FundScience Blog

Introduction to Evolution

February 12^th, 2009 was Charles Darwin’s 200^th birthday. That weekend, I had dinner with some friends, most of whom are scientists. I mentioned Darwin’s birthday and, being scientists, we raised our glasses and toasted Darwin. However, one of the ladies at the table, who is not a scientist, objected and said that evolution is just a theory and she doesn’t believe it. She was the only person at the table to hold this opinion, and much of the night was spent trying to convince her otherwise. Her primary stumbling block was her belief that evolution is an entirely random process, and she did not believe that ever-increasing complexity could arise by chance. There are a variety of things wrong with her idea of evolution, and what I quickly realized is that she simply did not understand evolution. Worse yet, I quickly learned that a table full of scientists could not do a sufficient job of explaining it to her! This led me to ask myself a couple of questions. First of all, how many people out there accept evolution without fully understanding it? Secondly, how many people do not believe in evolution because they simply do not understand it? Therefore, I decided to write this blog post as a simple introduction to evolution. Universities offer entire courses focused on explaining evolution. This post is not meant to substitute for a 4-month college class. Instead, I simply aim to address the basics of evolution and some of the common misconceptions.

In 1859, 150 years ago, Charles Darwin published On the Origin of Species, one of the most important and influential books ever written. In it, Darwin introduced his theory of evolution, which itself evolved over the course of Darwin’s 5 year journey around the world on the HMS Beagle, and in the subsequent years studying his notes from the journey. At its core, Darwin’s theory established a scientific explanation for diversity in nature. A minimal working definition of evolution is “a process that results in heritable changes in a population spread over many generations.”

Webster’s dictionary defines evolution as, “the development of a species, organism, or organ from its original or primitive state to its present or specialized state; phylogeny or ontogeny.” Definitions such as this one are inaccurate for a number of reasons. First, they imply that modern species/organisms/organs arose in their present form from original or primitive species/organisms/organs. This leads to anti-evolutionists saying things like, “I didn’t evolve from a monkey!” They are absolutely right! They did not evolve from a monkey. The primary problem with such definitions is that they ignore the most important parts of evolution, thus leading to a great deal of confusion. It is absolutely necessary to underscore the point that evolution is a gradual process, “spread over many generations.” It is absolutely necessary to point out that evolution “results in heritable changes,” meaning that the changes are genetic and can be passed from one generation to the next. Finally, it is imperative to point out that evolution applies to entire populations, not individuals.

Such inaccurate, but widely touted, definitions have given rise to many misconceptions of evolution. Many of these misconceptions have been dealt with elsewhere, and I encourage the reader to continue learning about this process by exploring the links and Related Articles section below. While I may be accused of oversimplification, I will now attempt to address a few of the most common misconceptions of evolution.

First of all, I will address my friend’s belief that evolution is entirely random. In fact, evolution may be considered a two-step process. It is true that there is some degree of randomness. The first step of evolution is the introduction of genetic mutations, which occur by chance or randomness. However, mutations constantly arise and the vast majority of mutations are lost. For a mutation to take hold and be passed on to subsequent generations, it must provide some advantage. This is part of the process of natural selection, or the second step of evolution. Natural selection is tightly regulated by the environment, and is anything but random.

That being said, natural selection is only a piece of the puzzle. If we ignore chance events, we are ignoring a large part of the process of evolution. As I said, mutations are constantly occurring, due to a multitude of factors. In fact, every human embryo contains at least 100 new mutations. Some of these mutations may be harmful and may be lost during natural selection, often resulting in death of the embryo. However, most mutations are neutral, meaning they provide no positive or negative influence. When a mutation is beneficial and passed along, or is harmful and lost, that is natural selection. If a mutation is neutral and is passed along, as will happen simply because there are so many neutral mutations, that is an example of random genetic drift. A specific example of genetic drift in a population is eye color. Humans, and other diploid organisms, have two copies (alleles) for each gene. In the case of eye color, if a person has brown eyes, they may have a brown allele and a blue allele, but brown is dominant and will be expressed while blue is recessive and not expressed. However, either the brown or blue allele can be passed on to offspring, creating the possibility that two brown-eyed parents can have blue-eyed offspring. In effect, genes of offspring are a random sampling of parental genes.

Another misconception voiced by my friend is that evolution leads to ever-increasing complexity. It is certainly true that evolution has produced a multitude of complex organisms, including humans, and this complexity is due in part to natural selection. However, recent research has led to a competing hypothesis, suggesting that increased complexity actually results when selection is weak or absent. In essence, this hypothesis suggests that weak selection may allow for things such as duplicate copies of genes, which may arise due to genetic drift and be weeded out when selection is strong. For instance, there is a great deal of evidence that some modern, “simple” species have actually evolved from more complex ancestors. Examples include many species of cavefish and other organisms that live in the murky depths of the ocean, which have lost their eyes due to natural selection. Living constantly in darkness, these organisms no longer needed their eyes. As other traits gradually evolved to aid survival in darkness, unnecessary features such as eyes gradually disappeared, illustrating that evolution giveth, and evolution taketh away.

Counter to the above misconception, many people also believe that evolution is unlikely to produce complexity. This view is often the result of the failure to understand the time necessary to produce complex organisms, and is another example of the confusion that can arise from inadequate definitions of evolution. It is true that a single mutation, or even a series of mutations, is unlikely to produce more complex organisms. But more complex organisms do not typically arise in a single generation. The evolution of complex organisms requires multiple generations. Life on earth, as we know it, has evolved over billions of years. The process has involved countless mutations, many of which have been positively selected, and many more of which have been eliminated. It is important to remember that natural selection is not intrinsically progressive, meaning it does not tend toward more complex organisms. Populations are selected for either increased or decreased complexity in response to local environmental conditions.

Another misconception is that natural selection always promotes the survival of species. In fact, natural selection applies not only to populations of organisms, but also to genes. While it may be difficult to comprehend, positive selection of genes can actually be detrimental to the whole organism. Examples include transposons, which are positively selected DNA elements that can cause genetic diseases such as hemophilia. Multiple other examples exist and are given a more thorough treatment here. It is important to note that evolution is not always a constructive process. While we are surrounded by examples of successful species, countless others have failed, resulting in extinction of species.

The last thing I would like to address is the teaching of evolution in this country. Much of the rest of the developed world accepts evolution more than the United States. To some degree, this is likely the result of religious influence. It is no surprise that the more devout a person, the less likely they are to believe in evolution. These beliefs have a tremendous influence on our politics and, thus, our education system. Therefore, the treatment of evolution in our schools is often meager, at best, and many states continue to push the teaching of intelligent design/creationism as a realistic alternative. The map below is from a 2002 Scientific American article and illustrates how and where evolution is taught in the US.

As you can see, as recently as 2002 only a handful of states received “Very good/excellent” ratings. For the record, I received a pretty good science education in a North Carolina public school, including the teaching of evolution. I distinctly remember that one of my favorite biology teachers, while teaching evolution, was asked by another student if she believed in God. The teacher said she did, but chose to believe evolution was God’s plan. That teacher was an example of someone who found a balance between her religious views and her scientific views. She did not let her religious beliefs mar her scientific views, and she did a good job of teaching evolution. Many other students are not so lucky.

There are those who argue that evolution is just a theory and has not, or even cannot be, proved, so should not be taught. In fact, evolution is supported by overwhelming evidence that has accumulated over billions of years. As a virologist, I see evolution on practically a daily basis. In fact, you can watch the process of evolution almost daily in any microbiology laboratory in the world. Viruses and bacteria, as examples, are constantly evolving. The process of natural selection leads to drug-resistant bacteria and the new strains of influenza virus we see every year, which make us create a new flu vaccine every year.

There are also those who say that it doesn’t matter whether or not we accept evolution. Believe it or not, evolution impacts our lives. People who do not understand, or choose to deny, the mountains of scientific evidence supporting evolution are all too often the people making decisions that affect the rest of us. A rejection of evolution is a rejection of basic science principles. These principles have shaped not only our country, but the entire world. To reject these principles is to deny our history, and to impede our future.

While this post is intended to be a simplified overview of evolution, I want it to be as accurate as possible. There are far too many inaccurate accounts out there, and this should not be yet another one. Therefore, if you believe that I have left out something particularly important, or that I have not given a proper treatment to any of the topics, please let me know in the comments. Similarly, if you would like additional clarification on anything I have written here, please do not hesitate to ask questions in the comments. This blog is, above all, a place for education.

Related Articles

• Evolution: 24 Myths and Misconceptions
• Understanding Evolution
• What is the evidence for evolution?
• July 1, 1858: Darwin and Wallace Shift the Paradigm
• New Findings Confirm Darwin’s Theory: Evolution Not Random
• New Insights into the Evolution of the Human Genome
• Fossils Challenge Old Evolution Theory
• Out Of Africa — Bacteria, As Well: Homo Sapiens And H. Pylori Jointly Spread Across The Globe
• Study Detects Recent Instance of Human Evolution
• 12 Elegant Examples of Evolution
• Darwin still making waves 200 years later
• Darwin 200 years:  Things you didn’t know about Charles Darwin
• At 200, Darwin Evolves Beyond Evolution
• The Human Pedigree: A Timeline of Hominid Evolution
• The Future of Man–How Will Evolution Change Humans?
• Putting Evolution to Use in the Everyday World

Antibiotics that Don’t Kill Bacteria.

Antibiotics and drug resistant bacteria are a little talked about yet growing problem. I recently saw a well written and lay person oriented article about creating antibiotics that don’t kill bacteria. The article is here. 

Ok. Now to the question everyone is probably asking by now: Why is that a good thing? Isn’t more bacteria around a bad thing ? 

In order to answer that question I have to say a few general things about bacteria in general:

1. Bacteria grow and reproduce very very quickly.
2. It usually only takes one or a few bacteria to re-grow a complete colony.
3. Most if not all therapies deal with inhibiting the bacteria and killing it off (usually while killing other types of bacteria as well)… 

Gene Therapy for Type-1 Diabetes

Introduction.

Type-1 diabetes is a chronic disease resulting from autoimmune-mediated destruction of insulin-producing pancreatic beta cells. Although progress has been made toward improving diabetes-associated pathologies and the quality of life for those living with diabetes, no therapy has been effective at eliminating disease manifestations or reversing disease progression. Therefore, novel therapeutic approaches are currently being sought. Among the approaches with the most promise is gene therapy.

Background on the Disease.

Type-1 diabetes (T1D), also known as insulin-dependent diabetes mellitus, is recognized as a rapidly growing health threat worldwide. The CDC estimates that 15,000 young people in the United States per year are diagnosed with T1D, with 19 new cases per 100,000 youth each year

Existing Therapies.

T1D patients require lifelong insulin replacement therapy, and are at risk of developing significant complications associated with hyperglycemia, such as retinopathy, neuropathy, nephropathy, and accelerated peripheral vascular and coronary artery disease. The goal of existing therapy is to provide tight glycemic control in all diabetic patients in order to minimize the complications associated with hyperglycemia.

Furthermore, while allogeneic islet transplantation has shown some evidence of success, the allo- and autoimmune response against the islets often leads to their destruction

Overview of Preclinical Gene Therapy Studies.

Until recently, gene therapy studies for T1D had focused primarily on ex vivo approaches to modify islets for transplantation. Although many different approaches have been examined, the goals of these modifications are similar: to transfer a gene encoding a protein which would confer some type of islet-protective effect to the grafted islets in order to protect them from allo- and autoimmune attack when transplanted into the patient. When successful, this prolongs graft survival and may potentially reduce the need for systematic immunosuppressive therapy to prevent loss of the graft. Some lingering concerns with the use of transduced islets are safety and efficacy. Particular concerns include whether expression of virally-encoded proteins from the islets will have some effect on the cellular function of the transplanted cells or immunological function of the patient receiving the graft.

Another major focus of ex vivo gene therapy strategies for T1D has been in the modification of immunological cells to promote tolerance upon adoptive transfer in vivo. Dendritic cells have been of particular interest for applications in T1D because of their unique role in regulating T cell responses. Both adenoviral and lentiviral gene transfer of IL-4 to DC have been shown to have protective effects in the NOD model of T1D

Overview of Clinical Gene Therapy Studies.

To date, few proposed gene therapy strategies for T1D have progressed to the point of clinical trials. A Phase I clinical trial to examine safety is currently ongoing using DC genetically modified using antisense oligonucleotides (AS-ODN) to the costimulatory molecules CD40, CD80, and CD86. In preclinical studies using the NOD mouse model of T1D, investigators demonstrated that the AS-ODN treated bone-marrow derived DC were able to delay the incidence of diabetes after a single injection, and observed that the AS-ODN treated DC resulted in an expansion of a CD4+CD25+CD62L+ regulatory T cell population

Conclusions.

Considerable progress has been made towards developing gene therapy approaches for T1D, leading to the development of some phase I clinical trials. Because this disease does not respond well to present biologics, the development of alternative approaches, such as gene therapy, seems highly appropriate. Overall the technology of gene transfer, along with efficacy of gene therapy in animal models of autoimmune diseases, such as T1D, has developed to the point where it is no longer the rate limiting step for many purposes. Instead, the focus of the field of gene therapy for autoimmune diseases is now on bringing these approaches into the clinic.

References.

Gene Therapy for Rheumatoid Arthritis

Introduction.
Gene therapy offers great possibilities for the treatment rheumatoid arthritis (RA). RA was the first orthopedic condition to be targeted by gene therapy. Initially, RA, a non-lethal disease that is not regulated by a single gene, may not have been an obvious target for gene therapy. However, while traditional surgical and pharmaceutical methods of treating RA have met with limited therapeutic success and have failed to produce a cure, the past several years have seen extensive progress toward development of gene therapy for arthritis. Numerous vectors and therapeutic genes have been investigated in animal models of arthritis, and the potential of gene therapy to treat or manage RA has been demonstrated in several clinical studies. Gene therapy offers the possibility of overcoming many of the limitations of current biologic therapies by providing long-term, high-level localized expression of therapeutic genes, potentially in as little as a single dose.

Gene therapy emerged as a novel strategy to treat arthritis in the early 1990s. Fundamentally, arthritis gene therapy involves the transfer of complementary DNA (cDNA) encoding antiarthritis gene products, which may be difficult to administer by more conventional methods. Gene therapy offers the promise of long-term expression of antiarthritis gene products, as well as targeted delivery to and expression in affected tissues, limiting potential systemic side effects.

Background on the Disease.
Arthritis is the leading cause of disability among adults in the United States, affecting approximately 21% (more than 46 million) adults. Rheumatoid arthritis (RA) affects approximately 1.3 million adults in the United States, and more than 60 million people worldwide [1]. RA is characterized by inflammation of the synovial lining and destruction of extraarticular bone and cartilage [2]. It is believed that arthritogenic peptides, either from foreign or self proteins, are presented to T cells preferentially by RA-associated MHC molecules on antigen-presenting cells [3]. Activated T cells produce a variety of proinflammatory cytokines, including TNF?, IL-1 and IL-6. The inflammatory response induced by these cytokines is directly responsible for the overt RA symptoms, including joint pain, swelling, effusion and stiffness.

Existing Therapies.
Despite the prevalence and rising economic burden of RA, effective therapies for this disease remain limited, and there is no cure. Current therapies consist of early, aggressive and continuous treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). Among the DMARDs, methotrexate has long been the drug of choice for RA, but newer biologic targeted therapies have emerged in recent years. These targeted therapies include Orencia®, a fusion protein composed of the extracellular domain of cytotoxic T lymphocyte antigen-4 fused to an immunoglobulin (CTLA4-Ig); Kineret®, an interleukin-1 receptor antagonist (IL-1Ra); Remicade®, a chimeric anti–TNF? antibody; Humira®, a fully human anti–TNF? antibody; and Enbrel®, a soluble TNF? receptor [4]. As a result of these therapies, the outlook for RA patients is better than at any time in our history. However, it is important to remember that these drugs provide treatment, not cures. In addition, the chronic nature of the disease necessitates lifelong treatment for most patients. Therefore, the long-term efficacy, safety and expense of these drugs remain concerns, particularly due to the high systemic doses and repeated intravenous or subcutaneous administrations necessary to achieve therapeutic results.

Overview of Preclinical Gene Therapy Studies.
Given the success of biologic targeted therapies, various strategies have been employed to utilize these immunomodulatory agents in RA gene therapy. Multiple preclinical RA gene therapy studies have demonstrated that gene therapy vectors, including retrovirus and adenovirus vectors, expressing IL-1Ra produce high levels of the transgene in target tissues and inhibit inflammation and cartilage loss in animal models. Similarly, numerous studies have demonstrated the effectiveness of blocking TNF? activity via gene therapy, including the suppression of inflammatory cell infiltration, pannus formation, cartilage and bone destruction, and expression of joint proinflammatory cytokines in animal models [4].

Furthermore, AAV expressing a TNFR:Fc fusion gene under the control of an inflammation-inducible NF-?B promoter delayed disease onset and decreased the incidence and severity of joint damage in mouse and rat arthritis models [4]. This type of gene therapy, utilizing a disease-inducible promoter, is of particular interest in autoimmune diseases like RA, which are characterized by flare-ups followed by periods of disease regression. By utilizing the inflammation-inducible NF-?B promoter, high levels of transgene expression are obtained only during disease flares, preventing unnecessary exposure of the patient to immunosuppressive agents during periods of disease regression.

In addition to proinflammatory cytokines, an important role for NF-?B signaling has been established in RA. NF-?B controls the expression of proinflammatory mediators of RA, including TNF?, thus may serve as a master regulator of the disease. In terms of gene therapy, both adenovirus and AAV have been utilized to deliver NF-?B inhibitors to synovium, successfully preventing expression of proinflammatory cytokines [5, 6].

A variety of growth factors have also been studied as therapeutics for RA. Bone morphogenetic proteins (BMPs), particularly BMP-2 and BMP-7, have been shown to induce chondrogenesis and osteogenesis when delivered by adenovirus or AAV vectors [4]. Additional growth factors that have been studied in relation to RA gene therapy include transforming growth factor (TGF)-?1 and insulin-like growth factor (IGF)-1. Adenovirus or AAV vectors expressing TGF-?1 have been used to transduce mesenchymal stem cells (MSCs) and drive ex vivo differentiation of MSCs into chondrocytes, facilitating cartilage repair in animal models [7]. Similarly, ex vivo chondrocytes transduced with an adenovirus expressing IGF-1 enhanced matrix synthesis and cartilage repair in horses [8]. These studies suggest important roles for growth factors in RA gene therapy, and indicate that a variety of growth factors may be able to join the list of effective RA therapies.

Overview of Clinical Gene Therapy Studies.
Early arthritis gene transfer trials used retrovirus vectors in ex vivo protocols to deliver IL-1Ra to the metacarpophalangeal joints of RA patients [9]. These safety and feasibility studies illustrated that gene transfer to RA joints could be safe and effective, but the low numbers of patients enrolled prevented any conclusions with regard to efficacy. A similar Phase I trial has been initiated by TissueGene, Inc utilizing retroviral vectors to transduce human chondrocytes, which are then mixed with normal human chondrocytes and injected into the knee of patients with degenerative joint disease. Currently, 16 patients have been treated in the United States and South Korea, with approximately 50% of the treated patients demonstrating symptomatic improvement [4, 10].

Another ongoing RA gene therapy trial is sponsored by Targeted Genetics, Inc and is evaluating the safety and efficacy of a single-stranded rAAV2 virus expressing the complete coding sequence of a TNFR:Fc fusion protein, which is identical to Enbrel®. This trial received much publicity in 2007 because of the death of an enrolled patient. Subsequent investigation determined that the death of the subject was not likely due to the virus vector [4]. Despite the death of this subject, the Targeted Genetics trial has shown promising results. The AAV vector appears safe, in that there is no evidence of circulating TNFR:Fc or extraarticular over-expression of TNFR-Fc, which would have indicated vector dissemination and amplification in extraarticular tissues. Clinical response was assessed using patient reported outcomes, revealing moderate improvement in target joint pain and swelling [11].

Conclusions.
Over the past several years, significant advancement has been made in the field of arthritis gene therapy. Numerous vectors and therapeutic genes have been tested and shown to have varying degrees of efficacy. However, while more than 1000 gene therapy clinical trials have been conducted or are ongoing, at least 32 of which have entered Phase III, only a limited number of these trials have been in the field of arthritis. Those trials that have attempted to combat arthritis have shown significant promise, while also serving as reminders that more work is needed. Future clinical trials are already being designed that will incorporate lessons learned from earlier trials, helping the field continue to move forward. With the recent Chinese approval of Gendicin [12], the world’s first commercially available gene therapy, for head and neck cancers, the field of gene therapy seems poised to finally realize its long-standing potential. The hope remains that gene therapy will soon join the arsenal against RA and other orthopedic diseases.

References.
1.    Lundkvist J., Kastäng F., and Kobelt G. (2008). The burden of rheumatoid arthritis and access to treatment: health burden and costs. The European Journal of Health Economics. 8, S49-S60.
2.    Smolen J., and Aletaha D. (2008). The burden of rheumatoid arthritis and access to treatment: a medical overview. The European Journal of Health Economics. 8, S39-S47.
3.    Gregersen P.K., Silver J., and Winchester R.J. (1987). The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30, 1205-1213.
4.    Gaddy D.F., and Robbins P.D. (2008). Current status of gene therapy for rheumatoid arthritis. Current Rheumatology Reports. 10, 398-404.
5.    Amos N., Lauder S., Evans A., Feldmann M., and Bondeson J. (2006). Adenoviral gene transfer into osteoarthritis synovial cells using the endogenous inhibitor IkappaBalpha reveals that most, but not all, inflammatory and destructive mediators are NFkappaB dependent. Rheumatology (Oxford, England). 45, 1201-1209.
6.    Tas S.W., Adriaansen J., Hajji N., Bakker A.C., Firestein G.S., Vervoordeldonk M.J., and Tak P.P. (2006). Amelioration of arthritis by intraarticular dominant negative Ikk beta gene therapy using adeno-associated virus type 5. Human gene therapy. 17, 821-832.
7.    Pagnotto M.R., Wang Z., Karpie J.C., Ferretti M., Xiao X., and Chu C.R. (2007). Adeno-associated viral gene transfer of transforming growth factor-beta1 to human mesenchymal stem cells improves cartilage repair. Gene therapy. 14, 804-813.
8.    Goodrich L.R., Hidaka C., Robbins P.D., Evans C.H., and Nixon A.J. (2007). Genetic modification of chondrocytes with insulin-like growth factor-1 enhances cartilage healing in an equine model. 89:672-685. J Bone Joint Surg Br. 89, 672-685.
9.    Evans C.H., Robbins P.D., Ghivizzani S.C., Herndon J.H., Kang R., Bahnson A.B., Barranger J.A., Elders E.M., Gay S., Tomaino M.M. et al. (1996). Clinical trial to assess the safety, feasibility, and efficacy of transferring a potentially anti-arthritic cytokine gene to human joints with rheumatoid arthritis. Human gene therapy. 7, 1261-1280.
10.    Lee K.H. (2008). Preclincal and early clinical analysis of allogeneic chondrocytes transfected retrovirally with TGF-beta1 gene for degenerative arthritis patients. 5th International Meeting of Gene Therapy of Arthritis and Related Disorders.
11.    Mease P., Wei N., Fudman E., Kivitz A., Schechtman J., Trapp R., Hobbs K., Anklesaria P., and Heald A. (2008). Safety, Local Tolerability and Clinical Response After Intra-articular Administration of a Recombinand Adeno-associated Vector Containing a TNF Antagonist in Inflammatory Arthritis. EULAR Congress 2008.
12.    Wilson J.M. (2005). Gendicine: the first commercial gene therapy product. Human gene therapy. 16, 1014-1015.

The Lowly Fruit Fly Takes a Giant Swat!

by Syam Anand

Who would imagine that scientists are mindlessly wasting taxpayer dollars on stupid fruit flies? That too, not the money that came through the NIH after peer review, but from ear marks- those wasteful “pork-barrel” projects that help politicians channel money for projects in their pet constituencies! Is it not a shame that this has been going on behind our backs until the most popular governor in USA decided to bring out this activity into the open in her first major policy speech?

During her first major policy speech, she made fun of the lowly fruit fly and the researchers who are after it. Amazingly, she even managed to garner a few laughs from the audience.

Watch the portion of the speech for yourself here.

http://www.youtube.com/watch?v=HCXqKEs68Xk

Poor fruit flies! Also, those poor souls of scientists who worked and continue to work on them!

Outrageously ignorant- that is how I would summarize the fruit fly remarks.

This is what happens if you don’t believe in science. This is exactly what happens if you don’t understand how science works. This is what happens if you don’t know that “WHAT IS TRUE FOR E. COLI IS ALSO TRUE FOR THE ELEPHANT”. This is what happens if you don’t understand evolution (whether you believe in it or not and to what scale). The list is long. But since it starts sounding personal, I will get back to the point.

The point is lowly organisms such as fruit flies have contributed more than what one can wish for when compared to studying “real patients”. Who could imagine that another low-life, in fact an even better description would be a “life-less thing” such as the T4 bacteriophage- a virus that infects E. coli- would lay the foundations of modern molecular biology and genetics? The answer is- those scientists who thought ahead of their time and understood the potential of systematically understanding how small “things” work in order to understand how big things also work. This is based on something called the universality of rules (with some exceptions for the sake of argument). Even laymen will get it, provided they keep their eyes and ears open. This is as simple as the laws of motion being the same in physics irrespective of what model you are using for your studies.

The fact is that studying fruit flies is exactly the way to accelerate research to understand how brain functions. I don’t know if fruit flies have a soul! But I sure know they have brains, even though they are tiny! In fruit flies, you can knock-out (functionally or physically remove) individual genes and proteins and ask questions about how it affects brain or any other bodily functions. And the fly would not complain, right? You can’t imagine doing that with so much convenience and economy in humans (even the dumbest person would agree). In fact, fruit fly research has identified components that affect not just brain function, but also developmental and genetics defects, thus helping scientists to extend these observations to other model systems and human beings.

FYI GOVERNOR: “About 75% of known human disease genes have a recognizable match in the genetic code of fruit flies (Reiter et al (2001) Genome Research: 11(6):1114-25), and 50% of fly protein sequences have mammalian analogues. An online database called Homophila is available to search for human disease gene homologues in flies and vice versa. Drosophila is being used as a genetic model for several human diseases including the neurodegenerative disorders Parkinson’s, Huntington’s, spinocerebellar ataxia and Alzheimer’s disease. The fly is also being used to study mechanisms underlying aging and oxidative stress, immunity,diabetes, and cancer, as well as drug abuse.”- CITED FROM WIKIPEDIA!

At this rate, the governor would argue to stop supporting research using mouse or guinea pig models, or the coveted Danio rerio (zebra fish), which is again another low-life not worthy of studying. Check out the following video, which is an example to understand how studying these low-lives help improve human health.

http://www.youtube.com/watch?v=ZItgyfuxsfM

There are similar countless examples in scientific literature.

If it is really true that a Senator or Congressman really used an earmark for funding fruit fly research, I congratulate that person for showing the courage to invest money for the future of public good. Flexibility is good, especially for funding science as there are too many ideas out there, which you cant clearly bet on, unless you give it a chance. That is what makes this country strong and a leader in fundamental and applied science. Hope better sense prevails in people. I hope laymen and CIPs (curious and interested people) educate themselves adequately from reliable sources before falling prey to misinformation campaigns about certain scientific investigations.

Long live T4 phages, fruit flies, zebra fishes, darwin’s finches and all low-lives!

Syam Anand

Pittsburgh, USA

Bug’s Life

Bacteria are ubiquitous microorganisms (typically in the scale of a few micro meters; a micrometer is one ten thousandth of a centimeter) that are present in almost every habitable nook and corner of earth. Some of them have even specialized for surviving seemingly uninhabitable places such as hot water springs and extremely dry or acidic environments. In an era of high personal hygiene what would amaze most of us is that there is an abounding presence of these minute life-forms in our own bodies. It is estimated that in our own bodies they outnumber our cells nearly one to ten! Most of these harmless bacteria live on our skin and inside our digestive tract. Among the advantages of harboring these bacteria are nutritional and immune system-stimulatory functions. This suggests that they are useful to us in many ways than we previously thought plausible. However, under certain circumstances such as immune depletion, these harmless bacteria can become dangerous and even fatal to the host. One notorious example is Staphylococcus aureus, which lives on our skin. It is estimated by CDC (Centers for Disease Control and Prevention), USA that S. aureus causes more infections than AIDS! Worse, this bug seems to be able to develop resistance to any drug that is thrown at it from time to time. Thus we have Methicillin Resistant Staphylococcus aureus (MRSA) and Vancomycin Resistant Staphylococcus aureus (VRSA) among others that make a substantially long list.

Watch the following video to get a grasp on the “grapes of wrath”.

More information about MRSA and the challenges it pose, is available in the following video.

So the question is what does one do if a superbug keeps developing resistance to every known antibiotic? The answers are not simple. In fact, it requires concerted action at all levels of our community as it involves both personal and policy initiatives. There are some simple steps that the public can do such as washing hands and taking care not to share personal stuff through which these bacteria spread most of the time. As for doctors, a simple step such as washing their hands after attending individual patients would decrease the risks of spreading the infection from one patient to another. Hospital management could step in and try to keep high-risk patients in isolation as S. aureus has been reported to flourish and spread in hospital environments. As for scientists like me, we have to up our ante to discover more viable targets and increase the available arsenal against these bugs. We should also try to take our discoveries from the “bench-top to the bed-side” by actively collaborating with the drug industry. Those of us with business acumen could even don the entrepreneurial hat ourselves. The demands for an ever-growing arsenal is always high in order to succeed in this fight. This is also true for a lot of other bugs as well, such as multi drug-resistant tuberculosis and AIDS.

In the beginning, screening for antibiotics was a relatively simple but laborious process where people hunted for fungal samples from soil for anything that kills bacteria in culture. In nature, several fungi produce antibiotics as means of efficiently competing with their smaller cousins for survival space, in this case soil. In the period that followed, people have successfully modified naturally occurring compounds isolated from such screens-such as penicillins-to increase their efficacy as more and more drug-resistant bugs evolved. However, we seem to have run out of steam with these approaches.

Fortunately, scientific advance provided us with alternatives. By screening synthetic combinatorial chemical libraries (such collections often contain several thousand compounds) and structure-based design principles, we can design drugs that specifically target essential proteins present inside these bugs. However, it is not easy to predict targets and perform large screens in the absence of supporting basic research. Basic research into fundamental life processes in bugs is capable of providing additional valuable targets that can be exploited for therapeutic purposes. Unique metabolic pathways and essential proteins discovered by basic researchers should provide viable antimicrobial targets for future.

The recent discovery of a potent agent against MRSA is a glaring example of the triumph of basic research, interdisciplinary approach and the entrepreneurial attitude of one scientist who lead the effort. The research group led by current director of the Institute of Cell and Molecular Biosciences, New Castle University (UK), Prof. Jeff Errington, discovered the Achille’s heel of the superbug while they were studying it’s cell division machinery. During his studies, he noticed that the rounded shape of S. aureus made it highly susceptible to the inhibition of cell division unlike some of its bacterial cousins who had a more elongated shape. He then went on to exploit these findings by starting a spin-out company Prolysis Ltd. Recently scientists from Prolysis published their findings of a novel lead compound directed against the cell division machinery of S. aureus in Science (Science. 2008, 321, pages 1673-1675). Interestingly the compound has “potent and selective anti-staphylococcal activity”. A new company Nugenis Ltd is expected to take over the drug screening opportunities emerging from the Errington lab as Prolysis evolves into a drug development company. The case serves as one more classic example where the entrepreneurial spirit of a basic researcher is set to pay big dividends for public health by taking his discovery from the “bench-top to the bed-side”.

Syam Anand

Pittsburgh, USA.

Scientist Who Discovered GFP Gene Left Out of Nobel Prize

On October 8th, the Nobel Prize in Chemistry was awarded to 3 scientists for their work on green fluorescence protein (GFP), a protein that is now utilized by scientists around the world to label cells and proteins and to study a variety of conditions. Congratulations to these scientists, and their brilliant work that has contributed enormously to the work of so many other scientists, including myself. However, a story that has been under-reported is that of the scientist who originally discovered and cloned the gene that encodes GFP. The work of Osamu Shimomura, Martin Chalfie, and Roger Tsien, the 3 winners of the prize, would not have been possible with the previous work of Douglas Prasher. Prasher originally cloned GFP and had the vision to see what an important impact this protein could have.

Prasher’s GFP work was funded by the National Cancer Institute. In his grant he suggested that it should be possible to take the GFP gene out of the jellyfish cell and attach it to cancer cells so that they would be labeled with a fluorescent tag. Prasher managed to find the gene for GFP in Aequorea victoria and was able to express it in bacteria. In 1992 he published a paper in Gene; it reported the cloning of GFP and the sequence of the 238 amino acids in GFP, shown below. Sadly it was only a two year grant and the funding ran out before he could express the GFP clone he had produced in a manner that would result in a fluorescent GFP.

Unfortunately, the NCI did not agree with his vision and see the potential impact of this major discovery. His funding ran out and, despite searching for several years, he was unable to find additional funding from other sources. Because of this, the career of an exceptional scientist came to an end. Douglas Prasher, Ph.D now drives the courtesy shuttle for an auto dealership in Alabama. Before leaving science, Prasher gave his cloned genes to two of the three scientists who won the Nobel Prize this year.

This story illustrates the importance of funding in science. The National Institutes of Health are responsible for providing most of the funding to the biomedical science community. Unfortunately, the budget for the NIH has remained stagnant for several years, and shows no signs of increasing in the near future. Because of this, thousands of worthwhile projects go unfunded each and every year in this country. We could sit back, cross our fingers and hope the best projects get funded. But, as history shows, that is simply not the case. How many unfunded projects could have led to a major discovery, a Nobel Prize, or a cure for a major disease? We will never know. But the goal of FundScience is to play a role in insuring that does not continue to happen in the future.

Douglas Prasher was interviewed this morning on NPR. You can hear his story here.

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PCR without the PCR machine!

Sounds like fiction? Guess not. It is a distinct possibility now. This innovation is likely to revolutionize field applications of PCR and further expand its commercial potential.

For those of you, who are unfamiliar with PCR: PCR stands for Polymerase Chain Reaction. Since 1983, when the idea of PCR was first conceived by Kary Mullis, it has grown to be the method of choice for economically amplifying fragments of DNA or RNA over a billion times with the help of polymerases- enzymes that make more copies of nucleic acids such as DNA and RNA. Due to its ability to make more of the same from very less of the starting material, PCR is the backbone of both basic-science labs and application-oriented labs such as biotech and forensics. The expiration of the original PCR patent is bound to bring in more innovations and cheaper methods from competing players in the multi-million dollar PCR industry!

Watch the following movie, which explains the molecular basis of the reaction in layman’s terms. In essence the two strands of DNA act as molds for making more DNA molecules that contain the same coded sequence information.

http://www.youtube.com/watch?v=_YgXcJ4n-kQ

Until recently, the PCR machine was an indispensable part of PCR reaction as it drives the temperature cycles in the PCR. Recently, scientists have successfully attempted to replace the PCR machine with helicases to achieve amplification of DNA. Currently PCR uses three different temperatures that cycle multiple times to accomplish amplification. The first step of denaturation melts the DNA by increasing the temperature to 94°C. In nature however, molecular machines called helicases carry out DNA melting. Helicases melt double helical DNA by using chemical energy provided as ATP. They hydrolyze ATP and utilize the energy released for mechano-chemical cycles that help them to physically separate DNA strands in a stepwise manner. Inside living cells, helicase reactions support a variety of DNA and RNA transactions.

There were a couple of challenges that had to be overcome to ensure specific and successful amplification of DNA with the help of helicases. Initially the process used a mesophilic (optimal temperature if neither too hot or too cold; typically between 30-37°C) version of a DNA helicase called UvrD from Escherichia coli (EMBO Reports, 2004, 5: 795-800). High temperatures increase the specificity of the annealing step in PCR. Therefore, in the next step, specificity was increased by using a thermophilic (high-temperature loving; typically between 50-72°C) version of UvrD helicase from Thermoanaerobacter tengcongensis (Journal of Biological Chemistry, 2005, 280: 28952-58). However the challenge of amplifying long stretches of DNA remained. Technically termed processivity, which is nothing but how long an enzyme stays and does its work on a molecule of DNA before falling off, this was another hurdle to be overcome. The longer an enzyme stays on the DNA without falling off, the longer it is likely to keep doing its job on the molecule. In this case, a highly processive helicase could melt long stretches of DNA and therefore help in amplifying long templates of DNA. This would increase the practical value of the technique.

The processivity issue was recently addressed by fusing the helicase to a DNA polymerase (Gene, 2008, 420: 17-22). Whereas the helicase alone could amplify only short substrates, its fusion to DNA polymerase (DNA polymerase by itself is so processive that it can copy the entire genome of E. coli, which is more than 4 million base pairs without falling off) made it much more processive. The helicase-DNA polymerase fusion can efficiently amplify DNA fragments upto couple of thousand base pairs length, which brings it into the realm of practical use.

Further improvements in processivity and specificity should see the technique finding wider use in biology laboratories. The technique christened Helicase-dependent amplification of DNA (HDA) would find applications in diagnostics and environmental monitoring by driving down costs and increasing its accessibility for applications in the field. HDA should be a huge benefit for people who do not want to routinely do PCR, to those who are not experts and also for whom investing in a PCR machine is not worth it. Along with the ability to detect amplified DNA by non-electrophoretic methods, HDA should make the PCR process user-friendlier. It would also increase the application potential of PCR-based techniques where there is a shortage of skilled personnel, especially in poorer nations. In the words of HDA’s original proponents, “the development of simple portable DNA diagnostic devices to be used in the field and at the point-of-care” should be around the corner.

Biological processes: purpose or outcome?

Given below are dictionary meanings for three words, which are used routinely by biologists.

Purpose: the reason for which something is done or created or for which something exists.

Function: an activity or purpose natural to or intended for a person or thing.

Outcome: the way a thing turns out or the consequence.

Selfish DNA….hmmm, sounds like this kind of DNA has no purpose or objective in life other than some goal of its own! While other pieces of DNA are altruistic, providing coded information for the cell that harbors them, these selfish bits of DNA contribute nothing and at the same time ensure that they are passed on to future generations.

Selfish: lacking consideration for others. Concerned chiefly with one’s own profit or pleasure.

The questions I wanted to pose is the following: Is it right to use these kinds of expressions to explain the existence of a piece of a chemical because we don’t understand its function yet? Why not call it DNA of unknown function? Just like, genes in sequenced genomes with no apparent function are called FUN genes (FUN standing for function unknown). Does giving it any other name such as passenger DNA help? Are transposons more selfish than “selfish DNA’’? How selfish can DNA get? What is the scale for measuring selfishness in chemicals? Is Sodium chloride (common salt) also selfish? As sea water it got into my alimentary canal leaving a bad taste in the mouth and an upset stomach for my sensitive friends…all this to ensure that they get a free ride from Florida beach to Oakland, Pittsburgh doing nothing for me and my gang, when all other Sodium chloride molecules we ingested from the Cuban restaurant was making us feel good and also keeping our salt balance in the hot summer.

“The dogma is that teleology is unscientific, and in some contexts it is. Statements that the sun is for lighting the world, or that the moon is for calculating the date of Easter, have no place in science. But teleological language is often used by biologists, and can hardly be avoided except by circumlocution. Some biologists may regard it merely as appropriate shorthand, but for many of us it is the best way to convey what we have to say” ^* (Science, 1998, 281: p927).

Hence, another related question: Is a bacterium a mere manifestation of the sum total of all the reactions that take place inside of it? Is it an outcome without a purpose? Is the purported purpose just a result of interaction with its environment? Are there two ways to explain life of a bacterium? For example: a) bacteria live with a purpose such as multiply indefinitely, develop resistance to man-made antibiotics, infect and kill hosts whenever they get a chance OR b) is the life of a bacterium the outcome of all the chemical reactions that underlie its existence without any specific purpose. But the purpose we observe is just an outcome of its interaction with the environment?

I could make the question simpler by quoting “The main purpose of glycolysis is to provide pyruvate for the trichloroacetic acid (TCA) cycle, not to make adenosine 5-triphosphate. The glycolytic production of pyruvate reduces the cytosol by increasing the ratio of NADH [a reduced form of NAD⁺ (nicotinamide adenine dinucleotide)] to NAD⁺. Thus, glycolysis cannot continue without “something” returning the cytosolic redox potential to normal” ^* (Science, 1997, 277: 459-463). Really? So glycolysis has a purpose? Is it just one purpose that was put into glycolysis when it was assembled in its present form or did every glycolytic reaction have a purpose of its own and then all of them came together and decided on a larger common purpose?

How about something more simpler: The purpose of water is to sustain life on earth (everybody), is to dilute the coolant that is poured into the 21^st century vehicle radiator (someone stuck with a can of concentrated coolant and a smoking car on a highway in the middle of nowhere), is to dilute the alcohol in your vodka (anyone?), is to solidify into ice at the artic poles (polar bears), is to fill large reservoirs so that golf courses can be made in a desert (Californians)…and so on and so forth.

Purpose in biological reactions, macromolecules and living systems? Is it not time we started talking about outcomes, especially when we are so close to making synthetic life in a lab from pure chemicals?

Finding answers to questions such as these is very important for expressing what we truly understand and report as science. Using the terms purpose (highly used), function (follows a close second) and outcome (very rarely used now) without sufficient thought puts us on a slippery slope.

<!–[if supportFields]> CONTACT _Con-3D61E5A91 c s l <![endif]–>Syam Anand<!–[if supportFields]><![endif]–>

Pittsburgh, USA.

^*Disclaimer: These references are just two examples. There could be (and there are) several other references in scientific literature that supports the general argument I am trying to make here.

Presidential Candidates Answer Science Questions

In the debates that took place during the Republican primaries earlier this year, some of the candidates for President proudly proclaimed that they did not believe in evolution. Many of us in the science world were aghast. Luckily, none of those candidates made it very far in the race, but it still raised an important issue: politicians of all stripes will pander to almost any group of people on almost any topic, but science is not one of them. With this in mind, Lawrence Krauss, a Case Western University professor of astrophysics, decided to try to do something about it. He joined with screenwriter/directer Matthew Chapman, journalist and author of The Republican War on Science Chris Mooney, and screenwriter Shawn Lawrence Otto to form a non-profit organization called Science Debate 2008. The primary purpose of this organization is to “elevate the visibility of science in the Presidential race,” with the hope of organizing science-oriented debates between candidates of both parties. More than 38,000 scientists, engineers, and other concerned Americans signed on and supported Science Debate 2008, including nearly every major American science organization, dozens of Nobel laureates, elected officials and business leaders, and the presidents of over 100 major American universities. More than 3400 questions were submitted for candidates to answer about science and the future of America.

Well, those debates never materialized, but Science Debate 2008 would not be defeated. Instead, they narrowed the list of 3400 questions down to the top 14 questions, addressing a broad range of topics including climate change, energy, health care, research, science education and American innovation. The questions were submitted to the candidates and, finally, the candidates decided these topics were important enough to address specifically.

The responses of both Barack Obama and John McCain are found here, allowing side-by-side comparison. Luckily, at least Obama and McCain both say they believe in evolution, although McCain’s running mate, Sarah Palin, may not.

Regardless of your political leanings, the stance of each candidate on these issues cannot be discounted. These issues affect our everyday lives. More importantly, many of these issues affect the overall health of not only our species, but our planet as a whole. America currently leads the world in science and technology, but all too often the politicians who lead the country and shape our interactions with the world prove themselves to be not only uneducated and unconcerned with science, but are openly hostile toward science and technology. The views of politicians, especially the President, are of particular importance because they shape science policy, and their decisions affect the entire world.

Because of this, we should all strive to elect a President who is scientifically literate, or at least scientifically aware. The worst possible move would be to elect someone who continues the tradition set forth by the current administration, which has been openly hostile toward science by severely restricting funding and scientific endeavor, and has also manipulated and suppressed science in order to achieve their political agenda. We at FundScience are not here to try to change your political views, but we strongly urge you to carefully read both Obama’s and McCain’s responses to these very important science questions. It is unlikely that science topics will swing many votes, but that does not discount their importance. Science Debate 2008 and other organizations, including FundScience, seek to raise awareness of science and science-related issues, and hope to gradually change the current culture that ignores or rejects the very innovation that drives this country, and the research that impacts our lives more than most people realize.

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