Archive for the 'Genomics' Category

07
Jan
11

is synthetic life approaching?

By Richard Wheeler (Zephyris) 2007. Lambda rep...
Image via Wikipedia

There has always been a metaphysical aura about life. In addition to the material in a cell or other living thing, most people seem to think that when we say “life” we’re talking about a spark or energy that transcends the material constituents of that living thing.

But suppose that organisms that show all the properties of life can be created by off-the-shelf raw materials of our world and made to function as living through human-designed processes? At no point would some spark or energy be added to jump-start life processes although complex chemical reactions are central to synthesizing the constituent parts. (Is the term Frankenmolecules already taken?)

Researchers are working on just such approaches in an effort to understand the details of how living things get organized, and just recently another step was  taken. Princeton chemist Howard Hecht and his team built proteins from scratch, put them in bacteria, and the bacteria used them to grow and carry on just like the proteins they naturally generate. They demonstrated that there’s nothing mystical or magical about molecules generated in vivo. Actually, there were two artificial steps: they designed artificial DNA that then generated the synthetic proteins.

“What we have here are molecular machines that function quite well within a living organism even though they were designed from scratch and expressed from artificial genes,” said Michael Hecht, a professor of chemistry at Princeton, who led the research. “This tells us that the molecular parts kit for life need not be limited to parts — genes and proteins — that already exist in nature.”

“What I believe is most intriguing about our work is that the information encoded in these artificial genes is completely novel — it does not come from, nor is it significantly related to, information encoded by natural genes, and yet the end result is a living, functional microbe,” said Michael Fisher, a co-author of the paper who earned his Ph.D. at Princeton in 2010 and is now a postdoctoral fellow at the University of California-Berkeley. “It is perhaps analogous to taking a sentence, coming up with brand new words, testing if any of our new words can take the place of any of the original words in the sentence, and finding that in some cases, the sentence retains virtually the same meaning while incorporating brand new words.”

Although millions of proteins from evolved DNA already exist, the ones Nature has produced is only a small fraction of the proteins that could be produced by heretofore unseen DNA and protein combinations. The potential design space is vast. Some people think living things were produced by intelligent design from the beginning, but I think these experiments are getting us closer to the truth. Evolution of the world’s material into living things over a hell of a long time gave us what has gone before, but we’re getting closer and closer to true design of life forms from a huge set of possibilities that will become part of our world in the not-too-distant future.

14
May
10

Paging Dr Nano…

I’m kind of obsessed with the nanoscale world because it’s the scale at which basic living systems start. The macromolecules of cells — the building blocks of organisms — are really doing meaningful processes down at the nanoscale.

Nanotechnology — the technology of things designed and engineered down to the molecular and atomic level — is beginning to show signs for remarkable devices not far from going on the market. And one of the first, robust markets for nanotech is going to be medical nanotechnology, especially for cancer. I’ve been watching this for a few years years now.

I recently stumbled across a nanotechnology newsletter I hadn’t seen before: Nanowerk. It’s a European site focused on technology developments in European countries. Every country with healthy science and technology resources is steaming ahead with nanotech R&D in anticipation of huge future development. The newsletter circulates 10 to 20 briefs per day.

An article from May 4 really got my attention. It’s titled: “Informatics moves into nanomedicine,” and reports on research recently published in Pediatric Research. There are what I think are some interesting assertions about the near future of the field.

…some nanoparticles and nanodevices have already been approved or are about to be approved by the United States Food and Drug Administration, including, for example, superparamagnetic nanoparticles to detect metastases in some types of cancer or new devices that combine microfluids or nanosensors to detect tumours.

These applications of nanomaterials open up new prospects for personalized medicine, the authors add, indicating that classical clinical studies need to be redesigned to adapt to the advances taking place in genomics, proteomics and pharmacogenetics. “The introduction of nanoparticles that can target different molecules or groups of atoms with high precision can significantly advance the personalization of clinical procedures”, the article says.

But the statement that blew my mind is:

The possibility of biomolecular devices acting not only in vitro but also in vivo within diseased human organisms is also opening up new prospects, where biomolecular automata could even intervene to intelligently deliver drugs to the diseased regions of the human body just where they are needed.

In this respect, the authors note that research on a “Doctor in a Cell” is already in progress. This is a genetically modified cell that can operate in a human body. It contains a biological computer that can process and analyse external biological signals, emit a diagnosis and deliver the desired molecular therapeutic signal to treat the patient.

The doc-in-a-cell is “already in progress“?! Not exactly the Fantastic Voyage, but close enough to get me excited!

13
May
10

Walgreens blinks

Well, that didn’t take long!

On Tuesday I blogged about Walgreens announcement they were going to start selling a OTC genetics testing kit. I say were… Today they announced that they’re putting that idea on hold. As I predicted, the move started a firestorm and in just two days it was hot enough to get the big retailer to back off.

The FDA and a bunch of doctors and genetics experts piled on and put the brakes on the project.

“These kits have not been proven safe, effective or accurate and patients could be making medical decisions based on data from a test that hasn’t been validated by the FDA,” said agency spokeswoman Erica Jefferson, in an earlier statement Wednesday.

I’m having deja vu. That’s pretty much the same thing that happened when 23andMe and other gene testing companies went public back in ’07. Of course, some of the concerns expressed are not trivial.

The proliferation of consumer-marketed genetic tests has troubled many public health officials and doctors who worry that the products are built on flimsy data.

“The problem with all of these products is they’re based on incomplete, invalidated data and we don’t know what the impact on consumers will be,” said Dr. Muin Khoury, director of the National Office of Public Health Genomics at the Centers for Disease Control and Prevention.

The biology of how DNA variations actually lead to certain diseases is still poorly understood, although a number of public and private institutions have been racing to find answers.

That’s true. One of the themes of this blog is the unexpected complexity of genetic expression that has been uncovered during the past decade. Genetics scientists have been rocked back on there heels to the point of having to rethink some of the earlier assumptions in the field.

It seems that both the public and scientists have held some simplistic assumptions about how genes work. Scientists are making new discoveries nearly every day. So experts say with almost every breath these days: “Genes are not destiny!” Yep, the biology of what happens to us over time is much more complicated than that. So one of the most intriguing questions is: Why aren’t our genes destiny? If our state of being is an interleaving of genetic (internal) influences and environment (external) factors, how do they come together in the organism? That’s a deep issue that will take much more time to plumb. It’s one of those areas where scientists say: “It’s not fully understood.” (That’s science-speak for, “Duh!”)

My thought is that this is an opportunity to bring the public up to date and let them know the puzzle has 1,000 pieces, not 500 as first thought. We have been getting a trickle information about genetics for a couple of decades through media, but that volume is about to increase to a torrent. So where is the effort to help the public have a solid source of up-to-the-minute information? The federal government‘s agencies all have web sites with bits and pieces of the necessary information, but all-in-all the information on genetics is fragmented in a thousand places of variable currency and veracity.

So here’s my wild appeal: As a mainstay of our so-called health care reform effort, let’s extend the charge to our health and scientific agencies (NIH, CDC, NSF, DOE, NLM, etc.) to include making available to the public coordinated, up-to-date, evidence-based information on human biology, health maintenance, medical and scientific frontiers, and a realistic perspective about the circuitous route by which scientific progress is made . Make this available through state-of-the-art communication technology, i.e., the internet and its future derivations. Every citizen, doctor, blogger, teacher, or mom should be able to access reliable information on anything they hear about health in a few swipes of their smartphone. This is a big job and will take money. Surely in the billions budgeted for health care reform in coming decades this would be worthwhile. And this could be an international effort both in information gathering and in paying for it. Health research is global and the findings apply to all of us. The US isn’t going to go to Mars by itself, so why don’t we throw in with all the nations facing the same health issues?

Learning is a process. Walgreens accommodation to the regulators may eventually turn out to be part of something positive.

11
May
10

another volley in the healthcare revolution

The Washington Post is reporting today that a company called Pathway Genomics on is going to start selling through Walgreen’s 6,000 drugstores an over-the-counter kit for testing certain genetic traits.

Beginning Friday, shoppers in search of toothpaste, deodorant and laxatives at more than 6,000 drugstores across the nation will be able to pick up something new: a test to scan their genes for a propensity for Alzheimer’s disease, breast cancer, diabetes and other ailments

The test also claims to offer a window into the chances of becoming obese, developing psoriasis and going blind. For those thinking of starting a family, it could alert them to their risk of having a baby with cystic fibrosis, Tay-Sachs and other genetic disorders. The test also promises users insights into how caffeine, cholesterol-lowering drugs and blood thinners might affect them.

Yeow, that’s going to set off a firestorm! A couple of years ago when companies like 23andMe began to offer tests to consumers the California and New York public health departments and the FDA tried to shut them down. They issued “cease and desist” orders and threatened to charge them with violating various violations of business practice laws. In fact the kerfuffle has already started.

The Food and Drug Administration questioned Monday whether the test will be sold legally because it does not have the agency’s approval. Critics have said that results will be too vague to provide much useful guidance because so little is known about how to interpret genetic markers.

The medical profession is conservative with good reason: lives are at stake. But in all this, in my opinion, is also a component protection of professional prerogatives. Professions in any field don’t give ground to the ordinary person easily.

I’ve had some experience with this. When I started in the cancer field 36 years ago we had two sets of printed literature: one set for the lay public and another for doctors and nurses. You were risking getting fired if you let a cancer patient get hold of the professional literature! The reasons then were the same ones physicians express now about internet information: “they (the public) won’t understand what it means; they will misinterpret it; they’ll suffer anxiety; they might make bad decisions about treatment.” But the internet irreversibly smashed the barrier to access to professional medical information. Doctors are still fighting a rear-guard action and complaining mightily about how it was better in the old days when they were the exclusive source of medical information. I’ve commented on that before.

I’m not dismissing the concerns. No doubt there will unfortunate incidents around these new tests. But what gets me is how unwilling the medical profession is to see the revolution of information that is underway and to rethink the medical paradigm. My pleas is for physicians to start — as a profession — to work on a more equitable and flexible basis with the citizens who want a greater and more equal role in their medical life. We’ll always have a doctor/patient relationship, but I think its going to be much different in the not far distant future.

The internet isn’t going away; instead it’s going to go much, much deeper into our health lives. And genetic tests are not going away either. Like it or not, deep personal knowledge about what lurks in our genes is on the way. Why isn’t the medical profession working with entrepreneurs, patients, futurists, and internet gurus to anticipate what’s coming and do something positive that works for everyone? There’s much, much work to be done, and soon. Without a collaborative movement of innovation and adaptation we’re going to suffer through repeated, time-wasting bouts of friction.

17
Apr
10

the paradigm for the genetics of complex diseases is changing

The structure of part of a DNA double helix

Image via Wikipedia

One of the themes of this blog is that living things are complex and making clinical gains from areas of research such as genetics is just plain hard. There’s been a lot of questioning of genetic research lately, but, as I’ve tried to point out, there are many factors other than plain ol’ DNA involved in finding the way genes manifest in disease. That basic situation got a better expectation this past week when two highly respected genetics researchers at the University of Washington, Mary-Claire King and John McClellan, published an essay in Cell titled, “Genetic Heterogeneity in Human Disease.”

For decades the basic genetics paradigm held that common diseases are caused by common variants (CDCV). That is, to look for genetic causes for cancers the reasonable thing would be to identify genetic variations (mutations) found most often in cancer cases. That makes sense, but it turns out that finding these common genetic variations is not enough to explain all the disease. King and McClellan say:

…from the perspective of genetics, we suggest that complex human disease is in fact a large collection of individually rare, even private, conditions…In molecular terms, we suggest that human disease is characterized by marked genetic heterogeneity, far greater than previously appreciated. Converging evidence for a wide range of common diseases indicates that heterogeneity is important at multiple levels of causation: (1) individually rare mutations collectively play a substantial role in causing complex illnesses; (2) the same gene may harbor many (hundreds or even thousands) different rare severe mutations in unrelated affected individuals; (3) the same mutation may lead to different clinical manifestations (phenotypes) in different individuals; and (4) mutations in different genes in the same or related pathways may lead to the same disorder.

There’s a huge idea here: Complex human diseases involve sets of complex genetic variations, so many, in fact, that each person’s case of a disease may have individual characteristics. We accept the idea that each individual is unique, but it’s perhaps surprising to think that your case of cancer, for instance, may bear individual characteristics.

The overall magnitude of human genetic variation, the high rate of de novo mutation, the range of mutational mechanisms that disrupt gene function, and the complexity of biological processes underlying pathophysiology all predict a substantial role for rare severe mutations in complex human disease. Furthermore, these factors explain why efforts to identify meaningful common risk variants are vexed by irreproducible and biologically ambiguous results.

Next-generation sequencing provides its own challenges. Whole-genome sequencing strategies detect hundreds of thousands of rare variants per individual (McKernan et al., 2009). Biological relevance must be established before a mutation can be causally linked to a disorder. The critical question is not whether cases as a group have more rare events than controls; but rather which mutation(s) disrupting a gene is responsible for the illness in the affected person harboring the variant. Variable penetrance, epistasis, epigenetic changes, and gene-environment interactions will complicate these efforts. It will be fun to sort out. [Emphasis mine.]
So, as I’ve remarked before, life is complicated. Living systems are the most complex things we know of in the universe, and we’re only now beginning to explore them in detail. We want results to save us now! But it’s going to be some time before we fully understand diseases like cancer and then a long time ’till effective therapies are widely available. Moreover, we have no idea what it’s all going to cost, and, as our recent rancorous debate on health care demonstrates, cost is no trivial matter.
22
Mar
10

Cancer costs breaking the bank?

Recent figures compiled by the Kaiser Foundation’s Medical News from a number of sources highlight how much the cost of cancer treatment has jumped in the last decade or so.

USA Today: “The cost of cancer treatment is ‘skyrocketing’ — both for individual patients and the nation, a new analysis shows. From 1990 to 2008, spending on cancer care soared to more than $90 billion from $27 billion. The increase was driven by the rising costs of sophisticated new drugs, robotic surgeries and radiation techniques, as well as the growing number of patients who are eligible to take them, says Peter Bach of New York’s Memorial Sloan-Kettering Cancer Cancer, co-author of an analysis in today’s Journal of the American Medical Association.

HealthDay News: “New chemotherapy agents for metastatic colon cancer improve patient survival but are costly, says a new study. Researchers at Emory University in Atlanta analyzed data from 4,665 patients, aged 66 and older, diagnosed with metastatic colon cancer between 1995 and 2005. Compared to those who received older chemotherapy agents, patients who received one or more of the six chemotherapy agents approved in the United States between 1996 and 2004 lived an average of 6.8 months longer. That increase in survival was associated with a lifetime cost increase of $37,100, which equates to $66,200 per year of life gained.”

As I’ve said before, one of the big surprises of my career in cancer public health was that cost would become as big a barrier to achieving reduction in cancer mortality as some of the characteristics of the disease itself. Between the early 1970s and maybe 2000 the cancer  control community never talked about cost. The advocacy organization I worked for kept focused on the rather idealistic goal of finding the cures for cancer and making them available regardless of the expense. That wasn’t seen as our concern.

Then the disparities in survival rates among ethnic groups began to show up, an indicator that is pretty closely associated with income. After that, the really expensive “targeted therapies” started to come out of the biotechnology companies. The shockingly high cost of rounds of treatment with the highly engineered molecules designed to disrupt specific cell growth “pathways” in cancer cells was a jaw-dropper. The first impulse was to condemn the biotech companies for greedy profiteering. I happened to be familiar with some of the main companies in the SF Bay Area, so I heard the other side of the story from them. I realized that it is not at all easy or cheap to pursue that way of dealing with cancer. I think we have to look at the drugs out there now as experimental drugs, almost research. There may be reason to hope that the technology for this will improve and drop in cost over time…but I wouldn’t bet the farm on it.

In the last year or so that I worked in the cancer community I began to say that — as an advocacy organization — we had a responsibility not only to push for progress on the disease but to develop recommendations as well for how to do it that took into consideration real-world issues like the overall cost. I doubt that many advocacy organizations in health have costed-out their goals in society-wide economic terms. I’m hoping that the rancor of the health insurance reform debate that is going on is also an eye-opener for nonprofit health organizations. Advocacy organizations tend to get tunnel vision. They need to step back and look at where their cause fits in the bigger picture of all the other needs.

11
Mar
10

The family genes

I’ve written several posts about how there’s been a lot of criticism this year of the meager results of gene sequencing in finding therapies for diseases. The genetic keys to diseases have proven elusive to the point there has been discouragement in the field. But there’s perhaps a more positive note in today’s NY Times about two studies being published in journals on Friday. For the last decade the operating assumption of genetics and disease is that common diseases like cancer come from common mutations in genes. But a lot of tests on the connection between genetic mutations commonly seen and common diseases was not strong. Instead the conclusion has been emerging that diseases are really linked to rare mutations. So all those news headlines you’ve seen over the last 10 years of so that declare “gene for depression found” were wrong. It’s not that simple.

For three diseases — Charcot-Marie-Tooth disease, Miller syndrome and ciliary dyskinesia — it turns out that the genetic inheritance comes from more obscure genetic changes by way of Mendelian family inheritance. The studies sequenced the whole genomes of not only the children with expressions of the disease but the parents as well. So they got what you might call the whole-family genome. Identifying diseases that manifest differently depending on the mix of genes coming from mom and dad means that the genomes of the whole troop might be needed.

Fortunately the cost of doing a whole genome is dropping, fast. Complete Genomics of Mountain View, Calif., did the genomes in one of the studies at $25,000 each. That’s a whole lot better than the $3 billion for the first genome ten years ago. They’re promising the $10,000 genome to be followed by the $5,000 genome. Remember, the holy grail is $1,000.

I said in my previous post about the 21st century medical model that our personal health record will need to contain our whole genome. This suggests that linking the genomes of the rest of the family will make the assessments of lifetime disease risk a lot better.

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26
Jan
10

Epigenomics in breast cancer

In my last post I talked about how empigenomics is a hot topic in understanding how genes get expressed in organismic development and how errant development can lead to disease. Well, here’s a specific case where epigenomics plays a role in a common form of cancer: breast cancer.

An article about research on Physorg.com — my favorite science news site — reports how epigenomics plays a role in breast cancer. The interesting thing is that, to understand it, you have to realize that there’s a kind of cellular double-back-flip involved. Let’s see if I can spell this out.

  1. There is a “signaling pathway” called tumor growth factor beta (TGF-beta) that gets over-expressed in some advanced cancers: in this case breast cancer.
  2. TGF-beta sustains the activity of an epigenetic molecule called DNA methyl transferase 1 when a cancerous cell divides and produces offspring cells. The combination of the two factors is key to sustaining the progression of the cancer because they block the expression of genes that have been turned off in the process of turning normal cells into cancer cells. In this case the “epigenetic environment” is essential to enabling the cancer promoting process to be passed on to new cancer cells.
  3. But if the TGFR-beta can be blocked it causes the methyl transferase — the epigenetic factor — to fade away. With the epigenetic factor reduced the offspring cells re-expresses normal genetics and retard the cancer characteristics.

In my last post on epigenetics I mentioned that epigenetics is ordinarily thought of as passing temporarily acquired factors from one generation of an organism to the next. But epigenetics happens also at the level of cell generations, and acquired, abnormal cancer characteristics need to be passed from one generation to the next for cancer cells to stay cancer cells through several generations as tumors grow.

So there you have it: epigenetics at work in cancer. But all this blocking and unblocking in order for cancer to be sustained opens up the possibility it can be disrupted by a drug and stop the disease.

25
Jan
10

Epigenetics: even Dr Oz is talking about it

A couple of days ago as I waited in line to buy a few groceries the cover of  Time Magazine among the tabloids caught my eye. The cover article was titled, “Why Your DNA Isn’t Your Destiny.” It turns out the article is about epigenetics, another one of the processes that produce options and variations in genetic impact. (A few days ago I mentioned RNA editing and how it affects gene expression.)

For a long time life scientists have debated whether some diseases or behaviors are a matter of “nature” or “nurture.” And if diseases — like various cancers — have a component of nurture (environmentally affected) how does that happen? Epigenetics is a kit of processes that modify how genes are expressed without permanently modifying the DNA that’s passed down generation after generation. Epigenetics is sort of the go-between of the nature v s. nurture conundrum. It’s another way genetics gets variability and complexity.

The odd thing about epigenetics is that things in the environment such as drugs or chemicals can change the chemical environment of DNA inside the nucleus of cells causing additional molecules (called methylation) to attach themselves to the DNA and change its expression. The result is cell characteristics that are different from unaffected genetic expression. Also these modifiers can be passed from parent to offspring, but they don’t change the DNA. The Time article says:

Can epigenetic changes be permanent? Possibly, but it’s important to remember that epigenetics isn’t evolution. It doesn’t change DNA. Epigenetic changes represent a biological response to an environmental stressor. That response can be inherited through many generations via epigenetic marks, but if you remove the environmental pressure, the epigenetic marks will eventually fade, and the DNA code will — over time — begin to revert to its original programming. That’s the current thinking, anyway: that only natural selection causes permanent genetic change.

Once again we find that the rather simplistic ideas that scientists had a few years ago about how genes turn into organisms needs to be further explored in light of this rather subtle process. All of these complicating factor might ultimately lead to disease solutions, but it’s going to take some time.

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22
Jan
10

What’s with the perverse link ‘tween cancer and brain disease?

Two weeks ago I posted a somewhat facetious piece about an epidemiological study that found lower risk of cancer in people diagnosed with Alzheimer’s disease and, inversely, lower risk of Alzheimer’s in those with cancer. That’s not just converse but perverse as well.

Now The Feinstein Institute for Medical Research reports that Katherine Burdick, PhD, looked at the relation between the proto-oncogene (a gene that, when mutated, can contribute to cancer) MET and schizophrenia. There are family data that suggest that having a higher risk for schizophrenia lowers a person’s risk of cancer.

Serious mental illness or debility is a lousy trade-off against cancer. But these are not choices you make; they’re biological outcomes that have a rather extraordinary association. The big issue here is that gene and biologic functions have effects that bridge what appear to be very different roles: brain function and cancer. There are clues.

“The results add to the growing evidence suggesting an intriguing relationship between cancer-related genes and schizophrenia susceptibility,” the scientists wrote.

It remains unclear exactly how the gene actually may increase the risk for schizophrenia while protecting against some forms of cancer. However, evidence from research on MET in autism provides some insight. Specifically, it is known that MET is activated (increased activity) when tumors develop and can increase the chance that cancer cells multiply and infiltrate other tissue.

The activation of MET during normal neurodevelopment is critical to ensure that neurons grow and migrate to position themselves correctly in the human cortex. In autism, it appears that while the brain is developing, reduced MET activity results in structural and functional changes in the brain that may increase a person’s risk for developing the disorder. The Feinstein investigators speculate that the same risk-inducing mechanism may be at play in its link to schizophrenia.




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