bases or proteins that bind to DNA that change the way genes are read. Such modifications can be passed on as cells divide, even though they are not strictly changes in the DNA itself. One of these epigenomic modifications is called methylation. As a human is developing, some early cells start to become brain cells. Specific small chemicals (called methyl groups) are added onto the DNA in front of genes that won't be needed for brain cells. Here, the methyl groups act like stop signs: in all future brain cells, the methyl groups will make sure the genes that aren't needed stay turned off. This and other cellular tools in your cells are how the body makes sure its roughly 20,000 genes are used correctly by each cell type. Did you know that your cells were so smart?

Although methyl groups are not changes in the sequence of the DNA bases, epigenomic modifications like these can act like mutations by directing if the bases are read or not.. For example, in cancer cells, methyl groups are often inappropriately added at specific places in the genome. Now the cells grow out of control because the "stop" signs have been added in front of genes that would keep the cell in check. Some cancer therapies are drugs designed to stop these methyl groups from being added where they should not be, like the medicine azacitidine which is used in some blood cancers.

How Epigenomics Affects You

In the last 15 years, we have learned how the environment influences how the genome works through epigenomics. Here's one example: in the winter of 1944-1945, Germany had blocked the food supply to the Netherlands, and the population suffered a terrible famine. The effects of the "Dutch Hunger Winter" could be seen in the children born from women who were pregnant during the famine. The babies from mothers who were malnourished only in the beginning of their pregnancy, but then had normal levels of food later, had a greater frequency of obesity throughout their lifetimes; they also had higher risks of chronic diseases like diabetes when compared to their siblings who were born before or after the famine. In a striking finding, the children of these babies were also found to have higher risks for the same chronic diseases. So it seemed like something could be passed down through generations, but not changes to the DNA sequence itself. Sure enough, research has shown that the methylation patterns in the DNA were altered in these children, and the altered patterns were inherited by their own children, changing their health outcomes.

We know that diet directly affects methylation because nutrients in our food provide the methyl groups themselves. This means that the diet of either parent can affect their children and grandchildren. But it's not just diet - there is strong evidence shows that smoking can change methylation patterns as well. Epigenomic patterns can also be altered by drinking alcohol during pregnancy, leading in extreme cases to fetal alcohol syndrome. While not everything is controlled through epigenomics, these modifications to our DNA play a central role in how the genome carries out its work. But they aren't the only controls we've learned about through the Human Genome Project.

What the Rest Of the Genome Does

If only 2 percent of the genome's bases are used to encode proteins, what is the other 98 percent doing? Some of the genome's bases help determine its structure. There are areas like the telomeres, the ends of each chromosome, that are very important. Just like the caps on the end of your shoelaces, telomeres keep the ends of your chromosomes from fraying. Some of the other parts of your genome position the genes in the right places to be read by the cell's machinery. So, although those bases might not encode proteins, the genome cannot function without their presence.

dark matter" or "junk DNA," we are learning that the 98 percent has all kinds of important roles. Some parts called "ultraconserved elements" have kept the exact same sequence for millions of years in mammals, even though they don't contain genes. Why would that be? Recent studies suggest that deleting these elements causes brain changes and could lead to some neurological diseases like Alzheimer disease, although we are still learning why.

Here's another fact that might be a little creepy: up to 45 percent of your genome is actually leftover DNA from viruses that infected mammals over millions of years. We haven't yet worked out what much of that old viral DNA is doing, but we know it's contributed to at least one very important mammalian trait: exchanging nutrients between mother and baby through the placenta. The rest of the genome includes regulatory elements, including areas that influence genes to be expressed at the same time in response to the environment; transcribed sequences that the cell reads but does not use for making protein; and material which acts as a hotspot for your chromosomes to exchange information with each other.

Background

The nation's investment in the Human Genome Project (HGP) was grounded in the expectation that knowledge generated as a result of that extraordinary research effort would be used to advance our understanding of biology and disease and to improve health. In the years since the HGP's completion there has been much excitement about the potential for so-called 'personalized medicine' to reach the clinic. More recently, a report from the National Academy of Sciences has called for the adoption of 'precision medicine,' where genomics, epigenomics, environmental exposure, and other data would be used to more accurately guide individual diagnosis. Genomic medicine, as defined above, can be considered a subset of precision medicine.

The translation of new discoveries to use in patient care takes many years. Based on discoveries over the past five to ten years, genomic medicine is beginning to fuel new approaches in certain medical specialties. Oncology, in particular, is at the leading edge of incorporating genomics, as diagnostics for genetic and genomic markers are increasingly included in cancer screening, and to guide tailored treatment strategies.

How do we get there?

It has often been estimated that it takes, on average, 17 years to translate a novel research finding into routine clinical practice. This time lag is due to a combination of factors, including the need to validate research findings, the fact that clinical trials are complex and take time to conduct and then analyze, and because disseminating information and educating healthcare workers about a new advance is not an overnight process.

Once sufficient evidence has been generated to demonstrate a benefit to patients, or "clinical utility," professional societies and clinical standards groups will use that evidence to determine whether to incorporate the new test into clinical practice guidelines. This determination will also factor in any potential ethical and legal issues, as well economic factors such as cost-benefit ratios.

The NHGRI Genomic Medicine Working Group (GMWG) has been gathering expert stakeholders in a series of genomic medicine meetings to discuss issues surrounding the adoption of genomic medicine. Particularly, the GMWG draws expertise from researchers at the cutting edge of this new medical toolset, with the aim of better informing future translational research at NHGRI. Additionally the working group provides guidance to the National Advisory Council on Human Genome Research (NACHGR) and NHGRI in other areas of genomic medicine implementation, such as outlining infrastructural needs for adoption of genomic medicine, identifying related efforts for future collaborations, and reviewing progress overall in genomic medicine implementation.

Did you know that the sequence of your genome can determine how you respond to certain medications? Understanding pharmacogenomics, or tailoring a person's medications based on their genome, would not be possible without sequencing the genomes of many people and comparing their responses to medicines.

One of the most important uses for DNA sequencing is not to just sequence one human genome - but rather to sequence many human genomes to understand how genomic differences relate to different traits. Some such traits reflect physical characteristics (like eye color), whereas others can be used to help in the clinical care of patients. Scientists in the field of pharmacogenomics study how specific variants in your genome sequence influence your response to medications.

Influencing How Medicines Work

In order for our bodies to use some medicines properly, the cells in our bodies must make a few chemical changes that convert them into an active form, just like we do when we eat food. Then, these active forms of the medicine must get to the right places in the body or inside cells to do the job that we want them to do. If we want to make sure this happens, it makes sense that we would target our bodies' pathways involved in changing the medicine's form or in getting medicines to the right places. For example, you probably know someone who takes an antidepressant. Many of these medicines get to the right places by interacting with a protein called ABCB1, which works like a traffic cop on the outside of your cells.

Given ABCB1's important role in controlling traffic, you might imagine that if someone has a genomic variant that changes the shape or function of their ABCB1 protein, they might have a different response than usual to any number of medicines. We now know that is the case for some antidepressants, as well as other medications like statins for cholesterol and certain chemotherapy medicines. As a result, there are at least 18 pharmacogenomic tests for variants in ABCB1 listed in the NIH's Genetic Test Registry, with suggestions that you be tested for these variants to help determine the correct dose for certain medications.

Stopping Dangerous Side Effects

Healthcare professionals and researchers are constantly seeking both to optimize medical treatments and to avoid adverse (or negative) reactions to treatments, which are estimated to affect between 7 percent and 14 percent of hospitalized patients. This makes adverse reactions a large cause of added days spent in a hospital, and the fourth leading cause of death in the United States.

One scary example of such an adverse reaction is Stevens-Johnson syndrome (SJS), a severe allergic reaction also called "scalded skin syndrome." It can be caused by infections, but also by very common medications like ibuprofen, anti-seizure medicines, or antibiotics. Patients may go from taking two pain pills to ending up in the hospital burn unit fighting for their lives if SJS progresses to a worse condition called toxic epidermal necrolysis (TEN). TEN is diagnosed when patients have shed at least one-third of the skin off of their bodies. Needless to say, anything we can do to prevent this allergic reaction is vitally important.

In Taiwan, married scientists Wen-Hung Chung (a physician) and Shuen-Iu Hung (an immunologist) noticed that SJS/TEN was much more common in patients taking carbamazepine, used to treat epilepsy and seizures, or allopurinol, used to treat gout. They showed that this was due to genomic variants in the HLA-B gene. Not surprisingly, this gene helps control the immune response. As a result of their work, the country of Thailand has implemented genomic testing before these medications are prescribed. The results of this "pharmacogenomic test" are used to decide whether it is safe to give a specific patient certain medicines, like carbamazepine or allopurinol. Thailand's government even covers the cost of this testing, and the frequency of SJS/TEN has been drastically reduced. We have since learned that different ancestries are associated with different HLA-B genomic variants, so countries may need to take different approaches to monitor which medications are most likely to be linked to SJS/TEN.

Relationships are Complicated

Understanding pharmacogenomics would not be possible without sequencing the genomes of many people and comparing them, and then comparing their response to medicines. But we have also learned that a person's genome sequence is not everything when it comes to medication responses. The human body is a very complicated machine, and the instructions written in our DNA are just part of the process.

There are some cases, as with the breast cancer treatment tamoxifen, where a small study showed that there might be a relationship between someone's response to the medicine and a variant in the CYP2D6 gene. However, this finding did not appear to be true in a larger study that involved many more people. That's why at this time, the U.S. Food and Drug Administration (FDA) labeling for tamoxifen does not recommend CYP2D6 pharmacogenomic testing, but the issue is still being reviewed as more research is conducted.

Another gene in the same CYP family, called CYP2C19, has variations which affect how your body can use clopidogrel (more commonly known as Plavix). This medication is a "blood thinner" which helps prevent blood clots, and thus reduces your risk of strokes or some heart attacks. If your CYP2C19 protein is not working properly due to a mutation in the gene, then you will not be able to process clopidogrel, and you need either a different dose or a different medication. As it turns out, these variants in CYP2C19 are also more common in those with Asian ancestry. Although testing for variants in this gene is also not routinely recommended, you may wish to speak with your healthcare provider about the test if you are given a prescription for clopidogrel, particularly if you have East Asian family members.

Did you know that in the 15 years since we finished reading the human genome sequence for the first time, we have developed powerful new technologies for editing a human (or any) genomes? We may not yet have jet packs or flying cars, but the ability to edit genomes precisely is now real. These new methods offer the ability to change the genome in a way that could be passed on for generations. But should we?

Some might think that, once we have decoded (that is, read out) the genome sequence of an organism, a logical next step would be to "edit" that genome - perhaps to cure a genetic disease or to alter the a trait in a plant or animal. Scientists have used laboratory methods to make changes in an organism's genome for many years, primarily to study its biology or to introduce commercially advantageous changes. For example, you might have seen "GloFish" - zebrafish that now produce a protein that makes them fluorescent. But in 2012, a new technique called CRISPR was developed and has revolutionized genome editing. The scientists who developed CRISPR recognized that they could borrow tools from the immune system of bacteria and develop "bacterial scissors" for surgically editing any DNA in any organism. CRISPR has made genome editing much simpler, faster, cheaper, and more accurate than previous methods, and the method is now used in laboratories all over the world.

Genome Editing and Human Disease

Already, we have seen some exciting early studies that use CRISPR to edit the human genome in an effort to study and, perhaps eventually, to treat a disease. Sickle cell disease causes severe pain and premature death in millions of people worldwide. Scientists have already used CRISPR to remove the mutation that causes sickle cell disease in a mouse model, and are working toward clinical trials in humans. For the latter, scientists will remove blood stem cells from a patient with sickle cell disease, edit the genome of those cells to remove the sickle cell mutation, and then re-insert the modified cells into the person's bone marrow. Since there are still no cures for sickle cell disease, such a genome-editing approach could be a major advance.

Another CRISPR application now entering clinical trials aims to combat human immunodeficiency virus (or HIV) infection. HIV enters human white blood cells and then alters those cells' genomes. Then, it makes copies of itself to infect the person's immune system, making them vulnerable to other infections. CRISPR is now being investigated for use in either cutting out the HIV-derived DNA from the genome as well as engineering a person's genome so that HIV cannot enter their cells. However, it is important to stress that these techniques are still relatively new and very much still in testing mode.

Technical Limitations of Genome Editing

CRISPR editing is not perfect and can even be inadvertently harmful. Although CRISPR is much more precise than previous genome-editing methods, it is sometimes imprecise and edits the wrong place in a genome. This means that it could randomly introduce mutations at the wrong sites rather than the genomic location being targeted. Many scientists are working to reduce this risk of imprecise editing.

Even when CRISPR precisely modifies a genome as desired, the introduced change does not always lead to the expected outcome. For example, some of the studies using CRISPR to combat HIV immediately found that on its own, the virus developed separate new mutations that allowed it to escape the CRISPR edits. These new mutations allowed the virus to start replicating again.

As scientists working on gene therapy for many years have found, there are also important technical issues to consider, especially when considering the use of CRISPR for treating a human disease. In order to get CRISPR-based genome editing to work at the right place at the right time for effective therapy, there needs to be a delivery system that works for that specific body location. This makes the bone marrow and the eye attractive for CRISPR-based therapies because they are more easily accessible; other tissues are not as easy to target with this CRISPR systems. In addition, scientists need to make sure that the human body does not mount an immune response to either the CRISPR tool itself or the components involved in its delivery.

Ethical Considerations

Beyond the technical issues, there are significant ethical issues surrounding the ability to edit the human and other genomes. Let's start with ourselves: so far, most CRISPR studies have focused on editing somatic (tissue or body) cells, so that none of the changes would get passed on to future generations. But CRISPR technologies can be used to edit germline cells, too - these make the sperm and eggs that could carry any genome edits to future children and potentially their children. On the one hand, some might think that it is a good idea to remove sickle cell disease mutations in all future generations. On the other hand, this could open the door to editing genomes to alter other traits, passing the changes on to all future generations. Where would we draw the line?

Is it okay to edit a genome to give a child better eyesight or a few inches more in height? Will we begin to create "designer babies" who might have "better" traits than their parents? As the ethicist and scientist Paul Knoepfler says in his 2015 TED talk, "what is better when we're talking about a human being?" Many groups are considering the important questions that need to be addressed, including the United States National Academies of Sciences, Engineering, and Medicine. Because of these unanswered questions, a current ban on using federal funds for conducting research on human embryos, and the unknown health risks of genome editing, creating "designer babies" is unlikely to happen in the United States anytime soon.

Like many health technologies and medications, genome editing is also likely to be quite expensive as a medical intervention, at least initially. This could worsen health disparities that already exist based on socioeconomic status. As discussed in the Social Context advance, there is also valid concern about informed consent. Can future parents of an unborn child truly give fully informed consent for that child to have their genome edited, particularly at the current time when such therapies are not fully tested or proven to be safe?

Gene Drives

Beyond human genomes ethical questions about editing other organisms' genomes are arising. Consider the mosquito and its unwelcome passengers: the malaria-causing parasite Plasmodium or viruses such as Zika or dengue. Genome-editing technologies can be used to introduce malaria-battling mutations in the mosquitoes' genome that blocks the parasite from infecting the mosquitoes in the laboratory. This might sound great, but let's think more about it. Introducing these genome-edited mosquitoes into the wild will not make much difference, because the malaria-battling mutations cannot spread through an enormous mosquito population by regular breeding alone. Our edited genome with the malaria-battling mutation will only be carried by half of the offspring from each pair of parents. After three generations, only half of the mosquito population will have the edited genomes.

Instead, it is now possible to couple the malaria-battling mutations with additional genomic changes designed to ensure a rapid spread throughout a population. The second new edit causes the malaria-battling mutation to get passed down to all offspring from that pair. So, when our new mosquitoes mate with "wild" mosquitoes, all of their babies will also have edited genomes, driving the malaria-battling mutation to spread more quickly through the population. In some instances, by thethird generation, all of the new mosquitoes could be malaria-free. This is called a "gene drive" and it has quickly become controversial.

For the first time, we can introduce genomic changes by genome editing and sweep them through populations of an entire species. On the one hand, you might feel like it's unethical not to introduce such changes if we could stop the spread of malaria. On the other hand, many scientists feel that letting such modified organisms out into the wild is too risky until we understand more about the resulting population-wide consequences. What happens if the malaria parasite develops resistance to the malaria-battling mutations, or comes up with a way to infect another organism? Who gets to decide which organisms are altered in such a large way? Again, the United States National Academies and other organizations are intensely studying the issues relating to these genome-editing technologies, and will issue recommendations as the circumstances change.

Genome editing is a method that lets scientists change the DNA of many organisms, including plants, bacteria, and animals. Editing DNA can lead to changes in physical traits, like eye color, and disease risk. Scientists use different technologies to do this.

Overview

Genome editing technologies enable scientists to make changes to DNA, leading to changes in physical traits, like eye color, and disease risk. Scientists use different technologies to do this. These technologies act like scissors, cutting the DNA at a specific spot. Then scientists can remove, add, or replace the DNA where it was cut.

The first genome editing technologies were developed in the late 1900s. More recently, a new genome editing tool called CRISPR, invented in 2009, has made it easier than ever to edit DNA. CRISPR is simpler, faster, cheaper, and more accurate than older genome editing methods. Many scientists who perform genome editing now use CRISPR.

In the Laboratory

One way that scientists use genome editing is to investigate different diseases that affect humans. They edit the genomes of animals, like mice and zebrafish, because animals have many of the same genes as humans. For example, mice and humans share about 85 percent of their genes! By changing a single gene or multiple genes in a mouse, scientists can observe how these changes affect the mouse's health and predict how similar changes in human genomes might affect human health.

Scientists at the National Human Genome Research Institute (NHGRI) are doing just this. The Burgess lab, for example, is studying zebrafish genomes. Scientists in this lab delete different genes in zebrafish one at a time using CRISPR to see how the deletion impacts the fish. The Burgess lab focuses on 50 zebrafish genes which are similar to the genes that cause human deafness so that they can better understand the genomic basis of deafness.

Treating Disease

Scientists are developing gene therapies - treatments involving genome editing - to prevent and treat diseases in humans. Genome editing tools have the potential to help treat diseases with a genomic basis, like cystic fibrosis and diabetes. There are two different categories of gene therapies: germline therapy and somatic therapy. Germline therapies change DNA in reproductive cells (like sperm and eggs). Changes to the DNA of reproductive cells are passed down from generation to generation. Somatic therapies, on the other hand, target non-reproductive cells, and changes made in these cells affect only the person who receives the gene therapy.

In 2015, scientists successfully used somatic gene therapy when a one-year old in the United Kingdom named Layla received a gene editing treatment to help her fight leukemia, a type of cancer. These scientists did not use CRISPR to treat Layla, and instead used another genome editing technology called TALENs. Doctors tried many treatments before this, but none of them seemed to work, so scientists received special permission to treat Layla using gene therapy. This therapy saved Layla's life. However, treatments like the one that Layla received are still experimental because the scientific community and policymakers still have to address technical barriers and ethical concerns surrounding genome editing.

Technical barriers

Even though CRISPR improved upon older genome editing technologies, it is not perfect. For example, sometimes genome editing tools cut in the wrong spot. Scientists are not yet sure how these errors might affect patients. Assessing the safety of gene therapies and improving upon genome editing technologies are critical steps to ensure that this technology is ready for use in patients.

Ethical concerns

Scientists and all of us should carefully consider the many ethical concerns that can emerge with genome editing, including safety. First and foremost, genome editing must be safe before it is used to treat patients. Some other ethical questions that scientists and society must consider are:

1. Is it okay to use gene therapy on an embryo when it is impossible to get permission from the embryo for treatment? Is getting permission from the parents enough?
2. What if gene therapies are too expensive and only wealthy people can access and afford them? That could worsen existing health inequalities between the rich and poor.
3. Will some people use genome editing for traits not important for health, such as athletic ability or height? Is that okay?
4. Should scientists ever be able to edit germline cells? Edits in the germline would be passed down through generations.

Most people agree that scientists should not edit the genomes of germline cells at this time because the safety and Scientific communities across the world are approaching germline therapy research with caution because edits to a germline cell would be passed down through generations. Many countries and organizations have strict regulations to prevent germline editing for this reason. The NIH, for example, does not fund research to edit human embryos.

Did you know that we are increasingly able to detect cancers by testing just a blood sample? Or that we are moving toward treating cancers not by where they are found in the body, but by how their genomes have changed? Cancer is caused by changes in your genome, but advances in DNA sequencing technology are leading to a new understanding of cancer and new ways for diagnosing and treating many types of cancer.

Cancer is a group of genetic diseases that result from changes in the genome of cells in the body, leading them to grow uncontrollably. These changes involve DNA mutations in the genome. Our cells are constantly finding and fixing mutations that occur in our genome as the cells divide over and over again. But on rare occasions, some mutations slip through our cells' repair machinery, and those mutations can lead to cancer. The Human Genome Project has allowed us to establish what "normal" usually looks like for a human genome, so that we can now tell when changes in our genome have taken place that lead to cancer.

Large projects around the world, like The Cancer Genome Atlas in the United States and the Catalogue of Somatic Mutations (COSMIC) in the United Kingdom, have now determined the genome sequences of thousands of cancer samples of many cancer types. These projects have shown that some cancers have mutations in the same group of genes, even though they may have started in completely different tissues. Many of the mutations activate genes that normally promote cell growth or break genes that normally prevent cell growth. If we know more about the specific mutations that led to someone's cancer, no matter what tissue it was located in, then we can look for more specific and effective treatments for their cancer.

Using the Genome to Treat Cancer

Dr. Lukas Wartman, a physician and a researcher at Washington University, has both led cancer genomics efforts and experienced them himself. Lukas was diagnosed with a blood cancer called acute lymphoblastic leukemia (or ALL) in 2003, when he was in his fourth year of medical school. This led him to specialize in treating patients with leukemia, and studying the disease in the laboratory. While his university was helping pioneer cancer genome sequencing, Lukas suffered a relapse of his ALL with severe symptoms. So the laboratory, including Lukas's mentor, asked if they could study him.

The team compared the genome sequences of his normal cells and those of his cancerous blood cells. In his cancer's genome, they found mutations in a gene called FLT3. The team then found that there was an existing medication that could be used for treating patients with mutations in this gene. Although it had originally been approved for treating other cancers, not blood cancer, they tried it anyway. Lukas started taking the medicine on a Friday, and his blood counts already showed better results by Monday. After a number of weeks, the leukemia cells were no longer detectable in his blood, meaning his cancer was in remission. He will still need more treatment, but Lukas would not have survived without the results of the genome sequencing that pointed him to a new therapy.

There are over 10,000 clinical trials for new therapies in cancer that are recruiting right now in the United States. In addition, cases like Lukas' have led to the resurgence of "n-of-1" clinical trials, where doctors can gather enough information from just one patient to try a new therapy. Such trials are aided by patients who share their genomic data with researchers or even openly with other patients. Increasingly there is hope that as clinicians evaluate new cancer patients, they will be able to compare each new case with these large databases that might include positive responses to medications approved for a different cancer but with the same mutation(s), just like Lukas found for ALL.

Blood Tests to Detect Cancer

Unfortunately, some cancers are harder to evaluate because looking at their genomes would require difficult and painful biopsies or operations where tiny parts of the cancer tissue are removed for study. This also makes it harder for clinicians to monitor how treatment is working for some cancers because repeated biopsies are just not possible. Recent breakthroughs now allow the detection of circulating tumor DNA (or ctDNA) in the blood of patients instead of directly sampling the tumor. As cancer cells grow very fast and die, they release some of their DNA into the bloodstream. We now have tests that are sensitive enough to detect and sequence these pieces of ctDNA in the bloodstream separately from the normal DNA of the patient - this is called a "liquid biopsy."

Although liquid biopsies are not yet in widespread use for cancer detection, improvements are being made all the time that move us closer to the routine use of ctDNA tests. One of the current approved uses for ctDNA is to test progression of non-small cell lung cancer by looking for specific mutations in the EGFR gene over time. Liquid biopsies can point to who will likely relapse after treatment, by detecting DNA with EGFR mutations that is circulating in the blood, sometimes better and more quickly than the now-used standard imaging techniques.

When Cancer Runs in Your Family

If you have a number of relatives who have developed cancer, you might be concerned about your own risk. By far, most cancers are not inherited, but there are a few examples of inherited cancers like Lynch syndrome (also known as hereditary non-polyposis colorectal cancer). This disorder is due to inherited mutations in any of six different genes, and leads to an increased risk of different types of cancers, most often in the colon. Breast cancer is another example; again most cases are not inherited, but men or women who have inherited mutations in the BRCA1 or BRCA2 genes have a much higher chance for developing breast cancer than other people. As we learn more about the genomic changes predisposing a person to cancer, we have been able to make screening tests available to many more people. The specific DNA sequences of the BRCA1 and BRCA2 genes were even the subject of a legal case that went all the way to the United States Supreme Court, who ruled that the sequences of your genes could not be patented. Before this ruling, only one company could provide BRCA1 or BRCA2 testing in the United States, but now there are a number of companies who can help if you'd like to have genomic testing for hereditary causes of breast cancer.