Good News from SCOTUS on Gene Patents, But Questions Remain

Today the U.S. Supreme Court issued a unanimous decision on the Myriad Patent case, having to do with the company’s ownership of BRCA-1 and BRCA-2 gene sequences. The main opinion, authored by Justice Thomas, says this:

“A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but cDNA is patent eligible because it is not naturally occurring.

At first glance, this is terrific news for patients world-wide. It means is that no company, university, other entity or individual can patent human genes.

Keep in mind – the case doesn’t just apply to BRCA and evaluating a person’s risk for breast and ovarian cancers. Rather, there are hundreds of human genes implicated in cancer that are potential targets for treatment, that might be evaluated, and thousands linked to other diseases. The decision continues:

“Myriad did not create or alter either the genetic information encoded in the BCRA1 and BCRA2 genes or the genetic structure of the DNA. It found an important and useful gene, but groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the… <patent law>

West façade of U.S. Supreme Court Building. (Franz Jantzen)

West façade, U.S. Supreme Court (Franz Jantzen), gov’t image

What’s clear is that gene sequences, as they occur in human cells, can’t be owned just because they’re found, no matter how important they are. This circumstance should allow other researchers and firms to create cDNA from the natural sequences to develop new (competing and potentially less costly) assays and, even better – do their own work – tantamount to providing “second” and “third” opinions (etc. & n.b. IMO more is better!) research to understand how the genes lead cause disease in some people and might targeted for therapy. Great –

But the decision suggests that many lab-generated complementary DNA (cDNA) strands remain patentable, or up for grabs once created – which may be the reason some biotech stocks have rising values today. I’m neither a lawyer nor an analyst, but I do know from my experience as a researcher that it’s essentially trivial to generate cDNA from a short DNA segment, potentially with a mutation of interest. So how might the cDNA be patented, if anyone who has access to the original genetic sequence might form the cDNA by routine lab methods?

Near the end of the opinion, the justice writes:

“…but the lab technician unquestionably creates something new when cDNA is made. cDNA retains the naturally occurring exons of DNA, but it is distinct from the DNA from which it was derived. As a result, cDNA is not a ‘product of nature’ and is patent eligible under <patent law §101>, except insofar as very short series of DNA may have no intervening introns to remove when creating cDNA. In that situation, a short strand of cDNA may be indistinguishable from natural DNA.

The document clarifies the cDNA issue just slightly:

“It is important to note what is not implicated by this decision. First, there are no method claims before this Court… the processes used by Myriad to isolate DNA were well understood by geneticists at the time of Myriad’s patents ‘were well understood, widely used, and fairly uniform insofar as any scientist engaged in the search for a gene would likely have utilized a similar approach’…

Nor do we consider the patentability of DNA in which the order of the naturally occurring nucleotides has been altered. Scientific alteration of the genetic code presents a different inquiry, and we express no opinion about the application of <patent law §101> to such endeavors.

How I interpret this is that if a researcher generates a short cDNA segment based on a gene, that’s not patentable, but if it’s a long strand involving lots of clipped introns, that might be patentable.

Taking in all this, which is far from simple, I have a question and a wider point:

What goes unaddressed by the justices is the patentability of cDNA based on common genetic variants in cancer. Those are “naturally occurring” mutations, inasmuch as they arise in humans. But the cDNA generated from those sequences might remain patentable. There are loads of examples in this regard: Consider, for example, the genetic mutations in EGFR, and ALK, that are used in lung cancer diagnosis, treatment decisions and development of new targeted drugs. In the current issue of the New England Journal of Medicine, doctors report on SALL4, a gene that occurs in some liver cancers and might be a good, useful target for therapy in that disease.

The point is that the Supremes – and those would be lawyers – need to know about biology. Justice Scalia, sadly in my view, wrote his own opinion not because he disagreed with the others, but because he felt there was too much science in the decision. From the Scotus Blog today:

“Many readers no doubt will share the view of Justice Antonin Scalia, in a short, separate opinion refusing to join in a section “going into the fine details of molecular biology,” of which he said he had neither knowledge nor belief.  Scalia said he did understand enough …

This scares me, that one of the Justices, our most accomplished lawyers who might make decisions on cloning, and stem cells and who knows what in the future, copped out because he lacks science education – what should be required high school biology in  U.S. schools, public and private – to form an opinion that matters so much.

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News on Occupational Exposure to N-PropylBromide, a Neuro-toxin

Yesterday’s NY Times drew my attention with a front-page article on the Occupational Safety and Health Administration (OSHA) and its inability to prevent harm among furniture and cushion factory workers in the U.S.  Even though hundreds of workers in North Carolina handling nerve-damaging glues have developed neurological toxicity, OSHA failed to suppress use of likely chemical culprits.

structure of n-propyl bromide (Wiki-image)

structure of n-propyl bromide (Wiki-image)

Regulating industry is complicated. The Times reporter, Ian Urbina, focuses on a compound, n-propyl bromide, aka nPB or 1-bromopropane, that’s used by “tens of thousands of workers in auto body shops, dry cleaners and high-tech electronics manufacturing plants across the nation.”

Problem is – it’s hard and possibly impossible, based on studies of factory workers, to prove cause and effect. He writes:

Pinpointing the cause of a worker’s ailment is an inexact science because it is so difficult to rule out the role played by personal habits, toxins in the environment or other factors. But for nearly two decades, most chemical safety scientists have concluded that nPB can cause severe nerve damage when inhaled even at low levels…

The lack of absolute proof – that a particular chemical substance has cause disease in an individual –is exacerbated by the fact that many cushion and glue workers’ symptoms, like numbness and tingling, are subjective: At one company, Royale, a ledger of employees’ illness is said to list “Alleged Neurologic Injury.” This phrase reflects the evaluators’ doubt of the handlers’ complaints and, by insinuation, adds insult to injury – some so severe the workers couldn’t button a shirt, feel a cut, bleeding foot, or stand for more than a few minutes.

The government agency that might respond, OSHA, is woefully understaffed. According to the Times:

“OSHA still has just 2,400 responsible for overseeing roughly eight million work sites — roughly one inspector per 60,000 workers, a ratio that has not changed since 1970. The federal budget for protecting workers is less than half of that set aside for protecting fish and wildlife…

Regulation of industry kills jobs, some say – it’s for this reason that some individuals most likely to suffer harm from manufacturing align with corporations. What’s more, if people lack education about chemistry and need employment, they may not choose or know what’s in their long-term best interests. This piece, like the story of Toms River, points to the unfortunate reality that many citizens tolerate and even take pride in a damaging local business, especially if the health problems it causes are insidious, affect some but not all exposed, and the facts aren’t in full view.

 

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Why Hurricanes Remind Me of Patient Care

Last week, Tropical Storm Isaac started tracking toward the Gulf of Mexico. As usual, the prediction models offered varying forecasts. Nonetheless, by this weekend a consensus emerged that the tempestuous weather system would, most likely, affect the City of New Orleans.

National Hurricane Center image

The Mayor, Mitch Landrieu, didn’t panic. I watched him on TV on Sunday evening in an interview with CNN’s Wolf Blitzer and Erin Burnett. Isaac wasn’t a hurricane yet, although a Category I or II storm was predicted by then. He didn’t order an evacuation. Rather, he emphasized the unpredictable nature of storms. There’d be business as usual the next day, on Monday morning August 27. Mind the weather reports, and do what you need to do, he suggested to the citizens. He did mention there’d be buses for people who registered.

“Don’t worry,” was the gist of his message to the citizens of New Orleans. The levees should hold. He exuded confidence. Too much, perhaps.

Some people are drawn to leaders – or doctors – who blow off signs of a serious problem. “It’s nothing,” they might say to a woman who fell after skiing and hit her head, or to a man with a history of lymphoma who develops swollen glands and fever. It’s trendy, now, and sensible, to be cost-conscious in medical care. This is a terrific approach except when it misses a treatable and life-threatening condition or one that’s much less expensive to fix earlier than later.

“Every storm is different,” meteorologist Chad Myers informs us.

Like tumors. Sometimes you see one that should have a favorable course, like a node-negative, estrogen-receptor breast tumor in a 65 year old woman, but it spreads to a woman’s bones within a year. Or a lymphoma in a 40 year old man that looks to be aggressive under the light microscope but regresses before the patient has gone for a third opinion. But these are both exceptions. Cancer can be hard to predict; each case is a little different. Still, there are patterns and trends, and insights learned from experience with similar cases and common ways of spreading. Sometimes it’s hard to know when to treat aggressively. Other times, the pathology is clear. Sometimes you’re wrong. Sometimes you’re lucky….

In New Orleans, the Mayor’s inclination was to let nature take its course. He’s confident in the new levees, tested now by Isaac’s slow pace and prolonged rains. I do hope they hold.

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FDA Approves Pertuzumab for Advanced, Her2+ Breast Cancer

We’re on a roll for new treatments of the Her2+ form of breast cancer. On Friday the FDA approved Pertuzumab, a monoclonal antibody, for advanced cases. As indicated, the drug would be given along with another monoclonal antibody, trastuzumab (Herceptin) and a chemotherapy, docetaxel (Taxotere) to patients with advanced breast tumors with high levels of Her2.

The new treatment’s brand name is Perjeta. Like Herceptin, this reagent works by attaching to the Her2 receptor on a cancer cell’s surface. But it differs by binding a distinct part of the molecule; its mechanism of action is said to complement that of Herceptin.  You might recall that HER protein family members are complex signaling molecules that span cell membranes. Her1 is the Epidermal Growth Factor Receptor; it’s turned on when bound by its partner, or molecular ligand, Epidermal Growth Factor(EGF). The others are Her2, -3 and -4.

EGFR (Her1) signaling, Wiki-Books image

The science behind drugs that interfere with Her2 receptors and signaling is nicely summarized in a recent, open-access Nature Reviews Clinical Oncology article. Herceptin binds a particular segment of Her2 on the outside of the cell; this leads to failed signaling on the inside, including cell division signals, and causes cell death by several mechanisms. Pertuzumab binds a distinct segment of Her2 in such a way that it can’t form a complex with the related Her3 molecule; this interaction is needed for Her2 to stimulate cell growth.

The FDA’s approval rests largely on results of the CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) study, published earlier this year in the NEJM. In that Phase III study, just over 800 patients were randomly assigned to receive a standard regiment – Herceptin in combination with Taxotere plus a placebo infusion, or the Herceptin-Taxotere combination plus Pertuzumab.

The patients who received Pertuzumab did better in terms of Progression Free Survival (PFS, 18.5 months vs. 12.4 months; this difference holds strong statistical merit). There is a trend, also, in terms of Overall Survival: at a median follow-up point of 19.3 months, there were more deaths in the placebo group. But a statistically significant difference was not reached. Toxicity was reported as “generally similar” in the two groups, but there was more diarrhea, dry skin and rashes among those who got Pertuzumab (Table 3). Heart problems, a known toxicity of the Herceptin-Taxotere regimen, were slightly less common with Pertuzumab. Hair loss, presumably from the chemotherapy part of the regimen, was common in both groups.

One curious thing I noticed, in re-reading the January report, is that although the median age for both patient groups was 54 years, the control patients ranged from 27 – 89 in age; those who got Pertuzumab ranged from 22 – 82 years. Although the younger “shift” of Pertuzumab-receiving patients relative to the controls is unlikely to affect the PFS, it’s odd to include an 89 year old patient on an experimental protocol involving infusions of two monoclonal antibodies along with chemo.

This is a super-costly regimen. Like Herceptin, and like the experimental compound antibody, DM1, about which I wrote last week, Perjeta is manufactured by Genentech. As detailed by Andrew Pollack in the NY Times: the wholesale price for Perjeta will be $5,900 per month for a typical woman; Herceptin costs $4,500 per month. So we’re talking about a treatment in which the monoclonal antibodies alone cost over $10K per month. “A typical 18-month course of treatment would be more than $187,000,” he indicated. But if you add on the costs of the Taxotere, drugs like Benadryl and Decadron to minimize allergic reactions, anti-nausea meds, charges for the infusion and monitoring…It’ll be a lot more than that.

As the FDA notes in its press release, production of Perjeta is currently limited due to a technical issue at the Genentech manufacturing plant. Meanwhile, investigators, doctors and patients will have to sort out the relative value of this drug, on top of the others – including pills – for Her2+ disease.

My opinion is not quite formed on this new antibody. The FDA’s decision was based on results from one trial of 808 patients, half of whom didn’t get the experimental drug. Accrual began in 2008; its broad clinical effects, and long-term toxicities, can’t be established yet. It may be, ten years from now, that Perjeta will be used routinely in patients with other, Her2+ kinds of cancer. Or it may be a toxic bust.  How (and if) we’ll test and compare different doses of Perjeta and potential combinations with other drugs, small pills and traditional chemotherapies – which are many – is not clear. You could, for example, combine one or both of the antibodies with a drug like Lapatinib (Tykerb), that inhibits Her2-triggered growth signals inside the cell.

The problem is that oncologists, and facilities including academic centers where revenue is generated by giving drugs by infusion, now have a huge financial incentive to give the Herceptin-Perjeta-Taxotere regimen. This regimen is approved for first-line treatment of metastatic, Her2+ breast cancer; you don’t have to have “failed” another regimen, as was required for the EMILIA trial. As I understand this approval, an oncologist seeing a woman with recurrent or metastatic Her2+ breast cancer could, immediately, prescribe the 3-drug combination.

It’s impressive that the CLEOPATRA folks included an 89 year old patient in the study. But at some point, you have to wonder where we might draw lines. I’ve no answers on that.

All for now, maybe for the week,

ES

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10 Newly-Defined Molecular Types of Breast Cancer in Nature, and a Dream

Breast cancer is not one disease. We’ve understood this for decades. Still, and with few exceptions, knowledge of BC genetics – information on tumor-driving DNA mutations within the malignant cells – has been lacking. Most patients today get essentially primitive treatments like surgical hacking, or carving, traditional chemotherapy and radiation. Some doctors consider hormone therapy as targeted, and thereby modern and less toxic. I don’t.

Until there’s a way to prevent BC, we need better ways to treat it. Which is why, upon reading the new paper in Nature on genetic patterns in breast cancer, I stayed up late, genuinely excited. As in thrilled, optimistic..The research defined 10 molecular BC subgroups. The distinct mutations and gene expression patterns confirm and suggest new targets for future, better therapy.

The work is an exquisite application of science in medicine. Nature lists 31 individuals and one multinational research group, METABRIC (Molecular Taxonomy of Breast Cancer International Consortium), as authors. The two correspondents, Drs. Carlos Caldas and Samuel Aparicio, are based at the University of Cambridge, in England, and the University of British Columbia in Vancouver, Canada. Given the vastness of the supporting data, such a roster seems appropriate, needed. The paper, strangely and for all its worth, didn’t get much press –

Just to keep this in perspective – we’re talking about human breast cancer. No mice.

The researchers examined nearly 2000 BC specimens for genetic aberrations, in 2 parts. First, they looked at inherited and acquired mutations in DNA extracted from tumors and, when available, from nearby, normal cells, in 997 cancer specimens – the “discovery set.” They checked to see how the genetic changes (SNPs, CNAs and/or CNVs) correlated with gene expression “landscapes” by probing for nearly 29,000 RNAs. They found that both inherited and acquired mutations can influence BC gene expression. Some effects of “driver” mutations take place on distant chromosomal elements, in what’s called a trans effect; others happen nearby (cis).

Next, they honed in on 45 regions of DNA associated with outlying gene expression. This led the investigators to discover putative cancer-causing mutations (accessible in supplementary Tables 22-24, available here). The list includes genes that someone like me, who’s been out of the research field for 10 years, might recall – PTEN, MYC, CDK3 and -4, and others. They discovered that 3 genes, PPP2R2A, MTAP and MAP2K4 are deleted in some BC cases and may be causative. In particular, they suggest that loss of PPP2R2A may contribute to luminal B breast cancer pathology. They find deletion of MAP2K4 in ER positive tumors, indicative of a possible tumor suppressor function for this gene in BC.

Curtis, et al. in "Nature": April 2012

The investigators looked for genetic “hotspots.” They show these in Manhattan plots, among other cool graphs and hard figures, on abnormal gene copy numbers (CNAs) linked to big changes in gene expression. Of interest to tumor immunologists (and everyone else, surely!), they located two regions in the T-cell receptor genes that might relate to immune responses in BC. They delineated a part of chromosome 5, where deletions in basal-like tumors marked for changes in cell cycle, DNA repair and cell death-related genes. And more –

Cluster Analysis (abstracted), Wikipedia

Heading toward the clinic, almost there…

They performed integrative cluster analyses and defined 10 distinct molecular BC subtypes. The new categories of the disease, memorably labeled “IntClust 1-10,” cross older pathology classifications (open-access: Supplementary Figure 31) and, it turns out, offer prognostic information based on long-term Kaplan-Meier analyses (Figure 5A in the paper: Supplementary Fig 34 and 35). Of note, here, and a bit scary for readers like me, is identification of an ER-positive group, “IntClust 2” with 11q13/14 mutations. This BC genotype appears to carry a much lesser prognosis than most ER-positive cases.

Finally, in what’s tantamount to a 2nd report, the researchers probed a “validation set” of 995 additional BC specimens. In a partially-shortened method, they checked to see if the same 10 molecular subtypes would emerge upon a clustering analysis of paired DNA mutations with expression profiles. What’s more, the prognostic (survival) information held up in the confirmatory evaluation. Based on the mutations and gene expression patterns in each subgroup, there are implications for therapy. Wow!

I won’t review the features of each type here for several reasons. These are preliminary findings, in the sense that it’s a new report, albeit a model of what’s a non-incremental published set of observations and analysis; it’s early for patients – but not for investigators – to act on these findings. (Hopefully, this will not be the case in 2015, or sooner, preferably, for testing some pertinent drugs in at least a subset of the subgroups identified.) Also, some of the methods these authors used came out in the past decade, after I stopped doing research. It would be hard for most doctors to fully appreciate the nuances, strengths and weaknesses of the study.

Most readers can’t know how skeptical I was in the 1990s, when grant reviewers at the NCI seemed to believe that genetic info would be the cure-all for most and possibly all cancers. I don’t think that’s true, nor due most people involved with the Human Genome Project, anymore. The Cancer Genome Atlas and Project should help in this regard, but they’re young projects, larger in scope than this work, and don’t necessarily integrate DNA changes with gene expression as do the investigators in this report. What’s clear, now, is that some cancers do respond, dramatically, to drugs that target specific mutations. Recently-incurable malignancies, like advanced melanoma and GI stromal tumors, can be treated now with pills, often with terrific responses.

Last night I wondered if, in a few years, some breast cancers might be treated without surgery. If we could do a biopsy, check for the molecular subtype, and give patients the right BC tablets. Maybe we’d just give just a tad of chemo, later, to “mop up” any few remaining or residual or resistant cells. The primary chemotherapy might be a cocktail of drugs, by mouth. It might be like treating hepatitis C, or tuberculosis or AIDS. (Not that any of those are so easy.) But there’d be no lost breasts, no reconstruction, no lymphedema. Can you imagine?

Even if just 1 or 2 of these investigators’ subgroups pans out and leads to effective, Gleevec-like drugs for breast cancer, that would be a dream. This can’t happen soon enough.

With innovative trial strategies like I-SPY, it’s possible that for patients with particular molecular subgroups could be directed to trials of small drugs targeting some of the pathways implicated already. The pace of clinical trials has been impossibly slow in this disease. We (and by this I mean pharmaceutical companies, and oncologists who run clinical trials, and maybe some of the BC agencies with funds to spend) should be thinking fast, way ahead of this post –

And given that this is a blog, and not an ordinary medical publication or newspaper, I might say this: thank you, authors, for your work.

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The Emperor of All Maladies: A Narrative of Cancer History and Ideas

This week I finished reading the Emperor of All Maladies, the 2010 “biography” of cancer by Dr. Siddhartha Mukherjee. The author, a medical oncologist and researcher now at Columbia University, provides a detailed account of malignancies – and how physicians and scientists have understood and approached a myriad of tumors – through history.

The encyclopedic, Pulitzer Prize-winning book is rich with details. In the first half, Mukherjee focuses on clinical aspects of malignancy. He works both ancient and modern stories into the narrative; the reader learns of Atossa, the Persian queen of the 6th Century BCE who covered her breast disease, and Thomas Hodgkin, who in the 19th Century dissected cadavers and noted a “peculiar” pattern of glandular swelling in some young men, and Einar Gustafson, aka Jimmy, who was among the first children cured of leukemia in the 1950s.

The second half is a tour-de force on cancer biology; the author winds distinct threads of cancer science. He moves from century-old observations of cells with abnormal chromatin, through viral theories and hard-to-prove carcinogens, to the brave new world of oncogenes, targeted therapies, and current cancer genomics. He narrates the rift between clinical oncologists who, primarily, treat patients empirically and think less about science, and cancer researchers, who generally attend separate conferences and concern themselves with mechanisms of tumor growth and theoretical ways of blocking them. He relates a gradual, albeit slow, coming together of those two fields – of clinical and molecular oncology.

Mukherjee leaves the reader with a sense of cancer as a vast, infinitely diverse group of diseases that can mutate and adapt while a person receives treatment. The oncologist’s new goal, he suggests, is not so much to eradicate the disease as to learn more about its nature and course, to monitor each patient’s tumor and adjust medications as the cancer – or burden, as the term implies – shifts and mutates within the person who carries it along, within, for years and even decades.

It takes a long time to understand the workings of cancer cells; this book offers insights for oncologists and patients alike.


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A Note on ‘Trial by Twitter’ and Peer Review in 2012

Nature just published a feature: Trial by Twitter. The piece considers the predicament of researchers who may find themselves ill-prepared to deal with a barrage of unsolicited and immediate on-line “reviews” of their published work. The author of the Nature News piece, science journalist A. Mandavilli, does a great job covering the pros and cons of Twitter “comments” on strengths and weaknesses of studies from the perspective of researchers whose work has been published by major journals.

She writes:

Papers are increasingly being taken apart in blogs, on Twitter and on other social media within hours rather than years, and in public, rather than at small conferences or in private conversation.

What I’d add is this:

Openness isn’t just about criticism. It can be a positive factor in bringing to light the work of small-lab researchers whose findings contradict dogma or conflict with heavily-financed work by leaders in a field. Through twitter and blogs, non-mainstream threads of data can gain attention, traction and, with time and merit, grant support.

Scientists who publish in major journals should be able to handle the flak. If their work is correct, it’ll stand through open peer review.

—-

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On Admitting Nice, Ethically-Minded People to Med School

This week the Times ran a leading story on a new med school admission process, with multiple, mini-interviews, like speed dating. The idea is to assess applicants’ social, communication and ethical thinking (?) skills:

…It is called the multiple mini interview, or M.M.I., and its use is spreading. At least eight medical schools in the United States — including those at Stanford, the University of California, Los Angeles, and the University of Cincinnati — and 13 in Canada are using it.

At Virginia Tech Carilion, 26 candidates showed up on a Saturday in March and stood with their backs to the doors of 26 small rooms. When a bell sounded, the applicants spun around and read a sheet of paper taped to the door that described an ethical conundrum. Two minutes later, the bell sounded again and the applicants charged into the small rooms and found an interviewer waiting. A chorus of cheerful greetings rang out, and the doors shut. The candidates had eight minutes to discuss that room’s situation. Then they moved to the next room, the next surprise conundrum…

This sounds great, at first glance. We all want friendly doctors who get along. It might even be fun, kind of like a game. (Sorry for the cynicism, injected in here, but it’s needed.) I’d even bet that the interviewers and successful interviewees would emerge feeling good about the process and themselves.

But don’t you think most premed students, who get through college, and numerous letters of recommendation, take the MCATS and achieve scores high enough to get an interview, are smart enough to get through this social test without failing? It’s what these young men and women are thinking, internally, that matters. According to the same article, the country’s 134 medical schools have long relied almost entirely on grades and the MCAT to sort through over 42,000 applicants for nearly 19,000 slots.

My math: that means nearly 19 out of 42 (almost half!) of med school applicants get in, here in the U.S.

If we want future doctors who are smart enough to guide patients through tough, data-loaded, evidence-based and ethically-complex decisions, we should make the academic requirements for entry more rigorous, especially in the areas of science, math and analytical thinking.

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Defining a Cluster of Differentiation, or CD

One of the goals of this blog is to introduce readers to some of the language of medicine. As much as jargon is sometimes unnecessary, sometimes the specificity and detail in medical terms aids precision.

So what is a cluster of differentiation, or CD?

In medical practice, the two-letter acronym specifies a molecule, or antigen, usually on a cell’s surface. In 1982, an international group of immunologists got together for the First International Workshop on Human Leukocyte Differentiation Antigens. The initial focus was on leukocyte (white blood cell) molecules. The goal was to agree on definitions of receptors and other complex proteins to which monoclonal antibodies bind, so that scientists could communicate more effectively.

A few examples of CDs about which you might be curious:

CD1 – the first-named CD; this complex glycoprotein is expressed in immature T cells, some B cells and other, specialized immune cells in the skin; there are several variants (CD1a, -b, -c…) encoded by genes on human chromosome 1.

CD4 – a molecule on a mature “helper” T cell surface; T lymphocytes with CD4 diminish in people with untreated HIV disease.

CD20 – a molecule at the surface of immature B lymphocytes that binds Rituxan, an antibody used to treat some forms of lymphoma, leukemia and immune disorders.

 

In this schematic, an antibody recognizes a specific molecule, or cluster of differentiation, at a cell surface.

The CDs were named (i.e. numbered) not necessarily by the order of discovery, but by the order of their being deemed as bona fide CDs by HLA Workshop participants. There’s a pretty good, albeit technical, definition in FEBS Letters, from 2009:

Cluster of differentiation (CD) antigens are defined when a surface molecule found on some members of a standard panel of human cells reacts with at least one novel antibody, and there is good accompanying molecular data.

Perhaps the best way to think about CDs is that they’re unique structures, usually at a cell’s surface, to which specific antibodies bind. By knowing the CDs, and by examining which antibodies bind to cells in a patient’s tumor specimen, pathologists can distinguish among cancer types. Another use is in the clinic, when oncologists give an antibody, like Campath – which binds CD52, the responsiveness might depend on whether the malignant cells bear the CD target.

Still, I haven’t come across an official (such as NIH), open-source and complete database for all the CDs. Most can be found at the Human Cell Differentiation Molecules website, and information gleaned through PubMed using the MeSH browser or a straight literature search.

Wikipedia is disappointing on this topic; the list thins out as the CD numbers go higher, and the external references are few. To my astonishment, I found a related page on Facebook. Neither makes the grade.

Where should patients get information about these kinds of things? Or doctors, for that matter?

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TV Meets Real Life Oncology, and Anticipating the MCATs

Yesterday I wrote on some tough decisions facing a TV show‘s protagonist. She’s got metastatic melanoma and might participate in a clinical trial when the show resumes.

Now imagine you’re an oncologist, or a real patient with this killing disease – you really need to be on top of new developments, to understand the pros and cons, because someone’s life depends on it.

If you’re the doctor in the relationship, you need keep abreast of current information for all the other tumors types of patients in your care: what are the new findings, if any, what are the limitations of the data. You need to know how the advances apply to an individual person who, most likely, has another condition or two, like high blood pressure or, say, osteoporosis.

Oncologists ought to be familiar with new drugs, and how those compare to old ones, and the side effects, and the distinctions between tumors with and without BRAF mutations. They should know what BRAF stands for.

Melanoma is one form of skin cancer. We understand now there are breast cancer subtypes – with distinct behavior and responsiveness to treatments, with and without inherited and acquired genetic mutations (BRCA-1 and -2 were identified well over 10 years ago; there’s much more known now), dozens of lymphoma forms and innumerable leukemia subtypes. Lung cancer, prostate cancer, brain cancer… Each is a group of diseases.

But the science physicians apply in their work doesn’t just apply in oncology. Even in traditionally “softer” fields of medicine, like pediatrics, doctors need to know how congenital diseases are diagnosed with newer, cheaper methods for testing mutations; in gynecology, doctors need to know about inherited clotting dispositions; in psychiatry, doctors give medicines with complex metabolic effects that involve, or should involve, some grounding in modern neuroscience.

This is why we need to keep the MCAT hard. (I’ll write more on this current issue in medical education, soon.)

Have a great weekend!

ES

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