I've recently been working to unearth the scientific genealogy of Carlos Bustamante's lab. With the aid of some labmates, we have made quite a bit of progress! We have the lineage to the 17th century, and it goes thusly:

Carlos José Bustamante

• 1951-present
  
• Ph.D. in Biophysics, University of California, Berkeley, 1981
  

• 1930-present
  
• Ph.D. University Wisconsin, 1954
  

• 1912-2003
  
• Ph.D., Stanford University, 1935
  

• 1894-1966
  
• Ph.D., University of California, Berkeley, 1919
  

• 1884-1959
  
• Ph.D., Universität Breslau, 1911
  
• [California Digital Library]
  

• 1860-1925
  
• Ph.D., Universität Berlin, 1884
  
• Dissertation: Über eine neue Interferenz-Erscheinung an planparallelen Glasplatten und eine Methode die Planparallelität solcher Gläser zu prüfen
  

• 1821-1894
  
• M.D., Königlich Medizinisch-chirurgische Friedrich-Wilhelm Institut, Berlin, 1842
  
• [Max Planck Institute for the History of Science]
  

• 1801-1858
  
• M.D., University of Bonn, 1822
  
• [Max Planck Institute for the History of Science]
  

• 1771-1832
  
• M.D., Ernst-Moritz-Arndt-Universität Greifswald, 1795
  
• [MGP]
  

• 1748-1831
  
• Georg-August-Universität Göttingen, 1771
  
• [MGP]
  

• 1744-1777
  
• Georg-August-Universität Göttingen, 1767
  
• [MGP]
  

• 1719-1800
  
• Ph.D., Universität Leipzig, 1739
  
• Dissertation: Theoria radicum in aequationibus
  
• [MGP]
  

• 1693-1743
  
• Ph.D., Martin-Luther-Universität Halle-Wittenberg, 1713
  
• Dissertation: De corpore scissuris figurisque non cruetando ductu
  
• [MGP]
  

• 1663-1727
  
• Ph.D., Universität Leipzig, 1685
  
• Dissertation: Disputationem Moralem De Divortiis Secundum Jus Naturae
  
• [MGP]
  

• 1644-1707
  
• Ph.D., Universität Leipzig, 1665
  
• Dissertation: Ex Theologia naturali — De Absoluta Dei Simplicitate, Micropolitiam, id est Rempublicam In Microcosmo Conspicuam
  
• [MGP]
  

Filed under biology · chemistry · physics · science · science history

Posted by H. C. Hodges at 11:19 AM | Permalink | Comments (1)

Getting the cover of a journal like Nature is a little bit like winning the scientific lottery. So we're very proud:

Congratulations all around, especially to Jin-Der, who has done a fantastic job of making this project work. Although we were the first to observe ribosome activity in real-time, there is so much yet to come!

Filed under berkeley · biology · chemistry · physics · science

Posted by H. C. Hodges at 10:23 AM | Permalink | Comments (2)

This makes me sick to my stomach:

After 27 years as a science teacher and 9 years as the Texas Education Agency’s director of science, Christine Castillo Comer said she did not think she had to remain “neutral” about teaching the theory of evolution.

“It’s not just a good idea; it’s the law,” said Ms. Comer, citing the state’s science curriculum. But now Ms. Comer, 56, of Austin, is out of a job, after forwarding an e-mail message on a talk about evolution and creationism [...]

Her departure, which has stirred dismay among science professionals since it became public last week, is a prelude to an expected battle early next year over rewriting the state’s science education standards, which include the teaching of evolution [...]

The chairman of the panel, Dr. Don McLeroy, a dentist and Sunday School teacher at Grace Bible Church in College Station, has lectured favorably in the past about intelligent design.

Having gone to school in College Station, I am familiar with Grace Bible Church. It's a very, very family-friendly evangelical church. I knew a lot of kids who went there, and they were definitely the classic evangelical type. I suppose that's beside the point; the real question is: how the hell is a dentist and Sunday school teacher heading up the panel for the TEA's standardized science curriculum? Is there really no better qualified person in the entire state of Texas? A trained scientist perhaps?

From the article, it isn't clear the text of the email that Comer sent out. Was it like "FYI -- attached message" or was it like "FYI -- let's get these creationist nutjobs!" (the difference is huge; while the former would be lawsuit worthy, the latter would obviously be grounds for disciplinary action).

In any case, I'm nervous that Texas will retreat from the required teaching of modern biology in school. Words cannot express how angry it makes me that we still have to debate the single unifying core tenet of modern biology. It's like "debating" GR. Ugh.

Filed under biology · evolution · intelligent design · science · texas · textbooks

Posted by H. C. Hodges at 11:30 AM | Permalink | Comments (2)

Recently, a group of student-organized protesters picketed on-campus and outside the Helen Wills 10th anniversary symposium. The Helen Wills Institute is a neuroscience institute with affiliated labs on the Berkeley campus. Most of the animal protesters wore bandanas over their faces and carried signs like "vivisection kills" and wrote on the sidewalks phrases like "animals die while demons rejoice." I have come to the conclusion that protesting like this is an unhelpful contribution to on-campus activism as well as a distraction from a fruitful animal-research debate.

Continue reading "Vivisection at Berkeley: Protest all life sciences!" »

Filed under animal studies · berkeley · biology · cancer · hiv · mammals · science · stem cells

Posted by H. C. Hodges at 2:52 PM | Permalink | Comments (7)

First, there was the controversial idea of hosting Bush's Presidential Library at Southern Methodist University in Dallas. Now, SMU apparently got picked to host an "intelligent design" conference. My favorite quote from the SMU faculty:

Other biologists compared the conference to a presentation by Holocaust deniers. Would the university allow that to happen?

That is an interesting question. It is clear that official government censorship should never be tolerated, but a private university like SMU has the First Ammendment right, as well as a responsibility, to limit the groups with which it associates. Clearly the University would cancel its hosting of the event and return all fees, even at this stage, if it found out the group advocated Holocaust denial. It's telling that the University does not see fit to cancel hosting an event for a group led by the Discovery Institute, which is devoted to denial of serious academic research. It's rather disgusting actually...

Filed under biology · dallas · evolution · intelligent design · texas

Posted by H. C. Hodges at 7:31 PM | Permalink | Comments (0)

I was reading a blog today wherein a professor made a post about the scientific support for evolution, and the lack of such support for intelligent design. He pointed out:

[Y]ou can access the websites of any major scientific organization [...] to read their statements affirming evolution as the unifying theory of biology and the disaffirming of all forms of creationism including intelligent design.

Although news organizations seem to be recognizing the false controversy stirred up by ID proponents in order to advance their political goals, it is still easy to be given the impression that there remains some controversy amongst learned scientists on the issue. So I was curious how clear scientific organizations have been in condemning "intelligent design" as pseudo-science.

I checked the largest, most influential and most recognized scientific organizations; below are their official statements on intelligent design and evolution:

• The National Academy of Sciences (NAS) — publishes The Proceedings of the National Academy of Sciences (PNAS), official organization that advises the US President on matters of science and technology [ref]:

  Creationism, intelligent design, and other claims of supernatural intervention in the origin of life or of species are not science because they are not testable by the methods of science [...] Documentation offered in support of these claims is typically limited to the special publications of their advocates. These publications do not offer hypotheses subject to change in light of new data, new interpretations, or demonstration of error. [...]
  
  No body of beliefs that has its origin in doctrinal material rather than scientific observation, interpretation, and experimentation should be admissible as science in any science course [...] Science has been greatly successful at explaining natural processes, and this has led not only to increased understanding of the universe but also to major improvements in technology and public health and welfare. The growing role that science plays in modem life requires that science, and not religion, be taught in science classes.

• American Association for the Advancement of Science (AAAS) — world's largest scientific organization, publisher of Science magazine, quite possibly the world's most widely respected peer-reviewed scientific journal [ref]:

  Over the past several years proponents of so-called "intelligent design theory," also known as ID, have challenged the accepted scientific theory of biological evolution. As part of this effort they have sought to introduce the teaching of "intelligent design theory" into the science curricula of the public schools. The movement presents "intelligent design theory" to the public as a theoretical innovation, supported by scientific evidence, that offers a more adequate explanation for the origin of the diversity of living organisms than the current scientifically accepted theory of evolution. In response to this effort, individual scientists and philosophers of science have provided substantive critiques of "intelligent design," demonstrating significant conceptual flaws in its formulation, a lack of credible scientific evidence, and misrepresentations of scientific facts.
  
  [...] AAAS calls upon its members to assist those engaged in overseeing science education policy to understand the nature of science, the content of contemporary evolutionary theory and the inappropriateness of "intelligent design theory" as subject matter for science education

• National Science Teacher's Association (NSTA) — the largest organization in the world committed to supporting science teaching, membership of more than 55,000 including science teachers, science supervisors, administrators, scientists, business and industry representatives [ref]

  The National Science Teachers Association (NSTA) strongly supports the position that evolution is a major unifying concept in science and should be included in the K-12 science education frameworks and curricula. Furthermore, if evolution is not taught, students will not achieve the level of scientific literacy they need [...] NSTA also recognizes that evolution has not been emphasized in science curricula in a manner commensurate to its importance because of official policies, intimidation of science teachers, the general public's misunderstanding of evolutionary theory, and a century of controversy. In addition, teachers are being pressured to introduce creationism, "creation science," and other nonscientific views, which are intended to weaken or eliminate the teaching of evolution.

• The American Physical Society (APS) — the APS is the leading American professional body of physicists, and represents over 46,000 physicists in academia and industry in the US and internationally [ref]

  Marvin Cohen, president of the American Physical Society (APS), has stated that only scientifically validated theories, such as evolution, should be taught in the nation’s science classes. He made this statement in response to recently reported remarks of President Bush about intelligent design, which is a type of creationism.

• The American Geophysical Union (AGU) — an organization of 43,000 Earth and space scientists; publishes a dozen peer reviewed journal series as well as scientific meetings [ref]:

  Scientific theories, like evolution and relativity and plate tectonics, are hypotheses that have survived extensive testing and repeated verification. Scientific theories are therefore the best-substantiated statements that scientists can make to explain the organization and operation of the natural world. Thus, a scientific theory is not equal to a belief, a hunch, or an untested hypothesis [...] "Creation science" is based on faith and is not supported by scientific observations of the natural world. Creationism is not science and does not have a legitimate place in any science curriculum. AGU opposes all efforts to require or promote teaching creationism or any other religious tenets as science. AGU supports the National Science Education Standards, which incorporate well-established scientific theories including the origin of the universe, the age of Earth, and the evolution of life.

• The American Astronomical Society (AAS) — membership of 6,500 scientists including physicists, mathematicians, geologists, engineers and others whose research interests lie within contemporary astronomy [ref]

  A small, but vocal, minority of religious individuals has been urging a major revision of how evolution is taught in U.S. schools. Based on the personal beliefs, they find fault not only with biological evolution, but also with modern astronomical ideas about the age, expansion, and evolution of the universe. They have been actively pressing their case in the political, media, and educational arenas, and their loud arguments sometimes drown out other perspectives, including science [...] Not only is evolution a unifying concept in biology but also describes the way in which the planets, stars, galaxies, and universe change over long periods of time [...] Research [...] has produced clear, compelling and widely accepted evidence that astronomical objects and systems evolve [...] Specifically, the scientific evidence clearly indicates that the Universe is 10 to 15 billion years old, and began in a hot, dense state we call the Big Bang.

• The American Chemical Society (ACS) — the leading, self-governed organization that consists of more than 160,000 members at all degree levels and in all fields of chemistry [ref]

  Evolutionary theory is not a hypothesis, but is the scientifically accepted explanation for the origin of species, and explains significant observations in chemistry, biology, geology, and other disciplines [...] Evolution cannot be dismissed or diminished by characterizing it as mere conjecture or speculation. Scientific explanations of the natural world have been reached through observation and experimentation, are testable through observation and manipulation of natural systems, and can be modified as a result of new information. The inclusion of non-scientific explanations in science curricula misrepresents the nature and processes of science.

• Federation of American Societies for Experimental Biology (FASEB) — represents 22 professional societies and 84,000 scientists in disciplines that range from single molecules to public health [ref]

  [I]t is critical to preserve the integrity of science education by opposing the mandatory teaching in science classes of creationism, intelligent design, and other concepts not based on sound scientific principles [...] Proponents for non-scientific accounts of the development of life, including creationism and intelligent design, contend that evolution alone should not be taught in science classes. Arguing that evolution is "just a theory," rather than a fact, they insist that intelligent design should be offered as an alternative to evolution or given "equal time", and that schools should "teach the controversy" surrounding evolutionary theory. FASEB does not support these views. We also affirm that these positions seriously undermine science education [...]
  
  [E]volution is categorized with other scientific theories such as gravity or atomic theory, which, like evolution, are universally accepted among scientists.
  
  Evolution is among the most thoroughly tested theories in the biological sciences. It is supported by volumes of scientific evidence in numerous fields, including genetics, biochemistry, developmental biology, comparative anatomy, immunology, geology, and paleontology. Moreover, evolution lays the foundation for much of what we know about genetics, immunology, antibiotic resistance, human origins, and the adaptation of species to a changing environment. Removing evolution from the classroom, or misrepresenting evolution as a flawed theory, deprives students [...]
  
  In contrast to evolution, intelligent design and creationism are not science because they fail to meet the essential and necessary requirements: they are not based on direct observation or experimentation nor do they generate testable predictions. Therefore, offering these beliefs as alternatives to evolution or giving them equal time in science classes completely misrepresents the nature of science [...] Proposals that call for “teaching the controversy” or singling out evolution for criticism are equally objectionable. While there may be some disagreement about the details of evolution, it is not a controversial theory among scientists. Rather, there is overwhelming scientific consensus that evolution is a valid explanation for the development of species. Although students should be encouraged to think critically about all ideas, introducing false controversy into science classes will ultimately impair science education.

There are countless more scientific organization with similar statements. As is obvious, there is no controversy in the physical, chemical, or biological sciences; the debate is one-sided, constructed by the proponents of "intelligent design" in order to justify their views. Universities, schools, and other organizations involved in education do a disservice to their students and to the public by even passively supporting these views.

Filed under biology · evolution · intelligent design · science

Posted by H. C. Hodges at 4:54 PM | Permalink | Comments (0)

I got this email 27 minutes ago from Robert Birgeneau, our Chancellor:

Colleagues, students, and friends:

I am proud and excited to tell you that a partnership led by UC Berkeley has been selected to receive an unprecedented $500 million from global energy firm BP to lead the way in research to develop new, clean, renewable sources of energy. With this remarkable support, the work Berkeley will undertake will be transformative for our nation and, indeed, our planet.

The campus will partner with Lawrence Berkeley National Laboratory and the University of Illinois at Urbana-Champaign in this 10-year effort, which was announced this morning at a campus press conference by Robert A. Malone, chairman and president of BP America Inc., along with Gov. Arnold Schwarzenegger and Illinois Gov. Rod Blagojevich.

This new research effort -- the Energy Biosciences Institute (EBI) -- will focus initially on biotechnology to produce biofuels, that is, transportation fuels that are made from plants. Berkeley and its partners will bring the most creative science, innovative technologies, and astute understanding of social sciences to bear to develop viable solutions to global energy challenges, among the most fundamental problems facing us today.

[...]

First thought: holy crap that's a lot of money (second thought: wow, BP is actually putting its money where its mouth is). I think this is fantastic news, not only for Berkeley, but also for energy research in general. For more information about this rather unprecedented research partnership, see here and here.

UPDATE: This article in the SF Chronicle more succinctly lays out what this all means.

Filed under berkeley · biology · energy · science

Posted by H. C. Hodges at 11:52 AM | Permalink | Comments (0)

While a thought-provoking piece, this article from The Sun is total bullshit.

Dr Curry continues: “People of the year 3000 will have reached the peak of human enhancement, leading the longest, healthiest and most accomplished lives in the entire history of the human race.

“Improved nutrition and understanding of the human body will see people grow taller, with men reaching an average height of between six and seven feet, while lifespans will also be far greater, with humans living for up to 120 years.”

Dr Curry also claims men and women will also become better-looking by the next Millennium in order to attract a mate.

The coffee-colored thing is pretty obvious and probably true, but the expectation that we'll all be more attractive? Evolution cares only about relative differences in reproductive success, therefore humanity becoming "more attractive" or "sportin' bigger junk" is only possible if people with those traits squeeze out kids more often than those lacking said traits. From my perspective, it's not obvious that the attractive or the well-endowed are having more children...

As a result men are expected to exhibit symmetrical facial features, athleticism and the classic signs of testosterone such as a square jaw, deeper voice and larger manhood...

“Skills such as communicating and interacting with others will be degraded, leaving humans less able to care for others."

Horse shiat. Current pressures still select for the people who are sociable and outgoing. Ever try living the life of a sociophobe? It's impossible for a man to send forth his homunculi into the fertile land-o-plenty without a little social skill. What reproductive mechanism (short of mass-conception-by-donor-sperm) allows humanity to shed its need for social skills?

If we really want to breed "better" humans, humanity will have to develop a mechanism of encouraging the successful to have more children than the unsuccessful (whatever "success" means). Technology may have allowed us to decouple successful behavior from reproductive success, in which case our selection would also be inverted. If true, then natural selection ain't directly headed towards a future full of symmetrical, intelligent, coffee-colored athletes. For the purposes of our species, social pressures and access to technology are probably much more powerful predictors of reproductive success than most innate tendencies.

Filed under biology · culture · evolution · intelligent design · science

Posted by H. C. Hodges at 6:26 PM | Permalink | Comments (0)

Andy Fire (now at Stanford) and Craig Mello (of the University of Massachusetts Medical School) are newly minted Nobel laureates. Just a few years back, they discovered a process called RNA interference ('RNAi') in the nematode worm C. elegans. Nature (free link) sums it up best:

RNAi, which occurs naturally in plants and animals, allows a gene to be specifically 'silenced'. This helps to regulate gene expression, and protects against viral infection and 'jumping genes' that can replicate and spread through the genome.

The process can also be induced experimentally by injecting tailor-made genetic sequences into cells, giving scientists a method for deliberately silencing a target gene. The method is now widely used as a basic genetic tool and is a promising candidate for future therapies.

These guys deserve it, and everybody knew they'd eventually win it. Personally, I'm still a little surprised some GFP folks haven't won yet (Roger Tsien, Douglas Prasher, Marty Chalfie). GFP is used everywhere, and some might argue that it has yielded more biological insights than has RNAi. Still, the RNAi guys did some great science, and I'm glad to see them win.

UPDATE: Aggie prof Jim Hu photoblogs the press conference at Stanford for Andy Fire. Nice work.

UPDATE: Of course, Berkeley is quick to note that Fire is a Berkeley alumn.

Filed under biology · science

Posted by H. C. Hodges at 11:47 AM | Permalink | Comments (0)

As you may recall from my previous post, a company called Ariad is suing Lilly & Co. over alleged infringement of a patent related to NF-κB activity. NF-κB is a protein which regulates inflammation and immune response in cells; as such, it is considered by many to be a great target for new drugs.

In my previous post, I expressed skepticism that the so-called 'Baltimore patent' will be upheld. I have since bothered slugging through some of the patent code (U.S.C. 35), and have refined my thoughts a little more.

One of the strongest arguments I can think of against Ariad is that the Baltimore patent had simply not reduced the claimed invention to practice. According to 35 U.S.C. § 112:

The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.

As an example, consider two fairly representative claims from the Baltimore patent:

1. A method of inhibiting expression, in a eukaryotic cell, of a gene whose transcription is regulated by NF-κB, the method comprising reducing NF-κB activity in the cell such that the expression of said gene is inhibited.

6. A method for diminishing induced NF-κB-mediated intracellular signaling comprising reducing NF-κB activity in cells such that NF-κB-mediated intracellular signaling is diminished.

Obviously creating a particular drug requires vastly more resources than claiming what amounts to a big-picture idea for a research project. The court will have to decide whether or not the Baltimore patent ever actually reduced to practice their claimed invention. It is a fundamental requirement that a patent describe an invention well enough for a person having ordinary skill in the art (of biochemistry, in this case) to be able to create and use the invention. This is what The People receive in exchange for granting an exclusive license to the inventor.

Furthermore, according to 35 U.S.C. § 102(g), Lilly need only show that it conceived of the two drugs and worked "with reasonable diligence" to create them before the priority date of the Baltimore patent. Lilly also has to show that it didn't "abandon, suppress, or conceal" those two drugs. Since Lilly claims it disclosed the medical properties of Xigris and Evista before the Baltimore inventors conceived of their idea, it will be very difficult for Ariad to show that Lilly had concealed Evista or Xigris before the Baltimore patent's priority date.

The courts must consider "not only the respective dates of conception and reduction to practice of the invention, but also the reasonable diligence of one who was first to conceive and last to reduce to practice." Lilly, it seems to me, need only prove that they worked with reasonable diligence to reduce their two drugs to practice, while Ariad and the patent holders have to prove that they have sufficiently disclosed their invention such that any skilled worker could create and use it.

As a fairly skilled worker in the art of biochemistry, I wouldn't have any idea where to start to create and use some of the claimed inventions in the Baltimore patent. It is pretty clear to me that the Baltimore patent has not sufficiently disclosed their invention; as such I continue to expect that the appellate court will decide for Lilly & Co. and set aside the jury's previous verdict.

Filed under biology · chemistry · patents · science

Posted by H. C. Hodges at 10:31 PM | Permalink | Comments (0)

GWB's stem-cell veto threat makes me too frustrated to say anything intelligent. It would mark his first veto EVER, and on a topic that about 70% of Americans support. Asshat.

Filed under biology · science · stem cells

Posted by H. C. Hodges at 3:22 PM | Permalink | Comments (0)

Last night, I read an old paper by Ernst Mayr on the position of biology amongst the sciences (Quarterly Review of Biology, 71(1): 97-106, 1996). In it, he posits that biology is rather radically different from other physical sciences; as a result, he says biology ought to be considered an autonomous branch of science, and not a provincial branch of physics or chemistry.

This, along with a more strident defense of biology (Science, 133: 1745-1748, 1961), surprised me more than a little bit. Since I do biophysics, I am not properly a biologist or a physicist, per se, but I do research that straddles the traditional boundaries of both fields. So I tend to look for good questions to be answered, and have not worried myself about whether my work is more "physics" or more "biology."

However, in his review, Mayr argues that there are questions dinstinctly biological in nature, and that these questions (along with some conceptual and methodological differences), make biology unique amongst the sciences. I thought I would paraphrase a few of the most interesting here:

Conceptual differences in biology

• The importance of historical narrative as an explanatory device.
• The prevalence of indeterminacy owing to the high frequency of stochastic processes, unknown factors, the presence of constraints, the interaction of multiple causes.
• The importance of quality (structure, form, function) in the properties and actions of objects, and a correlated reduction in the importance of purely quantitative differences.
• Presence of an historical constituent in the inherited program; hence legitimacy of "why" questions; capacity for the storage of historical information.

Methodological differences in biology

• The importance of observation in addition to experiment.
• The frequency of independent multiple solutions to the same problem.

Other autonomous aspects of biology

• All biological phenomena have two sets of causations, those controlled by the historically accumulated information of the genetic program (evolutionary or ultimate causations), and those controlled by the properties of the interacting system (proximate causations). The study of the historical components of each system is as legitimate a concern of biological science as the study of proximate causations.
• The outcome of biological processes is usually affected simultaneously by multiple causations, owing to the complexity of the systems interacting with complex biotic and physical environments
• Many properties of systems cannot be explained by a study of their isolated components.

It's interesting that many older biologists saw the successes of biochemistry and biophysics as a danger to the field of biology proper. Many early critics complained that such interdisciplinary research gave much to the other field, while returning relatively little to biology. In this light, the point about multiple causations (evolutionary and proximate) is still quite relevent, because the evolutionary causes are often unaddressed in many of the recent "hot" papers in biophysics.

Filed under biology · chemistry · physics · science

Posted by H. C. Hodges at 4:34 PM | Permalink | Comments (2)

Well, I read a rather surprising post from Derek Lowe today. Turns out, he thinks that most common buffer reagents are a bunch of hocus-pocus:

There's some reducing agent in there, naturally. Can't have those thiols turning into disulfides and balling up the protein, I understand - but does something bad happen if it's not in there? Generally, no one finds out, because, hey, why mess with it? And there's some EDTA, and some salt, and their function is? Well, as far as I can tell, they're also in there because they've sort of always been. Same goes for the squirt of detergent (Brij-35 or some such), and the tiny bit of bovine serum albumin, of all things. It's just part of the old-fashioned recipe from Grandma's Protein Kitchen.

Now, organic chemistry has a little of this, true, but it hasn't reached quite the Ancient Runestone levels of enzymology.

Lowe unexpectedly sounds like so many of the physicists I know that make snap judgments about how biology is done without the requisite background. As it turns out, many people do understand each reagent's use and shortcomings. We use many of those reagents for reasons that we understand pretty well:

1. Reducing agents protect methionines and cysteines from oxidation. If the protein is an intra-cellular protein, then this mimics the reducing environment of the cell. If there are structurally or functionally important cysteines on the protein, this prevents them from forming intra- or inter-molecular disulfide bridges. Generally, one doesn't want those, because they can lead to the protein becoming insoluble. You may also need them if you're going to do mass spectrometry, because you want to know the molecular weight of the monomers (not the disulfide-linked Nmers). Plus there are multiple types of reducing agents, and there are situations where you'd use one and not the other.
2. EDTA is in there because the researcher wants to prevent magnesium or other divalent cations from somehow affecting the molecule of interest. This "somehow" can include metalloprotease degradation or bacterial growth. Sometimes you have your own reasons for not wanting a protein to bind Mg²⁺ (like if an enzyme gains a certain reactivity upon binding). Also, magnesium is required by some nucleases, so the addition of EDTA can also prevent nucleases from degrading DNA or RNA, if those are present in solution.
3. Salt is just silly to question. Most proteins depend on salt for stability and solubility. Salt helps screen attractive and repulsive ionic interactions.
4. Depending on the protein, you may require the presence of detergents to make the molecule soluble. There are many different types of detergents, and you'd choose one (believe it or not) rationally, depending on the type of interaction you want with the protein. There are cationic, anionic, zwitterionic detergents, and polar (but uncharged) detergents too. These are especially important for hydrophobic proteins that would otherwise aggregate were detergent not present.
5. BSA may sound silly, but it's a stabilizing adjuvant. Not only does it tend to keep the test tube feeling like the cell by acting as a crowding agent, it also acts as a sink for protease degradation in the case that some contaminant makes it in the tube accidentally. In our lab, we use it regularly as a blocking agent to prevent nonspecific protein-protein interactions and protein-surface interactions. I imagine Lowe would be shocked to also find out that we use α-casein from milk for the same purpose. The reason we use these animal-derived proteins are because of their cost; they are also abundant, have no relevant enzymatic activity, and work well.

Thankfully, Lowe doesn't question the actual buffer itself, which is probably the most critical ingredient because it stabilizes pH. There are dozens of commonly used buffers, each one optimized for particular chemistries and with different pK_a values. For example, you might need a buffer without primary amines that buffers well at pH 8, in which case you may pick triethanolamine over the more common tris.

Each of these ingredients—even if one doesn't understand how it works—is often a required buffer component. These reagents are the moral equivalent of the glass flask in chemistry. Sure, I could deride Derek for using such stone-aged materials as "super-heated sand" for his Erlenmeyer flask, or "baked mud" for his Büchner funnel, but that would be silly and take a rather healthy amount of hubris. Instead, I recognize that these are the basic tools of chemists, and we move on.

In much the same way, these buffer reagents are some of the most basic tools in biology; they combine to provide a tightly controlled and consistent chemical microenvironment for proteins and other macromolecules.

Filed under biology · chemistry · science

Posted by H. C. Hodges at 8:05 AM | Permalink | Comments (0)

This is pretty cool. Thanks, HHMI.

Filed under berkeley · biology · science

Posted by H. C. Hodges at 11:02 AM | Permalink | Comments (0)

You may have heard recently in the news about the patent dispute between Ariad Pharmaceuticals and Lilly. Ariad had licensed a patent from Harvard, MIT, and Whitehead that covers use of NF-κB activity. This patent (No. 6,410,516), created by David Baltimore and colleagues, claims much about the NF-κB system — there are a total of 203 claims in the Baltimore patent.

While a patent can claim virtually anything, the patent office's examination should help rule out claims that will not be upheld in court. However, in general there is no guarantee that patent claims will be upheld unless they conform to certain rules. In particular, in the US patent system, patents must be:

• A patentable invention: patentable inventions are any new and useful process, machine, manufacture or composition of matter, or any new and useful improvement thereof.
• Novel: in contrast to the rest of the world, US patents are granted to the first-to-invent, not the first-to-file. The patent will be ruled invalid if the invention:
  • was invented previously by someone else,
  • was described in a US patent application that is later granted with an earlier priority date, or
  • was known or used by others in the USA or described in a printed publication in any part of the world.
• Non-obvious: One must convince the patent office that the invention would not be "obvious" to someone else with similar knowledge at their disposal.

(from Patents for Chemicals, Pharmaceuticals and Biotechnology, 4^th Ed., Philip W. Grubb)

The claimed methods as described in the Baltimore patent are to me of questionable specificity. The researchers discovered a process of nature, then patented many of the obvious theoretically possible therapeutic routes dealing with that natural process. While US patent law is sometimes a little vague about the novelty criterion, it is generally accepted that processes or phenomena of nature can not be inventions, but methods which harness natural processes are fair game. So is it obvious, after discovering NF-κB's natural function, that one could inhibit its activity for therapeutic benefit? That's perhaps a more nuanced question than it first seems, so I'll let you decide.

From what I understand, Ariad is suing Lilly because Ariad claims Lilly's Evista and Xigris drugs modulate the activity of NF-κB. In its response to the case, Lilly asserted that they had "discovered these drugs and disclosed their medicinal properties years before the patentees' scientists made their discovery." At first blush, I'm inclined to agree with Lilly, but I certainly haven't heard all the details of the case.

I suspect the patent will not be upheld on appeal. As a matter of commerce, if Ariad were to continue winning in court, most pharmaceutical research would come to a halt. This is really a test case, because if Baltimore, et al, can in effect patent the entire NF-κB signalling cascade, entire companies will stop small-molecule R&D out of fear of patent infringement.

However, before the courts is not a matter of commerce, but a matter of law. Although normally I think I would root for the scientists and academics, I think this patent just might be overly broad...

UPDATE: I almost forgot that about two years ago, a friend of mine had the pleasure of meeting David Baltimore when he was giving a talk down at Stanford. She got to drive him around campus on a little golf cart to take him to various labs, and said he told some great stories... Incidentally, Baltimore is now the president of Caltech, and Giao has his (actual) signature on her diploma. Sheesh it's a small world.

UPDATE: See also my more recent post: "Ariad v. Lilly, revisited"

Filed under biology · patents · science

Posted by H. C. Hodges at 8:51 AM | Permalink | Comments (0)

Happy Cesar Chavez day to you all.

Right here is the Greatest Thing Ever about being a scientist:

Fig 1. This is the first time this event has ever been directly observed.

Right now, nobody in the world but me knows what this signal is. I'm the only person who has ever observed this event and knows how to make it happen again (although it happens in cells all the time!). Who woulda thought I'd finally get this project to work on a Cesar Chavez Day? Looks like I celebrated the holiday through hard work with minimal pay (which I think is most appropriate).

Filed under biology · science

Posted by H. C. Hodges at 9:14 PM | Permalink | Comments (1)

Seed Magazine has a write-up on Larry Summers' departure as President of Harvard. Summers stepped down a few days ago, after it became clear that continued dissatisfaction with him amongst certain faculty members in the College of Arts & Sciences would prevent him from executing his plan for revitalizing the university. As you may recall, Summers (accidentally) provoked a fury of criticism when he suggested at a closed academic conference that women may be less inclined towards scientific work because of innate differences between the sexes.

One part of the report on Summers catches him channeling C. P. Snow:

In a February 2004 speech to the Harvard-Radcliffe Club of Southern California, Summers emphasized the need for the university's students to be well-versed in the life sciences. "If you didn't know the name of five plays by Shakespeare, you would be embarrassed to admit it," he said. "But if you didn't know the difference between a gene and a chromosome, that's a technical subject.”

Of course I've talked about an almost identical statement by C. P. Snow before. The sad part is that Summers was apparently deeply committed to improving and maintaining the quality of life science research at Harvard. His clumsy style and mismanagement of the whole innate-differences-between-the-sexes row is now hard to overlook, but I do hope that whoever replaces him at Old Crimson maintains his personal commitment to the physical and life sciences.

Filed under biology · culture · science

Posted by H. C. Hodges at 11:21 AM | Permalink | Comments (0)

The Lancelet has an awesome video of an octopus eating a shark. No kidding, go see it.

[via Afarensis]

Filed under biology

Posted by H. C. Hodges at 9:54 AM | Permalink | Comments (0)

As we speak, the CDC is testing the substance found in the Moore-Hill dorm at UT for ricin. I've been trying to figure out how exactly they confirm the presence of ricin, and luckily, the CDC (sort of) publishes its methods.

According to this page at the CDC, they use two methods for confirming the presence of ricin in environmental samples: PCR, and time-resolved fluorescence immunoassay (TRFIA).

PCR, of course, is a tool that most molecular biologists use all the time. It's a simple way of specifically amplifying a targeted DNA sequence. For diagnostic purposes, the CDC is counting on residual castor bean DNA being left in the ricin. They attempt to amplify it and, if they get amplification, they can confirm that the substance contains the gene(s) that produce ricin. This is probably not the most conclusive or sensitive test, because highly purified ricin should contain little DNA, and because the test doesn't confirm the toxic substance, it confirms the DNA that makes it. (It's also possible to get false positives, but this should be a relatively rare event because of the specificity of the PCR primers.)

An ideal test would not just confirm or deny the presence of castor bean DNA, it would quantitatively determine the number of toxic ricin molecules directly. And this is where TRFIA comes in. For those familiar with immunoassays, TRFIA is a very sensitive, fluorescent analog of ELISA. With TRFIA, one immobilizes the target compound and binds it with a primary antibody; after washing, a secondary antibody-Eu³⁺ conjugate then binds the primary antibody. The europium (Eu³⁺) has an exceptionally long fluorescence lifetime. To make use of this, the sample is pulsed with excitation light, then after a long delay (~400µs), the emitted fluorescence is measured. This is performed repeatedly, and only the compounds with very long fluorescence lifetimes on the average give fluorescence. This removes essentially all background fluorescence except that of the Eu³⁺. The result is a very sensitive immunoassay for confirming the presence of any antigenic substance.

The sensitivity, of course, depends in part on antibody affinity for the target compound (e.g. ricin), but the technique has demonstrated linearity over ranges of pg/mL to tens of ng/mL. It's also interesting to note that the CDC must keep stocks of anti-ricin antibodies. Presumably these aren't polyclonals obtained from animal exposure to ricin. Keeping that cell culture alive sounds like an important job!

Filed under biology · science

Posted by H. C. Hodges at 10:15 AM | Permalink | Comments (0)

According a recent review in the journal Nature, the leaders of the Bauhaus school of design found inspiration in the life sciences. When Walter Gropius, László Moholy-Nagy and others fled Germany for London in the 1930's, they found patrons in some rather unlikely places:

One of these was the ecologist Julian Huxley. As secretary of the Zoological Society of London he had an apartment at the zoo, which he used partly as a showroom for modernist design. Here, scientists, artists, architects, environmentalists and the science-fiction writer H. G. Wells regularly met for discussions about how to save humankind from environmental, economic and social destruction.

Bauhaus design was one of the group's chief passions, and Gropius looked to Huxley and his friends with hope and admiration. Traditional architecture and design reinforced an unfortunate dualism between people and nature, Huxley believed, whereas the Bauhaus approach promised a harmonious reunion. To Huxley, nothing less than the evolutionary survival of the human species was at stake.

[...]

Visitors to the zoo could observe their own primitive desires in animals, [...] so it was of moral importance to place the animals in a model home for healthy living. The gorilla house and the penguin pool, along with a series of other buildings, were therefore built in the Bauhaus style.

But it was also politically important to the group to display thriving animals such as penguins in a highly unnatural setting, to show that humans too could prosper in new environments. "The most unlikely animals seem to thrive under what would seem the most unnatural conditions," zoologist Peter Chalmers Mitchell observed, if they have "freedom from enemies, regular food and general hygiene". The same would hold for workers and the poor, who desperately needed to be liberated from their 'natural' condition of criminal and filthy slums.

Interesting. We've apparently gone full circle, as the current Zeitgeist places a much higher value on authenticity; zoos and natural history museums now aim to show animals in the most natural environments possible. Journalism, television, and Hollywood all now completely dismiss the ideal in favor of what is real (if you consider "reality tv" real).

Since we have a greater desire to see the world as it really is, I wonder if society still has the same expectations from architecture that it once had. I suspect that we no longer expect architects to solve the ills of the world; however, many cities are starting to realize the impact of good architecture on maintaining vibrant urban life.

Rather than indicating a retreat for design's promise to the world, I think this change signals a refinement towards a more realistic offering of how design can address the human condition. This is good—it means rather than promising the world, we're moving in a direction that has the potential to yield demonstrable results.

Filed under architecture · biology · culture

Posted by H. C. Hodges at 11:00 AM | Permalink | Comments (0)

Man, it just keeps geting worse.

Drudge links to an article in The Pittsburgh Tribune-Review about a ripple effect of disgraced Korean scientist Hwang Woo-Suk's falsified stem cell experiments:

A University of Pittsburgh reproductive biologist relied on the now-discredited stem-cell findings of a disgraced Korean scientist to win a $16.1 million federal grant last fall, according to federal documents and letters obtained by the Pittsburgh Tribune-Review.

[...] Because of Schatten's role in co-authoring the discredited work, Pitt officials should consider whether he remains eligible to lead research projects and receive grants, said Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania in Philadelphia.

[..] "It's hard for me to imagine it going forward the way it is, given the complete discrediting of a purported partner," Caplan said.

This whole thing is a nightmare. Letters to the editors at the major journals—along with the journals themselves—are positively shrieking about the virtues and pitfalls of peer review. Scientists are genuinely very bothered by this situation, both because it puts stem cell research in a bad light, and because it casts doubts about the overall worthiness of publically funded science.

Because science always takes place at the boundaries of the unknown, its practitioners have an easier time making things up as they go along. Luckily, science is also a profession in which its participants take great delight in disproving others' results. Nevertheless, let's hope we learn something about preventing falsified reports from reaching publication in the first place. Otherwise, the whole thing just gets ugly.

Filed under biology · science

Posted by H. C. Hodges at 10:54 AM | Permalink | Comments (0)

You heard it here first, readers.

The New York Times is running an article today entitled "Stem Cells May Be Key to Cancer." Go read it; it's definitely worth a couple minutes' time.

Nineteen days ago, I posted this report to HodgesLab called "Are cancers broken stem cells?"

Times 0, HodgesLab 1.

Filed under biology · cancer

Posted by H. C. Hodges at 3:04 PM | Permalink | Comments (0)

Many scientists I know have trouble explaining to laypeople why basic research is important. The fact of the matter is that not everybody in biology is working to cure a disease, not everyone in chemistry is making pharmaceuticals, and physicists aren't all working on quantum computing. It's difficult to respond positively to these assumptions, in part because most scientists do feel like they're making a contribution — but to explain that contribution means teaching a mini-review course in some area of science that has its own unique jargon.

So it's nice to have freebie examples of why basic research is so necessary. Typically, I think of quantum mechanics and how it seemed so exotic and far-removed from everyday life back in the 1910's and 20's. Now, however, we couldn't go a day without quantum mechanics: what with computers, LEDs, lasers, etc.

But for a biologist it can be even more challenging ("why study so-and-so if you could be curing a disease?"). I recently found one example of work in basic cell biology that has immediate contribution to cancer biology: Medical News Today reviews an article by researchers at HHMI/UPenn that study the cellular response to hypoxia (lack of oxygen). Their findings have implications for treatment of solid tumors (i.e. cancers that are not lymphomas, leukemias, or other cancers of the blood), where the tumor cells grow in hypoxic environments:

In addition to hypoxia, solid cancer tumors are comprised of abnormal cells and convoluted blood vessels, which allow the tumors to resist chemotherapy and radiation treatments. New treatments for cancer are now aiming to turn off [hypoxic response] activity, halting the ability of the cell to signal its low-oxygen alert system and undergo protein synthesis

So in doing basic cellular biology research, they realize that their findings might be used in the treatment of cancer. Results like these are strong arguments for why NIH and NSF should stay well funded — no corporation would have the R&D funding to support research like this, because the results aren't immediately profitable. However, work like this leads to treatments for cancer...

[PubMed link to research article here]

Filed under biology · cancer · science

Posted by H. C. Hodges at 1:33 PM | Permalink | Comments (0)

Treehugger picks up an article about deriving ethanol from microbial digestion as a means to energy independence. They remark on some recent commercial ventures, including:

Iogen opened a small, $40 million factory in 2004 to show it can produce cellulosic ethanol in commercial quantities. In the last two years, it has produced 65,000 gallons of ethanol that is blended with 85 percent gasoline to fuel about three dozen company and Canadian government vehicles. Oil giant Royal Dutch Shell has invested $40 million for a 30 percent ownership stake in Iogen; Petro-Canada and the Canadian government are also investors. The company will build a $350 million, commercial-scale factory next year if it can secure financing — which has long been a big if and remains one of the biggest stumbling blocks to bringing cellulosic ethanol to gas pumps. Under a best-case scenario, Passmore said Iogen won't be producing commercial quantities until 2009.

While I think this is awesome, I (apparently like many investors) am not quite so charmed by ethanol's promise just yet. There are contrarian reports as to its real energy costs, and when researchers do side with ethanol, it's often because of reduced greenhouse emissions and petrol consumption. Both of these things are good, but only incrementally.

Ethanol would be more sustainable than, say, gasoline, and this would increase our energy independence... but — if it takes a large amount of energy to make, then purify, then distribute — then where's the payoff? (I can just hear the second law of thermodynamics laughing at us now...)

Guess there's not much of a consensus just quite yet, at least among those who study energy. Which is probably why investors haven't jumped on-board yet. But with increased commercial activity comes innovation, so we'll just have to wait and see...

Filed under biology · energy · science

Posted by H. C. Hodges at 9:53 AM | Permalink | Comments (1)

Consider this question: if you wanted to build a virus de novo, what would be first on your parts-list? I don't mean this to sound like a bio-defense fellowship application, but instead I mean to ask, how much do we know, mechanically, about common viruses?

I'll start with what I think is the most important piece: a DNA (or RNA) packaging motor. The reason I think this is so critical is because the virus, at its simplest, is a structurally sound and chemically stable genome. Somehow after replication a virus must package into its daughter an entire copy of its genome. So how does the nucleic acid get in there?

Image courtesy Nature, Jiang Lab

If we wanted to build a virus, we obviously would need some sort of biological motor. One that can latch on somewhere, recognize viral (and not cellular!) DNA, then shove it into the empty viral shell. What specifications should we consider for this motor? Since this packaging motor needs some sort of energy input, I think it would be wise to use the host cell's ATP store. After all, it's just sitting around, right? What about once this virus particle find the next target cell; it will want to inject its DNA into that cell. Unfortunately for us, there isn't going to be much ATP lying around outside cells (not even in blood).

Luckily, nature has already solved this dilemma, and we can find out how if we ask the right questions. It turns out that you can monitor actual viral DNA packaging motors using optical tweezers, and gain some insights about how the virus operates. And this is something that the Bustamante lab here at Berkeley does very well. We've managed to measure the forces exerted by a single packaging motor of phi29, a bacteriophage (read "virus for bacteria").

The authors of this paper found that even a single motor can generate enormous forces when packaging DNA (well, enormous by biological standards). Using ATP alone, it can exert forces up to 50 pN (that's 50×10^-12 Newtons), which is astonishing for its size. By comparison, each molecule of myosin, the force-generating protein in your muscles, can generate a force of only 5 pN. Which means that the packaging motors in the bacteriophage are about 10 times stronger than an equivalent number of your myosin motors.

The authors did a quick back-of-the-envelope calculation that suggested the DNA inside the virus must be at a pressure equivalent to 60 atmospheres. The raison d'etre of the motor became clear—when the new virus finds a host cell, it must pop open like a champagne bottle and allow its DNA to shoot into the new target cell. The virus relies on this mechanism to infect a new cell precisely because there is no ATP (and therefore no energy source) available outside the target cell. Ingenious!

It turns out this calculation provided a prediction that was testable. It suggested that DNA inside virii should be so dense that it ought to have almost crystalline order, something DNA normally resists very much. And a recent paper from Nature provides confirmation of this prediction through cyro-electron microscopy. It appears that the DNA is so well ordered that electron microscopy imaging can make out the pattern inside the virus. Seed Magazine has a fascinating, and less technical, breakdown of this work on their site.

There is much insight to be gained by considering biological objects as mechanical devices. In my opinion, cell biology and biophysics is diverging into two complementary paths: (1) understanding the physical basis of biological activity, and (2) understanding how redudant, overlapping signalling pathways give rise to robust decision-making networks. Of course synthetic biology sometimes attempts to bridge this gap, by creating biology that performs some novel task.

Comments are open. Your thoughts?

Filed under biology · cancer · science

Posted by H. C. Hodges at 6:58 PM | Permalink | Comments (0)

How fun is this?

The Science Creative Quarterly, from the University of British Columbia, gives instructions on how to make and run a DNA gel using nothing more than parts obtained from regular consumer stores.

When I have kids, they are so going to win the science fairs...

UPDATE: According to this article in the Wall Street Journal, it looks like my kids will have some stiff competition!

Filed under biology · science

Posted by H. C. Hodges at 11:32 AM | Permalink | Comments (0)