We've Sequenced the Human Genome. So Why Haven't We Cured More Diseases? | Discover Magazine
Good evening all,
In class, we have talked a number of times about how our phenotype (our physical appearance and characteristics) stems from our genotype (the particular set of alleles that we have in our genome). We've also considered how phenotype and genotype are related, by examination of a handful of traits which are influenced (all, or mostly) by individual genes (such as the trait for freckles, or attached earlobes).
These examples allow us to evaluate the relationship between alleles (such as dominant and recessive forms), to consider patterns of gamete formation and potential crosses (via Punnett squares), and to assess familiar patterns of inheritance (via pedigrees).
These relatively straightforward examples suggest that other aspects of our genetic health, such as disease risk for a variety of conditions, might also be similarly simple: easy to diagnose, and potentially easy to fix, if problematic. Alas, this is not the case for most traits of human disease concern.
I'm forwarding here a link to an article which nicely describes why the genetic basis of our health is not so straightforward, or easy to manipulate. In reality, most of our important human diseases are only very weakly linked to individual genes, which themselves may play only a very small role in influencing our individual disease risk or expression.
So, of what value then is this massive Human Genome Project, this effort to sequence, and understand, every single one of our genes? Well, in short, we do not yet know its full value, as we are still learning how to mine this enormous database. It seems very likely to yield important insights into our genetic disease risks, but it has not led to the immediate creation of a broad spectrum of ready, easy-to-use, off-the-shelf treatments for our human diseases. That day of individualized, genetic approaches to health is coming, though - the first individually-based genetic treatments are now in use. They are as yet not broadly proven, and they remain enormously expensive. But, they represent proof-of-concept types of studies, which suggest that, as our knowledge and technology improve, the days of the 'genome card' are coming. Save some space in your wallets...
Have a great evening -
Good morning all,
I'm passing along here (at page bottom) a link to a recent news article about genetic sleuthing of the source for the 'Wuahn coronavirus', the virus that appears to have made its first appearance in humans and now is causing tens of thousands of infections, and perhaps >1,000 deaths, worldwide. As you now, this has been the top genetics and health news story for several weeks now.
Viruses are a bit of an evolutionary quandary. They are tiny objects, composed of protein and nucleic acid. They are not considered to be cells, and they are not considered to be 'alive'. They are parasitic 'replicating devices' - they can only replicate when they have successfully infected the cell of a host species. And, they are designed to take-over the protein machinery of their host's cell, causing it to make many more virus particles, and to spread them.
Mammals have evolved with viruses throughout our history, and our immune systems contain some viral defenses, just as our genomes contain bits and pieces of DNA that may have been viral in origin. In recent years and decades, we have increasingly been aware of 'new' viruses, not previously seen in humans, that are suddenly causing human disease. Swine flu, avian flu, MERS, SARS, and others - and now, the Wuhan coronavirus.
Why are viruses so common in mammals? Because we are really good hosts for them - lots of cellular protein machinery, warm-blooded cells which promote high rates of viral replication, dense social structure which promotes transmission. From rats to cats, bats, camels and more, each mammalian group bears its own viral load.
Why do viruses move between mammal species? Two words: mutation and opportunity. As viruses mutate, they can gain or lose features that make them better, or worse, suited for particular host species (e.g., cats versus dogs). As species co-mingle, the odds improve that a virus can successfully 'make the leap' to a host of a different species, one to which it is newly well-suited.
Why are so many of these novel viruses originating in Asia? Population density and food production practices. On the global scale, the U.S. is relatively sparsely populated (save our largest cities). Across the globe, it is very common for population densities to be much higher than those found here. And, high human densities require ramped-up food production. Much of food production here is commercialized and removed from the public, but again, this is a global exception. Across most of the world, food production tends to be on a smaller scale, and it tends to be much more personal - individuals tending their own animals, working with their tissues and bringing their own products to open market. Together, this density and close contact ups the risk of transmission of animal viruses to human hosts.
This article describes genetic efforts to identify the original animal source of the human virus, as well as to characterize the virus more fully. The more we know about the virus, the more likely we can stop the spread of infections and develop effective preventatives (such as a vaccine) and treatments.
I will occasionally pass along articles of this type during the semester. My purpose in doing so is to help you to become more aware of topics at the interface of biology and society, and also to help you assess how you obtain your science and health news.
Those of us working in science obtain our scientific news, quite often, directly from the original sources: the people conducting the studies and reporting the results. They publish their findings in science journals, or present them at conferences.
Most people do not obtain their news directly, but hear news via secondary sources, such as news releases from scientific organizations, or news stories from the major news outlets. These secondary reports often are then carried by tertiary outlets (smaller/other reporting sources).
Along the way from source to audience, science news is normally distilled (a lot) - much of the detail is excluded or simplified, and the reports often are boiled-down to singular take-home messages, which may (or may not) be good representations of the original work.
When you browse the links that I will forward, or when you access science and health news on your own, I'd encourage you to delve a little bit deeper into them, to read more than just the summaries, and to follow links back to original sources when possible. I'd also encourage you to think a little about the translation of news from source to consumer, and the reputability of the news outlets that you use.
You will not be formally tested on any of the material in the news stories that I will send you, but I do hope that the material in them makes its way into our classroom conversations.
Have a great weekend -
Good morning all,
Hot off of the presses - new information on the genetic basis of avian migratory behavior, a topic we have considered in class. Here, researchers believe that they have identified a single gene on one of the avian sex chromosomes that is linked to specific migratory targeting in warbler species of conservation concern. Interestingly, this avian gene is related to a human gene thought to be associated with movement.
This is a good example of the current state of much of the study between genetics and behavior. Through large-scale genomic analyses, it is possible to identify associations (correlations) between individual gene variants and particular aspects of behavior, but there is much to be learned "in the middle" - how does any one gene, and its gene product, mechanistically contribute to behavior? Or is the association identified in first-order analyses spurious, or non-causal? There is plenty of room for further work, as these researchers note.
Good luck with all of your remaining exams -
Good evening all,
As I indicated during class on Wednesday, we will not meet for lecture tomorrow (Friday 22 Nov), but instead will consider some topical science news:
We finished one of our recent lectures by introducing the concepts of gene therapy and cloning. Both of these stem from the application of modern genetic methods, and both exist already - but not without controversy.
As described in your text, gene therapy is an attempt to correct defective or missing genes, by using viruses to insert them into a person's cells. It remains very controversial and of relatively limited use, because many of the risks and complications of the technique have yet to be overcome. Indeed, some human gene therapy trials have resulted in patient deaths, and few would say that the technique has been proven to the point at which broad use is possible. Still, for some people with very specific types of genetic defects, gene therapy has proven to be a lifesaver (literally). We can expect to continue to hear much about gene therapy in the years to come.
Related to gene therapy is the concept of gene editing. The goal of this technique is not to replace defective genes with normal copies, but rather to use enzymes to edit (correct) the defective genes in place (e.g., within the cells of the organism). Gene editing utilizes techniques more recent than those employed in gene therapy, so it has been tested, and used, relatively less. Thus, it was of great surprise to the scientific community last Fall when a Chinese scientist (He Jiankui) claimed to have performed gene editing on several artificially (in lab) created human embryos, and then to have implanted those embryos into female surrogates to carry the developing embryos until birth.
The technique of gene editing is new enough that, one year ago, the ethical guidelines governing its use had not been fully developed. Nonetheless, there was a general understanding that the technique was not to be used in human embryonic tissue, that would result in *all* cells in the body inheriting the edited gene. This understanding was very broad, but was not universal, and scientists in several countries did use (or attempt to use) the technique on human embryos, in the hopes of creating a gene-edited person - a "designer baby".
The scientific backlash against this first report of human embryonic (germline) gene editing was relatively swift, and relatively severe. The scientist who conducted these first trials has been stripped of his research position, and charged with violating his country's biomedical research laws. The infants (twin girls) were reported to have been born, but little is known about their condition. Some researchers have suggested that they are at risk of a shortened life expectancy because of the gene editing. The gene that was edited in these now-children is thought to promote resistance to HIV infection, but also seems to play other roles in cells.
The article I am forwarding here comes from a few months ago, when the investigations into this researcher and his colleagues was still in process. In particular, there were a number of scientists here in the U.S. who were implicated as having supported this work. The researchers here have generally been cleared of any wrongdoing, but significant questions remain about who knew what, and the motivations (money? fame? patent-able technology?) for their involvement. This article also includes links to a number of related stories, of which there are many.
It is worth noting that somatic (non-germline gene editing) is gaining ground as a very powerful and promising technique. This variant of gene editing does not change the DNA in every cell in one's body, but only in focal tissues (such as a single organ) that may be malfunctioning due to a defective gene. Indeed, news reports of the promise of this (more-limited) application of gene editing are also prominent in the recent news, including:
I suspect that your generation will be forced to come to terms with the promises and perils of gene editing - it seems both incredibly promising, and incredibly dangerous at the same time. Having a robust set of regulations and ethical guidelines will be very important. If you were faced with the opportunity to correct a gene in yourself, in a loved one, would you? That's a very difficult question to answer a the moment, as we do not yet have enough experience with the pros and cons of these techniques. But, the evidence is beginning to accumulate...
Here's wishing you all the very best Thanksgiving break - please be safe, rest, relax, eat, and enjoy.
Good morning all,
At several points this term, we have discussed the genetics of behavior, including both the ability of single genes to influence behavior, as well as the heritability of individual behaviors and how traits can potentially be mapped onto phylogenetic histories. In the recent behavioral news is a report of a study that used large databases on dog behavior and genetics to look for behavioral traits that were associated with consistent genetic features. The researchers found >100 potential sites in the genome that were strongly associated with dog breed characteristics, including train-ability, aggression, excitability, and others.
One of the strengths of the method used here was that the researchers restricted themselves to a subset of the data pertaining to purebred dogs. This has the advantage of eliminating cross-breed variation which could dilute the strength of the genetic signals they were trying to detect. Dogs also are an advantageous species for a study like this, because they are popular, have long been bred in relatively pure lines, and have been artificially selected for a range of behavioral characteristics.
Some of the associations reported are quite strong, with heritability estimates as high as 60-70%. Those are very high values, near the limit reported for animal behavior-genetic comparisons. It's also surprising, in that, while this study has several strengths in its design, it also has one specific weakness: the researchers did not have genetic and behavioral information from the same individual animals, but instead were relying on databases (and breed averages) assessed across different individuals. That suggests that some of the associations, if tested within individual subjects, could be even stronger.
The human-dog relationship is a long one, and our artificial selection of dogs has been enormously powerful - when you think about all of the different dog breeds in the world, from Danes to dachshunds, Newfoundlands to chihuahuas, they all are the same species. That is testament to an enormous phenotypic plasticity (reaction norm) within their development. I'm going to request a copy of the original research article that this news report references, if anyone would like to see it - I'll bet it is interesting reading. Perhaps it will shed some light on my dog's (a rescue Rottweiler) behavior...
Have a great rest of the weekend - see you on Tuesday.
Good morning all,
As our term comes to a close, I'll use my last news message to send along the latest news from two ongoing news stories in genetics:
The first bit of news is about a newly reported fossil find, from a branch of ancestral hominins known as the Denisovans. While scientists and anthropologists have been studying our Neanderthal relatives for decades, Denisovans are only recently discovered. They are thought to have represented a 3rd lineage of ancestral hominin, that co-existed with and likely inter-bred with both Neanderthals as well as early humans.
Until very recently, all information on Denisovans came from fossils collected from a single location, the Denisova cave in modern Siberia (Russia). This new report describes a Denisova fossil from much farther south, in modern Tibet, which suggests that Denisovans were more broadly distributed, expanding the ranges of times and locations over which they may have interacted with modern humans. We know so little about Denisovans that this new information has been described as 'game changing'. If you recall the patterns of early human migration we considered, the first humans may well have had opportunity to interact with the last Denisovans. We all likely have some 'Neanderthal DNA' in us; we may come to realize that we all have a little 'Denisovan DNA', too.
The second news story I will send here relates to the promise, and difficulty, of genome editing. We've discussed a number of times the concept of genes and alleles, and we've considered both gene therapy as well as some of the news related to human genome editing. Recently, a group of prominent scientists has argued that, given our current state of knowledge, the use of gene editing to produce 'designer babies' is more fiction than fact. Even apart from the difficulty of successfully edited the human genome, they suggest that the likelihood of finding individual genes with pronounced effects is very, very low. If you remember, genome-wide association studies (GWAS) can be used to identify genes associated with particular aspects of our physiology and health, but the strength of these associations normally is very low (e.g., often <1%). As such, we may not yet have good, individual targets for gene manipulation.
That said, it is very likely that both our gene-editing as well as our genome evaluation skills are going to improve over time, so perhaps the current limitations on the likelihood of 'designer genome editing' are just that: current, but not permanent. It seems impossible that this topic, or interest in it, is going away any time soon.
I'm signing off for the term now. I hope that these weekly news messages have been useful to you. This is the first semester that I have used them to this extent, and it has been a learning experience for me. In particular,
In the end, though, I remain very optimistic. Science is "mankind's organized quest for knowledge" (Floyd Bloom), and we already know that "knowledge is power" (Francis Bacon). It is science that offers us the best hope to deeper understanding, new therapies and treatments, new cures, and new adventures. We will encounter many speed-bumps along the way, to be sure. I hope that our course has inspired you to be a part of this quest, and to make the best use of the knowledge that you gain while on it.
Have a great weekend, and best of luck with all of your exams next week.
WHO | UV Index
Good morning all,
As we head into warmer weather, thoughts inevitably turn to outdoor activities. With them comes, of course, exposure to sunlight and its radiation. Natural light offers us warmth, pleasurable sensations, and stimulates vitamin D production. As we have been discussing in lab, sunlight also contains dangerous levels of UV radiation.
One of the safety concepts we hear reported related to outdoor activities is the "UV index". This is a scale meant to represent the relative degree of exposure risk posed by harmful UV radiation. The World Health Organization, in partnership with other health agencies, promotes the use of this index as a way to keep the public quickly and easily informed of their exposure risk. The index is fairly easy to interpret: low index numbers, relatively low risk; higher numbers, more risk.
Behind the index is a fair amount of science, in which measured amounts of UV exposure were assessed for their ability to cause cell and tissue damage. Many of the initial studies were done without direct knowledge of what was changing in cells, or what was driving tissue damage. Now, health scientists are able to marry environmental exposure studies to genetic studies, leading to genetic profiles for many of our genes. For example, we now know that the gene responsible for directing production of the melanocortin 1 receptor (gene MC1R) is often mutated by UV radiation; its mutation is one of the leading agents of skin cancer. The normal role of the MC1R gene product is to regulate the production of melanin (eumelanin) in our skin cells, the same melanin which gives us a 'tan' after UV exposure. We all have different levels of melanin production; those of us with lighter skin produce relatively less of it and are at higher risk of UV damage.
Our lab exercise of the past two weeks demonstrated how even short durations of UV exposure can mutate DNA, and also showed how critical DNA monitoring/repair is to continued health. The plate coverings that we used all provided some degree of protection from radiation. While it may be impractical to cover ourselves with tin foil when we venture outside, sunscreen or even thin cloth provided very useful protection. Remember those plates which were empty of yeast the next time you think about spending long hours in the sun - be sure to use sunscreen!
Have a great weekend -
This Genetic Mutation Makes People Feel Full — All the Time - The New York Times
Good morning everyone,
Our lecture on Tuesday of this week described the essentials of digestion, and Thursday's topic followed with consideration of metabolism and energy balance as a whole. In the science news this week is a new study on these very topics, with description of a genetic mutation that influences both.
During our digestion lecture, I noted that much of its function is regulated autonomically, by local reflexes mediated in the ENS. That is to say, the digestive tract functions more or less on its own when food is presented to it. By inference then, regulation of food acquisition controls the overall amount of digestion we perform, and the number of calories we have available to use or store.
Regulation of hunger, food-seeking, and feelings of satiety (satisfaction of hunger, or "fullness") occur largely through the hypothalamus, where a variety of chemical signals are known to promote either orexigenic (food-seeking) or anorectic (satiety) states. These include a number of cryptically-named chemicals such as CART, alpha-MSH, agouti-related peptide (AgRP), and melanocortin (MC), each acting at hypothalamic cells bearing specific receptors for them. A great deal of experimental work over the last several decades (mostly in mouse models) has demonstrated that disruption of their signaling (via increased activation of their receptors, or blockade of them) can cause food consumption and body mass to either increase, or decrease.
Abnormally-elevated body mass to the point of obesity has reached critical levels in this country. Depending upon the guidelines one uses, it has been estimated that 30-40% of adults in this country are obese, with another substantial proportion of the population classified as overweight. Extra body mass is a significant health complication, raising one's risk of a number of diseases (including hypertension and diabetes) and complicating treatment and prevention of many others. As such, there is an enormous research effort underway to explore the roots of obesity. We know for certain that the issue is complex - socioeconomic status, willpower, behavior, access to high-quality foods, and sociality influence our food choices, eating habits, and body mass, in ways that are both many and complicated. Increasingly, there is growing appreciation of genetic components to obesity as well.
Modern genetic assessments of health have benefited by technological advances that allow sequencing of individual genomes, resulting in large databases of genetic information. When these are paired with health profiles and lifestyle data, they make possible genome-wide association studies (GWAS). GWAS represent a powerful way to take two very large sets of data (gene sequences and health/lifestyle data) and see how/where they intersect. In contrast to the twin study I described to you in my science news email last week, GWAS are useful only when based upon thousands (usually, hundreds of thousands) of individuals. These are not experimental methods, so they cannot provide definitive proof of anything, but they can reveal interesting "associations" - places where genetics and health vary in consistent ways.
This new study describes a GWAS that sought genetic bases for obesity. In a very large sample of human subjects (500,000 individuals), the researchers looked for consistent genetic mutations in people who were, or were not, obese. They found evidence for specific genetic variation in the MC4R gene (melanocortin receptor 4) that was associated with obesity: persons whose MCR4 gene was mutated (causing reduced function) were much more likely to be obese that those who carried the 'normal' version of the gene. To some extent, this finding was not new - this effect of MCR4 mutation had been described previously, in smaller studies. Here, though, the researchers also found evidence that if mutations in the gene(s) that regulate MCR4 cause it to be 'turned on' all of the time (instead of occasionally, such as after eating), it causes chronic satiety, or "fullness". Persons with this form of mutation are much less likely to be obese, so the researchers interpret this alteration of MCR4 function as protective, and preventive of obesity.
Thus, we may have a single gene, which if mutated in one fashion can contribute to obesity, and if dis-regulated in another way can protect against it. A second study described in this same article uses similar data to create a genetic risk assessment for obesity, with the hope of reducing its prevalence, potentially by intervening before it reaches criticality.
The genetic associations described in this study are not enormous, just a few percent (perhaps 6%). Still, they represent the largest known genetic association for obesity, and that in and of itself is a very worthwhile finding. Many persons who are obese suffer from anxiety, depression, and feelings of low self-worth, thinking (and too-often being told) that they are 'fat', or overweight, because of their behavior and lack of willpower. What if the problem lies in their genes, and not in their self-control? We all know how difficult it is to resist food when we are hungry - what if that feeling never goes away?
Like most science, these studies raise more questions than they answer. Obesity and weight control are such significant problems, though, that their investigation is crucial to improved public health. Here's to more studies and more information on these topics - they are likely to benefit us at a variety of levels: individually, via our loved ones, or as part of society as a whole.
Have a great weekend -
Don’t Count on 23andMe to Detect Most Breast Cancer Risks, Study Warns - The New York Times
Good morning all,
In lab recently, we have been considering some of the aspects of personalized genetics, with particular reference to genetic ancestry and the use of DNA databases in forensic and criminal investigations. During our introduction to this topic of personalized genetics, I noted that there also are significant interests in using personalized genetics as a way to assess health. Indeed, many of the commercial entities that offer to analyze an individual's DNA also offer to provide some estimate of their health risks for a variety of conditions. I also said at the time that, in our discussions, we would largely stay away from the health aspects of these services, as they are much less well-established than are the ancestry ones.
I described to you recently how using DNA in criminal investigations relies upon combining two large databases (of individual genomes, and police records) to look for intersections, in order to highlight potential crime suspects or their relatives. Using DNA to assess health risks works in a very similar way, this time by evaluating databases of individual gene sequences against databases of individual health and lifestyle records. These types of tests are called genome-wide association studies (GWAS). GWAS are useful only when based upon thousands (usually, hundreds of thousands) of individuals. These are not experimental methods, so they cannot provide definitive proof of anything, but they can reveal interesting "associations" - places where genetics and health vary in consistent ways.
There are lots of large databases of public health records and DNA sequences, and many researchers and even some governments are using them to investigate public health. The commercial operatives also offer to do the same for their subscribers. In the news this week is a reminder that simply claiming that such a service is available does not mean that it is a complete or accurate one. Researchers at not-for-profit health institutions are warning that those who use 23andMe health assessments of genetic risks for breast cancer (the leading type of cancer in women) are potentially being misinformed of their genetic risks. This is a big deal - many people make dramatic decisions about their health and life when learning of their genetic risks for breast cancer, such as undergoing mastectomy (breast removal). At the opposite extreme, what if a person has a substantial risk, but is told that they do not?
The federal Food and Drug Administration (FDA) has given its approval for 23andMe (and other commercial) genetic health assessments, and this is an important reminder that FDA approval is not meant to imply that the services are the best available, more so that the services are generally safe and perhaps useful. Anyone who is using a commercial service to evaluate their genetic health risk should follow-up with their physician if they have any concerns - the better hospitals can perform some of these tests on their own. "Caveat emptor", or "buyer beware" - commercials services, by design, place emphases on their interests, first. When in doubt, a second opinion from an independent health professional is the best course of action.
Have a great weekend -
A cold case killing from 1972 was cracked with the help of genetic genealogy - CNN
Good morning all,
In lab this past week, we considered some of the aspects of personalized genetic testing, including the ability to estimate one's genetic heritage and family history through evaluation of genetic dissimilarities to others. Fresh on the heels of that discussion is another news report of more decades-old crimes being solved by similar kinds of genetic comparisons.
When a person offers their genetic information to 23andMe, Ancestry.com, or other of the genetic history services, their DNA sequence and its identified markers are entered into massive databases. It is only against these databases that useful comparisons can be made - we can't learn much about our genetic history by comparing our DNA to that of one or two others.
Remember that these DNA sequences can be compared for similarities and dissimilarities, and they also can be clustered into haplotypes - groups that share some common ancestry. Haplotypes are the basis for construction of genetic pedigrees, or genetic 'family trees'.
How can we solve crimes using this information? Imagine that 5 or 10% of the population of a city have their DNA stored in one of these databases. If a crime (new or old) is committed, investigators can
1) collect DNA evidence from a crime scene (easy to do, as we leave hair and cells everywhere we go)
2) compare the DNA from the crime scene to that of the collected database
3) Evaluate whether there is a direct DNA match to someone in the database. If so, that person may be the culprit! Well, if only 10% of a population has been genetically profiled, the odds of that are low. It's also likely that that people who commit crimes are not likely to freely offer their DNA to public databases.
4) But, we all have relatives. Investigators can often find similarities between the DNA collected at a crime scene, and the DNA of some family group within a database. Then, they look at the personal and family backgrounds of just those individuals. Are any of those people in the DNA database related to someone who has committed other crimes, and has a criminal history already in the police records?
This represents a very powerful way to quickly sort through a lot of information. One the one hand is a large database of genetic information. On the other hand is a large database of police records of crimes and criminals. Finding out specifically where they intersect is the key, and such a comparison often produces leads to a small number of individuals as suspects.
5) Suspects can then be watched/followed, and their DNA then sampled (for example, by collecting from the trash a drinking cup they had used). If this new DNA sample matches that collected at the crime scene, the crime may be solved.
It is exactly these methods which are being used in many cases, both new and old. Notice that they rely very heavily on personal genetic data, and, importantly, notice that suspects can be identified even if they don't offer their own DNA, as long as someone related to them already has. This is a challenge for the courts, too - what is an individual's right to privacy and protection from suspicion when your relatives implicate you, just by being related?
It's exciting to think of the possibilities for learning about one's self through DNA. It's equally important to remember that these are discoveries that we cannot make on our own - we are relying upon public and commercial databases, that can be used in ways we may not have intended or not even thought about. Science is about progress - new ideas, information, and abilities. Even as we reap the benefits of these advances, it is important that, as a society, we stay abreast of the social and ethical challenges that come with them.
Have a great weekend -